A class of RBJ small molecule inhibitors

Abstract

The present invention relates to the field of medicinal chemistry, and specifically to a class of RBJ small molecule inhibitors, and more specifically to compounds shown in Formula I, and pharmaceutical compositions, preparation methods and uses thereof. The compounds of the present invention can be used as highly selective and very effective RET inhibitors, and such compounds can inhibit RBJ expression and / or activity, and have excellent inhibitory activity on GTPase / MEK1 protein interaction.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of RBJ small molecule inhibitors. Background Art

[0002] Studies have found that small GTPases (GTPases) refer to single-subunit G proteins with a molecular weight between 20 and 30 kDa. Among them, the Ras superfamily can be divided into 6 subfamilies based on homology, structure and function: Ras, Rab, Rho, Arf, Ran and RJL, with a total of more than 60 members. Rab mutations or functional abnormalities are closely related to their different cellular localizations and are involved in regulating the occurrence and development of a variety of diseases. A series of studies have shown that Rab-related small GTPases play an important role in tumor proliferation, invasion, metastasis and drug resistance. In 1998, our research team independently discovered a small GTPase (GenBank No. AF178983) from a human dendritic cell cDNA library through large-scale sequencing. The molecule contains two types of characteristic functional domains: its amino terminus contains a GTP binding site and a GTPase activity domain with high homology to the Rab protein molecule; its carboxyl terminus contains a J functional domain of about 70 amino acid residues, named RBJ (also called RJL, DNAJC27).

[0003] Previous studies by this research team have shown that RBJ can promote the accumulation of phosphorylated MEK / ERK and prolong its activation time by directly anchoring MEK / ERK in the nucleus of tumor cells, thereby promoting the occurrence and development of tumors. When RBJ expression is inhibited, the proliferation, colony formation and in vivo growth ability of colon cancer cells can be significantly inhibited, and the sensitivity of colon cancer cells to the MEK1 / 2 inhibitor CI-1040 can be promoted. RBJ promotes the secretion of inhibitory cytokines (TGF-b, IL-6) to form an inhibitory tumor microenvironment. Lung cancer patients or melanoma patients whose tumor cells highly express RBJ have worse survival time and prognosis. Therefore, it is necessary to develop a compound that inhibits RBJ and its pharmaceutical composition, and apply it to the inhibition and treatment of tumors. Summary of the invention

[0004] To solve the above problems, the present invention provides a compound as shown in the following formula I, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts:

[0005]

[0006] Wherein, A is selected from: C3-C 20 Cycloalkyl, C6-C 20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl;

[0007] L is selected from L1, a cyclic group, L1-cyclic group, cyclic group-L1, L1-cyclic group-L1, cyclic group-L1-cyclic group;

[0008] Among them, L1 is C1-C 10 Alkyl, the C1-C 10 Any carbon atom in the alkyl group may be optionally replaced by NR 2 , O, S or is replaced by an oxo (=O) group;

[0009] The cyclic group is selected from C3-C 20 Cycloalkyl, 3-20 membered heterocyclic group, C6-C 20 Aryl, 5-20 membered heteroaryl, the cyclic group is optionally independently substituted by 1-5 (e.g., 1, 2 or 3) selected from H, halogen, CN, CF3, C1-C 10 Alkyl, -C1-C 10 Alkyl-C6-C 14 Aryl, NR C R D , OR A , SR A 、C(O)OR A 、C(O)NR C R D NR C C(O)R B The group substitution;

[0010] n is 0, 1, 2, 3, 4, 5; each R 1 independently selected from H, halogen, CN, oxo (=O), NO2, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 20 Aryl, C3-C 20 Cycloalkyl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, -NR C R D 、-C1-C 10 Alkyl-NR C R D 、-OR A 、-SR A 、-C(O)OR A 、-C(O)NR C R D 、-NR C C(O)R B 、-S(O)2R B 、-S(O)2NR C R D ; wherein the C1-C10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C6-C 20 Aryl, C3-C 20 Cycloalkyl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl are optionally independently substituted with one or more (e.g. 1-5) R E replace;

[0011] Every R 2 independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl, -C1-C6 alkyl-C6-C 14 Aryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl, -C1-C6 alkyl-C6-C 14 The aryl group is optionally independently substituted with one or more (eg, 1-5) R J replace;

[0012] R 3 , R 4 , R 5 Independently selected from H, halogen, CN, NH2, -NH-C1-C6 alkyl, -OH, C1-C6 alkyloxy, -SH, -S-C1-C6 alkyl, -COOH, -CO-OC1-C6 alkyl, -CO-NH2, -CO-NH-C1-C6 alkyl, -NH-CO-C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl;

[0013] Each of the R A , R B are independently selected from H, unsubstituted or substituted with one or more (e.g. 1-5) R F Substituted groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl;

[0014] Each of the R C , R D independently selected from H, CN, OH, NH2, unsubstituted or substituted with one or more (e.g. 1-5) R G Substituted groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl;

[0015] R E independently selected from H, halogen, CN, OH, NH2, oxo (=O), NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl, -NR C R D 、-C1-C6 alkyl-NR C R D 、-OR A , SR A 、C(O)OR A 、C(O)NR C R D NR C C(O)R B 、S(O)2R B 、S(O)2NR C R D wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl are optionally independently substituted with one or more (eg 1-5) R H replace;

[0016] R F , R G , R H , R J The same or different groups are independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyloxy (e.g. Me, Et, CF3, OMe, OCF3, OEt).

[0017] According to an embodiment of the present invention, R 3 , R 4 , R 5 Independently selected from H, halogen, -OH, NH2, -COOH, -NH-CO-C1-C6 alkyl.

[0018] In some embodiments, R 5 It is -OH.

[0019] In some embodiments, R 3 , R 4 is H or halogen.

[0020] In some embodiments, R 3 , R 4 is halogen, R 5 It is -OH.

[0021] In some embodiments, R 3 , R 4 is Br or Cl, R 5 It is -OH.

[0022] In some embodiments, R 3 , R 4 Cl, R 5 It is -OH.

[0023] According to an embodiment of the present invention, ring A is selected from the following groups: C 3-10 Cycloalkyl; C 6-14 aryl; 5-14 membered heteroaryl, for example, 5-10 membered heteroaryl having a monocyclic or bicyclic ring, which may contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally, the 5-14 membered heteroaryl is selected from 5-10 membered heteroaryl having a monocyclic or bicyclic ring, wherein at least one heteroatom is selected from N, for example, 1, 2 or 3 heteroatoms are selected from N; 3-10 membered heterocyclyl, for example, 5-10 membered heterocyclyl having a monocyclic or bicyclic ring, which may contain 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally, the 3-10 membered heterocyclyl is selected from 5-10 membered heterocyclyl having a monocyclic or bicyclic ring, wherein at least one heteroatom is selected from N, for example, 1, 2 or 3 heteroatoms are selected from N.

[0024] According to an embodiment of the present invention, ring A is selected from: C 6-14 Aryl, for example phenyl, naphthyl; N-containing heterocyclic groups, for example pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroquinolinyl; N-containing heteroaryl groups, for example pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolinyl, isoquinolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, imidazopyridinyl.

[0025] In some embodiments, Ring A is selected from the following groups:

[0026]

[0027] In some embodiments, Ring A is selected from phenyl.

[0028] In some embodiments, Ring A is selected from piperidinyl.

[0029] In some embodiments, each R 1 independently selected from H, halogen, CN, oxo (=O), NO2, C1-C 10 Alkyl, C6-C14 Aryl, C3-C 10 Cycloalkyl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, -NR C R D 、-C1-C 10 Alkyl-NR C R D 、-OR A 、-SR A 、-C(O)OR A 、-C(O)NR C R D 、-NR C C(O)R B 、-S(O)2R B 、-S(O)2NR C R D ; wherein the C1-C 10 Alkyl, C6-C 14 Aryl, C3-C 10 Cycloalkyl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl are optionally independently substituted with one or more (e.g. 1-5) R E replace.

[0030] In some embodiments, R 1 independently selected from H, halogen (such as fluorine, chlorine, bromine, iodine), CN, oxo (=O), NO2, C1-C6 alkyl, C6-C10 aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -NR C R D 、-C1-C6 alkyl-NR C R D 、-OR A 、-SR A 、-C(O)OR A 、-C(O)NR C R D 、-NR C C(O)R B 、-S(O)2R B 、-S(O)2NR C R D wherein the C1-C6 alkyl, C6-C10 aryl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl are optionally independently substituted by 1, 2 or 3 R E replace.

[0031] In some embodiments, R A , R B independently selected from H, unsubstituted or substituted with 1, 2 or 3 RF Substituted groups: C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl.

[0032] In some embodiments, R C , R D independently selected from H, unsubstituted or substituted with 1, 2 or 3 R G Substituted groups: C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl.

[0033] In some embodiments, R E independently selected from H, halogen, CN, OH, NH2, oxo (=O), NO2, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, -NR C R D 、-C1-C6 alkyl-NR C R D 、-OR A , SR A 、C(O)OR A 、C(O)NR C R D NR C C(O)R B 、S(O)2R B 、S(O)2NR C R D wherein the C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-14 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl are optionally independently substituted by 1, 2 or 3 R H replace.

