Heterocyclic compound as MEK inhibitor

Abstract

The present disclosure relates to a compound targeting MEK, and specifically provides a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the compound having the substituents and structural features described in the present application. The present application further describes a pharmaceutical composition comprising the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as well as a medical use of the compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof.

Description

Heterocyclic compounds as MEK inhibitors

[0001] Cross-references to related applications

[0002] This application claims priority and benefits from the following patent application, the entire contents of which are incorporated herein by reference:

[0003] Chinese Invention Patent Application No. 202411592342.7 was filed with the State Intellectual Property Office of the People's Republic of China on November 8, 2024. Technical Field

[0004] This disclosure pertains to the pharmaceutical field and relates to a compound as a MEK inhibitor or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing the same, and their use in the prevention or treatment of related diseases. Background Technology

[0005] In healthy cells, the mitogen-activated protein kinase (MAPK) (MEK) signaling pathway is one of the key signal transduction pathways in eukaryotes, driving and promoting cell proliferation, differentiation, apoptosis, and stress responses. The RAS-RAF-MEK-ERK signaling pathway is one of three different MAPK pathways, and overexpression or mutation of related proteins has been found in many malignant tumors, especially gain-of-function mutations in the RAS family (including KRAS, NRAS, and HRAS) or the RAF family (including ARAF, BRAF, and CRAF / RAF1), which are common in cancer. Statistics show that 31% of non-small cell lung cancer patients and 90% of pancreatic cancer patients are driven by KRAS mutations. In addition, 21% of endometrial cancer, 45% of colorectal cancer, and 5% of ovarian cancer are driven by KRAS mutations; 28% of melanoma and 20% of multiple myeloma are driven by NRAS mutations; and 60% of melanoma, 35-60% of ovarian cancer, and 30-80% of papillary thyroid carcinoma are driven by BRAF mutations. The patient population is enormous. However, due to the lack of effective treatments, these cancer patients often face poor prognosis and limited treatment options.

[0006] MEK, as a central node in the MAPK signaling pathway, has been an attractive drug target for over two decades. However, existing MEK inhibitors all have some significant drawbacks. First-generation MEK inhibitors, such as trametinib, cobimetinib, binimetinib, and selumetinib, have long or medium half-lives but are administered frequently. These drugs can continuously inhibit MEK function throughout the dosing cycle (i.e., chronic inhibition) to combat MAPK pathway reactivation, leading to dose-limiting toxicities and increased sensitivity to pathway reactivation. Second-generation MEK inhibitors, such as VS-6766 (with a mean terminal half-life of 53.6 hours), are resistant to pathway reactivation, but they still occupy MEK for extended periods, resulting in sustained inhibition of MAPK pathway activity. Therefore, they exhibit similar toxicities to first-generation inhibitors.

[0007] Therefore, further improvements are needed for MEK inhibitors, such as novel MEK inhibitors with shorter half-lives that can achieve dual inhibition of MEK / RAF. By completely inhibiting the MAPK / ERK pathway, these inhibitors can reverse the disease to the greatest extent possible while preventing the reactivation of abnormal pathways (such as ERK-dependent negative feedback triggering CRAF-mediated pathway reactivation) and limiting drug-related toxicities, thereby significantly impacting the morbidity and mortality rates of cancer patients. Summary of the Invention

[0008] This disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] L1 is selected from NH, CH2, O, or S;

[0011] Ring A is selected from Where * represents the connection site with L1, and ** represents the connection site with methylene;

[0012] Z 1 Selected from CR c Or N; Z represents a single or double bond. 2 Z 3 Selected independently from N and NR g or CR h ;

[0013] R a R b R c R e R f R g R hThe components are independently selected from H, deuterium, halogen, OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 3a Replace; or when Z 1 For CR c At that time, R b R c Together with the atoms connected to it, they form an optional structure formed by one or more R atoms. 4a Substituted 5-6 heteroaryl groups; or when Z 2 Z 3 Selected independently from NR g or CR h At that time, two R g and the atoms connected to it, or R g R h Together with the atoms attached to it, they form a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, or two R atoms. h Together with the atoms attached to it, they form a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, wherein the benzene ring, 5-6 membered heteroaromatic ring, or 5-6 membered heterocycle is optionally surrounded by one or more R... 5a replace;

[0014] R d Selected from C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R 6a replace;

[0015] X 1 X 2 X 4 X 5 X 6 X 7 Selected independently from CR 4 Or N; X 3 Selected from CR 3 Or N;

[0016] R 1 R 2 R 3 R 4 The elements are independently selected from H, deuterium, halogen, OH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 1a Replace; or, R 1 R 2 Together with the atoms attached to it, it forms a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, wherein the 4-7 membered heterocyclic group, the 5-6 membered heteroaryl group, or the phenyl group is optionally surrounded by one or more R 1breplace;

[0017] R 5 Selected from H, deuterium, or C1-C4 alkyl; or when X 3 For CR 3 At that time, R 3 R 5 Together with the atoms attached to it, they form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 2a replace;

[0018] R 6 Selected from S(=O)2R 8 S(=O)2NR 8a R 8b S(=O)(=NR) 9 )R 8 Or P(=O)R 8a R 8b , where R 9 Selected from H, deuterium, or C1-C4 alkyl; R 8 R 8a R 8b The groups are independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally separated by one or more R groups. 8c Replace; or, R 8a and R 8b Together with the atoms attached to it, they form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 8e replace;

[0019] R 1a R 2a R 3a R 4a R 5a R 6a They are independently selected from deuterium, halogens, C1-C4 alkyl groups, or C1-C4 haloalkyl groups;

[0020] R 1b Selected from halogens, CN, =O, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 1c replace;

[0021] R 8cThe compounds are independently selected from deuterium, halogens, CN, =O, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 8d replace;

[0022] R 1c R 8d R 8e They are independently selected from deuterium, halogens, =O, OH or C1-C3 alkyl groups.

[0023] In some implementations, L1 is NH.

[0024] In some implementations, ring A is Where * represents the connection site with L1, and ** represents the connection site with methylene.

