Coumarin compound and use thereof

Abstract

The content of the present disclosure relates to an MEK-targeting compound. Specifically provided is a compound of formula (IA) or formula (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compound has the substituents and structural features as described in the present application. Further described in the present application are a pharmaceutical composition containing the compound of formula (IA) or formula (IB) or the stereoisomer thereof or the pharmaceutically acceptable salt thereof, and the pharmaceutical use of the compound or the stereoisomer thereof or the pharmaceutically acceptable salt thereof.

Description

Coumarin compounds and their applications

[0001] Cross-reference to related applications

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

[0003] Chinese Invention Patent Application No. 202411192859.7, filed with the State Intellectual Property Office of the People's Republic of China on August 28, 2024, and

[0004] Chinese Invention Patent Application No. 202411970980.8 was filed with the State Intellectual Property Office of the People's Republic of China on December 30, 2024. Technical Field

[0005] This disclosure pertains to the pharmaceutical field and relates to a coumarin compound or its stereoisomer or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing the same, and their use in the prevention or treatment of related diseases. Background Technology

[0006] In healthy cells, the mitogen-activated protein kinase (MAPK) 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, HRAS) or the RAF family (including ARAF, BRAF, 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.

[0007] 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 counteract 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 maintain long-term MEK occupancy, resulting in sustained inhibition of MAPK pathway activity. Therefore, they exhibit similar toxic effects to first-generation inhibitors.

[0008] 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. Complete inhibition of the MAPK / ERK pathway can reverse the disease to the greatest extent while preventing the reactivation of abnormal pathways (such as ERK-dependent negative feedback triggering CRAF-mediated pathway reactivation) and limiting drug-related toxicity, thus having a significant impact on the morbidity and mortality of cancer patients. Summary of the Invention

[0009] This disclosure relates to a compound of formula (IA) or formula (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0010] in:

[0011] L1 is selected from CH2, O, or S;

[0012] L2 is selected from CR a R b O, S, CR a R b O or CR a R b S;

[0013] R a R b The groups are independently selected from H, halogens, C1-C4 alkyl groups, OH, or NH2, wherein the C1-C4 alkyl groups, OH, or NH2 are optionally substituted by one or more groups selected from halogens or C1-C4 alkyl groups, or R a R b Together with the C connected to it, they form C=O;

[0014] R 1 Selected from

[0015] X 1 X 2 X 3 They are selected independently from CH or N;

[0016] R 5 Selected from halogens, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 5a replace;

[0017] R 5a Selected from halogens, C1-C4 alkyl groups, =O, OH, or NH2;

[0018] R 2 R 3 The groups are independently selected from H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl are optionally separated by one or more R 2a replace;

[0019] R 2a Selected from halogens, CN, =O, OH, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy or C3-C6 cycloalkyl;

[0020] Ring A is arbitrarily controlled by one or more R 6 Substituted 5-10 membered heteroaryl or phenyl groups;

[0021] R 6 Selected from halogens, CN, OH, NH2, or C1-C6 alkyl groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. 6a replace;

[0022] R 4 Selected from NH2, -N(R) 7 )S(=O)2R 8 -N(R) 7 )S(=O)2NR 8a R 8b -N(R) 7 )S(=O)(=NR 9 )R 8 -S(=O)2NR 8aR 8b -S(=O)(=NR) 9 )R 8 -S(=O)2R 8 -OS(=O)2R 8 -P(=O)R 8a R 8b or Among them, R 7 R 9 They are independently selected from H or C1-C4 alkyl groups;

[0023] Or, R 6 R 7 Together with their respective attached atoms, 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 6a Replace; R 8 R 8a and R 8b The groups are independently selected from H, 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;

[0024] R 6a R 8c The groups are independently 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. d replace;

[0025] R d Selected from halogens, =O, OH, or C1-C3 alkyl groups;

[0026] n is 0 or 1;

[0027] m is 0 or 1;

[0028] k is 0, 1, or 2;

[0029] The condition is: in equation (IB), (L2) n When R is a key or O, 4 Not NH2 or -N(R) 7 )S(=O)2NR 8a R 8b Furthermore, compounds of formula (IB) do not contain...

[0030] This disclosure relates to a compound of formula (IA) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0031] in:

[0032] L1 is selected from CH2, O, or S;

[0033] L2 is selected from CR a R b O, S, CR a R b O or CR a R b S;

[0034] R a R b The groups are independently selected from H, halogens, C1-C4 alkyl groups, OH, or NH2, wherein the C1-C4 alkyl groups, OH, or NH2 are optionally substituted by one or more groups selected from halogens or C1-C4 alkyl groups, or R a R b Together with the C connected to it, they form C=O;

[0035] R 1 Selected from

[0036] X 1 X 2 X 3 They are selected independently from CH or N;

[0037] R 5 Selected from halogens, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 5a replace;

[0038] R 5a Selected from halogens, C1-C4 alkyl groups, =O, OH, or NH2;

[0039] R 2 R 3 The groups are independently selected from H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl are optionally separated by one or more R 2a replace;

[0040] R 2aSelected from halogens, CN, =O, OH, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy or C3-C6 cycloalkyl;

[0041] Ring A is arbitrarily controlled by one or more R 6 Substituted 5-10 membered heteroaryl or phenyl groups;

[0042] R 6 Selected from halogens, CN, OH, NH2, or C1-C6 alkyl groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. 6a replace;

[0043] R 4 Selected from NH2, -N(R) 7 )S(=O)2R 8 -N(R) 7 )S(=O)2NR 8a R 8b -N(R) 7 )S(=O)(=NR 9 )R 8 -S(=O)2NR 8a R 8b -S(=O)(=NR) 9 )R 8 -S(=O)2R 8 -OS(=O)2R 8 -P(=O)R 8a R 8b or Among them, R 7 R 9 They are independently selected from H or C1-C4 alkyl groups;

[0044] Or, R 6 R 7 Together with their respective attached atoms, 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 6a Replace; R 8 R 8a and R 8b The groups are independently selected from H, 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;

[0045] R 6a R 8cThe groups are independently 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. d replace;

[0046] R d Selected from halogens, =O, OH, or C1-C3 alkyl groups;

[0047] n is 0 or 1;

[0048] m is 0 or 1;

[0049] k can be 0, 1, or 2.

[0050] In some implementations, L1 is selected from CH2 or O. In some implementations, L1 is CH2.

[0051] In some implementations, L2 is selected from CR a R b O, S or CR a R b O. In some implementations, L2 is selected from CR. a R b O or CR a R b O.

[0052] In some implementations, L2 is selected from O or CR. a R b O.

[0053] In some implementations, L2 is 0.

[0054] In some implementation schemes, R a R b Each is independently selected from H, halogen, or C1-C4 alkyl; or, R a R b Together with the C it is connected to, they form C=O. In some implementations, R a R b Each is independently selected from H, halogens, or C1-C4 alkyl groups. In some embodiments, R... a R b They are independently selected from H or halogens. In some embodiments, R a R b All are H.

[0055] In some implementations, n is 1. In some implementations, n is 0.

[0056] In some implementations, (L2) n Selected from key, CRa R b O, S or CR a R b O. In some implementations, (L2) n Selected from bonds, O, S, -CH(F)-, or CH2O. In some embodiments, (L2) n Selected from O or CH2O. In some implementations, (L2) n Selected from CH2O.

[0057] In some implementation schemes, X 1 For CH.

[0058] In some implementation schemes, X 2 For CH.

[0059] In some implementation schemes, X 3 For CH.

[0060] In some implementation schemes, R 1 Selected from Where X 1 For CH, X 2 For CH or N, X 3 For CH.

[0061] In some implementation schemes, R 1 Selected from

[0062] In some implementation schemes, R 1 Selected from Among them, X 1 For CH, X 2 It can be CH or N.

[0063] In some implementation schemes, R 1 for

[0064] In some implementation schemes, R 1 for

[0065] In some implementation schemes, R 5 Selected from halogens, CN, OH, NH2, or C1-C4 alkyl groups, wherein the OH, NH2, or C1-C4 alkyl group is optionally converted by one or more R groups. 5a replace.

[0066] In some implementation schemes, R 5a Selected from halogens or C1-C4 alkyl groups. In some embodiments, R 5a Selected from F or methyl.

[0067] In some implementation schemes, R5 Selected from F, Cl, CN, methyl, CF3, ethyl, NHCH3 or OCH3.

[0068] In some implementations, k is 0 or 1.

[0069] In some implementation schemes, R 1 Selected from

[0070] In some implementation schemes, Selected from

[0071] In some implementations, ring A is optionally controlled by one or more R... 6 Substituted 5-10 heteroaryl groups.

[0072] In some implementations, ring A is optionally controlled by one or more R... 6 Substituted pyridyl or phenyl.

[0073] In some implementations, ring A is optionally controlled by one or more R... 6 Substituted pyridinyl group.

[0074] In some implementations, ring A is The asterisk (*) represents the connection point with L1.

[0075] In some implementations, ring A is The asterisk (*) represents the connection point with L1.

[0076] In some implementation schemes, R 6 Selected from halogens or C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally converted by one or more R 6a Replace; or, R 6 R 7 Together with their respective attached atoms, 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 6a replace.

[0077] In some implementation schemes, R 6 Selected from halogens, CN, OH, NH2, or C1-C6 alkyl groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. 6a replace.

[0078] In some implementation schemes, R 6 Selected from halogens, or, R 6 R 7 Together with their respective connected atoms, they form an optional structure controlled by one or more R atoms. 6aSubstituted 5-6 aryl groups.

[0079] In some implementation schemes, R 6 Selected from F or Cl, or R 6 R 7 Together with their respective connected atoms, they form a pyrazol group.

[0080] In some implementation schemes, R 6 Selected from F, or R 6 R 7 Together with their respective connected atoms, they form a pyrazol group.

[0081] In some implementation schemes, R 6 Selected from F or Cl.

[0082] In some implementations, m is 0.

[0083] In some implementation schemes, R 4 Selected from -N(R) 7 )S(=O)2R 8 -N(R) 7 )S(=O)2NR 8a R 8b -N(R) 7 )S(=O)(=NR 9 )R 8 -S(=O)2NR 8a R 8b -S(=O)(=NR) 9 )R 8 or -S(=O)2R 8 .

[0084] In some implementation schemes, R 4 Selected from -N(R) 7 )S(=O)2R 8 or -N(R) 7 )S(=O)2NR 8a R 8b .

[0085] In some implementation schemes, R 4 -N(R) 7 )S(=O)2NR 8a R 8b In some implementations, R 4 -NHS(=O)2NR 8a R 8b In some implementations, R 4 -NHS(=O)2NHR 8b In some implementations, R 4Selected from -NHS(=O)2NHCH3 or -NHS(=O)2N(CH3)2.

[0086] In some implementation schemes, R 4 -N(R) 7 )S(=O)2R 8 In some implementations, R 4 -NHS(=O)2R 8 .