[0034] In some embodiments, the C1-C 10 Alkyl is, for example, methyl, ethyl, n-propyl, isopropyl; the C3-C 10 Examples of the cycloalkyl group include cyclopentyl and cyclohexyl; examples of the 3-14-membered heterocyclic group include piperidinyl, morpholinyl and piperazinyl.

[0035] In some embodiments, R A , R B , R C , R D , R EIndependently selected from H, methyl, ethyl, n-propyl, isopropyl, phenyl, wherein the methyl, ethyl, n-propyl, isopropyl, phenyl is optionally independently substituted by 1, 2 or 3 groups selected from halogen, CN, OH, CF3, OMe, OCF3, OEt, NH2.

[0036] In some embodiments, in the group L, L1 is C1-C 10 Alkyl, the C1-C 10 Any carbon atom in the alkyl group may be optionally replaced by NR 2 , O, S or substituted by an oxo (=O) group; for example, L1 can be: any 1-3 carbon atoms in the alkyl chain are replaced by NR 2 Replaced C1-C 10 Alkyl (such as -NR 2 -C1-C6 alkyl-NR 2 -、-NR 2 -、-NR 2 -C1-C6 alkyl-), any 2-4 carbon atoms in the alkyl chain are replaced by NR 2 and CO replaced C1-C 10 Alkyl (such as -NR 2 -CO-, -NR 2 -C1-C6 alkyl-CO-NR 2 -), any 2-4 carbon atoms are NR 2 and CO replaced C1-C 10 Alkyl (such as -NR 2 -C1-C6 alkyl-O-); the cyclic group is selected from C3-C 10 Cycloalkyl, 3-14 membered heterocyclic group, C6-C 14 Aryl, 5-14 membered heteroaryl, the cyclic group is optionally independently substituted by 1-5 (e.g., 1, 2 or 3) selected from H, D, halogen, CN, CF3, C1-C 10 Alkyl, -C1-C 10 Alkyl-C6-C 14 Aryl, NR C R D , OR A , SR A 、C(O)OR A 、C(O)NR C R D NR C C(O)R B The group is substituted.

[0037] In some embodiments, L is selected from the following structures:

[0038] L is selected from L1;

[0039] Or L is selected from L1-cyclic group, cyclic group-L1, wherein the cyclic group is C6-C 14 Aryl, 3-14 membered heterocyclic group, the heterocyclic group is a heterocyclic group having a monocyclic or bicyclic structure, which may contain 1, 2, 3 or 4 heteroatoms independently selected from N;

[0040] Or L is selected from L1-cyclic group-L1, wherein the cyclic group is C6-C 14 Aryl;

[0041] Or L is selected from the cyclic group -L1-cyclic group, wherein the cyclic group is a 3-14-membered heterocyclic group, the heterocyclic group is a heterocyclic group having a monocyclic or bicyclic structure, which may contain 1, 2, 3 or 4 heteroatoms independently selected from N;

[0042] Alternatively, L is selected from a cyclic group, wherein the cyclic group is a 3-14-membered heterocyclic group, and the heterocyclic group is a heterocyclic group having a spirocyclic structure, which may contain 1, 2, 3 or 4 heteroatoms independently selected from N.

[0043] In some embodiments, L1 is C1-C 10 Alkyl, the C1-C 10 Any carbon atom in the alkyl group may be optionally replaced by NR 2 , O, S or is replaced by an oxo (=O) group.

[0044] In some embodiments, L is selected from the group consisting of: -NR 2 -C1-C6 alkyl-NR 2 -、-NR 2 -C1-C6 alkyl-NR 2 -C1-C6 alkyl-, -NR 2 -C1-C6 alkyl-, -NR 2 -C6-C 14 Aryl-NR 2 -、-NR 2 -C6-C 14 Aryl-, -NR 2 -C1-C6 alkyl-C6-C 14 Aryl-NR 2 -、-NR 2 -C1-C6 alkyl-C6-C 14 Aryl-C1-C6 alkyl-, -NR 2 -C1-C6 alkyl-C6-C 14 Aryl-C1-C6 alkyl-NR 2 -、-NR 2 -C1-C6 alkyl-NR 2 -C6-C 14 Aryl-NR2 -C1-C6 alkyl-NR 2 -、-N-containing heterocyclic group-C1-C6 alkyl-NR 2 -、-N-containing heterocyclic group-NR 2 -、-N-containing heterocyclic group-NR 2 -N-containing heteroaryl-, -N-containing heterocyclic group-C1-C6 alkyl-N-containing heterocyclic group-, -NR 2 -、-NR 2 -CO-、-NR 2 -C1-C6 alkyl-CO-NR 2 -、-NR 2 -C1-C6 alkyl-O-, -N-containing spirobicyclic group-, -benzo-N-containing spirobicyclic group-.

[0045] In some embodiments, L1 is selected from the following groups:

[0046]

[0047]

[0048] In some embodiments, the cyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, naphthyl. In some embodiments, the cyclic group is selected from the following groups:

[0049]

[0050] In some embodiments, the cyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl.

[0051] In some embodiments, the cyclic group is selected from the following groups:

[0052]

[0053] In some embodiments, the cyclic group is selected from phenyl and naphthyl.

[0054] In some embodiments, the cyclic group is selected from the following groups:

[0055]

[0056] In some embodiments, the cyclic group is selected from the following groups:

[0057]

[0058] In some embodiments, the cyclic group is optionally substituted independently by 1, 2 or 3 groups selected from halogen, CN, OH, Me, CF3, OMe, OCF3, OEt, NH-3-14 membered heterocyclic group (such as NH-pyrrolidine).

[0059] In some embodiments, R 2 Independently selected from H, C1-C6 alkyl.

[0060] In some embodiments, H is D. In some embodiments, CH3 is CD3.

[0061] According to an embodiment of the present invention, the compound is selected from the following compounds:

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by Formula I, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts.

[0071] According to an embodiment of the present invention, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable carriers or excipients.

[0072] According to an embodiment of the present invention, the pharmaceutical composition further contains one or more additional therapeutic agents.

[0073] According to an embodiment of the present invention, the pharmaceutical composition further contains one or more other chemotherapeutic drugs or targeted drugs.

[0074] According to an embodiment of the present invention, the pharmaceutical composition further contains one or more other tumor immunotherapy drugs, such as immune checkpoint inhibitor drugs PD1 / PDL1 inhibitors, such as PD1 / PDL1 antibody combinations, etc.

[0075] The present invention also provides a method for inhibiting tumor cell proliferation in vitro or in vivo, which comprises contacting tumor cells with an effective amount of the compound represented by formula I of the present invention, its stereoisomer, racemate, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0076] The present invention also provides a method for treating RBJ-mediated diseases, comprising administering to a patient a therapeutically effective amount of at least one of the compound of Formula I, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts.

[0077] The present invention also provides a method for treating RBJ-related diseases or conditions in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I of the present invention, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0078] The present invention also provides a method for treating cancer and / or inhibiting metastasis associated with a specific cancer in a patient in need of treatment, the method comprising administering to the patient a therapeutically effective amount of a compound represented by formula I of the present invention, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0079] The present invention also provides the use of at least one of the compound represented by formula I, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts for preparing RBJ inhibitors.

[0080] The present invention also provides the use of at least one of the compound represented by formula I, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts in the preparation of a drug for inhibiting RBJ expression.

[0081] The present invention also provides the use of at least one of the compound represented by Formula I, its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts in the preparation of a drug for treating cancer and / or inhibiting metastasis associated with a specific cancer.

[0082] The present invention also provides a method for treating an individual with RBJ-related cancer, the method comprising administering at least one of the compounds of Formula I, stereoisomers, racemates, tautomers, isotope labels, nitrogen oxides, or pharmaceutically acceptable salts thereof before, during, or after administering one or more other anticancer drugs. The one or more other anticancer drugs may be chemotherapeutic drugs or targeted drugs, or may be tumor immunotherapy drugs, such as immune checkpoint inhibitor drugs PD1 / PDL1 inhibitors, such as PD1 / PDL1 antibody combinations, etc.

[0083] The present invention provides a method for treating cancer (eg, RBJ-related cancer) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one of the compounds of Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0084] In some embodiments, the cancer is, for example, lung cancer (such as non-small cell lung cancer), melanoma, breast cancer, ovarian cancer, prostate cancer, liver cancer, kidney cancer, intestinal cancer (such as colon cancer), head and neck cancer, skin cancer, bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, glioma, neuroblastoma, laryngeal cancer, nasopharyngeal cancer, thyroid cancer, leukemia, lymphoma, malignant pleural mesothelioma.

[0085] In some embodiments, the patient is a mammal, such as a human.

[0086] The compounds of formula I and their pharmaceutically acceptable salts can also be used to treat cancers associated with RBJ.

[0087] Definition and explanation of terms

[0088] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0089] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to recording each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-20", namely 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. It should be understood that in the one or more used herein when describing substituents, "multiple" should refer to an integer ≥ 2, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0090] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0091] The term "C1-C 10“Alkyl” is understood to mean preferably a straight-chain or branched saturated monovalent hydrocarbon radical having 1 to 10 carbon atoms. For example, “C1-C6 alkyl” means straight-chain and branched alkyl radicals having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl or the like or isomers thereof.

