A pan-kras inhibitor compound

Abstract

The present application relates to pan-KRAS inhibitor compounds of Formula (I) or Formula (II) and pharmaceutical compositions comprising the same, and the use of compounds of Formula (I) or Formula (II) for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

Technical Field

[0001] This invention relates to a compound, and more particularly to a highly active pan-KRAS inhibitor and its uses. Background Technology

[0002] RAS is one of the most frequently mutated genes in human tumors, occurring in approximately 30% of cancer patients, with KRAS accounting for about 85% of RAS mutations. KRAS mutations are found in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas, and 32% of lung adenocarcinomas, making the development of KRAS-targeting inhibitors of great clinical significance and value.

[0003] KRAS is a membrane-bound protein with GTPase activity. It acts as a "molecular switch" by cycling between the GDP-binding inactive conformation and the GTP-binding active conformation through nucleotide exchange. In its GTP-bound state, KRAS can activate multiple downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT, to regulate life processes such as cell growth, proliferation, differentiation, and apoptosis.

[0004] KRAS mutations (such as G12C, G12D, G12V, and G13D) affect GTP hydrolysis mediated by GTPase-activating proteins (GAPs), increasing the number of KRAS in a GTP-bound activated state. This overactivation of downstream signaling pathways ultimately leads to tumor development and progression. However, due to the lack of a suitable hydrophobic pocket for drug binding in the KRAS protein, and its affinity for GTP and GDP being in the picomolar range (~20 pM), the development of inhibitors that competitively bind to KRAS is extremely difficult. For decades, KRAS has been considered an untreatable target.

[0005] In May 2021, AMG510 was approved by the FDA for the treatment of patients with KRAS. G12C The emergence of mutations in locally advanced or metastatic non-small cell lung cancer has broken the historical barrier of KRAS being "untreatable." However, G12C mutations account for only a small fraction of KRAS mutations. For mutations at other KRAS sites, there is currently a lack of satisfactory and effective inhibitory compounds, leaving a large unmet clinical need. Therefore, the development of effective pan-KRAS inhibitory compounds is a necessity given the current technology. Summary of the Invention

[0006] This invention provides a pan-KRAS inhibitor. This structure differs from existing KRAS inhibitors that function through covalent binding. G12CInstead of acting as an inhibitor, KRAS exerts its effects by mediating the formation of a ternary complex between KRAS and ubiquitous intracellular chaperone proteins (such as Cyclophilin A). The formation of this ternary complex can sterically block the binding of KRAS to its downstream effector molecules (such as RAF), inhibiting the activation of the MAPK and PI3K-AKT signaling pathways, thereby suppressing tumor development and progression, and playing a therapeutic role in diseases such as cancer.

[0007] In one aspect, the present invention provides a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof:

[0008]

[0009] in:

[0010] R1 represents C1-C6 alkyl, -(C1-C6 alkylene)-(C3-C8 cycloalkyl), -(C1-C6 alkylene)-(4-8 heterocyclic alkyl), -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRa or -(C1-C6 alkylene)-NRaRa';

[0011] R2 represents halogen, cyano, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 or fewer substituents: -ORa, -SRa, or -NRaRa';

[0012] R3 represents hydrogen, -O (C0-C6 alkylene)Ra, -S (C0-C6 alkylene)Ra, -N (C0-C6 alkylene)Ra (C0-C6 alkylene)R a ', which may optionally be substituted by 0, 1 or 2 substituents selected from the following: -ORa, -SRa, or NRaRa';

[0013] Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups;

[0014] R4 can independently represent hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(4-8-membered)heterocyclic alkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6... -(C0-C6 alkylene)S(O)2Ra, -(C0-C6 alkylene)NRaS(O)2Ra', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(C6-C10 aryl) or -(C0-C6 alkylene)(5-12 heteroaryl); wherein, the R4 atoms on the two C atoms of Cy1, together with the C atoms attached thereto and the atoms between the two C atoms, can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or the two R4 atoms on the same C atom of Cy1, together with the C atoms attached thereto, can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0015] R6 and R6' each independently represent hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or -(C0-C6 alkylene)CN;

[0016] R5 and R5' independently represent C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8 cycloalkyl), -(C0-C6 alkylene)(4-12 membered heterocyclic alkyl), -(C1-C6 alkylene)ORa, -(C1-C6 alkylene)SRa, -(C1-C6 alkylene)NRaRa', -(C1-C6 alkylene)CN, -(C1-C6 alkylene)C(O)Ra, -(C0-C6 alkylene)C(O)ORa, -(C0-C -6-alkylene)C(O)NRaRa', -(C0-C6 alkylene)OC(O)NRaRa', -(C0-C6 alkylene)NRaC(O)Ra', -(C0-C6 alkylene)S(O)Ra, -(C0-C6 alkylene)S(O)2Ra, which may optionally be substituted with 0, 1 or 2 substituents selected from the following: -(C1-C6 alkylene)ORa, -(C1-C6 alkylene)SRa, -(C1-C6 alkylene)NRaRa';