[0025] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R a R b R c The components are independently selected from H, deuterium, halogen, OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 3a Replace; or R b R c Together with the atoms attached to it, they form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally surrounded by one or more R 4a replace.

[0026] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R a R b R c The components are independently selected from H, halogens, OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 3a replace.

[0027] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R a Selected from H, deuterium, halogens, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R 3a Replace; Rb R c The components are independently selected from H, deuterium, halogen, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally mixed with one or more R. 3a replace.

[0028] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R a Selected from H, F, or methyl; R b Selected from methyl, ethyl, CF3, SCH3, N(CH3)2 or cyclopropyl; R c Selected from H or methyl.

[0029] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R b R c Together with the atoms attached to it, they form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally surrounded by one or more R 4a replace.

[0030] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R b R c Together with its attached atoms, the pyridinyl group forms a pyridinyl group, which is optionally bonded by one or more R atoms. 4a replace.

[0031] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and n is selected from 0, 1, or 2.

[0032] In some implementations, ring A is Where * represents the connection site with L1, and ** represents the connection site with methylene.

[0033] In some implementations, ring A is selected from... Where * represents the connection site with L1, and ** represents the connection site with methylene.

[0034] In some implementations, ring A is Where * represents the connection site with L1, and ** represents the connection site with methylene.

[0035] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 Selected independently from N or CR h .

[0036] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 One is N, and the other is CR h .

[0037] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 Selected independently from NR g or CR h And two R g and the atoms connected to them, or two R h and the atoms connected to it, or R g R h Together with the atoms attached to it, they form a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, wherein the benzene ring, 5-6 membered heteroaromatic ring, or 5-6 membered heterocycle is optionally surrounded by one or more R... 5a replace.

[0038] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 One of them is NR g The other is CR h , or Z 2 Z 3 All are CR h And two R h and the atoms connected to it, or R g R h Together with its associated atoms, the 5-6 membered heteroaromatic ring forms a 5-6 membered heteroaromatic ring, which is optionally surrounded by one or more R atoms. 5a replace.

[0039] In some implementations, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 One of them is NR g The other is CR h , or Z 2 Z3 All are CR h And two R h and the atoms connected to it, or R g R h Together with the atoms attached to it, they form a pyrazole ring or a furan ring, said pyrazole ring or furan ring optionally being formed by one or more R 5a replace.

[0040] In some implementations, ring A is Where * represents the connection site with L1, and ** represents the connection site with methylene.

[0041] In some implementation schemes, R a Selected from H, deuterium, halogens, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R 3a replace.

[0042] In some implementation schemes, R a Selected from H, halogens, or C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally converted by one or more R groups. 3a replace.

[0043] In some implementation schemes, R a Selected from H, F or methyl.

[0044] In some implementation schemes, R b R c The components are independently selected from H, deuterium, halogen, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally mixed with one or more R. 3a replace.

[0045] In some implementation schemes, R b R c The components are independently selected from H, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally separated by one or more R. 3a replace.

[0046] In some implementation schemes, R 3a Selected from halogens or C1-C4 alkyl groups.

[0047] In some implementation schemes, R 3a Selected from F or methyl.

[0048] In some implementation schemes, R b R cThey are independently selected from H, methyl, ethyl, CF3, SCH3, NHCH3, N(CH3)2 or cyclopropyl.

[0049] In some implementation schemes, R b Selected from methyl, ethyl, CF3, SCH3, N(CH3)2 or cyclopropyl.

[0050] In some implementation schemes, R b It is CF3.

[0051] In some implementation schemes, R c Selected from H or methyl. In some embodiments, R c For H.

[0052] In some implementation schemes, R d It is selected from C1-C4 alkyl or C1-C4 haloalkyl.

[0053] In some implementation schemes, R d It is a methyl group.

[0054] In some implementation schemes, R e R f The components are independently selected from H, deuterium, halogen, or C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally converted by one or more R groups. 3a replace.

[0055] In some implementation schemes, R e R f They are independently selected from H, methyl, or CF3.

[0056] In some implementation schemes, R e Selected from methyl or CF3. In some embodiments, R e It is CF3.

[0057] In some implementation schemes, R h For H.

[0058] In some implementations, ring A is selected from... Where * represents the connection site with L1, and ** represents the connection site with methylene.

[0059] In some implementation schemes, R 1 R 2 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace; or R 1 R 2Together with the atoms attached to it, it forms a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, wherein the 4-7 membered heterocyclic group, the 5-6 membered heteroaryl group, or the phenyl group is optionally surrounded by one or more R 1b replace.

[0060] In some implementation schemes, R 1 R 2 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace; or R 1 R 2 Together with the atoms attached to it, they form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 1b replace.

[0061] In some implementation schemes, R 1 R 2 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a replace.

[0062] In some implementation schemes, R 1 R 2 Each is independently selected from H, halogen, methoxy, OCF3, OCHF2, CF3, ethyl, CH2CF3, CH2CHF2 or cyclopropyl, or R 1 R 2 Together with the atoms connected to it, they form

[0063] In some implementation schemes, R 2 For H, R 1 Selected from halogen, methoxy, OCF3, OCHF2, CF3, ethyl, CH2CF3, CH2CHF2 or cyclopropyl, or R 1 R 2 Together with the atoms connected to it, they form

[0064] In some implementation schemes, R 3 R 4 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace, R 5 Selected from H, deuterium, or C1-C4 alkyl; or when X 3 For CR3 At that time, R 3 R 5 Together with the atoms attached to it, they form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 2a replace.

[0065] In some implementation schemes, R 3 R 4 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace, R 5 Selected from H, deuterium, or C1-C4 alkyl groups.

[0066] In some implementation schemes, R 1a It is selected from halogens, C1-C4 alkyl groups, or C1-C4 haloalkyl groups.

[0067] In some implementation schemes, R 1a Selected from F, methyl, CF3 or CHF2.

[0068] In some implementation schemes, R 3 Selected from F or Cl.

[0069] In some implementation schemes, R 4 Choose from H or F.

[0070] In some implementation schemes, R 4 For H.

[0071] In some implementation schemes, R 5 For H.