[0092] The term "C2-C 10"Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, "C2-C6 alkenyl", in particular 2 or 3 carbon atoms ("C2-C3 alkenyl"), it being understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)- )-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex -2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2 -methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0093] The term "C2-C 10“Alkynyl” is to be understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, “C2-C6-alkynyl”, in particular 2 or 3 carbon atoms (“C2-C3-alkynyl”). The C2-C6-alkynyl radical is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methyl In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl, prop-2-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0094] The term "C3-C 20 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or polycyclic hydrocarbon ring (bicyclic, tricyclic, etc.) having 3 to 20 carbon atoms, preferably "C3-C 10 The cycloalkyl group may be a benzo-fused or bridged ring and / or a spiro ring. The term "C 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or polycyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.

[0095] The term "3-20 membered heterocyclyl" means a saturated monovalent monocyclic or polycyclic hydrocarbon ring (such as a bicyclic or tricyclic ring, etc.), which contains 1-5 heteroatoms independently selected from N, O and S, and a total number of ring atoms of 3-20 (such as 3, 4, 5, 6, 7, 8, 9, 10, etc.), and is preferably a "3-14 membered heterocyclyl". The term "3-14 membered heterocyclyl" means a saturated monovalent monocyclic or polycyclic hydrocarbon ring, which contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, such as 1, 2, 3 heteroatoms independently selected from N, O and S. The heterocyclyl group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl (such as azetidin-1-yl); a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be a benzo-fused or bridged ring and / or a spirocyclic ring. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic. When the 3-20-membered heterocyclic group is connected with other groups to form the compound of the present invention, the carbon atom on the 3-20-membered heterocyclic group may be connected with other groups, or the heterocyclic atom on the 3-20-membered heterocyclic group may be connected with other groups. For example, when the 3-20-membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl may be connected with other groups. Or when the 3-20-membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom on the para position thereof may be connected with other groups.

[0096] The term "C6-C 20 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic or polycyclic hydrocarbon ring (such as a bicyclic or tricyclic ring) having 6 to 20 carbon atoms, preferably "C6-C 14 The term "C6-C 14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic or polycyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C6-C 14or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 When the C6-C 14 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0097] The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, polycyclic hydrocarbon ring (such as bicyclic, tricyclic, etc.) aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, polycyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, may additionally be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. When the 5-20 membered heteroaryl is connected to other groups to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be connected to other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be connected to other groups. When the 5-20 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. In addition, there is no limitation on the substitution site, for example, the hydrogen connected to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen connected to the heteroatom on the heteroaryl ring may be substituted.

[0098] Unless otherwise specified, heterocyclic groups, heteroaryls or heteroarylene groups include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at one or more positions of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene groups include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0099] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom or a sulfur atom is oxidized to form an oxy group (=O).

[0100] Unless otherwise stated, the definitions of terms herein also apply to groups containing the term, e.g. 1-6 The definition of alkyl also applies to C 1-6 Alkyloxy, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl or -S(O)2-C 1-6 Alkyl, etc.

[0101] It will be appreciated by those skilled in the art that the compounds of Formula I may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an internal salt.

[0102] The compounds of the present invention may exist in the form of solvates (e.g. hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.

[0103] According to their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. These compounds may thus exist in racemic form or in optically active form. The compounds of the present invention or their intermediates may be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolution agents. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in the R and S forms. Chromatographic enantiomer resolution may also be advantageously performed with the aid of optically active resolution agents (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0104] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0105] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0106] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0107] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

[0108] Beneficial Effects

[0109] The compounds of the present invention can be used as RBJ inhibitors with high selectivity or inhibitory effects. The compounds of the present invention have excellent inhibitory activity on GTPase / MEK1 protein interactions, effectively inhibit RBJ expression and / or activity, and can be used to treat tumors associated with RBJ. In addition, the compounds of the present invention also have good pharmacokinetic properties, and can be administered to patients in smaller doses as active ingredients, thereby reducing the treatment costs of patients. DETAILED DESCRIPTION

[0110] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0111] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0112] The substances represented by the abbreviations in the examples are as follows:

[0113] AcOH represents acetic acid, BBr3 represents boron tribromide, BINAP represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, BrettPhos Pd G3 represents methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), Cs2CO3 represents cesium carbonate, DCM represents dichloromethane, DIEA represents N,N-diisopropylethylamine, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, EtOAc represents ethyl acetate, EtOH represents ethanol, Fe represents iron powder, H2O represents water, HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HBr represents hydrobromic acid, K2CO3 represents potassium carbonate, LiAlH4 represents lithium aluminum hydride, MeOH represents methanol, MTBE represents methyl tert-butyl ether, NaBH3CN represents sodium cyanoborohydride, Na2CO3 represents sodium carbonate, Na2SO4 represents anhydrous sodium sulfate, NaH represents sodium hydride, NaHCO3 represents sodium bicarbonate, NaOH represents sodium hydroxide, NH4Cl represents ammonium chloride, NMP represents N-methylpyrrolidone, Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium, Pd(OAc)2 represents palladium acetate, PE represents petroleum ether, TEA represents triethylamine, THF represents tetrahydrofuran, and TLC represents thin layer chromatography.

[0114] Example 1: Preparation of intermediates

[0115] Preparation of intermediate int 1:

[0116]

[0117] Compound 1,5-dichloro-3-pentanone (500.0 mg, 3.23 mmol) and Na2CO3 (859.9 mg, 8.11 mmol) were added to MeOH (5 mL) and then heated to 70°C. A solution of int 1.1 (588.0 mg, 3.25 mmol) in MeOH (5 mL) was then added dropwise. The mixture was reacted at 70°C for 4 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with DCM (15 mL×2). The organic phase was washed with saturated brine (10 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=20:1-10:1) to obtain compound int1. LC-MS: 264.3[M+H] + . 1H NMR (400MHz, CDCl3) δ7.29-7.27(m,1H),7.09-7.08(m,1H),6.67(t,J=6.0Hz,1H),3.91(s,3H),3.85(s,3H),3.66-3.63(m,4H),2.57-2.54(m,4H).

[0118] Preparation of intermediate int 2:

[0119]

[0120] Step 1:

[0121] The compound 4-bromo-2,6-dichloroanisole (2000.0 mg, 7.82 mmol) was dissolved in toluene (20 mL), and then int 2.1 (1252.1 mg, 7.82 mmol), Cs2CO3 (7638.9 mg, 23.45 mmol), BINAP (973.3 mg, 1.56 mmol) and Pd2(dba)3 (715.7 mg, 0.78 mmol) were added. The mixture was reacted at 115 ° C in N2 atmosphere for 12 hours. After cooling to room temperature, the reaction was quenched with H2O (25 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with saturated brine (25 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=15:1-10:1) to obtain compound int2.2. LC-MS: 334.8[M+H] + .

[0122] Step 2:

[0123] Compound int 2.2 (700.0 mg, 2.09 mmol) was dissolved in DCM (7 mL) and HCl dioxane (4 mL, 4 M) solution was added at 0°C. The mixture was reacted at room temperature for 2 hours. After concentration under reduced pressure, int 2 was obtained. The crude product was used directly in the next step without purification. LC-MS: 234.9 [M+H] + .

[0124] Preparation of intermediate int 3

[0125]

[0126] Step 1:

[0127] Compound int 3.1 (10.0 g, 52.08 mmol) was dissolved in MeOH (150 mL), and then AcOH (5 mL, 13.32 mmol), N-tert-butyloxycarbonyl-4-piperidone (20.8 g, 104.17 mmol) and NaBH3CN (6.5 g, 104.17 mmol) were added. The mixture was reacted at 70°C for 12 hours. After cooling to room temperature, it was concentrated under reduced pressure. The crude product was poured into H2O (50 mL) and extracted with DCM:MeOH (10:1, 50 mL×2). The organic phase was washed with saturated brine (30 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was recrystallized from DCM (40 mL) to obtain compound int 3.2. LC-MS: 319.0 [M+H-56] + . 1 H NMR (400MHz, DMSO-d6) δ6.64 (s, 2H), 5.86 (d, J = 10.0Hz, 1H), 3.86-3.82m, 2H), 3.68 (s, 3H) ,3.48-3.35(m,1H),3.00-2.80(m,2H),1.85-1.81(m,2H),1.40(s,9H),1.24-1.08(m,2H).

[0128] Step 2:

[0129] Compound int 3.2 (3.6 g, 9.59 mmol) was dissolved in DCM (40 mL), and then HCl dioxane (40.00 mL, 4 M) solution was added at 0°C. The mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain crude int 3. It was used directly in the next step without purification. LC-MS: 275.0 [M+H] + .