[0017] W represents NR7 or CR7R7', where,

[0018] R7 and R7' are each independently selected from: hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8 cycloalkyl), -(C0-C6 alkylene)(4-12 membered heterocyclic alkyl), -(C0-C6 alkylene)CN, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)C(O)Ra, -(C0-C6 alkylene)C(O)O Ra, -(C0-C6 alkylene)C(O)NRaRa', -(C0-C6 alkylene)OC(O)NRaRa', -(C0-C6 alkylene)NRaC(O)Ra', -(C0-C6 alkylene)S(O)Ra, -(C0-C6 alkylene)S(O)2Ra, or R7, R7' can form a 3-8 membered ring with the C atom attached thereto, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O, S;

[0019] R8a, R8b, R8c, and R8d are each independently selected from hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8 cycloalkyl), -(C0-C6 alkylene)(4-8 membered heterocyclic alkyl), -(C0-C6 alkylene)CN, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0 -C6 alkylene)C(O)ORa, -(C0-C6 alkylene)C(O)NRaRa', -(C0-C6 alkylene)OC(O)NRaRa', -(C0-C6 alkylene)NRaC(O)Ra', -(C0-C6 alkylene)S(O)Ra, -(C0-C6 alkylene)S(O)2Ra; or R8a and R8b, or R8c and R8 d can form a 4-8 membered ring with the C atom it is attached to, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two of R8a, R8b, R8c or R8d that are not attached to the same C atom can form a 4-8 membered ring with the C atom attached to them and the atom between the two C atoms, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or one of R8a, R8b, R8c or R8d can form a 4-8 membered ring with R7 or R7' on an adjacent or non-adjacent W, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S, and when one of R8a, R8b, R8c or R8d forms a 4-8 membered ring with R7 or R7' on an adjacent W, the ring may optionally contain 0, 1, 2 or 3 unsaturated bonds;

[0020] Where p represents 0, 1, 2, 3 or 4;

[0021] m and n can each independently represent 1, 2, or 3;

[0022] Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 4-8 membered heterocyclic alkyl; wherein, when Ra and Ra' are attached to the same N atom, Ra and Ra' and the commonly attached N atom can form a 4-8 membered ring, and the 4-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S;

[0023] The alkyl, cycloalkyl, heterocycloalkyl, and alkylene groups can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0024] In some embodiments, R1 in the above-described compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers represents C1-C6 alkyl, -(C1-C6 alkylene)-(C3-C8 cycloalkyl), or -(C1-C6 alkylene)-(4-8 heterocyclic alkyl); preferably, R1 represents C1-C6 alkyl; more preferably, R1 represents C1-C3 alkyl.

[0025] In some embodiments, R2 in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotopic derivatives, or stereoisomers represents a C1-C6 alkyl group, which may optionally be substituted with 0, 1, or 2 -ORa substituents; preferably, R2 represents More preferably, R2 represents More preferably, R2 represents Where * indicates the site where R2 is connected to the part connected to it in equation (I).

[0026] In some embodiments, R3 in the compound having the structure of formula (I) or formula (II) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer represents hydrogen or -O(C1-C6)alkyl, -O(C0-C6 alkylene)(C3-C8)cycloalkyl, -O(C0-C6 alkylene)(4-8-membered)heteroalkyl, optionally substituted with 0 or 1 substituent selected from ORa, -SRa, or NRaRa'.

[0027] In some embodiments, Cy1 in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers represents a C3-C8 cycloalkyl or a 4-8 membered heterocycloalkyl.

[0028] In some embodiments, R4 in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, and stereoisomers independently represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene)OCONRaRa', -(C0-C The R4 atoms on the two C atoms of Cy1, together with the C atoms attached thereto and the atoms between the two C atoms, can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or the two R4 atoms on the same C atom of Cy1, together with the C atoms attached thereto, can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0029] In some preferred embodiments, the R4 in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers, each independently represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)(5-12-membered heteroaryl), or the R4 on the two C atoms of Cy1 together with the C atom attached thereto and the atom between the two C atoms can form a 3-8 membered ring, the 3-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S; or the two R4 on the same C atom of Cy1 together with the C atom attached thereto can form a 3-8 membered ring, the 3-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0030] In some embodiments, R6 and R6' in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers independently represent hydrogen or C1-C6 alkyl; more preferably, R6 and R6' independently represent hydrogen or methyl.

[0031] In some embodiments, R5 and R5' in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, stereoisomers, each independently represent C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8 cycloalkyl), -(C0-C6 alkylene)(4-12 membered heterocyclic alkyl), or -(C1-C6 alkylene)NRaRa' substituted with 0 or 1 substituent selected from -(C1-C6 alkylene)ORa, -(C1-C6 alkylene)SRa.

[0032] Furthermore, in some preferred embodiments, at least one of R5 and R5' in the above-mentioned compound having the structure of formula (I) or formula (II) or its pharmaceutically acceptable salt, isotope derivative, or stereoisomer contains at least one heteroatom selected from N, O, and S, preferably an N atom, and more preferably a secondary or tertiary amine.