[0072] In some implementation schemes, X 3 For CR 3 R 3 Selected from H or halogens.

[0073] In some implementation schemes, X 3 For CR 3 R 3 R 5 Together with the atoms connected to it, they form

[0074] In some implementation schemes, X 1 X 2 For CR 4 X 7 For CR 4 Or N; or X 1 X 2 Let N, X7 For CR 4 .

[0075] In some implementation schemes, X 1 X 2 For CR 4 X 7 For CR 4 Or N.

[0076] In some implementation schemes, X 1 X 2 X 7 All are CR 4 .

[0077] In some implementation schemes, X 1 X 7 Both are CH, X 2 For CR 4 .

[0078] In some implementation schemes, X 5 X 6 All are CR 4 X 4 For CR 4 Or N.

[0079] In some implementation schemes, X 5 X 6 All are CR 4 X 4 Let N be the number of elements in the array.

[0080] In some implementation schemes, X 5 X 6 Both are CH, X 4 Let N be the number of elements in the array.

[0081] In some implementation schemes, X 5 X 6 Both are CH, X 4 Let N, X 3 For CR 3 .

[0082] In some implementation schemes, R 3 Selected from H or halogens. In some embodiments, R 3 Choose from H or F.

[0083] In some implementation schemes, R 6 Selected from S(=O)2R 8 Or S(=O)2NR 8a R 8b .

[0084] In some implementation schemes, R 6S(=O)2NR 8a R 8b .

[0085] In some implementation schemes, R 8 Selected from C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 8c replace.

[0086] In some implementation schemes, R 8 It is a C1-C6 alkyl group.

[0087] In some implementation schemes, R 8a R 8b The groups are independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally surrounded by one or more R groups. 8c Replace, or, R 8a and R 8b Together with the atoms attached to it, they form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 8e replace.

[0088] In some implementation schemes, R 8a R 8b The components are independently selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 8c Replace, or, R 8a and R 8b Together with the atoms attached to it, they form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. 8e replace.

[0089] In some implementation schemes, R 8e Halogens such as F.

[0090] In some implementation schemes, R 8a R 8b The groups are independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally surrounded by one or more R groups. 8c replace.

[0091] In some implementation schemes, R 8a R 8b Each is independently selected from H, methyl, or cyclopropyl, or R 8a and R8b Together with the atoms connected to it, they form

[0092] In some implementation schemes, R 6 Selected from

[0093] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0094] Among them: L1, R a R b R c X 1 X 2 X 3 X 4 X 5 X 6 X 7 R 1 R 2 R 5 and R 6 As defined above.

[0095] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0096] Where: R a R b R c X 1 X 2 X 3 X 4 X 5 X 6 X 7 R 1 R 2 R 8a and R 8b As defined above.

[0097] In some embodiments, the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from the following compounds or their stereoisomers or pharmaceutically acceptable salts:

[0098] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), (II), or (III) of this disclosure, or a specific compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0099] On the other hand, this disclosure provides a method for treating MEK-mediated diseases in mammals, including administering to a mammal, preferably a human, a therapeutically effective amount of a compound of general formula (I), (II), or (III) of this disclosure, or a specific compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100] On the other hand, this disclosure provides a method for treating tumors in mammals, including administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of a compound of general formula (I), formula (II), or formula (III), or a specific compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0101] On the other hand, this disclosure provides the use of compounds of general formula (I) or formula (II) or formula (III) or specific compounds thereof or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of MEK-mediated diseases.

[0102] On the other hand, this disclosure provides the use of compounds of general formula (I) or formula (II) or formula (III) or specific compounds thereof or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of tumors.

[0103] On the other hand, this disclosure provides the use of compounds of general formula (I) or formula (II) or formula (III) in the prevention or treatment of MEK-mediated diseases, including specific compounds thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0104] On the other hand, this disclosure provides the use of compounds of general formula (I) or formula (II) or formula (III) or specific compounds thereof or their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of tumors.

[0105] On the other hand, this disclosure provides compounds of general formula (I), formula (II), or formula (III) for the prevention or treatment of MEK-mediated diseases, or specific compounds thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0106] On the other hand, this disclosure provides compounds of general formula (I), formula (II), or formula (III) for the prevention or treatment of tumors, or specific compounds thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0107] In some implementations, MEK-mediated diseases are selected from tumors.

[0108] In some implementations, the tumor is selected from colon cancer or pancreatic cancer.

[0109] Terminology Definitions and Explanations

[0110] Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0111] In this article Indicates the connection site.

[0112] The diagrammatic representation of racemic or enantiomerically pure compounds in this article is derived from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, wedge bonds and virtual wedge bonds are used. The absolute configuration of a solid center is represented by black solid bonds and imaginary bonds. It indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

[0113] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this disclosure can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0114] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0115] The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds. Therefore, the compounds disclosed herein may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups and other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents and mixtures thereof are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0116] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on the aromatic group.

[0117] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0118] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0119] When any variable appears more than once in the composition or structure of a compound, its definition is independent in each case. For example... When n is 2, it means there exist 2 R. 4aSubstituents, at this time each R 4a Each has its own independent options.

[0120] For substituents whose substitution positions are not fixed in this paper, such as R in 4a The substitution position can be any site on the pyridine ring, as long as there is a hydrogen atom that can be substituted at that site.

[0121] Unless otherwise specified, the linking direction of the linking groups mentioned in this article is arbitrary.

[0122] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a bond.

[0123] C in this article m -C n It refers to having an integer number of carbon atoms, either mn or in the range m to n. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Similarly, "m-membered" to "n-membered" indicates that the number of ring atoms is m to n. For example, 5-14-membered rings include 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, and 14-membered rings. It also includes any range from n to m. For example, 5-14-membered rings include 6-14-membered, 6-11-membered, 5-10-membered, 6-10-membered, and 6-8-membered rings.

[0124] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The hydrocarbon group is a straight-chain or branched 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, more preferably an alkyl group containing 1 to 6 carbon atoms. The term "C1-C" is used. 10"Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, 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, etc.; the term "C1-C6 alkyl" can be understood as referring to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. The "C1-C6 alkyl" 10 "alkyl" can include the range of "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and "C1-C6 alkyl" can further include "C1-C4 alkyl" or "C1-C3 alkyl", and "C1-C4 alkyl" can further include "C1-C3 alkyl".