[0130] Preparation of intermediate int 4:

[0131]

[0132] Step 1:

[0133] Compound int 4.1 (500.0 mg, 2.48 mmol) was dissolved in toluene (30 mL), and then Cs2CO3 (2.42 g, 7.43 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (892.2 mg, 3.71 mmol) and BrettPhos Pd G3 (224.4 mg, 0.25 mmol) were added. The mixture was reacted at 120 °C in N2 atmosphere for 6 hours. After cooling to room temperature, the reaction was quenched with H2O (100 mL) and extracted with EtOAc (50 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, EtOAc:PE=1:3) to obtain compound int 4.2. LC-MS: 362.1 [M+H] + .

[0134] Step 2:

[0135] Compound int 4.2 (170.0 mg, 0.47 mmol) was dissolved in EtOAc (30 mL), and HCl dioxane (10 mL, 4 M) solution was added at 0°C. The mixture was reacted at room temperature for 4 hours. The mixture was concentrated under reduced pressure to obtain compound int 4. It was used directly in the next step without purification. LC-MS: 262.1 [M+H] + .

[0136] Preparation of intermediate int 5:

[0137]

[0138] Step 1:

[0139] The compound 2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5.0 g, 20.8 mmol) was dissolved in toluene (100 mL), and then int 5.1 (6.39 g, 25.00 mmol), Cs2CO3 (20.33 g, 62.4 mmol) and BrettPhosPd G3 (1.89 g, 2.08 mmol) were added. The mixture was reacted at 120°C in a N2 atmosphere for 4 hours. After cooling to room temperature, the mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL×3). The organic phase was washed with saturated brine (200 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=20:1-15:1) to obtain compound int 5.2. LC-MS: 415.2[M+H] + .

[0140] Step 2:

[0141] Compound int 5.2 (5.60 g, 13.48 mmol) was dissolved in DCM (10 mL), and then HCl dioxane solution (33.7 mL, 135.0 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The crude product int 5 was obtained by concentration under reduced pressure and used directly in the next step without purification. LC-MS: 315.1 [M+H] + .

[0142] Example 2: Preparation of Compound 1

[0143]

[0144] Step 1:

[0145] Compound int 1 (500.0 mg, 1.90 mmol) was added to MeOH (5 mL), and then 3,5-dichloro-4-methoxyaniline (243.1 mg, 1.27 mmol) and AcOH (0.1 mL, 1.75 mmol) were added at room temperature and stirring was continued for 30 minutes. NaBH3CN (159.0 mg, 2.53 mmol) was then added at 0°C. The mixture was reacted at room temperature for 7 hours. The reaction was quenched with H2O (20 mL) and extracted with DCM (20 mL×2). The organic phase was washed with saturated brine (10 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=20:1-10:1) to obtain compound 1.1. LC-MS: 438.9 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.27-7.26(m,1H),7.06-7.05(m,1H),6.66-6.65(m,1H),6.52(s,2H),3.90(s,3H),3.83(s ,3H),3.81(s,3H),3.71-3.66(m,2H),3.38-3.33(m,1H),2.98-2.91(m,2H),2.15-2.11(m,2H),1.59-1.50(m,3H).

[0146] Step 2:

[0147] Compound 1.1 (20.0 g, 4.55 mmol) was dissolved in DCM (10 mL), and then BBr3 (5 mL, 51.90 mmol) was added at 0°C. The mixture was reacted at room temperature for 18 hours. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 5-6 with NaHCO3 solution and then extracted with EtOAc (40 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified by preparative liquid phase (SHIMADZU, LC-20AP, Column: YMC Triart C18, 20×250 mm, 5 μm; Mobile Layer: from 25% to 65% ACN [0.1% FA]; Flow rate: 15 mL / min; Retention Time: 15 min of 30 min) to obtain compound 1. LC-MS: 397.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.67(s,1H),9.47(s,1H),8.87(s,1H),6.98-6.97(m,1H),6.78-6.77(m,1H),6.62(s,2H),6.56- 6.55(m,1H),5.47(s,1H),3.64-3.60(m,2H),2.92-2.86(m,2H),2.51-2.50(m,1H),1.95-1.91(m,2H),1.44-1.34(m,2H).

[0148] The following compounds can be prepared in a similar manner.

[0149]

[0150]

[0151] Example 3: Preparation of Compound 2

[0152]

[0153] Step 1:

[0154] Compound 1.1 (300.0 mg, 0.68 mmol) was added to toluene (5 mL), followed by 3-iodotoluene (446.6 mg, 2.05 mmol), Cs2CO3 (667.5 mg, 2.05 mmol), tri-tert-butylphosphine tetrafluoroborate (39.6 mg, 0.14 mmol) and Pd(OAc)2 (15.3 mg, 0.07 mmol). The mixture was reacted at 130°C in a N2 atmosphere for 10 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (15 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=20:1-14:1) to obtain compound 2.1. LC-MS: 529.3 [M+H] + .

[0155] Step 2:

[0156] Compound 2.1 (30.0 mg, 0.06 mmol) was added to HBr (5 mL, 48%). The temperature was then raised to 100°C and the reaction was allowed to react for 6 hours. After cooling to room temperature, the reaction was quenched with H2O (10 mL) at 0°C. The pH was adjusted to 5-6 with NaHCO3 solution, and then extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative liquid phase (SHIMADZU, LC-20AP, Column: YMC Triart C18, 20×250 mm, 5 μm; Mobile Layer: from 45% to 75% ACN [0.1% HCl]; Flow rate: 15 mL / min; Retention Time: 10 min of 30 min) to obtain compound 2. LC-MS: 486.9 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.73-7.72(m,1H),7.58-7.57(m,1H),7.28(t,J=6.0Hz,1H),7.21(t,J=8.0Hz,1H),6.93(s,2H),6.88(d,J=8.0Hz, 1H),6.75-6.71(m,2H),4.48-4.40(m,1H),3.98-3.91(m,2H),3.74-3.71(m,2H),2.35(d,J=16.0Hz,2H),2.31(s,3H),1.99-1.89(m,2H).

[0157] The following compounds can be prepared in a similar manner.

[0158]

[0159]

[0160] Example 4: Preparation of Compound 6

[0161]

[0162] Step 1:

[0163] Compound 6.1 (5.0 g, 24.97 mmol) was dissolved in toluene (50 mL), and then 3-bromo-5-methoxy-benzoic acid ethyl ester (4.08 g, 16.64 mmol), Cs2CO3 (16.27 g, 49.93 mmol), BINAP (1.04 g, 1.66 mmol) and Pd2(dba)3 (1.52 g, 1.66 mmol) were added. The mixture was reacted at 115°C under N2 atmosphere for 3 hours. After cooling to room temperature, the reaction was quenched with H2O (100 mL) and extracted with EtOAc (50 mL×2). The organic phase was washed with saturated brine (30 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=30:1-25:1) to obtain compound 6.2. LC-MS: 365.1 [M+H] + .

[0164] Step 2:

[0165] Compound 6.2 (1.50 g, 4.12 mmol) was dissolved in EtOAc (15 mL), and then a solution of HCl in EtOAc (7.5 mL, 4 M) was added at 0°C. The mixture was reacted at room temperature for 3 hours. After concentration, the crude product was redissolved in MTBE (30 mL). After 30 minutes, the crude product was filtered and rinsed with MTBE (10 mL) to obtain compound 6.3. LC-MS: 265.1 [M+H] + .

[0166] Step 3:

[0167] Compound 6.3 (340.0 mg, 1.29 mmol) was dissolved in toluene (3.5 mL), and then 4-bromo-2,6-dichloroanisole (219.5 mg, 0.86 mmol), Cs2CO3 (838.2 mg, 2.57 mmol), BINAP (53.4 mg, 0.09 mmol) and Pd2(dba)3 (78.5 mg, 0.09 mmol) were added. The mixture was reacted at 115°C in N2 atmosphere for 18 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (10 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=15:1-12:1) to obtain compound 6.4. LC-MS: 439.0 [M+H] + .

[0168] Step 4:

[0169] Compound 6.4 (285.0 mg, 0.65 mmol) was dissolved in DCM (3 mL), and then BBr3 (0.5 mL, 5.19 mmol) was added at 0°C and stirred for 12 hours. The reaction was quenched with H2O (10 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 5-6 with NaHCO3 and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU, LC-20AP, Column: YMCTriart C18, 20×250 mm, 5 μm; Mobile Layer: from 35% to 55% ACN [0.1% HCl]; Flowrate: 15 mL / min; Retention Time: 8.5 min of 20 min) to obtain compound 6. LC-MS: 397.0 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ9.84(s,1H),7.39(s,1H),7.13-6.97(m,4H),4.00-3.75( m,3H),3.70-3.38(m,3H),3.18-3.05(m,2H),1.96-1.87(m,3H),1.61-1.56(m,1H).

[0170] The following compounds can be prepared in a similar manner.

[0171]

[0172]

[0173] Example 5: Preparation of Compound 10

[0174]

[0175] Step 1:

[0176] Compound int 2 (500.0 mg, 2.13 mmol) was dissolved in toluene (5 mL), and then methyl 3-bromo-5-nitrobenzoate (460.8 mg, 1.77 mmol), Cs2CO3 (1732.2 mg, 5.32 mmol) and BrettPhos Pd G3 (160.6 mg, 0.18 mmol) were added. The mixture was reacted at 115 °C in N2 atmosphere for 12 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=15:1-10:1) to obtain compound 10.1. LC-MS: 413.8 [M+H] + .