[0087] In some implementation schemes, R 7 Selected from H or C1-C4 alkyl groups, or R 6 R 7 Together with their respective attached atoms, 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 6a replace.

[0088] In some implementation schemes, R 7 For H, or R 6 R 7 Together with their respective connected atoms, they form an optional structure controlled by one or more R atoms. 6a Substituted 5-6 aryl groups.

[0089] In some implementation schemes, R 7 For H, or R 6 R 7 Together with their respective connected atoms, they form a pyrazol group.

[0090] 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 Replacement. In some implementations, R 8 Selected from C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally surrounded by one or more R groups. 8c replace.

[0091] In some implementation schemes, R 8c Selected from halogens, CN, 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. d replace.

[0092] In some implementation schemes, R d Selected from halogens.

[0093] In some implementation schemes, R 8c Selected from CN, F, methyl, CH2F, cyclopropyl or

[0094] In some implementation schemes, R 8 Selected from ethyl, n-propyl, CH2CH2CH2F, CH2CH(CH3)2, cyclopropyl,

[0095] In some implementation schemes, R 8a and R 8b The groups are independently selected from H, C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally separated by one or more R groups. 8c replace.

[0096] In some implementation schemes, R 8a Selected from H or C1-C4 alkyl groups. In some embodiments, R 8a Selected from H or methyl.

[0097] In some implementation schemes, R 8b Selected from C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 8c replace.

[0098] In some implementation schemes, R 8b Selected from methyl, CH2CF3, CH2CH2CN,

[0099] In some implementation schemes, R 4 Selected from

[0100] In some implementation schemes, R 4 Selected from

[0101] In some implementation schemes, R 2 The group is selected from H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally converted by one or more R 2a replace.

[0102] In some implementation schemes, R 2Selected from H, halogen, CN, or optionally by one or more R 2a Substituted C1-C4 alkyl groups.

[0103] In some implementation schemes, R 2 Selected from H, F, Cl, CN or methyl.

[0104] In some implementation schemes, R 3 The radicals are selected from H, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 heterocyclic, phenyl, or 5-6 heteroaryl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 heterocyclic, phenyl, or 5-6 heteroaryl are optionally replaced by one or more R radicals. 2a replace.

[0105] In some implementation schemes, R 3 The group is selected from OH, C1-C4 alkyl, C2-C6 alkynyl, 4-7 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl, wherein the OH, C1-C4 alkyl, C2-C6 alkynyl, 4-7 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl group is optionally surrounded by one or more R... 2a replace.

[0106] In some implementation schemes, R 2a Selected from halogens, C1-C4 alkyl groups, or C3-C6 cycloalkyl groups. In some embodiments, R... 2a Selected from F or cyclopropyl.

[0107] In some implementation schemes, R 3 Selected from methyl, ethyl, ethynyl, OCF3, OCHF2, Phenyl, pyrazolyl or aziridine butyl.

[0108] This disclosure also relates to the following compounds or their stereoisomers or pharmaceutically acceptable salts:

[0109] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound represented by formula (IA) or (IB) of this disclosure, or a specific compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0110] On the other hand, this disclosure provides a method for treating MEK-mediated diseases in mammals, including administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of a compound of general formula (IA) or (IB) of this disclosure, or a specific compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0111] On the other hand, this disclosure provides a method for treating tumors in mammals, comprising administering to a mammal in need of treatment, preferably a human, a therapeutically effective amount of a compound of general formula (IA) or (IB) or a specific compound thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0112] On the other hand, this disclosure provides the use of compounds of general formula (IA) or (IB) or specific compounds described above, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of MEK-mediated diseases.

[0113] On the other hand, this disclosure provides the use of compounds of general formula (IA) or (IB) or specific compounds described above, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of tumors.

[0114] On the other hand, this disclosure provides the use of compounds of general formula (IA) or (IB) or specific compounds described above, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of MEK-mediated diseases.

[0115] On the other hand, this disclosure provides the use of compounds of general formula (IA) or (IB) or specific compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of tumors.

[0116] On the other hand, this disclosure provides compounds of general formula (IA) or (IB) for the prevention or treatment of MEK-mediated diseases, or specific compounds thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0117] On the other hand, this disclosure provides compounds of general formula (IA) or (IB) for the prevention or treatment of tumors, or specific compounds thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0118] In some implementations, MEK-mediated diseases are selected from tumors.

[0119] In some implementations, the tumor is selected from colon cancer or pancreatic cancer.

[0120] Terminology Definitions and Explanations

[0121] 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.

[0122] In this article Indicates the connection site.

[0123] 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).

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] When any variable (e.g., R) 5 When (R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, when (R) appears more than once in the composition or structure of a compound, its definition is independent in each case. 5When k is 2 in k, it means that it is controlled by 2 R. 5 Replaced, and each R 5 Each has its own independent options.

[0131] For substituents whose substitution positions are not fixed in this paper, such as R in 2 This indicates that the substitution position can be any site on the benzene ring, as long as that site contains a hydrogen atom that can be substituted; for example, R in 5 The ' ' indicates that the substitution position can be any site on the ring, as long as there is a hydrogen atom that can be substituted at that site.

[0132] Unless otherwise specified, the linking direction of the linking groups mentioned in this article is arbitrary. For example, when L2 is selected from CR... a R b O or CR a R b When S, it can be connected to R via O or S. 1 They can be connected, or they can be connected via C and R. 1 Connected.

[0133] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a bond.

[0134] 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.

[0135] The term "alkyl" refers to a compound with the general formula C10. 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".

[0136] 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".

[0137] 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.

[0138] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C6 alkynyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms. "C2-C6 alkynyl" can include "C2-C4 alkynyl," C2, or C3 alkynyl. Examples of "C2-C6 alkynyl" include, but are not limited to, ethynyl (-C≡CH) and propynyl (-C≡CCH). 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl.

[0139] 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".

[0140] 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".

[0141] 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 independently selected heteroatoms or heterogroups as described above. The term "4-14 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, and whose ring atoms contain 1-5 independently selected heteroatoms or heterogroups as described above. "4-14 membered heterocyclic group" can include "4-10 membered heterocyclic group," "4-7 membered heterocyclic group," "4-6 membered heterocyclic group," "5-6 membered heterocyclic group," or "6-10 membered heterocyclic group." The term "3-6 membered heterocyclic group" can include "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "3-5 membered heterocyclic group", or "4-5 membered heterocyclic group". Specific examples of 4 membered heterocyclic groups include, but are not limited to, azacyclobutane 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, diazacyclobutane. Cycloheptyl. 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]pyrazin-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 including, but 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.

[0142] 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."

[0143] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0144] The term "hydroxyl group" refers to the -OH group.

[0145] The term "cyano" refers to the -CN group.

[0146] The term "amino" refers to the -NH2 group.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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”.

[0153] 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 13C 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0161] 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 (IA) or (IB) described herein, or its stereoisomer or a pharmaceutically acceptable salt thereof, is from 0.01 mg / kg to 1000 mg / kg.

[0162] 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.

[0163] 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.

[0164] In some embodiments, some compounds of general formula (IA) or (IB) of this application can be prepared by those skilled in the art of organic synthesis via the following route:

[0165] Scheme 1

[0166] Among them, R 1 R 2 R 3R 6 R 8 R 8a and R 8b As defined in formula (IA) or (IB), X represents halogen or OTf.

[0167] Scheme 2

[0168] Among them, R 1 R 2 R 3 R 6 R 8 R 8a R 8b And n as defined in equation (IA) or (IB), R a and R b It is hydrogen or fluorine, and X represents halogen or OTf.

[0169] Scheme 3

[0170] Among them, R 1 R 2 R 3 R 6 R 8 R 8a and R 8b As defined in formula (IA) or (IB), X represents a halogen. Detailed Implementation

[0171] The following detailed description of specific implementation schemes illustrates the contents 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.

[0172] All reagents used in this disclosure are commercially available and can be used without further purification.

[0173] Unless otherwise stated, proportions expressed for mixed solvents are volume-based. Unless otherwise stated, % refers to wt%.

[0174] 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, 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.

[0175] The eluent described below may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0176] Abbreviations:

[0177] DCM: Dichloromethane; Tf: Trifluoromethanesulfonyl; (BPin)2: Pinacol diboronate; MeOH: Methanol; TEA or Et3N: Triethylamine; THF: Tetrahydrofuran; Ms: Methanesulfonyl; Ms2O: Methanesulfonic anhydride; t-BuOLi: Lithium tert-butoxide; t-BuOH: Tert-butanol; DMSO: Dimethyl sulfoxide; NH2Boc: Tert-butyl carbamate; XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); Xphos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; dioxane: 1,4-dioxane; Py or pyridine: pyridine; DMF: N,N-dimethylformamide; PE: petroleum ether; EA: ethyl acetate; M: mol / L; FA: formic acid; PPh3: triphenylphosphine; DIAD: azodicarbonamide Diisopropyl acetate; MeCN or ACN: acetonitrile; BPMPO: N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide; DMA: N,N-dimethylacetamide; NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile; AcOH: acetic acid; KOAc: potassium acetate; B2Pin2: pinacolyl diboronate; Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride; FBS: fetal bovine serum; formic acid acid: formic acid; 2,6-lutidine: 2,6-dimethylpyridine; TFA: trifluoroacetic acid; selectflour: 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt; NMP: N-methyl-2-pyrrolidone; Tf2O: trifluoromethanesulfonic anhydride; Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium dichloride; DAST: diethylaminosulfur trifluoride.

[0178] Example 1: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)-pyridin-4-yl]methyl]-4-methyl-7-pyridazin-3-yloxy-chromen-2-one (compound 1)

[0179] Step 1: Preparation of (2-chloro-3-fluoropyridin-4-yl)methanol (compounds 1-2)

[0180] 2-Chloro-3-fluoro-pyridin-4-carboxaldehyde (25 g, 156.70 mmol) was dissolved in ultradry methanol (250 mL). Sodium borohydride (6.52 g, 172.36 mmol) was slowly added in portions under ice bath conditions. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, acetone (25 mL) was added to quench the reaction, and the mixture was evaporated to dryness. Ethyl acetate and water were added for extraction, and the organic phase was concentrated under reduced pressure to give the crude product, namely the title compound 1-2 (25 g, yield: 98.75%). No purification was required, and it was used directly in the next reaction.

[0181] LC-MS: m / z (ESI): 162.0 [M+H] + .

[0182] Step 2: Preparation of 2-chloro-3-fluoropyridin-4-ylmethylmethanesulfonate (compounds 1-3)

[0183] Compounds 1-2 (25 g, 154.74 mmol) were added to THF (250 mL), followed by triethylamine (31.32 g, 309.48 mmol, 43.14 mL), and then methanesulfonic anhydride (32.35 g, 185.69 mmol) was added in portions under ice bath conditions. The resulting mixture was stirred at room temperature for 2.0 hours. 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 (PE:EA = 2:1) to give the title compound 1-3 (30 g, yield: 80.90%).