[0125] The term "haloalkyl" refers to the group obtained by further substituting the alkyl group with a halogen, such as "C1-C6 haloalkyl" which refers to C1-C6 alkyl groups further substituting with a halogen, and "C1-C4 haloalkyl" which refers to C1-C4 alkyl groups further substituting with a halogen. The "C1-C6 haloalkyl" may further include "C1-C4 haloalkyl".

[0126] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. The term "C2-C6 alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms; "C2-C6 alkenyl" can include "C2-C4 alkenyl," C2, or C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds can be separable or conjugated. Specific examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, etc.

[0127] The term "alkoxy" refers to a monovalent group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols; it can be understood as "alkyloxy" or "alkyl-O-", where alkyl is defined as described above. The term "C1-C"... 10 "Alkoxy" can be understood as "C1-C" 10 "alkyloxy" or "C1-C" 10 "alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". "C1-C4 alkoxy" can be understood as "C1-C4 alkyloxy" or "C1-C4 alkyl-O-". The "C1-C" 10 "Alkoxy" can include the range of "C1-C6 alkoxy" and "C1-C4 alkoxy", and the "C1-C6 alkoxy" can further include "C1-C4 alkoxy".

[0128] The term "cycloalkyl" refers to a fully saturated carbon ring existing in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C" is also used. 10 "Cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C3-C8 cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, or 8 carbon atoms. The term "C3-C6 cycloalkyl" should be understood as indicating a saturated monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, or 6 carbon atoms, specific examples including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C3-C6 cycloalkyl" may include "C3-C5 cycloalkyl" or "C3-C4 cycloalkyl".

[0129] The term "heterocyclic group" refers to a fully saturated or partially saturated (not aromatic as a whole) monovalent monocyclic, fused, spirocyclic, or bridged ring group containing 1, 2, 3, 4, or 5 heteroatoms or heterogroups (i.e., groups containing heteroatoms). These "heteroatoms or heterogroups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, and optionally substituted -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=NH)-, -S(=O)2NH-, S(=O)NH-, or -NHC(=O)NH-, etc., which typically contain 3 to 20 ring atoms. The term "4-7 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, or 7 ring atoms, and whose ring atoms contain 1-2 heteroatoms or heterogroups independently selected from those described above. The term "5-6 membered heterocyclic group" refers to a heterocyclic group with 5 or 6 ring atoms, and whose ring atoms contain 1-2 heteroatoms or heterogroups independently selected from those described above. The term "4-7 membered heterocyclic group" can include "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", or "4-5 membered heterocyclic group". Specific examples of 4 membered heterocyclic groups include, but are not limited to, azirrocyclobutane or oxacyclobutane; specific examples of 5 membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic groups include, but are not limited to, diazacycloheptane. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazinolo-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group can be a benzofused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl. Although some bicyclic heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0130] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system containing at least one, preferably 1, 2, 3, or 4 ring atoms selected from N, O, and S, with the remaining ring atoms being 5-14 membered aromatic cyclic groups of carbon. The heteroaryl is preferably 5-10 membered, more preferably 5- or 6-membered heteroaryl. The term "5-10 membered heteroaryl" should be understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, particularly 5, 6, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5, preferably 1, 2, or 3 heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. The term "5-6-membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and comprising 1, 2, or 3, preferably 1 or 2, heteroatoms independently selected from N, O, and S. The term "6-membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and comprising 1, 2, or 3, preferably 1 or 2, heteroatoms independently selected from N, O, and S. The term "5-10-membered heteroaryl" can include either "5-6-membered heteroaryl" or "6-membered heteroaryl," and the term "5-6-membered heteroaryl" can include "6-membered heteroaryl."

[0131] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0132] The term “therapeutic effective amount” means the amount of a compound of this disclosure used to treat a particular disease, condition, or symptom; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or symptom; or (iii) to delay the onset of one or more symptoms of a particular disease, condition, or symptom described herein. The amount of a compound of this disclosure constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0133] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0134] The term “pharmaceutically acceptable salt” or “medicinal salt” refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0135] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this disclosure or their stereoisomers or pharmaceutically acceptable salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this disclosure to an organism.

[0136] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0137] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0138] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0139] Compounds of this disclosure labeled with certain isotopes (e.g., using...) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0140] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds of this disclosure with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0141] Typical routes of administration of the compounds or stereoisomers thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof disclosed herein include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0142] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0143] In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0144] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0145] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0146] The dosage of compounds or compositions used in the treatments described in this disclosure will generally vary depending on the severity of the disease, the patient's weight, and the relative efficacy of the compound. However, as a general guideline, a suitable daily dose of the compound of formula (I), (II), or (III) described herein, or its stereoisomers or pharmaceutically acceptable salts thereof, is from 0.01 mg / kg to 1000 mg / kg.

[0147] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this disclosure.

[0148] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required by this disclosure. To obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0149] In some embodiments, some compounds of general formula (I) of this application can be prepared by those skilled in the art of organic synthesis via the following route:

[0150] Scheme 1

[0151] Among them, R a R b R c X 1 X 2 X 3 X 4 X 5 X 6 X 7 R 1 R 2 R 8a and R 8b As defined in formula (I), X represents a halogen, X' represents a halogen or OMs or OTf or OTs, and PG represents an amino protecting group. Detailed Implementation

[0152] The following detailed description of specific implementation schemes illustrates the content of this disclosure, but does not imply any adverse limitation thereof. Various specific implementation schemes of this disclosure have been described in detail herein, and it will be apparent to those skilled in the art that various changes and modifications can be made to these specific implementation schemes without departing from the spirit and scope of this disclosure.

[0153] All reagents used in this disclosure are commercially available and can be used without further purification.

[0154] Unless otherwise stated, proportions expressed for mixed solvents are volume-based. Unless otherwise stated, % refers to wt%.