[0177] Step 2:

[0178] Compound 10.1 (300 mg, 0.72 mmol) was added to EtOH (9 mL) and H2O (3 mL), and then Fe (202.1 mg, 3.62 mmol) and NH4Cl (387.5 mg, 7.24 mmol) were added. The mixture was reacted at 80°C for 2 hours. Filtered through celite, rinsed with MeOH (20 mL), and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAc=8:1-5:1) to obtain compound 10.2. LC-MS: 384.2 [M+H] + .

[0179] Step 3: Compound 10.2 (100.0 mg, 0.26 mmol) was dissolved in DCM (5 mL), and then BBr3 (0.5 mL, 5.19 mmol) was added at 0°C. The mixture was reacted at room temperature for 18 hours. The reaction was quenched with H2O (5 mL) at 0°C, concentrated under reduced pressure, and the crude product was purified by preparative liquid phase (SHIMADZU, LC-20AP, Column: YMC Triart C18, 20×250 mm, 5 μm; Mobile Layer: from 20% to 50% ACN [0.1% HCl]; Flow rate: 15 mL / min; Retention Time: 4.5 min of 7 min) to give compound 10. LC-MS: 356.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.80(s,2H),7.18-7.16(m,1H),7.09-7.06(m,1H),6.84(s,2H),6.80-6.78(m,1H),5.75-5.50(m,4H),3.26(s,4H).

[0180] The following compounds can be prepared in a similar manner.

[0181]

[0182]

[0183]

[0184]

[0185] Example 6: Preparation of Compound 17

[0186]

[0187] Step 1:

[0188] Compound int 3 (520.0 mg, 1.89 mmol) was dissolved in NMP (5 mL), and then 17.1 (376.2 mg, 1.89 mmol) and DIEA (0.94 mL, 5.67 mmol) were added. The mixture was reacted at 130 ° C for 3 hours. After cooling to room temperature, the mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=15:1-10:1) to obtain compound 17.2. LC-MS: 453.9 [M+H]+ .

[0189] Step 2:

[0190] Compound 17.2 (470.0 mg, 1.04 mmol) was added to EtOH (6 mL) and H2O (2 mL), followed by NH4Cl (553.5 mg, 10.35 mmol) and Fe (289.2 mg, 5.17 mmol). The mixture was reacted at 80°C for 3 hours. The mixture was filtered through celite and rinsed with MeOH (20 mL). The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (SiO2, PE:EtOAc=8:1-5:1) to give compound 17.3. LC-MS: 424.0 [M+H] + .

[0191] Step 3:

[0192] Compound 17.3 (185.0 mg, 0.44 mmol) was dissolved in DCM (2 mL), and then BBr3 (0.5 mL, 5.19 mmol) was added at 0°C. The mixture was reacted at room temperature for 12 hours. The reaction was quenched with H2O (10 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 5-6 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU, LC-20AP, Column: Welch XB-C18, 20×250 mm, 10 μm; Mobile Layer: from 10% to 50% ACN [0.1% HCl]; Flowrate: 20 mL / min; Retention Time: 20 min of 35 min) to obtain compound 17. LC-MS: 396.0 [M+H] + . 1 HNMR (400MHz, CD3OD) δ7.94 (d, J=2.0Hz, 1H), 7.84-7.81 (m, 1H), 7.54 (s, 2H), 7.20 (d, J= 8.0Hz,1H),3.75-3.68(m,1H),3.27-3.24(m,2H),3.00-2.93(m,2H),2.14-2.10(m,4H).

[0193] The following compounds can be prepared in a similar manner.

[0194]

[0195] Example 7: Preparation of Compound 20

[0196]

[0197] Step 1:

[0198] Compound 20.1 (5.0 g, 25.11 mmol) was dissolved in NMP (50 mL), and then DIEA (12.48 mL, 75.34 mmol) and 4-piperidone ethylene glycol acetal (5.39 g, 37.67 mmol) were added. The mixture was reacted at 130 ° C for 3 hours. After cooling to room temperature, the reaction was quenched with H2O (80 mL) and extracted with EtOAc (80 mL×2). The organic phase was washed with saturated brine (100 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=15:1-10:1) to obtain compound 20.2. LC-MS: 323.3 [M+H] + .

[0199] Step 2:

[0200] Compound 20.2 (2.00 g, 6.21 mmol) was dissolved in HCl (30 mL, 8 M), and the mixture was reacted at 100 ° C for 2 hours. After cooling to room temperature, the reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL × 2). The organic phase was washed with saturated brine (100 mL × 2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE: EtOAc = 5: 1-3: 1) to obtain compound 20.3. LC-MS: 279.3 [M + H] + .

[0201] Step 3:

[0202] Compound 20.3 (500.0 mg, 1.80 mmol) was dissolved in MeOH (5 mL), and then 3,5-dichloro-4-methoxyaniline (345.0 mg, 1.80 mmol) and AcOH (0.01 mL, 0.18 mmol) were added. The mixture was stirred at room temperature for 1 hour. NaBH3CN (225.7 mg, 3.59 mmol) was then added at 0°C. The mixture was reacted at 75°C for 5 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with DCM (30 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=10:1-8:1) to obtain compound 20.4. LC-MS: 454.2 [M+H] + .

[0203] Step 4:

[0204] Compound 20.4 (160.0 mg, 0.35 mmol) was dissolved in DMF (5 mL), and then NaH (140.8 mg, 3.52 mmol, 60%) was added at 0°C. The mixture was reacted at room temperature for 30 minutes. Then 2-bromoethanol (0.50 mL, 7.04 mmol) was added at 0°C, and the mixture was reacted at 50°C for 9.5 hours. After cooling to room temperature, the reaction was quenched with H2O (10 mL) at 0°C, the pH was adjusted to 5-6 with 2N HCl, and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, MeOH:DCM=30:1-20:1) to obtain compound 20.5. LC-MS: 484.3 [M+H] + .

[0205] Step 5:

[0206] Compound 20.5 (100.0 mg, 0.21 mmol) was added to EtOH (3 mL) and H2O (1 mL), and then Fe (57.5 mg, 1.03 mmol) and NH4Cl (110.2 mg, 2.06 mmol) were added. The mixture was reacted at 80°C for 2 hours. The mixture was filtered through celite, rinsed with MeOH (20 mL), and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, PE:EtOAc=2:1-1:2) to obtain compound 20.6. LC-MS: 454.3 [M+H] + .

[0207] Step 6:

[0208] Compound 20.6 (60.0 mg, 0.13 mmol) was dissolved in DCM (5 mL), and then BBr3 (0.25 mL, 2.60 mmol) was added at 0°C. The mixture was reacted at room temperature for 10 hours. After the reaction was completed, it was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 9-10 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to obtain compound 20. LC-MS: 440.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.86(s,1H),6.77-6.75(m,1H),6.70-6.68(m,1H),6.63(s,2H),6.44-6.62(m,1H),5.48(d,J=8.0Hz,1H),5.19(s,2 H),4.89(t,J=6.0Hz,1H),4.23-4.20(m,2H),3.70-3.66(m,2H),3.60- 3.55(m,2H),2.92-2.81(m,2H),1.96-1.92(m,2H),1.44-1.36(m,2H).

[0209] Example 8: Preparation of Compound 25

[0210]

[0211] Step 1:

[0212] Compound 25.1 (200.0 mg, 0.96 mmol) was dissolved in MeOH (5 mL), and then 3,5-dichloro-4-methoxyaniline (220.3 mg, 1.1 mmol) and AcOH (0.1 mL, 0.96 mmol) were added. The mixture was reacted at room temperature for 30 minutes. NaBH3CN (120.1 mg, 1.91 mmol) was then added at 0°C. The mixture was reacted at 70°C for 7 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (10 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=50:1-30:1) to obtain compound 25.2. LC-MS: 385.2 [M+H] + .

[0213] Step 2:

[0214] Compound 25.2 (110.0 mg, 0.29 mmol) was added to EtOH (1.2 mL) and H2O (0.4 mL), and then Fe (79.9 mg, 1.43 mmol) and NH4Cl (152.8 mg, 2.86 mmol) were added. The mixture was reacted at 80°C for 1 hour. Filtered through celite and rinsed with MeOH (20 mL). Concentrated under reduced pressure, the crude product was purified by preparative TLC (SiO2, PE:EtOAc=3:1) to obtain compound 25.3. LC-MS: 355.2 [M+H] + .

[0215] Step 3:

[0216] Compound 25.3 (60.0 mg, 0.17 mmol) was dissolved in DCM (5 mL), and then BBr3 (0.1 mL, 1.70 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 5-6 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU LC-20AP, Column: YMC Triart C18, 20×250 mm, 5μm; Mobile Layer A: 0.1% HCl, B: ACN; Flow rate: 15 mL / min; gradient: 5% to 20%; Retention Time: 10 min of 20 min) to obtain compound 25. LC-MS: 327.2[M+H] + . 1 H NMR (400MHz, CD3OD) δ8.18-8.17(m,1H),8.01-8.00(m,1H),7.73-7.72(m,1H),7.06(s,2H),4.58(s,2H).