[0184] LC-MS: m / z (ESI): 240.0 [M+H] + .

[0185] Step 3: Preparation of ethyl 2-[(2-chloro-3-fluoropyridin-4-yl)methyl]-3-oxo-butyrate (compounds 1-4)

[0186] Ethyl acetoacetate (32.58 g, 250.36 mmol, 31.79 mL) was dissolved in THF (300 mL), sodium iodide (18.76 g, 125.18 mmol) was added, and lithium tert-butoxide (2.2 M, 62.59 mL) was added dropwise under an ice bath. The resulting mixture was stirred at room temperature for 1 hour. Subsequently, under a nitrogen atmosphere, a tetrahydrofuran solution of compound 1-3 (30 g, 125.18 mmol) was added dropwise under an ice bath. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, a saturated aqueous sodium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was separated by a normal-phase column (PE:EA = 5:1) to obtain the title compound 1-4 (28 g, yield: 81.73%).

[0187] LC-MS: m / z (ESI): 274.1 [M+H] + .

[0188] Step 4: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-hydroxy-4-methyl-chromen-2-one (compounds 1-5)

[0189] Compounds 1-4 (16 g, 58.46 mmol) were dissolved in concentrated sulfuric acid (28.67 g, 292.30 mmol, 15.67 mL), and m-diphenol (12.87 g, 116.92 mmol) was slowly added under ice bath conditions. The resulting mixture was stirred at room temperature for 16.0 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, filtered, and the filter cake was purified by slurrying with methyl tert-butyl ether to give the crude product, title compound 1-5 (13 g, yield: 69.55%).

[0190] LC-MS: m / z (ESI): 320.1 [M+H] + .

[0191] Step 5: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-7-pyridazin-3-yloxy-chromen-2-one (compounds 1-6)

[0192] Compounds 1-5 (110 mg, 344.06 μmol), 3-chloropyridazine hydrochloride (259.75 mg, 1.72 mmol), cesium fluoride (341.12 mg, 2.25 mmol), and TEA (348.15 mg, 3.44 mmol, 479.54 μL) were added to a mixture of DMSO (0.5 mL), and nitrogen was used to purge the mixture. The resulting mixture was heated to 120 °C under nitrogen protection and stirred for 12.0 h. After the reaction was complete, the mixture was cooled to room temperature, and the crude product was 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% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 min) to obtain title compounds 1-6 (90 mg, yield: 65.76%).

[0193] LC-MS: m / z (ESI): 398.1 [M+H] + .

[0194] Step 6: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-methyl-7-pyridazin-3-yloxy-chromene-2-one (compounds 1-7)

[0195] Compounds 1-6 (80 mg, 201.11 μmol), tert-butyl carbamate (117.80 mg, 1.01 mmol), XPhos Pd G2 (15.81 mg, 20.11 μmol), XPhos (19.19 mg, 40.22 μmol), and cesium carbonate (130.72 mg, 402.23 μmol) were added to a mixture of 1,4-dioxane (1 mL), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3.0 hours. 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 then separated by a preparative high-performance liquid chromatography column (Welch Xtimate C18 column: 150 mm in length, 30 mm in inner diameter, and 5 μm in 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 compounds 1-7 (30 mg, yield: 39.43%).

[0196] LC-MS: m / z (ESI): 379.1 [M+H] + .

[0197] Step 7: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)-pyridin-4-yl]methyl]-4-methyl-7-pyridazin-3-yloxy-chromen-2-one (compound 1)

[0198] Compounds 1-7 (20 mg, 52.89 μmol) and pyridine (39.91 mg, 504.61 μmol, 40.81 μL) were added to DMF (1 mL), and nitrogen was purged. A DCM solution (0.5 mL) of N-methylaminosulfonyl chloride (13.08 mg, 100.92 μmol) 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 (3 mg, yield: 11.27%).

[0199] LC-MS: m / z (ESI): 472.1 [M+H] + .

[0200] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.07(d,J=4.5Hz,1H),7.93(dd,J=14.7,6.9Hz,2H),7.84(dd,J=8.9,4.5Hz,1H),7.58(d, J=8.8Hz,1H),7.39(d,J=2.4Hz,1H),7.29(dd,J=8.7,2.4Hz,1H),6.93(s,1H),6.80(d,J=5.7Hz,1H),4.02(s,2H),2.50(s,6H).

[0201] Example 2: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)-pyridin-4-yl]methyl]-4-methyl-7-(thiazolyl-2-ylmethoxy)chromen-2-one (compound 2)

[0202] Step 1: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(thiazolyl-2-ylmethoxy)chromen-2-one (compound 2-1)

[0203] Compounds 1-5 (300 mg, 938.34 μmol), 2-(chloromethyl)thiazole hydrochloride (319.15 mg, 1.88 mmol), and potassium carbonate (647.45 mg, 4.69 mmol) were added to MeCN (2 mL). The resulting mixture was heated to 90 °C and stirred for 12.0 h. After the reaction was complete, the mixture was cooled to room temperature. The crude product was 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% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 min) to obtain title compound 2-1 (150 mg, yield: 38.35%).

[0204] LC-MS: m / z (ESI): 417.1 [M+H] + .

[0205] Step 2: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(thiazolyl-2-ylmethoxy)chromen-2-one (compound 2-2)

[0206] Compound 2-1 (150 mg, 359.84 μmol), tert-butyl carbamate (421.54 mg, 3.60 mmol), XPhos Pd G2 (56.57 mg, 71.97 μmol), XPhos (68.66 mg, 143.94 μmol), and cesium carbonate (233.90 mg, 719.68 μmol) were added to a mixture of 1,4-dioxane (3 mL), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3.0 hours. 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 then separated by a preparative high-performance liquid chromatography column (Welch Xtimate C18 column: 150 mm in length, 30 mm in inner diameter, and 5 μm in 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 2-2 (40 mg, yield: 27.97%).

[0207] LC-MS: m / z (ESI): 398.1 [M+H] + .

[0208] Step 3: Preparation of 3-[[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(thiazolyl-2-ylmethoxy)chromen-2-one (compound 2)

[0209] Compound 2-2 (20 mg, 50.32 μmol) and pyridine (39.81 mg, 503.24 μmol, 40.70 μL) were added to DMF (1 mL), and nitrogen was introduced to replace the atmosphere. A DCM solution (0.5 mL) of N-methylaminosulfonyl chloride (13.04 mg, 100.65 μmol) 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 2 (11 mg, yield: 44.5%).

[0210] LC-MS: m / z (ESI): 491.1 [M+H] + .

[0211] 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.90(d,J=5.1Hz,1H),7.87(d,J=3.2Hz,1H),7.84–7.78(m,2H),7.17(d,J=2.6Hz, 1H),7.11(dd,J=8.9,2.6Hz,1H),6.93(s,1H),6.77(t,J=5.0Hz,1H),5.59(s,2H),3.97(s,2H),2.50(s,3H),2.43(s,3H).

[0212] Example 3: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(5-fluorothiazolyl-4-yl)oxy-4-methyl-chromen-2-one (compound 3)

[0213] Step 1: Preparation of methyl 4-[3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-2-oxochromen-7-yl]oxythiazol-5-carboxylic acid (compound 3-2)

[0214] Compound 3-1 (1 g, 3.13 mmol), methyl 4-bromothiazol-5-carboxylate (2.08 g, 9.38 mmol), cuprous oxide (223.78 mg, 1.56 mmol), N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide (263.05 mg, 625.56 μmol), and potassium phosphate (1.99 g, 9.38 mmol) were added to tert-butanol (15 mL), and nitrogen was purged. The resulting mixture was heated to 120 °C and stirred for 15 hours under a nitrogen atmosphere. 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 purified by reversed-phase column chromatography (Welch Xtimate C18 column: 150 mm in length, 30 mm in inner diameter, and 5 μm in 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 3-2 (200 mg, yield: 13.87%).

[0215] LC-MS: m / z(ESI): 461.0 [M+H] + .

[0216] Step 2: Preparation of 4-[3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-2-oxo-chromen-7-yl]oxythiazol-5-carboxylic acid (compound 3-3)

[0217] Compound 3-2 (200 mg, 433.97 μmol) was added to a mixture of methanol (3 mL) and water (3 mL), followed by sodium hydroxide (86.79 mg, 2.17 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the pH was adjusted to 1 with hydrochloric acid (1 M). The crude product was purified by reversed-phase column chromatography (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 minutes) to obtain the title compound 3-3 (60 mg, yield: 30.94%).

[0218] LC-MS: m / z (ESI): 447.0 [M+H] + .

[0219] Step 3: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-(5-fluorothiazo-4-yl)oxy-4-methyl-chromen-2-one (compounds 3-4)

[0220] Compound 3-3 (350 mg, 783.29 μmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (5.55 g, 15.67 mmol), and potassium fluoride (910.13 mg, 15.67 mmol) were added to a mixture of cyclohexane (10 mL) and water (5 mL), and nitrogen was purged. The resulting mixture was heated to 70 °C under nitrogen protection and stirred for 15 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (column: Welch Xtimate C18: column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 3-4 (65 mg, yield: 19.72%).

[0221] LC-MS: m / z(ESI): 421.0 [M+H] + .

[0222] Step 4: Preparation of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-7-((5-fluorothiazolyl-4-yl)oxy)-4-methyl-2H-chromen-2-one (compounds 3-5)

[0223] Compounds 3-4 (65 mg, 154.46 μmol), tert-butyl carbamate (271.42 mg, 2.32 mmol), XPhos Pd G2 (12.14 mg, 15.45 μmol), XPhos (14.74 mg, 30.89 μmol), and cesium carbonate (150.60 mg, 463.38 μmol) were added to a mixture of 1,4-dioxane (2 mL), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 2 hours. 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 purified by reversed-phase column chromatography (column: Welch Xtimate C18: column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 3-5 (10 mg, yield: 12.91%).

[0224] LC-MS: m / z (ESI): 402.1 [M+H] + .

[0225] Step 5: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(5-fluorothiazolyl-4-yl)oxy-4-methyl-chromen-2-one (compound 3)

[0226] Compounds 3-5 (10 mg, 24.91 μmol) and pyridine (19.71 mg, 249.14 μmol) were added to DMA (0.2 mL), and nitrogen was purged. A DMA solution (0.5 mL) of N-methylaminosulfonyl chloride (6.46 mg, 49.83 μmol) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was purified by reversed-phase column chromatography (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 minutes) to give title compound 3 (2 mg, yield: 8.04%).

[0227] LC-MS: m / z (ESI): 495.1 [M+H] + .

[0228] 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.69(d,J=2.5Hz,1H),7.88(dd,J=10.9,3.8Hz,2H) ,7.10(d,J=7.1Hz,2H),6.93(s,1H),6.78(s,1H),3.99(s,2H),2.51(s,3H),2.45(s,3H).