[0155] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻¹⁰. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibitory concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0156] The eluent described below may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0157] Abbreviations:

[0158] TBSCl: tert-butyldimethylchlorosilane; TBS: tert-butyldimethylsilyl; DCM: dichloromethane; Ph: phenyl; Pd2(dba)3: tris(dibenzylacetone)dipalladium; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); TBAF: tetrabutylammonium fluoride; LDA: (diisopropylamino)lithium; Pd(OAc)2: palladium acetate; NaOMe: sodium methoxide; MeOH: methanol; THF: tetrahydrofuran; Ms: methanesulfonyl; Ms2 O: Methanesulfonic anhydride; DMSO: Dimethyl sulfoxide; Py or pyridine: Pyridine; DMF: N,N-Dimethylformamide; XantPhos: 4,5-Bisdiphenylphosphine-9,9-Dimethyloxanthracene; PE: Petroleum ether; NIS: N-Iodosuccinimide; p-TsOH: p-Toluenesulfonic acid; EA: Ethyl acetate; imidazole: Imidazole; TMSI: Trimethyliodosilane; M: Moles per liter; FA: Formic acid; FBS: Fetal bovine serum.

[0159] Example 1: Synthesis of 3-fluoro-4-(2-fluoro-4-iodo-aniline)-1-[[3-fluoro-2-(methylaminosulfonamido)-pyridin-4-yl]methyl]-5-(trifluoromethyl)pyridin-2-one (compound 1)

[0160] Step 1: tert-butyl-[(2-chloro-3-fluoropyridin-4-yl)methoxy]-dimethylsilane (compounds 1-2)

[0161] (2-chloro-3-fluoropyridin-4-yl)methanol (3 g, 18.57 mmol) and imidazole (3.79 g, 55.71 mmol) were added to DMF (50 mL). TBSCl (5.60 g, 37.14 mmol, 6.91 mL) was added in portions under ice bath conditions. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was separated by normal phase column chromatography (PE:DCM = 5:1) to give the title compounds 1-2 (5 g, yield: 97.62%).

[0162] LC-MS: m / z (ESI): 276.1 [M+H] + .

[0163] Step 2: N-[4-[[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]-1,1-benzophenone imine (compounds 1-3)

[0164] Compounds 1-2 (1 g, 3.63 mmol), benzophenone imine (985.60 mg, 5.44 mmol, 912.59 μL), Pd2(dba)3 (166.00 mg, 181.28 μmol), BINAP (225.75 mg, 362.55 μmol), and cesium carbonate (2.36 g, 7.25 mmol) were added to 1,4-dioxane (15 mL), and nitrogen was purged. The resulting mixture was heated to 90 °C under nitrogen protection and stirred for 5.0 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by normal-phase column chromatography (PE:DCM = 5:1) to give the title compound 1-3 (1 g, yield: 65.58%).

[0165] LC-MS: m / z (ESI): 421.2 [M+H] + .

[0166] Step 3: [2-(benzophenone imino)-3-fluoropyridin-4-yl]methanol (compounds 1-4)

[0167] Compounds 1-3 (1 g, 2.38 mmol) were added to THF (10 mL), and TBAF (1 M, 2.85 mL) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1.0 h. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added dropwise to quench the reaction, followed by extraction with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then separated by a normal-phase column (DCM:EA = 2:1) to give the title compounds 1-4 (400 mg, yield: 54.92%).

[0168] LC-MS: m / z (ESI): 307.1 [M+H] + .

[0169] Step 4: Methyl [2-(benzophenone imino)-3-fluoropyridin-4-yl]methanesulfonate (compounds 1-5)

[0170] Compounds 1-4 (400 mg, 1.31 mmol) and triethylamine (264.26 mg, 2.61 mmol, 364.00 μL) were added to a mixture of THF (5 mL). Methanesulfonyl methanesulfonic acid (341.19 mg, 1.96 mmol) was added in portions under ice bath conditions. The resulting mixture was stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal-phase column chromatography (DCM:EA = 10:1) to give title compounds 1-5 (400 mg, yield: 79.69%).

[0171] LC-MS: m / z (ESI): 385.1 [M+H] + .

[0172] Step 5: 3-Fluoro-2-methoxy-5-(trifluoromethyl)pyridine (compounds 1-7)

[0173] Compounds 1-6 (10 g, 54.62 mmol) were added to a mixture of methanol (50 mL), and sodium methoxide (4.43 g, 81.93 mmol) was slowly added. The resulting mixture was heated to 70 °C under a nitrogen atmosphere and stirred for 2.0 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was then separated by a normal-phase column (PE:DCM = 10:1) to give the title compounds 1-7 (6 g, yield: 56.30%).

[0174] Step 6: 3-Fluoro-4-iodo-2-methoxy-5-(trifluoromethyl)pyridine (compounds 1-8)

[0175] Compounds 1-7 (3 g, 15.38 mmol) were added to a mixture of THF (50 mL), and nitrogen was introduced. A tetrahydrofuran solution of (diisopropylamino)lithium (2 M, 9.23 mL) was slowly added dropwise at -78 °C, followed by stirring for 1 hour. Then, a tetrahydrofuran solution of iodine (3.90 g, 15.38 mmol) was slowly added dropwise, followed by stirring for 1 hour. After the reaction was complete, the temperature was raised to 0 °C, quenched with a saturated ammonium chloride aqueous solution, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was separated by a normal-phase column (PE:DCM = 10:1) to give the title compounds 1-8 (4 g, yield: 81.04%).

[0176] Step 7: 3-Fluoro-N-(2-fluorophenyl)-2-methoxy-5-(trifluoromethyl)pyridine-4-amine (compounds 1-9)

[0177] Compounds 1-8 (2.5 g, 7.79 mmol), 2-fluoroaniline (1.73 g, 15.58 mmol, 1.50 mL), palladium acetate (174.85 mg, 778.79 μmol), XantPhos (901.25 mg, 1.56 mmol), and cesium carbonate (5.07 g, 15.58 mmol) were added to 1,4-dioxane (30 mL), and nitrogen was used to purge the mixture. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3.0 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by a normal-phase column (PE:DCM = 5:1) to give title compounds 1-9 (2 g, yield: 84.42%).