[0217] The following compounds can be prepared in a similar manner.

[0218]

[0219]

[0220] Example 9: Preparation of Compound 17

[0221]

[0222] Step 1:

[0223] Compound int 4 (110.0 mg, 0.42 mmol) was dissolved in toluene (5 mL), and then Cs2CO3 (700.0 mg, 2.15 mmol), 4-bromo-2,6-dichloroanisole (110.0 mg, 0.43 mmol), BINAP (53.4 mg, 0.086 mmol) and Pd2(dba)3 (39.4 mg, 0.04 mmol) were added. The mixture was reacted at 120°C in N2 atmosphere for 4 hours. After cooling to room temperature, the reaction was quenched with H2O (50 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, EtOAc:PE=1:3) to obtain compound 32.1. LC-MS: 435.8 [M+H] + .

[0224] Step 2:

[0225] Compound 32.1 (70.0 mg, 0.16 mmol) was added to EtOH (10 mL) and H2O (2 mL), and then Fe (89.8 mg, 1.60 mmol) and NH4Cl (85.8 mg, 1.60 mmol) were added. The mixture was reacted at 50°C for 1 hour. Filtered through celite, rinsed with MeOH (20 mL), concentrated under reduced pressure, and the crude product was purified by preparative TLC (SiO2, EtOAc:PE=1:1) to obtain compound 32.2. LC-MS: 405.7 [M+H] + .

[0226] Step 3:

[0227] Compound 32.2 (22.0 mg, 0.054 mmol) was dissolved in DCM (10 mL), and then BBr3 (135.3 mg, 0.54 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (50 mL) at 0°C. The aqueous phase was adjusted to pH 7-8 with NaHCO3 solution, and the aqueous phase was extracted with DCM (50 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU, LC-20AP, Column: YMC Triart C18, 20×250 mm, 5μm; Mobile Layer: from 30% to 50% ACN [0.1% FA]; Flow rate: 15 mL / min; Retention Time: 15 min of 20 min) to obtain compound 32. LC-MS: 392.0 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.90(s,1H),6.86-6.83(t,J=6.0Hz,1H),6.53(s,2H),6.20-6.14(m,2H),6.03-6.01(m,1H) ,5.50-4.50(m,2H),3.27-3.24(m,2H),3.20-3.14(m,2H),3.11-3.00(m,4H),1.90-1.79(m,2H),1.72-1.55(m,4H).

[0228] The following compounds can be prepared in a similar manner.

[0229]

[0230]

[0231]

[0232]

[0233] Example 11: Preparation of Compound 46

[0234]

[0235] Step 1:

[0236] Compound 46.1 (300 mg, 1.22 mmol) was dissolved in toluene (3 mL), and then 4-bromo-O-(tert-butyldimethylsilyl)-2,6-dichlorophenol (520.6 mg, 1.46 mmol), Cs2CO3 (1.19 g, 3.65 mmol) and BrettPhos Pd G3 (110.1 mg, 0.12 mmol) were added. The mixture was reacted at 115°C in a N2 atmosphere for 3 hours. After cooling to room temperature, the reaction was quenched with H2O (50 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with saturated brine (30 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, PE:EtOAc=10:1) to obtain compound 46.2. LC-MS: 521.3 [M+H] + .

[0237] Step 2:

[0238] Compound 46.2 (180.0 mg, 0.35 mmol) was dissolved in MeOH (2 mL), and then HCl (0.1 mL, 12 N) was added. The mixture was allowed to react for 1 hour. The reaction was quenched with H2O (30 mL) and extracted with DCM (20 mL×3). The organic phase was washed with saturated brine (20 mL×3), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU LC-20AP, Column: Welch XB-C18, 20×250 mm, 10 μm; Mobile Layer A: 0.1% FA, B: ACN; Flow rate: 20 mL / min; gradient: 33% to 53%; Retention Time: 16 min of 20 min) to obtain compound 46. LC-MS: 407.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.90(s,1H),6.93-6.91(m,2H),6.83-6.81(m,2H),6.53(s,2H),3.69(s,3H ),3.27-3.24(m,2H),3.13-308(m,4H),3.04-2.98(m,2H),1.86(t,J=6.0Hz,2H),1.68-1.63(m,4H).

[0239] Example 12: Preparation of Compound 48

[0240]

[0241] Step 1:

[0242] Compound 48.1 (350.0 mg, 0.91 mmol, prepared in a similar manner to Example 33) was dissolved in MeOH (15 mL), and then formaldehyde (0.1 mL, 2.73 mmol), AcOH (0.1 mL, 0.91 mmol) and NaBH3CN (228.8 mg, 3.64 mmol) were added at 0°C. The mixture was reacted at 50°C for 4 hours. After cooling to room temperature, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=15:1-3:1) to obtain compound 48.2. LC-MS: 397.9 [M+H] + .

[0243] Step 2:

[0244] Compound 48.2 (140.0 mg, 0.35 mmol) was added to H2O (2 mL) and EtOH (6 mL), and then Fe (98.2 mg, 1.76 mmol) and NH4Cl (94.0 mg, 1.76 mmol) were added. The mixture was reacted at 60°C for 1 hour. The mixture was filtered through celite and rinsed with MeOH (20 mL). The mixture was concentrated under reduced pressure and the crude product was purified by TLC (SiO2, PE:EtOAc=3:1) to obtain compound 48.3. LC-MS: 368.1 [M+H] + .

[0245] Step 3:

[0246] Compound 48.3 (80.0 mg, 0.22 mmol) was dissolved in DCM (15 mL), and then BBr3 (0.6 mL, 6.22 mmol) was added at 0°C. The mixture continued to react at room temperature for 2 hours. The reaction was quenched with H2O (10 mL) at 0°C and extracted with DCM:MeOH (22 mL×2, 10:1). The aqueous phase was adjusted to pH 9-10 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, PE:EtOAc=3:1) to obtain compound 48. LC-MS: 354.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 6.79 (t, J = 8.0Hz, 1H), 6.68 (s, 2H), 5.96-5.8 7(m,3H),4.73(s,2H),3.27-3.22(m,4H),2.80(d,J=4.0Hz,6H),1.71-1.64(m,2H).

[0247] Example 13: Preparation of Compound 53

[0248]

[0249] Step 1:

[0250] Compound 3,5-dichloro-4-methoxyaniline (300.0 mg, 1.56 mmol) was dissolved in DMF (5 mL), and then benzoic acid (190.8 mg, 1.56 mmol), HATU (653.5 mg, 1.72 mmol) and DIEA (0.8 mL, 4.69 mmol) were added. The mixture continued to react for 1 hour. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed with saturated brine (10 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=10:1-8:1) to obtain compound 53.2. LC-MS: 296.2 [M+H] + .

[0251] Step 2:

[0252] Compound 53.2 (250.0 mg, 0.84 mmol) was dissolved in DCM (5 mL), and then BBr3 (0.5 mL, 5.19 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=8:1-5:1) to obtain compound 53. LC-MS: 282.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),9.93(s,1H),7.96-7.93(m,2H),7.86-7.84(m,2H),7.63-7.59(m,1H),7.56-7.52(m,2H).

[0253] The following compounds can be prepared in a similar manner.

[0254]

[0255]

[0256] Example 14: Preparation of Compound 70

[0257]

[0258] Step 1:

[0259] Compound 70.1 (180.0 mg, 0.43 mmol, prepared in a similar manner to Example 33) was dissolved in MeOH (10 mL), and then formaldehyde (38.5 mg, 1.28 mmol), AcOH (0.1 mL, 1.75 mmol) and NaBH3CN (107.6 mg, 1.71 mmol) were added at 0°C. The mixture continued to react for 1 hour at room temperature. The reaction was quenched with H2O (50 mL) and extracted with EtOAc (50 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (PE:EtOAc=3:1) to obtain compound 70.2. LC-MS: 448.1 [M+H] + .

[0260] Step 2:

[0261] Compound 70.2 (50.0 mg, 0.11 mmol) was dissolved in DCM (10 mL), and then BBr3 (0.7 mL, 7.27 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (22 mL×2, 10:1). The organic phase was adjusted to pH 9-10 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, PE:EtOAc=2:1) ​​to give compound 70. LC-MS: 434.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.90 (s, 1H), 6.95-6.93 (m, 1H), 6.81-6.70 (m, 2H), 6.52 (s, 2H), 3.25 (t, J = 8. 0Hz, 2H), 3.17-3.01 (m, 6H), 2.58-2.54 (m, 6H), 2.23 (s, 3H), 1.85 (t, J = 8.0Hz, 2H), 1.66-1.63 (m, 4H).

[0262] Example 15: Preparation of Compound 91

[0263]

[0264] Step 1:

[0265] Compound 91.1 (150.0 mg, 0.32 mmol, prepared in a similar manner to Example 11) was dissolved in DMF (2 mL), and then NaH (25.2 mg, 0.63 mmol, 60%) was added at 0°C. The mixture was reacted at room temperature for 30 minutes, and then 2-iodoethanol (109 mg, 0.63 mmol) was added at 0°C. The mixture was reacted at 80°C for 5 hours. After cooling to room temperature, the reaction was quenched with H2O (10 mL) at 0°C, extracted with EtOAc (20 mL×2), and the organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, DCM:MeOH=20:1) to obtain compound 91.2. LC-MS: 519.2 [M+H] + .