[0229] Example 4: Preparation of 3-[[2-chloro-3-(methylaminosulfonylamino)phenyl]methyl]-4-methyl-7-(pyridazin-3-yloxy)chromen-2-one (compound 4)

[0230] Step 1: Preparation of 1-(bromomethyl)-2-chloro-3-nitrobenzene (compound 4-2)

[0231] In a dry single-necked flask, 2-chloro-1-methyl-3-nitrobenzene (3 g, 17.48 mmol), NBS (4.05 g, 22.73 mmol), and AIBN (574.23 mg, 3.50 mmol) were added. The mixture was purged with argon gas, and 20 mL of ACN was added. The mixture was then heated to 80 °C and reacted for 3 hours. After cooling to room temperature, the mixture was concentrated to obtain a crude product, which was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 20:1) to give a white solid product, compound 4-2 (3.6 g, yield: 82.20%).

[0232] LC-MS:m / z(ESI):249.9 / 251.9[M+H] +

[0233] Step 2: Preparation of ethyl 2-(2-chloro-3-nitrobenzyl)-3-oxobutyrate (compound 4-3)

[0234] In a dry single-necked flask under argon atmosphere, compound 4-2 (3.6 g, 14.37 mmol) was dissolved in 50 mL of THF, and NaI (2.15 g, 14.37 mmol) was added. The mixture was stirred at room temperature for 30 minutes to obtain mixture one. In another dry reaction tube, ethyl acetoacetate (2.06 g, 15.81 mmol) was dissolved in 50 mL of THF, and argon atmosphere was replaced. Lithium tert-butoxide (2 M THF solution, 7.9 mL, 15.81 mmol) was slowly added dropwise under an ice-water bath. After reacting for 1 hour, mixture two was obtained. Mixture two was added dropwise to mixture one, and the reaction was continued at room temperature for 1 hour. The reaction was quenched with water under an ice-water bath, extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain product compound 4-3 (2.7 g, yield: 65.76%).

[0235] LC-MS: m / z (ESI): 300.0 [M+H] +

[0236] Step 3: Preparation of 3-[(2-chloro-3-nitrophenyl)methyl]-7-hydroxy-4-methylchromen-2-one (compound 4-4)

[0237] In a dry reaction tube, under ice-water bath conditions, resorcinol (1.04 g, 9.45 mmol) and compound 4-3 (2.7 g, 9.03 mmol) were dissolved in HClO4 (5 mL) and reacted for 1 hour. The reaction solution was then added dropwise to ice water (100 mL), filtered, and dried to give the white solid product compound 4-4 (1.9 g, yield: 58.15%).

[0238] LC-MS: m / z (ESI): 346.0 [M+H] +

[0239] Step 4: Preparation of 3-[(2-chloro-3-nitrophenyl)methyl]-4-methyl-7-(pyridazin-3-yloxy)chromen-2-one (compounds 4-5)

[0240] In a reaction tube, 3-chloropyridazine (596.30 mg, 5.21 mmol), compound 4-4 (600 mg, 1.74 mmol), cesium fluoride (790.86 mg, 5.21 mmol), and triethylamine (526.82 mg, 5.21 mmol) were added sequentially. Argon gas was purged, and DMF (5 mL) was added. The mixture was heated to 130 °C and reacted overnight. After cooling to room temperature, the mixture was purified by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) lyophilized to give solid product compound 4-5 (220 mg, yield: 29.91%).

[0241] LC-MS: m / z (ESI): 424.0 [M+H] +

[0242] Step 5: Preparation of 3-[(3-amino-2-chlorophenyl)methyl]-4-methyl-7-(pyridazin-3-yloxy)chromen-2-one (compounds 4-6)

[0243] Compound 4-5 (160 mg, 377.53 μmol) was dissolved in AcOH (3 mL), and iron powder (210.83 mg, 3.78 mmol) was added. The mixture was heated to 80 °C and reacted for 3 hours. After cooling to room temperature, the mixture was filtered, concentrated, and purified by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) lyophilized to give solid product compound 4-6 (60 mg, yield: 40.35%).

[0244] LC-MS: m / z(ESI): 394.0 [M+H] +

[0245] Step 6: Preparation of 3-[[2-chloro-3-(methylaminosulfonylamino)phenyl]methyl]-4-methyl-7-(pyridazin-3-yloxy)chromen-2-one (compound 4)

[0246] In a dry reaction tube, compounds 4-6 (60 mg, 152.35 μmol), pyridine (36.15 mg, 457.06 μmol), and DMF (2 mL) were added sequentially to replace the argon gas. Under an ice-water bath, N-methylaminosulfonyl chloride (29.61 mg, 228.53 μmol) was slowly added. The reaction was allowed to proceed for 1 hour, and the reaction solution was purified by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) lyophilized to give a white solid product, compound 4 (50 mg, yield: 66.23%).

[0247] LC-MS: m / z (ESI): 487.0 [M+H] +

[0248] 1 H NMR (400MHz, DMSO-d6) δ9.08(dd,J=4.6,1.2Hz,1H),8.99(s,1H),7.95(d,J=8.8Hz,1H),7.84(dd,J=8.9,4.5Hz,1H),7.59(dd,J=8.9,1.2Hz,1H),7.4 0(dt,J=4.1,2.0Hz,2H),7.28(dt,J=9.5,4.7Hz,2H),7.17(t,J=7.9Hz,1H) ,6.81(dd,J=7.8,1.4Hz,1H),4.04(s,2H),2.61–2.55(m,3H),2.41(s,3H).

[0249] Example 5: Preparation of 5-fluoro-3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 5)

[0250] Step 1: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-5-fluoro-7-hydroxy-chromen-2-one (compound 5-2)

[0251] Compound 5-1 (1.2 g, 4.38 mmol) was dissolved in concentrated sulfuric acid (2.15 g, 21.92 mmol), and 5-fluororesorcinol (842.50 mg, 6.58 mmol) was slowly added under ice bath conditions. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, filtered, and the filter cake was purified by slurrying with methyl tert-butyl ether to give the crude product, title compound 5-2 (450 mg, yield: 29.18%).

[0252] LC-MS: m / z (ESI): 338.0 [M+H] + .

[0253] Step 2: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 5-3)

[0254] DMF (5 mL) was added to a mixture of compound 5-2 (400 mg, 1.18 mmol), 3-chloropyridazine hydrochloride (894.24 mg, 5.92 mmol), cesium fluoride (2.70 g, 17.77 mmol), and triethylamine (1.20 g, 11.84 mmol, 1.65 mL), and nitrogen was added to purge the mixture. The resulting mixture was heated to 120 °C under nitrogen protection and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and the crude product was purified by reversed-phase column chromatography (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to give title compound 5-3 (220 mg, yield: 44.67%).

[0255] LC-MS: m / z (ESI): 416.1 [M+H] + .

[0256] Step 3: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 5-4)

[0257] 1,4-Dioxane (5 mL) was added to a mixture of compound 5-3 (220 mg, 529.13 μmol), tert-butyl carbamate (619.85 mg, 5.29 mmol), XPhos Pd G2 (41.59 mg, 52.91 μmol), XPhos (50.48 mg, 105.83 μmol), and cesium carbonate (343.93 mg, 1.06 mmol), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3 hours. 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 purified by reversed-phase column chromatography (Welch Xtimate C18 column: 150 mm in length, 30 mm in inner diameter, and 5 μm in particle size; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 5-4 (110 mg, yield: 52.45%).

[0258] LC-MS: m / z (ESI): 397.1 [M+H] + .

[0259] Step 4: Preparation of 5-fluoro-3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 5)

[0260] Compound 5-4 (20 mg, 50.46 μmol) and pyridine (39.91 mg, 504.61 μmol) were added to DMF (0.3 mL), and nitrogen was purged. A DCM solution (0.5 mL) of N-methylaminosulfonyl chloride (32.69 mg, 252.30 μmol) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was purified by reversed-phase column chromatography (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 minutes) to give title compound 5 (2.5 mg, yield: 10.00%).

[0261] LC-MS: m / z (ESI): 490.1 [M+H] + .

[0262] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.10(dd,J=4.5,1.2Hz,1H),7.93(d,J=5.1Hz,1H),7.86(dd,J=8.9,4.5Hz,1H),7.61 (dd,J=9.0,1.3Hz,1H),7.29(d,J=11.6Hz,2H),6.97(s,1H),6.86(s,1H),4.03(s,2H),2.54(d,J=6.0Hz,3H),2.51(s,3H).

[0263] Example 6: Preparation of 4-ethyl-3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(pyridazin-3-yloxy)-chromene-2-one (compound 6)

[0264] Step 1: Preparation of ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3-oxovalerate (compound 6-1)

[0265] Ethyl propionyl acetate (3.61 g, 25.04 mmol) and sodium iodide (1.88 g, 12.52 mmol) were dissolved in tetrahydrofuran (30 mL). A tetrahydrofuran solution of lithium tert-butoxide (2.2 M, 6.26 mL, 12.52 mmol) was slowly added dropwise under an ice bath. The resulting mixture was stirred at room temperature for 1 hour. Subsequently, a tetrahydrofuran solution of compound 1-3 (3 g, 12.52 mmol) was slowly added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, a saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was separated by normal-phase column chromatography (PE:EA = 5:1) to give the title compound 6-1 (1 g, yield: 27.80%).

[0266] LC-MS: m / z (ESI): 288.1 [M+H] + .

[0267] Step 2: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-ethyl-7-hydroxy-chromene-2-one (compound 6-2)

[0268] Compound 6-1 (1.5 g, 5.21 mmol) was dissolved in concentrated sulfuric acid (2.56 g, 26.07 mmol), and resorcinol (1.15 g, 10.43 mmol) was slowly added under ice bath conditions. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, filtered, and the filter cake was purified by slurrying with methyl tert-butyl ether to give the crude product, title compound 6-2 (250 mg, yield: 14.37%).

[0269] LC-MS: m / z (ESI): 334.1 [M+H] + .

[0270] Step 3: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-ethyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 6-3)

[0271] DMF (3 mL) was added to a mixture of compound 6-2 (250 mg, 749.08 μmol), 3-chloropyridazine hydrochloride (565.54 mg, 3.75 mmol), cesium fluoride (1.71 g, 11.24 mmol), and triethylamine (758.00 mg, 7.49 mmol, 1.04 mL), and nitrogen was added to purge the mixture. The resulting mixture was heated to 120 °C under nitrogen protection and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and the crude product was purified by reverse-phase column chromatography (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to give title compound 6-3 (170 mg, yield: 55.11%).

[0272] LC-MS: m / z (ESI): 412.1 [M+H] + .

[0273] Step 3: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-ethyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 6-4)

[0274] 1,4-Dioxane (4 mL) was added to a mixture of compound 6-3 (170 mg, 412.81 μmol), tert-butyl carbamate (483.59 mg, 4.13 mmol), XPhos Pd G2 (32.45 mg, 41.28 μmol), XPhos (39.38 mg, 82.56 μmol), and cesium carbonate (268.33 mg, 825.62 μmol), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3 hours. 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 purified by reverse phase column chromatography (column: Welch Xtimate C18: column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 6-4 (90 mg, yield: 55.56%).