[0178] LC-MS: m / z (ESI): 305.1 [M+H] + .

[0179] Step 8: 3-Fluoro-N-(2-Fluoro-4-iodophenyl)-2-methoxy-5-(trifluoromethyl)pyridine-4-amine (compounds 1-10)

[0180] Compounds 1-9 (2 g, 6.57 mmol), NIS (1.77 g, 7.89 mmol), and p-toluenesulfonic acid (1.36 g, 7.89 mmol) were added to a mixture of acetonitrile (30 mL), and nitrogen was purged. The resulting mixture was heated to 60 °C under nitrogen protection and stirred for 1.0 h. After the reaction was complete, the mixture was separated by a preparative high-performance liquid chromatography column (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (containing 0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 min) to obtain title compound 1-10 (2.5 g, yield: 88.41%).

[0181] LC-MS: m / z (ESI): 431.0 [M+H] + .

[0182] Step 9: 3-Fluoro-4-(2-Fluoro-4-iodoanilino)-5-(trifluoromethyl)pyridin-2-one (compounds 1-11)

[0183] Compound 1-10 (500 mg, 1.16 mmol) and trimethyliodosilane (348.91 mg, 1.74 mmol, 242.30 μL) were added to acetonitrile (5 mL), and nitrogen was used to purge the mixture. The resulting mixture was heated to 60 °C under nitrogen protection and stirred for 2.0 h. After the reaction was complete, the mixture was separated by a preparative high performance liquid chromatography column (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 min) to obtain the title compound 1-11 (450 mg, yield: 99.03%).

[0184] LC-MS: m / z (ESI): 417.0 [M+H] + .

[0185] Step 10: 1-[[[2-(benzophenone imino)-3-fluoropyridin-4-yl]methyl]-3-fluoro-4-(2-fluoro-4-iodo-aniline)-5-(trifluoromethyl)pyridin-2-one (compounds 1-12)

[0186] Compounds 1-11 (150 mg, 360.50 μmol), methyl [2-(benzophenone imino)-3-fluoropyridin-4-yl]methanesulfonate (1-5, 138.59 mg, 360.50 μmol), and potassium carbonate (99.50 mg, 721.01 μmol) were added to DMF (2 mL), and the mixture was stirred at room temperature for 1.0 h. After the reaction was complete, the mixture was separated by a preparative high performance liquid chromatography column (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (containing 0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 1-12 (200 mg, yield: 78.76%).

[0187] LC-MS: m / z (ESI): 705.1 [M+H] + .

[0188] Step 11: 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-3-fluoro-4-(2-fluoro-4-iodo-aniline)-5-(trifluoromethyl)pyridin-2-one (compounds 1-13)

[0189] Compound 1-12 (200 mg, 283.93 μmol) was added to 1,4-dioxane (1 mL), followed by 1,4-dioxane hydrochloride solution (4 M, 2 mL). The mixture was stirred at room temperature for 1.0 h. After the reaction was complete, the solution was evaporated to dryness and separated by preparative high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (containing 0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain title compound 1-13 (120 mg, yield: 78.24%).

[0190] LC-MS: m / z (ESI): 541.1 [M+H] + .

[0191] Step 12: 3-Fluoro-4-(2-Fluoro-4-iodoaniline)-1-[[3-Fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-5-(trifluoromethyl)pyridin-2-one (Compound 1)

[0192] Compounds 1-13 (50 mg, 92.56 μmol) and pyridine (73.21 mg, 925.58 μmol, 74.86 μL) were added to DMF (1 mL), and nitrogen was purged. N-methylaminosulfonyl chloride (59.96 mg, 462.79 μmol) solution was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1.0 h under nitrogen protection. After the reaction was complete, the mixture was separated using a preparative high-performance liquid chromatography column (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (containing 0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain title compound 1 (35 mg, yield: 59.60%).

[0193] LC-MS: m / z (ESI): 634.0 [M+H] + .

[0194] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.39(s,1H),8.03(d,J=5.1Hz,1H),7.92(s,1H),7.60(dd,J=10.7,1.9 Hz,1H),7.46(dd,J=8.4,1.8Hz,1H),7.03(t,J=8.6Hz,2H),6.74(t,J=4.9Hz,1H),5.25(s,2H),2.51(s,3H).

[0195] Biological activity and related property test examples

[0196] Test Example 1: Effect of the disclosed compound on the in vitro cell proliferation of HCT116 and AsPC1 cells.

[0197] Experimental apparatus:

[0198] Experimental materials:

[0199] Both HCT116 and AsPC1 cells used in the experiment were purchased from ATCC; HCT-116 cells were cultured in McCoy's 5A medium (containing 10% FBS + penicillin-streptomycin antibiotic solution 100X); AsPC1 cells were cultured in RPMI 1640 medium (containing 10% FBS + penicillin-streptomycin antibiotic solution 100X).

[0200] Experimental methods:

[0201] Plate formation: HCT116 / AsPC1 cells were digested with 0.25% trypsin EDTA solution, counted, and plated into 96-well plates (#062096). The wells around the perimeter were left unplated but culture medium was added. 600 HCT116 cells were plated per well, and 2500 AsPC1 cells were plated per well. The plates were incubated overnight in a cell culture incubator.

[0202] Administration: The compound was diluted with DMSO at a storage concentration of 10 mM. The final concentration after dilution was up to 10 μM. Then, it was diluted 3-fold sequentially, resulting in a total of 9 dose points (administered group) and 1 DMSO group. Each concentration point was replicated twice. After administration, the mixture was incubated in an incubator for 5 days.

[0203] Plate reading: Remove the cell plate and allow it to equilibrate to room temperature. Add 50 μL of cell viability assay reagent to each well. Luminescent Cell Viability Detection Kit), the left side only contains the culture medium group, to which 50 μL of cell viability detection reagent was also added. The Luminescent Cell Viability Detection Kit was used to remove background effects. After incubation at room temperature for 15 minutes, the chemiluminescence signal value was read using Envision.