[0266] Step 2:

[0267] Compound 91.2 (110.0 mg, 0.21 mmol) was dissolved in DCM (5 mL), and then BBr3 (0.2 mL, 2.12 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O (10 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 8-9 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU LC-20AP, Column: YMC Triart C18, 20×250 mm, 5 μm; Mobile Layer A: 0.1% FA, B: ACN; Flow rate: 15 mL / min; gradient: 15% to 45%; Retention Time: 16 min of 25 min) to obtain compound 91. LC-MS: 505.1[M+H] + . 1 H NMR(500MHz,DMSO-d6)δ8.21(s,1H,HCO2H salt),7.12(t,J=6.0Hz,1H),6.81-6.77(m,2H),6.64(d,J=4.0Hz,1H),6.52(s,2H),3.58-3.55(m,5H),3.26-3.23(s,2H),3.15-3 .10(m,2H),3.10-3.08(m,4H),2.59-2.56(m,2H),2.28-2.23(m,2H),1.85(t,J=6.0Hz,2H),1.75-1.70(m,4H),1.66-1.61(m,4H).

[0268] The following compounds can be prepared in a similar manner.

[0269]

[0270] Example 16: Preparation of Compound 92

[0271]

[0272] Step 1:

[0273] Compound 92.1 (200 mg, 0.32 mmol, prepared in a similar manner to Example 11) was dissolved in THF (5 mL), and then LiAlH4 (23.96 mg, 0.63 mmol) was added at 0°C. Stirring was continued for 1 hour. The reaction was quenched with H2O (3 mL) and 15% NaOH (1 mL). The mixture was concentrated under reduced pressure, and the crude product was purified by preparative TLC (SiO2, PE:EtOAc=2:1) ​​to give compound 92.2. LC-MS: 605.1 [M+H] + .

[0274] Step 2:

[0275] Compound 92.2 (35.0 mg, 0.058 mmol) was dissolved in DCM (10 mL), and then BBr3 (0.027 mL, 0.289 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The organic phase was adjusted to pH 9-10 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL × 2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid chromatography (SHIMADZULC-20AP, Column: YMC Triart C18, 20 × 250 mm, 5 μm; Mobile Layer A: 0.1% FA, B: ACN; Flow rate: 15 mL / min; gradient: 10%-30%; Retention Time: 15 min of 20 min) to obtain compound 92. LC-MS: 491.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.26(s,1H,HCO2H salt),7.04(t,J=8.0Hz,1H),6.52(s,2H),6.47-6.41(m,2H),6.38-6.35(m,1H),3.62-3.48(m,4H),3.45-3.42(m,2H),3.26-3. 19(m,6H),3.15-3.08(m,4H),2.92-2.83(m,2H),2.69-2.63(m,1H),2.43-2.37(m,1H),1.85(t,J=6.0Hz,2H),1.68-1.60(m,4H).

[0276] Example 17: Preparation of Compound 93

[0277]

[0278] Step 1:

[0279] Compound 93.1 (200.0 mg, 0.50 mmol, prepared in a similar manner to Example 37) was dissolved in MeOH (2 mL), and then formaldehyde (22.6 mg, 0.75 mmol) and TEA (0.7 mL, 4.76 mmol) were added. The mixture continued to react for 30 minutes. NaBH3CN (95 mg, 1.51 mmol) was then added at 0°C. The mixture was reacted at room temperature for 4 hours. The reaction was quenched with H2O (20 mL), extracted with DCM (20 mL×2), the organic phase was washed with saturated brine (10 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to obtain compound 93.2. LC-MS: 412.1 [M+H] + .

[0280] Step 2:

[0281] Compound 93.2 (160.0 mg, 0.39 mmol) was dissolved in DCM (8 mL), and then BBr3 (972.0 mg, 3.88 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The organic phase was adjusted to pH 9-10 with NaHCO3, and then extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZULC-20AP, Column: YMC Triart C18, 20×250 mm, 5 μm; Mobile Layer A: 0.1% FA, B: ACN; Flow rate: 15 mL / min; gradient: 5% to 25%; Retention Time: 7 min of 20 min) to obtain compound 93. LC-MS: 398.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.27(s,2H,HCO2H salt),6.50(s,2H),3.22-3.19(m,2H),3.04-2.98(s,3H),2.86-2.81(m,1H),2.69- 2.56(m,6H),2.32(s,3H),2.12-2.00(m,2H),1.83-1.71(m,5H),1.55-1.45(m,5H).

[0282] The following compounds can be prepared in a similar manner.

[0283]

[0284] Example 18: Preparation of Compound 95

[0285]

[0286] Step 1:

[0287] Compound 95.1 (100.0 mg, 0.16 mmol, prepared in a similar manner to Example 11) was dissolved in MeOH:THF:H2O (10 mL, 1:2:2), and then NaOH (12.6 mg, 0.32 mmol) was added. The mixture was reacted at 50°C for 4 hours. After cooling to room temperature, the reaction was quenched with H2O (30 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, DCM:MeOH=12:1) to obtain compound 95.2. LC-MS: 619.2 [M+H] + .

[0288] Step 2:

[0289] Compound 95.2 (50.0 mg, 0.08 mmol) was dissolved in DMF (2 mL), and then DIEA (0.04 mL, 0.24 mmol), HATU (46.0 mg, 0.12 mmol) and methylamine hydrochloride (10.9 mg, 0.16 mmol) were added. The mixture was stirred for 1 hour. The reaction was quenched with H2O (30 mL) and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative TLC (SiO2, EtOAc:PE=3:1) to obtain compound 95.3. LC-MS: 632.2 [M+H] + .

[0290] Step 3:

[0291] Compound 95.3 (25.0 mg, 0.04 mmol) was dissolved in DCM (10 mL), and then BBr3 (0.02 mL, 0.20 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (20 mL×2, 10:1). The organic phase was adjusted to pH 9-10 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL × 2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid chromatography (SHIMADZU LC-20AP, Column: YMC Triart C18, 20 × 250 mm, 5 μm; Mobile Layer A: 0.1% FA, B: ACN; Flowrate: 15 mL / min; gradient: 10% to 30%; Retention Time: 15 min of 20 min) to obtain compound 95. LC-MS: 516.2 [MH]- . 1 H NMR(400MHz,DMSO-d6)δ8.27(s,2H),6.89-6.88(m,1H),6.82-6.80(m,1H),6.59-6.58(m,1H),6.52(s,2H),3.30-3.23( m,5H),3.18-3.12(m,5H),3.10(s,2H),2.94-2.92(m,4H),2.74(d,J=4.0Hz,3H),1.87-1.84(m,2H),1.66-1.62(m,4H).

[0292] Example 19: Preparation of Compound 97

[0293]

[0294] Step 1:

[0295] Compound int 5 (500.0 mg, 1.59 mmol) was dissolved in DMF (10 mL), and then K2CO3 (219.0 mg, 1.59 mmol) and 2,4-dichloroquinazoline (474.0 mg, 2.38 mmol) were added. The mixture was stirred for 5 hours. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with saturated brine (50 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=10:1-3:1) to obtain compound 97.1. LC-MS: 476.9 [M+H] + .

[0296] Step 2:

[0297] Compound 97.1 (200.0 mg, 0.42 mmol) was dissolved in DMSO (8 mL), and then N-tert-butyloxycarbonyl-piperazine (156 mg, 0.84 mmol) and K2CO3 (116 mg, 0.84 mmol) were added. The mixture was reacted at 80°C for 2 hours. After cooling to room temperature, the mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed with saturated brine (20 mL×2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by column chromatography (SiO2, PE:EtOAc=10:1-3:1) to obtain compound 97.2. LC-MS: 627.2 [M+H-56] + .

[0298] Step 3:

[0299] Compound 97.2 (150.0 mg, 0.24 mmol) was dissolved in DCM (10 mL), and then BBr3 (599.0 mg, 2.39 mmol) was added at 0°C. The mixture was reacted at room temperature for 1 hour. The reaction was quenched with H2O (20 mL) at 0°C and extracted with DCM:MeOH (33 mL×2, 10:1). The aqueous phase was adjusted to pH 5-6 with NaHCO3 solution and extracted with EtOAc (20 mL×2). The organic phase was washed with saturated brine (20 mL × 2), dried over Na2SO4, filtered and concentrated, and the crude product was purified by preparative liquid phase (SHIMADZU LC-20AP, Column: YMC Triart C18, 20 × 250 mm, 5 μm; Mobile Layer A: 0.1% FA, B: ACN; Flowrate: 15 mL / min; gradient: 15% to 35%; Retention Time: 11 min of 20 min) to obtain compound 97. LC-MS: 513.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),7.75(d,J=8.2Hz,1H),7.56(t,J=7.6Hz,1H),7.39(d,J=8.3Hz,1H),7.12(t,J=7.6Hz,1H),6.54(s,2H),3.83( d,J=4.8Hz,4H),3.74(d,J=4.6Hz,4H),3.68(s,1H),3.27(s,2H),3.16(s ,2H),2.91(d,J=5.1Hz,4H),1.92(t,J=6.8Hz,2H),1.73(t,J=5.6Hz,4H).