[0275] LC-MS: m / z (ESI): 393.1 [M+H] + .

[0276] Step 4: Preparation of 4-ethyl-3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(pyridazin-3-yloxy)-chromen-2-one (compound 6)

[0277] DMF (0.3 mL) was added to a mixture of compounds 6-4 (20 mg, 50.97 μmol) and pyridine (40.32 mg, 509.71 μmol), and nitrogen was added to displace the mixture. A DCM solution of N-methylaminosulfonyl chloride (33.02 mg, 254.85 μmol) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was purified by reverse-phase column chromatography (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 minutes) to give title compound 6 (4 mg, yield: 16.10%).

[0278] LC-MS: m / z (ESI): 486.1 [M+H] + .

[0279] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.08(dd,J=4.6,1.3Hz,1H),7.97(d,J=8 .9Hz,1H),7.93(d,J=5.0Hz,1H),7.84(dd,J=8.9,4.5Hz,1H),7.59(dd,J=8.9,1 .3Hz,1H),7.40(d,J=2.4Hz,1H),7.29(dd,J=8.8,2.4Hz,1H),6.97(s,1H),6.82 (s,1H),4.01(s,2H),2.92(q,J=7.4Hz,2H),2.50(s,3H),1.13(t,J=7.5Hz,3H).

[0280] Example 7: Preparation of 6-chloro-3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 7)

[0281] Step 1: Preparation of 6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-7-hydroxy-chromen-2-one (compound 7-2)

[0282] Compound 7-1 (1.5 g, 5.48 mmol) was dissolved in concentrated sulfuric acid (2.69 g, 27.40 mmol), and 4-chlororesorcinol (1.58 g, 10.96 mmol) was slowly added under ice bath conditions. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, filtered, and the filter cake was purified by slurrying with methyl tert-butyl ether to give the crude product, title compound 7-2 (150 mg, yield: 7.43%).

[0283] LC-MS: m / z (ESI): 354.0 [M+H] + .

[0284] Step 2: Preparation of 6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 7-3)

[0285] DMF (2 mL) was added to a mixture of compound 7-2 (150 mg, 423.54 μmol), 3-chloropyridazine hydrochloride (319.76 mg, 2.12 mmol), cesium fluoride (964.56 mg, 6.35 mmol), and triethylamine (428.58 mg, 4.24 mmol, 590.33 μL), and nitrogen was added to purge the mixture. The resulting mixture was heated to 120 °C under nitrogen protection and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and the crude product was purified by reverse-phase column chromatography (Welch Xtimate C18 column: 150 mm length, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to give title compound 7-3 (90 mg, yield: 49.16%).

[0286] LC-MS: m / z (ESI): 432.0 [M+H] + .

[0287] Step 3: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-6-chloro-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 7-4)

[0288] 1,4-Dioxane (2 mL) was added to a mixture of compound 7-3 (90 mg, 208.22 μmol), tert-butyl carbamate (243.92 mg, 2.08 mmol), XPhos Pd G2 (16.37 mg, 20.82 μmol), XPhos (19.86 mg, 41.64 μmol), and cesium carbonate (135.34 mg, 416.44 μmol), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3 hours. 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 purified by reverse phase column chromatography (column: Welch Xtimate C18: column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 7-4 (40 mg, yield: 46.54%).

[0289] LC-MS: m / z (ESI): 413.1 [M+H] + .

[0290] Step 4: Preparation of 5-fluoro-3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(pyridazin-3-yloxy)-chromen-2-one (compound 7)

[0291] DMF (0.3 mL) was added to a mixture of compounds 7-4 (20 mg, 48.45 μmol) and pyridine (38.32 mg, 484.49 μmol), and nitrogen was added to purge the mixture. A DCM solution of N-methylaminosulfonyl chloride (31.39 mg, 242.25 μmol) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was purified by reverse-phase column chromatography (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 minutes) to obtain title compound 7 (6 mg, yield: 23.86%).

[0292] LC-MS: m / z (ESI): 506.1 [M+H] + .

[0293] 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),9.06(dd,J=4.6,1.3Hz,1H),8.13(s,1H),7.90(d,J=5.1Hz,1H),7.86(dd, J=9.0,4.6Hz,1H),7.68(dd,J=9.0,1.3Hz,1H),7.66(s,1H),6.91(s,1H),6.80(s,1H),4.03(s,2H),2.50(s,6H).

[0294] Example 8: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(thiazolyl-4-yloxy)-chromen-2-one (compound 8)

[0295] Step 1: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(thiazol-4-yloxy)-chromen-2-one (compound 8-2)

[0296] 3 mL of tert-butanol was added to a mixture of compound 8-1 (300 mg, 938.34 μmol), 4-bromothiazole (769.55 mg, 4.69 mmol), cuprous oxide (134.27 mg, 938.34 μmol), N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxalamide (197.29 mg, 469.17 μmol), and potassium phosphate (398.42 mg, 1.88 mmol), and nitrogen was purged. The resulting mixture was heated to 120 °C under nitrogen protection and stirred for 15 hours. 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 purified by reverse phase column chromatography (Welch Xtimate C18 column: 150 mm in length, 30 mm in inner diameter, and 5 μm in particle size; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 8-2 (30 mg, yield: 7.94%).

[0297] LC-MS: m / z (ESI): 403.0 [M+H] + .

[0298] Step 2: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(thiazol-4-yloxy)-chromen-2-one (compound 8-3)

[0299] 1,4-Dioxane (1 mL) was added to a mixture of compound 8-2 (30 mg, 74.47 μmol), tert-butyl carbamate (87.24 mg, 744.74 μmol), XPhos Pd G2 (11.71 mg, 14.89 μmol), XPhos (14.21 mg, 29.79 μmol), and cesium carbonate (48.41 mg, 148.95 μmol), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3 hours. 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 purified by reverse phase column chromatography (column: Welch Xtimate C18: column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 8-3 (8 mg, yield: 28.02%).

[0300] LC-MS: m / z (ESI): 384.1 [M+H] + .

[0301] Step 3: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-4-methyl-7-(thiazol-4-yloxy)-chromen-2-one (compound 8)

[0302] DMA (1 mL) was added to a mixture of compound 8-3 (8 mg, 20.87 μmol) and pyridine (16.51 mg, 208.66 μmol), and nitrogen was purged. A DCM solution of N-methylaminosulfonyl chloride (13.52 mg, 104.33 μmol) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete, the mixture was purified by reverse-phase column chromatography (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 minutes) to give title compound 8 (2.5 mg, yield: 21.37%).

[0303] LC-MS: m / z (ESI): 477.1 [M+H] + .

[0304] 1¹H NMR (400 MHz, DMSO-d⁶) δ 10.38 (s, 1H), 9.07 (d, J = 2.1 Hz, 1H), 7.93–7.86 (m, 2H), 7.28 (d, J = 2.2 Hz, 1H), 7.07 (d, J = 7.5 Hz, 2H), 6.87 (s, 1H), 6.74 (t, J = 4.6 Hz, 1H), 3.98 (s, 2H), 2.49 (s, 3H), 2.46 (s, 3H). Example 9: Preparation of 3-[[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl]-4-methyl-7-(pyridazin-3-yloxy)-2H-chromene-2-one (compound 9)

[0305] Step 1: Preparation of 2-fluoro-3-nitrobenzenemethyl methanesulfonate (compound 9-2)

[0306] In a dry single-necked flask, compound 9-1 (513 mg, 3.0 mmol) and triethylamine (909 mg, 9.0 mmol) were dissolved in dichloromethane (20 mL). Methanesulfonic anhydride (513 mg, 3.0 mmol) was added under ice bath, and the mixture was stirred overnight under argon protection. The mixture was concentrated, and the crude product was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 1:1) to give the pale yellow gelatinous target product compound 9-2 (550 mg, yield: 73.6%).

[0307] Step 2: Preparation of ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutyrate (compound 9-3)

[0308] In a dry single-necked flask under argon atmosphere, compound 9-2 (550 mg, 2.21 mmol) was dissolved in 10 mL of THF, and NaI (497 mg, 3.32 mmol) was added. The mixture was stirred at room temperature for 30 minutes. In another dry reaction tube, ethyl acetoacetate (344 mg, 2.65 mmol) was dissolved in 10 mL of THF, and argon atmosphere was displaced. Lithium tert-butoxide (2 M, 1.4 mL, 2.8 mmol) was slowly added dropwise to the reaction system under an ice-water bath, and the reaction was allowed to proceed for 1 hour. The lithium tert-butoxide reaction solution was then added dropwise to another system, and the reaction was continued for 6 hours after the addition was complete. The reaction was quenched with water under an ice-water bath, extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 9-3 (510 mg, yield: 81.5%).

[0309] Step 3: Preparation of 3-[(2-fluoro-3-nitrophenyl)methyl]-7-hydroxy-4-methylchromen-2-one (compound 9-4)

[0310] In a dry reaction tube, under ice-water bath conditions, resorcinol (238 mg, 2.16 mmol) and compound 9-3 (510 mg, 1.80 mmol) were dissolved in HClO4 (5 mL) and reacted for 1 hour. The reaction solution was then added dropwise to ice water (50 mL), filtered, and dried to give the brown solid product compound 9-4 (573 mg, yield: 97%).

[0311] LC-MS: m / z (ESI): 330.3 [M+H] +

[0312] Step 4: Preparation of 7-((6-chloropyridazin-3-yl)oxy)-3-(2-fluoro-3-nitrobenzyl)-4-methyl-2H-chromen-2-one (compound 9-5)

[0313] In a reaction tube, 3,6-dichloropyridazine (135 mg, 0.91 mmol), compound 9-4 (250 mg, 0.76 mmol), and cesium fluoride (347 mg, 2.28 mmol) were added sequentially. Argon gas was purged, and DMF (3 mL) was added. The system was heated to 90 °C and reacted for 3 hours. After cooling to room temperature, the mixture was purified by reverse-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 15 minutes) lyophilized to give a gray solid product, compound 9-5 (110 mg, yield: 32.8%).

[0314] LC-MS: m / z(ESI): 442.0 [M+H] +

[0315] Step 5: Preparation of 3-(2-fluoro-3-nitrobenzyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-chromen-2-one (compound 9-6)

[0316] To a mixture of compound 9-5 (90 mg, 204.08 μmol), pinacol diborate (62 mg, 244.92 μmol), Pd(dppf)Cl2 (1.5 mg, 2.04 μmol), and potassium acetate (60 mg, 612.24 μmol), 1,4-dioxane (3 mL) was added, purging with argon three times. The mixture was heated to 100 °C and stirred for 2 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by normal-phase column chromatography (dichloromethane: ethyl acetate = 1:1) to give the brown solid product compound 9-6 (60 mg, yield: 72.3%).