[0204] Data Analysis: The inhibition rate was calculated using the formula: Inhibition rate (%) = (Chemiluminescence signal value of DMSO group - Chemiluminescence signal value of Dose group) / (Chemiluminescence signal value of DMSO group - Chemiluminescence signal value of culture medium only group) * 100%. Then, the IC50 was calculated using XLfit four-parameter fitting. 50 .

[0205] Experimental results:

[0206] Test Example 2: Determination of pERK (Thr202 / Tyr204) levels in HCT116 cells

[0207] Experimental apparatus:

[0208] Experimental materials:

[0209] The HCT116 cells used in the experiment were purchased from ATCC and cultured in McCoy's 5A medium (containing 10% FBS).

[0210] Experimental methods:

[0211] Plate formation: HCT116 cells were digested with 0.25% trypsin EDTA solution, counted, and plated into 96-well plates with 50,000 cells per well. The plates were then incubated overnight in a cell culture incubator.

[0212] Starvation: Replace with serum-free McCoy's 5A medium and incubate for 4 hours.

[0213] Administration: The compound was diluted with DMSO at a storage concentration of 10 mM. The final concentration after dilution was 1 μM. Then, it was diluted 3-fold sequentially, for a total of 9 dose points and 1 DMSO group. Each concentration point was replicated twice. After administration, the mixture was incubated in an incubator for 30 min.

[0214] Assay: Prepare lysis buffer according to the HTRF kit, 50 μL per well, and incubate at 450 rpm for 1 h at room temperature. Then, transfer 16 μL of lysis buffer from each well to a 384-well plate. Prepare mixed detection antibody according to the kit, add 4 μL of detection antibody to each well, centrifuge at 1000 rpm for 1 min, and incubate overnight at room temperature in the dark.

[0215] Reading: Using Envision, select the HTRF program to read the fluorescence intensity values ​​at 665nm and 615nm wavelengths, and calculate the ratio of the 665nm / 615nm fluorescence intensity values.

[0216] Data analysis: Using the formula: Inhibition rate (%) = (Ratio of fluorescence intensity values ​​at 665nm / 615nm) DMSO组 -665nm / 615nm fluorescence intensity ratio 给药组 The ratio of fluorescence intensity at 665nm to 615nm DMSO组 -665nm / 615nm fluorescence intensity ratio 仅培养基组 The inhibition rate was calculated by multiplying the result by 100%, and then the IC was calculated using XLfit four-parameter fitting. 50 and IC 90 .

[0217] Experimental results:

[0218] Although specific embodiments of this disclosure have been illustrated and described, those skilled in the art will recognize that, where feasible, the technical features described in one embodiment may be applied to another embodiment or combined with the technical features described in another embodiment. Therefore, those skilled in the art can make various changes and modifications to the embodiments of this disclosure without departing from the spirit and scope of this disclosure.

Claims

1. The compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt, in: L1 is selected from NH, CH2, O, or S; Ring A is selected from Where * represents the connection site with L1, and ** represents the connection site with methylene; Z 1 Selected from CR c Or N; Z represents a single or double bond. 2 Z 3 Selected independently from N and NR g or CR h ; R a R b R c R e R f R g R h The components are independently selected from H, deuterium, halogen, OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 3a Replace; or when Z 1 For CR c At that time, R b R c Together with the atoms connected to it, they form an optional structure formed by one or more R atoms. 4a Substituted 5-6 heteroaryl groups; or when Z 2 Z 3 Selected independently from NR g or CR h At that time, two R g and the atoms connected to it, or R g R h Together with the atoms attached to it, they form a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, or two R atoms. h Together with the atoms attached to it, they form a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, wherein the benzene ring, 5-6 membered heteroaromatic ring, or 5-6 membered heterocycle is optionally surrounded by one or more R... 5a replace; R d Selected from C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R 6a replace; X 1 X 2 X 4 X 5 X 6 X 7 Selected independently from CR 4 Or N; X 3 Selected from CR 3 Or N; R 1 R 2 R 3 R 4 The components are independently selected from H, deuterium, halogen, OH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally mixed with one or more R. 1a Replace; or, R 1 R 2 Together with the atoms attached to it, it forms a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, wherein the 4-7 membered heterocyclic group, the 5-6 membered heteroaryl group, or the phenyl group is optionally surrounded by one or more R groups. 1b replace; R 5 Selected from H, deuterium, or C1-C4 alkyl; or when X 3 For CR 3 At that time, R 3 R 5 Together with the atoms attached to it, they form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 2a replace; R 6 Selected from S(=O)2R 8 S(=O)2NR 8a R 8b S(=O)(=NR) 9 )R 8 Or P(=O)R 8a R 8b , where R 9 Selected from H, deuterium, or C1-C4 alkyl; R 8 R 8a R 8b The groups are independently selected from H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally separated by one or more R groups. 8c Replace; or, R 8a and R 8b Together with the atoms attached to it, they form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 8e Replace; R 1a R 2a R 3a R 4a R 5a R 6a They are independently selected from deuterium, halogens, C1-C4 alkyl groups, or C1-C4 haloalkyl groups; R 1b Selected from halogens, CN, =O, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 1c replace; R 8c The compounds are independently selected from deuterium, halogens, CN, =O, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 8d replace; R 1c R 8d R 8e They are independently selected from deuterium, halogens, =O, OH or C1-C3 alkyl groups.

2. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, L1 is NH.

3. The compound of formula (I) according to claim 1 or 2, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Ring A is Where * represents the connection site with L1, and ** represents the connection site with the methylene group; or, ring A is... Where * represents the connection site with L1, ** represents the connection site with methylene, and R a R b R c The components are independently selected from H, deuterium, halogen, OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 3a Replace, or R b R c Together with the atoms attached to it, they form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally surrounded by one or more R 4a Replace; or, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R a R b R c The components are independently selected from H, halogens, OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally converted by one or more R. 3a Replace; or, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R b R c Together with the atoms attached to it, they form a 5-6 membered heteroaryl group, wherein the 5-6 membered heteroaryl group is optionally surrounded by one or more R 4a Replace; or, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and R b R c Together with its attached atoms, the pyridyl group forms a pyridyl group, which is optionally bonded by one or more R atoms. 4a Replace; or, ring A is Where * represents the connection site with L1, and ** represents the connection site with methylene.