[0300] Biological activity test examples

[0301] 1 Experimental Materials and Instruments

[0302] Experimental reagents

[0303] Protein: GST-GTPase-4, His-MEK1, stored at -80℃.

[0304] Detection reagents: MAb Anti-6HIS Tb cryptate Gold, Cat#61HI2TLB; MAb Anti-GSTd2, Cat#61GSTDLB; stored at -80℃.

[0305] Buffer: Tris-HCl, pH 7.5, Cat#H3375; NaCl, Cat#746398-500G; Tween 20, Cat#P9416-100ML; TCEP, Cat#A600974.

[0306] Experimental consumables

[0307] ·Microplate,96Well,PP,v-bottom,Greiner,Cat#GN651201-100EA.

[0308] ·384-LDV plate,LABCYTE,Cat#LP-0200.

[0309] ·384Well Low Volume plate,corning,Cat#4512.

[0310] instrument

[0311] • Plate reader: Envision 2104 Multilabel Reader (PerkinElmer).

[0312] Liquid handler: Echo (LABCYTE Echo550).

[0313] Centrifuge: Thermo Centrifuge ST 40R; Thermo LEGEND Micro 21R.

[0314] Incubator: Incubator (CIMO, SPX-60BSH-Ⅱ).

[0315] 2 Experimental methods

[0316] Compound dilution

[0317] 1) The compound was prepared into a 10 mM solution in DMSO and diluted in DMSO to different concentration gradient solutions 100 times the final concentration.

[0318] 2) Transfer 8 μL of the diluted compound solution to a 384-LDV Echo plate, centrifuge at 1000 rpm for 1 min, transfer 100 nL of the compound solution to a 384-well plate (Cat#4512) via Echo 550, and centrifuge at 1000 rpm for 1 min.

[0319] Experimental procedures

[0320] 1) Prepare the experimental buffer: 50 mM Tris-HCl, pH 7.5, 0.05% Tween 20, 1 mM TCEP.

[0321] 2) Dilute the protein GST-GTPase-4 to 2X final concentration (660nM) with assay buffer, then add 5uL of 660nM GST-GTPase-4 solution to each well of the positive control well and compound well, add 5uL of assay buffer to the negative control well, centrifuge at 1000rpm for 1min, and incubate in a 30°C incubator for 30min.

[0322] 3) Dilute the His-MEK1 protein to 2X final concentration (660 nM) with assay buffer, then add 5 uL of 660 nM His-MEK1 solution to each of the positive control wells and compound wells, add 5 uL of assay buffer to the negative control wells, centrifuge at 1000 rpm for 1 min, and incubate in a 30°C incubator for 90 min.

[0323] 4) Dilute the stock solutions of Anti-6His-Tb and Anti-GST-d2 by 20 times with the experimental buffer, mix the two, add 10uL of the mixed solution to each well, centrifuge at 1000rpm for 1min, and incubate in a 30°C incubator for 24h.

[0324] 5) After the incubation on the second day, the fluorescence value was read on the Envision 2104 Multilabel Reader (excitation at 340 nm, detection of emission light at 665 nm and 615 nm, and the 665 nm / 615 nm fluorescence ratio was the raw data of the reaction signal value in the well).

[0325] Data analysis

[0326] The protein interaction detection experiment uses XLfit, a software written by IDBS and integrated into the Microsoft Excel environment, to process and analyze the test data. First, the average reaction signals of the positive control wells and negative control wells are calculated respectively, and then the reaction inhibition rate of each compound well can be calculated according to the formula "single well inhibition rate = (1-(single well signal value-negative control signal average) / (positive control signal average-negative control signal average)) × 100%". Then the concentration and corresponding inhibition rate data are imported into the XLfit software, and the Dose Response One Site 205 model in the software is used to fit the inhibition rate-concentration curve using the four-parameter method, and the IC50 value of the compound is calculated.

[0327] The mean and standard deviation were calculated using the Excel built-in function equation. The calculation formulas for the coefficient of variation, Z factor, and experimental window are as follows:

[0328] Coefficient of variation = standard deviation / mean value*100

[0329] Z factor = 1-3*(positive control standard deviation + negative control standard deviation) / (positive control mean value - negative control mean value)

[0330] Experimental window: Positive control average value / Negative control average value

[0331] The inhibitory effects of the example compounds on the GTPase / MEK1 protein interaction are shown in Table 1, where A represents IC 50 ≤1μM; B represents 1μM <IC 50 ≤10μM; C represents 10μM <IC 50 ≤50μM; D represents IC 50 >50μM.

[0332] Table 1

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358] The above results show that the example compounds have excellent inhibitory activity on GTPase / MEK1 protein interaction.

[0359] The above describes the exemplary embodiments of the present invention. However, it should be understood that the protection scope of the present invention is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof as shown in the following formula I: in, Ring A is selected from the following groups: phenyl, naphthyl; L is selected from L1-cyclic group; Among them, L1 is -NR 2 -; the cyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl; n is 0, 1, 2, or 3; each R 1 independently selected from H, halogen, CN, NO2, C1-C 10 Alkyl, -NR C R D 、-OR A 、-SR A 、-C(O)OR A 、-C(O)NR C R D 、-NR C C(O)R B 、-S(O)2R B 、-S(O)2NR C R D ; Among them, R A , R B , R C , R D Independently selected from H, methyl, ethyl, n-propyl, isopropyl, phenyl, wherein the methyl, ethyl, n-propyl, isopropyl, phenyl is optionally independently substituted by 1, 2 or 3 groups selected from halogen, CN, OH, CF3, OMe, OCF3, OEt, NH2; Every R 2 Independently selected from H, C1-C6 alkyl, C6-C 14 Aryl, wherein the C1-C6 alkyl, C6-C 14 The aryl group is optionally independently substituted with one or more R J replace; R J are the same or different and are independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyloxy; R 3 , R 4 is optionally H or halogen, and R 3 , R 4 H; R 5 is -OH; Wherein, the compound represented by the formula I does not include the compound represented by the following structure:

2. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that Ring A is selected from the following groups:

3. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that In the group L, the cyclic group is selected from the following groups:

4. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that R J The same or different, independently selected from Me, Et, CF3, OMe, OCF3, OEt.

5. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that Ring A is selected from phenyl; L is selected from L1-cyclic group; Among them, L1 is -NR 2 -; the cyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl; Where R 2 Independently selected from H, C1-C6 alkyl, C6-C 14 Aryl, wherein the C1-C6 alkyl, C6-C 14 The aryl group is optionally independently substituted with one or more R J replace; R J The same or different, independently selected from H, halogen, CN, OH, NH2, C1-C6 alkyl; n is 0, 1, 2, or 3; R 1 independently selected from H, halogen, CN, NO2, C1-C6 alkyl, -NR C R D 、-OR A 、-SR A 、-C(O)OR A 、-C(O)NR C R D 、-NR C C(O)R B 、-S(O)2R B 、-S(O)2NR C R D ; Among them, R A , R B , R C , R D Independently selected from H, methyl, ethyl, n-propyl, isopropyl, wherein the methyl, ethyl, n-propyl, isopropyl is optionally independently substituted by 1, 2 or 3 groups selected from halogen, CN, OH, CF3, OMe, OCF3, OEt, NH2.

6. The compound or pharmaceutically acceptable salt according to claim 1, characterized in that The compound is selected from the following compounds:

7. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds or pharmaceutically acceptable salts of any one of claims 1 to 6.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition further contains one or more other chemotherapeutic drugs or targeted drugs.

9. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition further contains one or more other tumor immunotherapy drugs.

10. The pharmaceutical composition according to claim 9, characterized in that Tumor immunotherapy drugs are immune checkpoint inhibitors PD1 / PDL1 inhibitors.

11. The pharmaceutical composition according to claim 10, characterized in that The immune checkpoint inhibitor drug PD1 / PDL1 inhibitor is a PD1 / PDL1 antibody combination.

12. Use of at least one of the compounds or pharmaceutically acceptable salts of any one of claims 1 to 6, or the pharmaceutical composition of claim 7 in the preparation of an RBJ inhibitor; or, use in the preparation of a drug for inhibiting RBJ expression.

13. Use of at least one of the compounds or pharmaceutically acceptable salts of any one of claims 1 to 6, or the pharmaceutical composition of claim 7, in the preparation of a medicament for treating cancer and / or inhibiting metastasis associated with a specific cancer, wherein the cancer is lung cancer, melanoma, breast cancer, ovarian cancer, prostate cancer, liver cancer, kidney cancer, intestinal cancer, head and neck cancer, skin cancer, bladder cancer, pancreatic cancer, gastric cancer, esophageal cancer, glioma, neuroblastoma, laryngeal cancer, nasopharyngeal cancer, thyroid cancer, leukemia, lymphoma, or malignant pleural mesothelioma.

14. The use according to claim 13, characterized in that The lung cancer is non-small cell lung cancer, and the intestinal cancer is colon cancer.

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