[0317] LC-MS: m / z (ESI): 408.0 [M+H] +

[0318] Step 6: Preparation of 3-(3-amino-2-fluorobenzyl)-4-methyl-7-(pyridazin-3-yloxy)-2H-chromen-2-one (compound 9-7)

[0319] Compound 9-6 (55 mg, 135.14 μmol) was dissolved in AcOH (3 mL), and Fe (38 mg, 675.68 μmol) was added. The system was heated to 80 °C and reacted for 2 hours. After cooling to room temperature, the mixture was filtered and concentrated for purification using a reverse-phase column (column: [column name missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 15 minutes) lyophilized to give a brown solid product, compound 9-7 (10 mg, yield: 19.6%).

[0320] LC-MS: m / z (ESI): 378.1 [M+H] +

[0321] Step 7: Preparation of 3-[[2-fluoro-3-(methylaminosulfonylamino)phenyl]methyl]-4-methyl-7-(pyridazin-3-yloxy)-2H-chromen-2-one (compound 9)

[0322] In a dry reaction tube, compound 9-7 (10 mg, 26.52 μmol) and pyridine (1 mL) were added sequentially, purging with argon gas. Under ice-water bath conditions, a DMA solution (0.5 mL) of N-methylaminosulfonyl chloride (5.1 mg, 39.53 μmol) was slowly added. The reaction was carried out at 50°C for 1 hour. The reaction solution was purified by reverse-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water (0.5% formic acid), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 15 minutes) lyophilized to give a white solid, title compound 9 (9.8 mg, yield: 78.6%).

[0323] LC-MS: m / z (ESI): 471.0 [M+H]+

[0324] 1H NMR (400MHz, DMSO-d6): 9.37(s,1H),9.07(dd,J=4.5,1.1Hz,1H),7.94(d,J=8.8Hz,1H),7.84(dd,J=8.9,4.6Hz,1H),7.58(dd,J=8.9,1.1Hz,1H),7.38( d,J=2.3Hz,1H),7.33–7.25(m,2H),7.22(q,J=4.9Hz,1H),7.02(t,J=7.9Hz, 1H), 6.89 (t, J = 6.7Hz, 1H), 4.00 (s, 2H), 2.53 (d, J = 5.0Hz, 3H), 2.47 (s, 3H).

[0325] Example 10: Preparation of 3-[3-[[2-(dimethylaminosulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-methyl-2-oxo-chromen-7-yl]oxypyridazine (compound 10)

[0326] In a dry single-necked flask, compounds 1-7 (100 mg, 264.30 μmol) and pyridine (3 mL) were added sequentially, purging with argon gas. N,N-dimethylaminosulfonyl chloride (115 mg, 800.88 μmol) was added under ice bath conditions. The reaction was carried out at 120 °C for 16 hours, followed by concentration and purification using a reverse-phase column (column: [column name missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 15 minutes) lyophilized to give a white solid product, compound 10 (10 mg, yield: 7.6%).

[0327] LC-MS: m / z (ESI): 486.1 [M+H] + .

[0328] 1 H NMR(400MHz, DMSO-d6):10.33(s,1H),9.07(d,J=4.2Hz,1H),7.96-7.94(m,2H),7.84(dd,J=8.8,4.5Hz,1H) ,7.59(d,J=8.9Hz,1H),7.39(d,J=1.8Hz,1H),7.29(d,J=8.8Hz,1H),6.85(s,1H),4.03(s,2H),2.81(s,6H).

[0329] Example 11: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-methylthio-chromen-2-one (compound 11)

[0330] Step 1: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4,7-dihydroxy-chromen-2-one (compound 11-2)

[0331] 2-Chloro-3-fluoro-pyridin-4-carboxaldehyde (895.61 mg, 5.61 mmol) and 4,7-dihydroxy-2H-chromene-2-one (1 g, 5.61 mmol) were dissolved in a mixed solution of formic acid (2.58 g, 56.14 mmol, 2.12 mL) and triethylamine (2.27 g, 22.45 mmol). The mixture was heated to 110 °C and reacted for 1 hour. After cooling to room temperature, the reaction solution was added dropwise to ice water (100 mL), and filtered to give a white solid compound 11-2 (1.81 g, yield: 100%).

[0332] LC-MS: m / z (ESI): 322.0 [M+H] +

[0333] Step 2: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-hydroxy-chromen-2-one (compound 11-3)

[0334] Add 2,3-difluoropyridine (1.94 g, 16.88 mmol), compound 11-2 (1.81 g, 5.63 mmol), triethylamine (1.71 g, 16.88 mmol), and cesium fluoride (2.56 g, 16.88 mmol) to a dry flask, purge with argon gas, add DMF (10 mL), heat the mixture to 115°C, and react overnight. Cool to room temperature, filter, and purify the reaction solution directly by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: s, mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) yielded a white solid compound 11-3 (500 mg, yield: 21.3%).

[0335] LC-MS: m / z (ESI): 417.0 [M+H] +

[0336] Step 3: Preparation of [3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-[(3-fluoropyridin-2-yl)oxy]-2-oxo-chromene-4-yl]trifluoromethanesulfonate (compound 11-4)

[0337] Compound 11-3 (500 mg, 1.20 mmol) and 2,6-dimethylpyridine (386 mg, 3.60 mmol) were dissolved in dichloromethane (5 mL). Trifluoromethanesulfonic anhydride (1.02 g, 3.6 mmol) was slowly added under ice bath conditions. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to give the product compound 11-4 (500 mg, yield: 75.9%).

[0338] LC-MS: m / z (ESI): 549.1 [M+H] + .

[0339] Step 4: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-methylthio-chromen-2-one (compounds 11-5)

[0340] Compound 11-4 (500 mg, 911.04 μmol) was dissolved in NMP (3 mL), and sodium methanethiol (319 mg, 4.55 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified by reversed-phase column chromatography (column: Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) lyophilized to give a white solid product, compound 11-5 (140 mg, yield: 34.39%).

[0341] LC-MS: m / z (ESI): 447.0 [M+H] + .

[0342] Step 3: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-methylthio-chromen-2-one (compound 11-6)

[0343] 1,4-Dioxane (3 mL) was added to a mixture of compound 11-5 (130 mg, 290.92 μmol), tert-butyl carbamate (68 mg, 580.47 μmol), XPhos Pd G2 (22 mg, 28.00 μmol), XPhos (30 mg, 62.93 μmol), and cesium carbonate (200 mg, 613.84 μmol), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3 hours. 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 purified by reversed-phase column chromatography (column: Welch Xtimate C18: column length 150 mm, inner diameter 30 mm, particle size 5 μm; mobile phase A: water (0.225% FA), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 11-6 (20 mg, yield: 16.08%).

[0344] LC-MS: m / z (ESI): 428.1 [M+H] + .

[0345] Step 4: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-methylthio-chromen-2-one (compound 11)

[0346] Compound 11-6 (20 mg, 46.79 μmol) and pyridine (11.10 mg, 140.38 μmol) were added to DMF (2 mL), and nitrogen was used to purge the mixture. N-methylaminosulfonyl chloride (12.13 mg, 93.58 μmol) was slowly added dropwise under ice bath conditions, and the resulting mixture was stirred at room temperature for 20 minutes under nitrogen protection. After the reaction was complete, the mixture was purified by reversed-phase column chromatography (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 minutes) to give title compound 11 (2.25 mg, yield: 9.05%).

[0347] LC-MS: m / z (ESI): 521.1 [M+H] + .

[0348] 1H NMR(400MHz, DMSO-d6):8.11(d,J=8.8Hz,1H),8.02(d,J=4.0Hz,1H),7.99–7.90(m,1H),7.58(d,J=5.2Hz,1H),7.3 8(d,J=2.2Hz,1H),7.35–7.23(m,2H),6.19(t,J=4.9Hz,1H),5.76(brs,1H),4.15(s,2H),2.45(s,3H),2.32(s,3H).

[0349] Example 12: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-((difluoromethyl)thio)-2H-chromen-2-one (compound 12)

[0350] Step 1: Preparation of 3-((2-chloro-3-fluoropyridin-4-yl)methyl)-7-((3-fluoropyridin-2-yl)oxo)-4-mercapto-2H-chromen-2-one (compound 12-1)

[0351] Sodium sulfide (106.79 mg, 1.37 mmol) was dissolved in water (1 mL) and heated to 80 °C. A pyridine solution of compound 11-4 (250 mg, 455.52 μmol) (1 mL) was slowly added dropwise to the above aqueous solution, and the mixture was stirred for 1 hour. After cooling to room temperature, the mixture was purified by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water, mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes), lyophilized to give a yellow solid compound 12-1 (40 mg, yield: 20.29%).

[0352] LC-MS: m / z (ESI): 433.0 [M+H] +

[0353] Step 2: Preparation of 3-((2-chloro-3-fluoropyridin-4-yl)methyl)-4-((difluoromethyl)thio)-7-((3-fluoropyridin-2-yl)oxy)-2H-chromen-2-one (compound 12-2)

[0354] Compound 12-1 (97 mg, 224.11 μmol) was dissolved in DMF (3 mL), followed by the addition of potassium carbonate (47 mg, 340.07 μmol) and sodium difluorochloroacetate (64 mg, 459.14 μmol), purging with nitrogen gas. The resulting mixture was heated to 95 °C for 2 hours, cooled to room temperature, filtered, and purified by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water (0.5% ammonia), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) lyophilized to give a pale yellow solid product, compound 12-2 (60 mg, yield: 55.45%).

[0355] LC-MS: m / z (ESI): 483.0 [M+H] +

[0356] Step 3: Preparation of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-4-((difluoromethyl)thio)-7-((3-fluoropyridin-2-yl)oxy)-2H-chromen-2-one (compound 12-3)

[0357] In a dry reaction tube, compound 12-2 (15.58 mg, 32.27 μmol), tert-butyl carbamate (56.70 mg, 484.03 μmol), XphosPdG2 (2.54 mg, 3.23 μmol), Xphos (1.54 mg, 3.23 μmol), and cesium carbonate (31.54 mg, 96.81 μmol) were added, purging with argon gas. 1,4-dioxane (0.5 mL) was added vial, and the mixture was heated to 100 °C and reacted for 1 hour. After cooling to room temperature, ethyl acetate and water were added, and the mixture was extracted, dried, filtered, and concentrated to obtain a crude product. The crude product was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was reacted at room temperature for 1 hour and concentrated to obtain crude compound 12-3 (14.4 mg).

[0358] LC-MS: m / z (ESI): 464.1 [M+H] +

[0359] Step 4: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-[(3-fluoropyridin-2-yl)oxy]-4-((difluoromethyl)thio)-2H-chromen-2-one (compound 12)

[0360] In a dry reaction tube, compound 12-3 (14.36 mg, 30.98 μmol) was dissolved in DMF (0.5 mL), purged with argon, and then pyridine (2.45 mg, 30.98 μmol) and N-methylaminosulfonyl chloride (12.04 mg, 92.95 μmol) were added. The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the product was purified by reversed-phase column chromatography (column: [column information missing]). Rapid silica column chromatography; mobile phase A: water, mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 10 minutes) lyophilized to give compound 12 (1.0 mg, yield: 5.8%) as a white solid.