4. The compound of formula (I) according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from Where * represents the connection site with L1, and ** represents the connection site with the methylene group; or, ring A is... Where * represents the connection site with L1, and ** represents the connection site with the methylene group; or, ring A is... Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 Selected independently from N or CR h ; Alternatively, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 One is N, and the other is CR h Or, ring A is Where * represents the connection site with L1, ** represents the connection site with methylene, and Z 2 Z 3 Selected independently from NR g or CR h And two R g and the atoms connected to them, or two R h and the atoms connected to it, or R g R h Together with the atoms attached to it, they form a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle, wherein the benzene ring, 5-6 membered heteroaromatic ring, or 5-6 membered heterocycle is optionally surrounded by one or more R... 5a Replace; or, ring A is Where * represents the connection site with L1, and ** represents the connection site with methylene.

5. The compound of formula (I) according to any one of claims 1-3, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R a Selected from H, deuterium, halogen, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R 3a Replace; or, R a Selected from H, halogens, or C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally converted by one or more R groups. 3a Replace; or, R a Selected from H, F or methyl.

6. The compound of formula (I) according to any one of claims 1-3, 5, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R b R c The components are independently selected from H, deuterium, halogen, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally mixed with one or more R. 3a Replace; or, R b R c The components are independently selected from H, SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the SH, NH2, C1-C4 alkyl or C3-C6 cycloalkyl are optionally separated by one or more R. 3a Replace; or, R b R c Each is independently selected from H, methyl, ethyl, CF3, SCH3, NHCH3, N(CH3)2, or cyclopropyl; or, R b Selected from methyl, ethyl, CF3, SCH3, N(CH3)2 or cyclopropyl; or, R b For CF3; or, R c Selected from H or methyl; or, R c For H.

7. The compound of formula (I) according to any one of claims 1-2, 4, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R d Selected from C1-C4 alkyl or C1-C4 haloalkyl; or, R d It is a methyl group.

8. The compound of formula (I) according to any one of claims 1-2, 4, and 7, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R e R f The components are independently selected from H, deuterium, halogen, or C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally converted by one or more R groups. 3a Replace; or, R e R f Each is independently selected from H, methyl, or CF3; or, R e Selected from methyl or CF3; or, R e For CF3; or, R h For H.

9. The compound of formula (I) according to any one of claims 1-8, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 R 2 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace; or R 1 R 2 Together with the atoms attached to it, it forms a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, wherein the 4-7 membered heterocyclic group, the 5-6 membered heteroaryl group, or the phenyl group is optionally surrounded by one or more R groups. 1b Replace; or, R 1 R 2 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace; or, R 1 R 2 Each is independently selected from H, halogen, methoxy, OCF3, OCHF2, CF3, ethyl, CH2CF3, CH2CHF2 or cyclopropyl, or R 1 R 2 Together with the atoms connected to it, they form 10. The compound of formula (I) according to any one of claims 1-9, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3 R 4 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace, R 5 Selected from H, deuterium, or C1-C4 alkyl, or when X 3 For CR 3 At that time, R 3 R 5 Together with the atoms attached to it, they form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 2a Replace; or, R 3 R 4 The components are independently selected from H, deuterium, halogen, OH, C1-C4 alkyl or C3-C6 cycloalkyl, wherein the OH, C1-C4 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 1a Replace, R 5 Selected from H, deuterium, or C1-C4 alkyl; or, R 3 Selected from F or Cl; or, R 4 Choose from H or F.

11. The compound of formula (I) according to any one of claims 1-10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X 3 For CR 3 R 3 Selected from H or halogen; or, X 3 For CR 3 R 3 R 5 Together with the atoms connected to it, they form 12. The compound of formula (I) according to any one of claims 1-11, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X 1 X 2 For CR 4 X 7 For CR 4 Or N, or X 1 X 2 Let N, X 7 For CR 4 Or, X 1 X 2 For CR 4 X 7 For CR 4 Or N; or X 1 X 2 X 7 All are CR 4 Or, X 1 X 7 Both are CH, X 2 For CR 4 .

13. The compound of formula (I) according to any one of claims 1-12, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X 5 X 6 All are CR 4 X 4 For CR 4 Or N; or X 5 X 6 All are CR 4 X 4 For N; or, X 5 X 6 Both are CH, X 4 Let N be the number of elements in the array.

14. The compound of formula (I) according to any one of claims 1-13, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from S(=O)2R 8 Or S(=O)2NR 8a R 8b Or, R 6 S(=O)2NR 8a R 8b .

15. The compound of formula (I) according to any one of claims 1-14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 8 Selected from C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 8c Replace; or, R 8 It is a C1-C6 alkyl group.

16. The compound of formula (I) according to any one of claims 1-14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 8a R 8b The groups are independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally surrounded by one or more R groups. 8c Replace, or, R 8a and R 8b Together with the atoms attached to it, they form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally surrounded by one or more R 8e Replace; or, R 8a R 8b The components are independently selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally mixed with one or more R. 8c Replace, or, R 8a and R 8b Together with the atoms attached to it, they form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. 8e Replace; or, R 8a R 8b The groups are independently selected from H, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally surrounded by one or more R groups. 8c Replace; or, R 8a R 8b Each is independently selected from H, methyl, or cyclopropyl, or R 8a and R 8b Together with the atoms connected to it, they form 17. The compound of formula (I) according to any one of claims 1-16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt. Among them: L1, R a R b R c X 1 X 2 X 3 X 4 X 5 X 6 X 7 R 1 R 2 R 5 and R 6 As defined in any one of claims 1-16.

18. The compound of formula (I) according to any one of claims 1-16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from the following compounds or their stereoisomers or pharmaceutically acceptable salts:

19. A pharmaceutical composition comprising the compound of any one of claims 1-18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A method for treating MEK-mediated diseases in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of the compound of any one of claims 1-18 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 19.

21. A method of treating tumors in mammals, comprising administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of the compound of any one of claims 1-18 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 19.

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