[0361] LC-MS: m / z (ESI): 557.1 [M+H] +

[0362] 1 H NMR(400MHz, DMSO-d6):10.35(s,1H),8.10(d,J=8.8Hz,1H),8.06–8.01(m,1H),7.99–7.89 (m,2H),7.70–7.44(m,2H),7.37–7.29(m,2H),7.04–6.85(m,2H),4.26(s,2H),2.52(s,3H).

[0363] Example 13: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(isothiazolyl-3-ylmethoxy)-4-methyl-chromen-2-one (compound 13)

[0364] Step 1: Preparation of isothiazol-3-ylmethanol (compound 13-2)

[0365] At room temperature, compound 13-1 (250 mg, 1.9 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), followed by a tetrahydrofuran solution of the borane tetrahydrofuran complex (5.8 mL, 1 M, 5.8 mmol). The air was purged three times with nitrogen, and the reaction was then carried out at 50 °C for 2 hours. After cooling to room temperature, the reaction was quenched with 1 N hydrochloric acid aqueous solution, followed by extraction with ethyl acetate (50 mL * 3). The organic phases were combined, and the residue was concentrated and purified by normal-phase chromatography (petroleum ether: ethyl acetate = 20:1) to give the target compound 13-2 (180 mg, yield 81%).

[0366] LC-MS: m / z(ESI): 116.1[M+H]+.

[0367] Step 2: Preparation of 3-(chloromethyl)isothiazolium (compound 13-3)

[0368] Compound 13-2 (70 mg, 0.61 mmol) was dissolved in anhydrous chloroform (10 mL), and thionyl chloride (145 mg, 1.22 mmol) was added dropwise at 0 °C. The reaction was carried out at room temperature for 0.5 hours. The organic solvent was removed by rotary evaporation, and the resulting product, compound 13-3, could be used directly in the next step without purification.

[0369] LC-MS: m / z(ESI): 134.1[M+H]+.

[0370] Step 3: Preparation of 3-((2-chloro-3-fluoropyridin-4-yl)methyl)-7-(isothiazolyl-3-ylmethoxy)-4-methyl-2H-chromen-2-one (compound 13-5)

[0371] At room temperature, compound 13-4 (60 mg, 0.19 mmol), compound 13-3 (75 mg, 0.57 mmol), and anhydrous potassium carbonate (130 mg, 0.94 mmol) were dissolved in anhydrous acetonitrile (5 mL). The air in the solution was replaced three times with nitrogen. The reaction mixture was then heated to 90 °C and reacted for 16 hours. After the reaction mixture cooled to room temperature, insoluble matter was removed by filtration. The filtrate was concentrated, and the residue was purified by reversed-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain the target compound 13-5 (50 mg, yield 64%).

[0372] LC-MS: m / z (ESI): 417.2 [M+H] + .

[0373] Step 4: Preparation of 3-((2-amino-3-fluoropyridin-4-yl)methyl)-7-(isothiazolyl-3-ylmethoxy)-4-methyl-2H-chromen-2-one (compound 13-6)

[0374] At room temperature, compound 13-5 (50 mg, 0.12 mmol), tert-butyl carbamate (141 mg, 1.20 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9.4 mg, 0.012 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (11.5 mg, 0.024 mmol), and anhydrous cesium carbonate (78 mg, 0.24 mmol) were dissolved in anhydrous 1,4-dioxane (4 mL), and the air in the solution was replaced three times with nitrogen. The reaction was then carried out at 100 °C for 3 hours. After the reaction was cooled to room temperature, the insoluble matter was removed by filtration, the filtrate was concentrated, and the residue was purified by reversed-phase chromatography (C18, 0.05% formic acid: acetonitrile = 20:1 to 1:20) to obtain the target compound 13-6 (18 mg, yield 38%).

[0375] LC-MS: m / z (ESI): 398.1 [M+H] + .

[0376] Step 5: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(isothiazolyl-3-ylmethoxy)-4-methyl-chromen-2-one (compound 13)

[0377] Compound 13-6 (18 mg, 45 μmol) was dissolved in anhydrous N,N-dimethylformamide (2 ml), and then N-methylaminosulfonyl chloride (12 mg, 91 μmol) and pyridine (7.2 mg, 91 μmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by reversed-phase chromatography (C18, 0.05% formic acid:acetonitrile = 20:1 to 1:20) to give target compound 13 (4.8 mg, yield 20%).

[0378] LC-MS: m / z (ESI): 491.39 [M+H] + .

[0379] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.13(d,J=4.6Hz,1H),7.90(d,J=5.1Hz,1H),7.80(d,J=8.9Hz,1H),7.51(d,J=4.6Hz,1H), 7.13(d,J=2.5Hz,1H),7.09(dd,J=8.9,2.6Hz,1H),6.94(s,1H),6.76(s,1H),5.40(s,2H),3.97(s,2H),2.50(s,3H),2.44(s,3H).

[0380] Example 14: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-[(3-fluoropyridin-2-yl)methoxy]-4-methyl-chromone-2-one (compound 14)

[0381] Step 1: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(3-fluoropyridin-2-ylmethoxy)chromen-2-one (compound 14-2)

[0382] Compounds 1-5 (200 mg, 625.56 μmol), 2-(chloromethyl)-3-fluoropyridine (273.17 mg, 1.88 mmol), and potassium carbonate (431.64 mg, 3.13 mmol) were added to a mixture of MeCN (3 mL). The resulting mixture was heated to 90 °C and stirred for 12.0 h. After the reaction was complete, the mixture was cooled to room temperature. The crude product was 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 min) to obtain the title compound 14-2 (200 mg, yield: 74.56%).

[0383] LC-MS: m / z (ESI): 429.1 [M+H] + .

[0384] Step 2: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-methyl-7-(3-fluoropyridin-2-ylmethoxy)chromen-2-one (compound 14-3)

[0385] Compound 14-2 (200 mg, 466.40 μmol), tert-butyl carbamate (546.37 mg, 4.66 mmol), XPhos Pd G2 (73.32 mg, 93.28 μmol), XPhos (88.99 mg, 186.56 μmol), and cesium carbonate (303.16 mg, 932.80 μmol) were added to a mixture of 1,4-dioxane (2 mL), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 3.0 hours. 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 then separated by a preparative high-performance liquid chromatography column (Welch Xtimate C18 column: 150 mm in length, 30 mm in inner diameter, and 5 μm in 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 14-3 (80 mg, yield: 41.90%).

[0386] LC-MS: m / z (ESI): 410.1 [M+H] + .

[0387] Step 3: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-[(3-fluoropyridin-2-yl)methoxy]-4-methyl-chromen-2-one (compound 14)

[0388] Compound 14-3 (30 mg, 73.28 μmol) and pyridine (57.96 mg, 732.81 μmol, 59.27 μL) were added to DMF (1 mL), and nitrogen was purged. A DCM solution of N-methylaminosulfonyl chloride (47.47 mg, 366.40 μmol) 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 14 (15 mg, yield: 36.31%).

[0389] LC-MS: m / z (ESI): 503.1 [M+H] + .

[0390] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.48(dt,J=4.7,1.5Hz,1H),7.92(d,J=5.1Hz,1H),7.85–7.77(m,2H),7.55(dt,J=8.6,4.4Hz,1H),7 .16(d,J=2.6Hz,1H),7.08(dd,J=8.9,2.6Hz,1H),6.97(s,1H),6.80(s,1H),5.37(d,J=1.9Hz,2H),3.97(s,2H),2.52(s,3H),2.43(s,3H).

[0391] Example 15: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(5-fluoropent-1-ynyl)-4-methyl-chromen-2-one (compound 15)

[0392] Step 1: Preparation of [3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-4-methyl-2-oxo-chromene-7-yl]trifluoromethanesulfonate (compound 15-2)

[0393] Compound 1-5 (2 g, 6.26 mmol) and triethylamine (5.81 g, 57.40 mmol, 8.00 mL) were added to a mixture of DCM (20 mL), and nitrogen was introduced to purge the mixture. Trifluoromethanesulfonic anhydride (2.65 g, 9.38 mmol, 1.58 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and stirred for 12.0 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to adjust the pH to 7. The mixture was extracted with dichloromethane and concentrated under reduced pressure to obtain the crude product. The crude product was separated by a normal-phase column (PE:EA = 5:1) to give the title compound 15-2 (1.5 g, yield: 53.08%).

[0394] LC-MS: m / z (ESI): 452.0 [M+H] + .

[0395] Step 2: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-(5-hydroxypent-1-ynyl)-4-methyl-chromen-2-one (compound 15-3)

[0396] Compound 15-2 (700 mg, 1.55 mmol), pentan-4-yn-1-ol (143.37 mg, 1.70 mmol), palladium dichloride (108.76 mg, 154.94 μmol), and cuprous iodide (59.02 mg, 309.89 μmol, 10.50 μL) were added to a mixture of tetrahydrofuran (7 mL), and nitrogen was purged. The resulting mixture was heated to 80 °C under nitrogen protection and stirred for 12.0 hours. 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 then separated by preparative high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm long, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 15-3 (400 mg, yield: 66.91%).

[0397] LC-MS: m / z (ESI): 386.1 [M+H] + .

[0398] Step 3: Preparation of 3-[(2-chloro-3-fluoropyridin-4-yl)methyl]-7-(5-fluoropentan-1-ynyl)-4-methyl-chromen-2-one (compound 15-4)

[0399] Compound 15-3 (450 mg, 1.17 mmol) was added to dichloromethane (5 mL), and nitrogen was used to replace the atmosphere. DAST (376.01 mg, 2.33 mmol, 308.20 μL) was slowly added dropwise at -78 °C, and the mixture was stirred at room temperature for 1.0 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, quenched with water, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (150 mm long, 30 mm inner diameter, 5 μm particle size; mobile phase A: water (containing 0.225% NH3), mobile phase B: acetonitrile; gradient: mobile phase B from 5% to 95% in 18 minutes) to obtain the title compound 15-4 (200 mg, yield: 44.22%).

[0400] LC-MS: m / z (ESI): 388.1 [M+H] + .

[0401] Step 4: Preparation of 3-[(2-amino-3-fluoropyridin-4-yl)methyl]-7-(5-fluoropentan-1-ynyl)-4-methyl-chromone-2-one (compound 15-5)

[0402] Compound 15-4 (200 mg, 515.72 μmol), tert-butyl carbamate (604.15 mg, 5.16 mmol), XPhos Pd G2 (40.54 mg, 51.57 μmol), XPhos (49.20 mg, 103.14 μmol), and cesium carbonate (335.22 mg, 1.03 mmol) were added to a mixture of 1,4-dioxane (2 mL), and nitrogen was purged. The resulting mixture was heated to 100 °C under nitrogen protection and stirred for 8.0 hours. 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 then separated using a preparative high-performance liquid chromatography column (column: Welch Xtimate C18, 150 mm long, 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 15-5 (60 mg, yield: 31.58%).

[0403] LC-MS: m / z (ESI): 369.1 [M+H] + .

[0404] Step 5: Preparation of 3-[[3-fluoro-2-(methylaminosulfonylamino)pyridin-4-yl]methyl]-7-(5-fluoropent-1-ynyl)-4-methyl-chromen-2-one (compound 15)

[0405] Compound 15-5 (20 mg, 54.29 μmol) and pyridine (42.95 mg, 542.92 μmol) were added to acetonitrile (0.2 mL), and nitrogen was purged. A solution of N-methylaminosulfonyl chloride (14.07 mg, 108.58 μmol) in acetonitrile (0.2 mL) was slowly added dropwise under an ice bath. The resulting mixture was stirred at room temperature for 1.0 h under nitrogen protection. After the reaction was complete, the mixture was separated by a preparative high-performance liquid chromatography column (column: Welch Xtimate C18, 150 mm long, 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 minutes) to obtain title compound 15 (11 mg, yield: 42.43%).

[0406] LC-MS: m / z (ESI): 462.1 [M+H] + .

[0407] 1H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.91(d,J=5.1Hz,1H),7.83(d,J=8.3Hz,1H),7.47–7.38(m,2H),6.94(s,1H),6.80(t,J=5.1Hz ,1H),4.65(t,J=5.8Hz,1H),4.53(t,J=5.8Hz,1H),4.01(s,2H),2.59(t,J=7.1Hz,2H),2.50(s,3H),2.46(s,3H),2.02–1.90(m,2H).

[0408] Test Example 1: Effect of the disclosed compound on the in vitro cell proliferation of HCT116 and AsPC1 cells.

[0409] Experimental apparatus:

[0410] Experimental materials:

[0411] 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).

[0412] Experimental methods:

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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 .

[0417] Experimental results are shown in Table 1.

[0418] Table 1

[0419] Test Example 2: Determination of pERK (Thr202 / Tyr204) levels in HCT116 cells

[0420] Experimental apparatus:

[0421] Experimental materials:

[0422] The HCT116 cells used in the experiment were purchased from ATCC and cultured in McCoy's 5A medium (containing 10% FBS).

[0423] Experimental methods:

[0424] Plate formation: HCT116 cells were digested with trypsin, counted, and plated into 96-well plates with 50,000 cells per well. The plates were then incubated overnight in a cell culture incubator.

[0425] Starvation: Replace with serum-free McCoy's 5A medium and incubate for 4 hours.

[0426] Administration: The compound was diluted with DMSO at a storage concentration of 10 mM. The final concentration after dilution was up to 1 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 30 min.

[0427] 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.

[0428] 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.

[0429] 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 仅裂解液组 The inhibition rate is calculated by multiplying the result by 100%, and then the IC is calculated using XLfit four-parameter fitting. 50 .

[0430] Experimental results are shown in Table 2.

[0431] Table 2

[0432] 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. A compound of formula (IA) or formula (IB) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in: L1 is selected from CH2, O, or S; L2 is selected from CR a R b , O, S, CR a R b O or CR a R b S; R a R b The groups are independently selected from H, halogens, C1-C4 alkyl groups, OH, or NH2, wherein the C1-C4 alkyl groups, OH, or NH2 are optionally substituted by one or more groups selected from halogens or C1-C4 alkyl groups, or R a R b Together with the C connected to it, they form C=O; R 1 Selected from X 1 X 2 X 3 They are selected independently from CH or N; R 5 Selected from halogens, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 5a replace; R 5a Selected from halogens, C1-C4 alkyl groups, =O, OH, or NH2; R 2 R 3 The groups are independently selected from H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, or 5-6 membered heteroaryl are optionally separated by one or more R 2a replace; R 2a Selected from halogens, CN, =O, OH, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy or C3-C6 cycloalkyl; Ring A is arbitrarily controlled by one or more R 6 Substituted 5-10 membered heteroaryl or phenyl groups; R 6 Selected from halogens, CN, OH, NH2, or C1-C6 alkyl groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. 6a replace; R 4 Selected from NH2, -N(R) 7 )S(=O)2R 8 -N(R) 7 )S(=O)2NR 8a R 8b -N(R) 7 )S(=O)(=NR 9 )R 8 -S(=O)2NR 8a R 8b -S(=O)(=NR) 9 )R 8 -S(=O)2R 8 -OS(=O)2R 8 -P(=O)R 8a R 8b or Among them, R 7 R 9 They are independently selected from H or C1-C4 alkyl groups; Or, R 6 R 7 Together with their respective attached atoms, 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 6a Replace; R 8 R 8a and R 8b The groups are independently selected from H, 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; R 6a R 8c The groups are independently 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. d replace; R d Selected from halogens, =O, OH, or C1-C3 alkyl groups; n is 0 or 1; m is 0 or 1; k is 0, 1, or 2; The condition is: in equation (IB), (L2) n When R is a key or O, 4 Not NH2 or -N(R) 7 )S(=O)2NR 8a R 8b Furthermore, compounds of formula (IB) do not contain...

2. The compound of formula (IA) or formula (IB) according to claim 1, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, L1 is selected from CH2 or O; or, L1 is selected from CH2.

3. The compound of formula (IA) or formula (IB) according to claim 1 or 2, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, L2 is selected from CR a R b O, S or CR a R b O; or, L2 is selected from CR a R b O or CR a R b O; or, L2 is selected from O or CR. a R b O; or, L2 is selected from O.

4. The compound of formula (IA) or formula (IB) according to any one of claims 1-3, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R a R b Each is independently selected from H, halogen, or C1-C4 alkyl; or, R a R b Together with the C connected to it, they form C=O; or, R a R b Each is independently selected from H, halogen, or C1-C4 alkyl; or, R a R b They are selected independently from H or halogens.

5. The compound of formula (IA) or formula (IB) according to any one of claims 1-4, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, n is 1; Alternatively, n can be 0.

6. The compound of formula (IA) or formula (IB) according to any one of claims 1-5, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from Where X 1 For CH, X 2 For CH or N, X 3 For CH; or, R 1 Selected from Or, R 1 Selected from Where X 1 For CH, X 2 For CH or N; or, R 1 for Or, R 1 for 7. The compound of formula (IA) or formula (IB) according to any one of claims 1-6, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 5 Selected from halogens, CN, OH, NH2, or C1-C4 alkyl groups, wherein the OH, NH2, or C1-C4 alkyl group is optionally converted by one or more R groups. 5a replace.

8. The compound of formula (IA) or formula (IB) according to any one of claims 1-7, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 5a Selected from halogens or C1-C4 alkyl groups; or, R 5a Selected from F or methyl.

9. The compound of formula (IA) or formula (IB) according to any one of claims 1-8, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Selected from 10. The compound of formula (IA) or formula (IB) according to any one of claims 1-9, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Ring A is arbitrarily controlled by one or more R 6 The substituted 5-10 heteroaryl group; or, ring A is optionally replaced by one or more R groups. 6 Substituted pyridyl or phenyl; or, ring A is optionally replaced by one or more R 6 Substituted pyridinyl group; or, ring A is Where * represents the connection point with L1; or, ring A is... The asterisk (*) represents the connection point with L1.

11. The compound of formula (IA) or formula (IB) according to any one of claims 1-10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from halogens or C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally converted by one or more R 6a Replace, or, R 6 R 7 Together with their respective attached atoms, 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 6a Replace; or, R 6 Selected from halogens, CN, OH, NH2, or C1-C6 alkyl groups, wherein the OH, NH2, or C1-C6 alkyl group is optionally converted by one or more R groups. 6a Replace; or, R 6 Selected from halogens, or, R 6 R 7 Together with their respective connected atoms, they form an array optionally bounded by one or more R atoms. 6a Substituted 5-6 aryl groups.

12. The compound of formula (IA) or formula (IB) according to any one of claims 1-11, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 4 Selected from -N(R) 7 )S(=O)2R 8 -N(R) 7 )S(=O)2NR 8a R 8b -N(R) 7 )S(=O)(=NR 9 )R 8 -S(=O)2NR 8a R 8b -S(=O)(=NR) 9 )R 8 or -S(=O)2R 8 Or, R 4 Selected from -N(R) 7 )S(=O)2R 8 or -N(R) 7 )S(=O)2NR 8a R 8b Or, R 4 -N(R) 7 )S(=O)2NR 8a R 8b Or, R 4 -NHS(=O)2NR 8a R 8b Or, R 4 -NHS(=O)2NHR 8b Or, R 4 Selected from -NHS(=O)2NHCH3 or -NHS(=O)2N(CH3)2; or, R 4 -N(R) 7 )S(=O)2R 8 Or, R 4 -NHS(=O)2R 8 .

13. The compound of formula (IA) or formula (IB) according to any one of claims 1-12, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 7 Selected from H or C1-C4 alkyl groups, or R 6 R 7 Together with their respective attached atoms, 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 6a Replace; or, R 7 For H, or R 6 R 7 Together with their respective connected atoms, they form an array optionally bounded by one or more R atoms. 6a Substituted 5-6 aryl groups.

14. The compound of formula (IA) or formula (IB) according to any one of claims 1-13, 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 Selected from C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, or 4-6 membered heterocyclic group is optionally surrounded by one or more R groups. 8c replace.

15. The compound of formula (IA) or formula (IB) according to any one of claims 1-14, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 8c Selected from halogens, CN, 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. d Replace; or, R 8c Selected from CN, F, methyl, CH2F, cyclopropyl or 16. The compound of formula (IA) or formula (IB) according to any one of claims 1-15, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 8a and R 8b The groups are independently selected from H, C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups are optionally separated by one or more R groups. 8c Replace; or, R 8a Selected from H or C1-C4 alkyl; or, R 8b Selected from C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl, C3-C8 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R groups. 8c replace.

17. The compound of formula (IA) or formula (IB) according to any one of claims 1-16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 2 The group is selected from H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally converted by one or more R 2a Replace; or, R 2 Selected from H, halogen, CN, or optionally by one or more R 2a Substituted C1-C4 alkyl groups.

18. The compound of formula (IA) or formula (IB) according to any one of claims 1-17, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 3 The radicals are selected from H, OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 heterocyclic, phenyl, or 5-6 heteroaryl, wherein the OH, NH2, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 heterocyclic, phenyl, or 5-6 heteroaryl are optionally replaced by one or more R radicals. 2a Replace; or, R 3 The group is selected from OH, C1-C4 alkyl, C2-C6 alkynyl, 4-7 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl, wherein the OH, C1-C4 alkyl, C2-C6 alkynyl, 4-7 membered heterocyclic group, phenyl, or 5-6 membered heteroaryl group is optionally surrounded by one or more R... 2a replace.

19. Selected from the following compounds or their stereoisomers or pharmaceutically acceptable salts:

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

21. 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 1-19 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 20.

22. 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 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20.

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