[0033] In some embodiments, R7 and R7' in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers independently represent hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8 cycloalkyl), -(C0-C6 alkylene)(4-12 membered heterocyclic alkyl), -(C0-C6 alkylene)CN, -(C0-C6 alkylene)ORa, and -(C0-C6 alkylene)S Ra, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)C(O)NRaRa', -(C0-C6 alkylene)OC(O)NRaRa', -(C0-C6 alkylene)NRaC(O)Ra', -(C0-C6 alkylene)S(O)2Ra, or R7, R7' can form a 3-8 membered ring with the C atom attached thereto, which may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O, and S.

[0034] In some embodiments, the R8a, R8b, R8c, and R8d of the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers are each independently selected from hydrogen, halogens, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C8 cycloalkyl), -(C0-C6 alkylene)(3-8 membered heterocyclic alkyl), -(C0-C6 alkylene)CN, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)C(O)NRaRa'; or R8a and R8b, or R8c and R8d, attached to the same C atom can form a 4-8 membered ring with the C atom attached thereto, which may optionally contain 0, , One, two, or three heteroatoms selected from N, O, and S; or two of R8a, R8b, R8c, and R8d not attached to the same C atom can form a 4-8 membered ring with the C atom attached to them and the atom between the two C atoms, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S; or one of R8a, R8b, R8c, and R8d forms a 4-8 membered ring with R7 or R7' on an adjacent or non-adjacent W, the ring optionally containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S, and when one of R8a, R8b, R8c, and R8d forms a 4-8 membered ring with R7 or R7' on an adjacent W, the ring optionally contains 0, 1, 2, or 3 unsaturated bonds, preferably, the ring is an aromatic heterocycle.

[0035] In some embodiments, in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers, when W is not NR7, at least one of R7, R7', R8a, R8b, R8c, R8d, or the ring formed therebetween, includes at least one heteroatom selected from N, O, and S, preferably an N atom, more preferably a secondary or tertiary amine.

[0036] In some embodiments, in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers, p is preferably 0, 1, or 2, or m and n are each preferably 1 or 2 independently.

[0037] In some embodiments, in the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers, the structure of -Cy1-(R4)p in formula (I) is selected from the following:

[0038]

[0039] Where * indicates the site where -Cy1-(R4)p is connected to the part connected to it in equation (I).

[0040] In some embodiments, in the compounds having the structure of formula (I) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers, the structure in formula (I) is... Selected from the following:

[0041]

[0042] Where * represents The site connected to the part of equation (I).

[0043] In some embodiments, in the compounds having the structure of formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers, the structure in formula (II) Selected from the following:

[0044]

[0045] Where * represents The site connected to the part of equation (II).

[0046] In some embodiments, among the compounds having the structure of formula (I) or formula (II) or their pharmaceutically acceptable salts, isotope derivatives, or stereoisomers, the compound of formula (I) has the structure of formula (III), and the compound of formula (II) has the structure of formula (IV):

[0047]

[0048] In another aspect, the present invention provides compounds having the following structures:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054] In another aspect, the present invention also provides a pharmaceutical composition comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt, isotope derivative, or stereoisomer thereof.

[0055] In another aspect, the present invention also provides the use of the aforementioned compounds or pharmaceutically acceptable salts, isotope derivatives, stereoisomers or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0056] In another aspect, the present invention also provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases, comprising administering to a patient in need a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt, isotope derivative, stereoisomer and / or pharmaceutical composition thereof.

[0057] It is particularly noteworthy that, in this article, when referring to “compounds” with structures of formulas (I), (II), (III), and (IV), the term generally also includes their stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives.

[0058] As is known to those skilled in the art, the salts, solvates, and hydrates of a compound are alternative forms of the compound, and they can all be converted into the compound under certain conditions. Therefore, it is particularly noteworthy that when referring to compounds with the structures of formulas (I), (II), (III), and (IV) herein, pharmaceutically acceptable salts are generally also included, as well as their solvates and hydrates.

[0059] Similarly, when referring to a compound in this article, its prodrug, metabolites, and nitrogen oxides are generally also included.

[0060] The pharmaceutically acceptable salts described in this invention can be formed using, for example, inorganic or organic acids: “Pharmaceutically acceptable salt” means a salt that, within a reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. The salts can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent, as outlined below. For example, the free base function can react with a suitable acid. Examples of pharmaceutically acceptable inorganic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other methods in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-enolate, glyceryl phosphate, gluconate, hernisulfate, heptaate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, bitter salts, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically usable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed by counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0061] The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example by dissolving the compounds of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, and acetonitrile), adding an excess of an aqueous solution of an organic or inorganic acid to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid, and then separating the precipitated salt.

[0062] The precursors or metabolites described in this invention can be precursors or metabolites known in the art, as long as they are metabolized and transformed in vivo to form compounds. For example, "prodrug" refers to those prodrugs of the compounds of this invention that, within a reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio and are effective for their intended use. The term "prodrug" refers to a compound that is rapidly transformed in vivo to produce the parent compound of the above formula, for example, through in vivo metabolism, or through N-demethylation of the compounds of this invention.

[0063] The term "solvate" as used in this invention refers to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0064] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration undergo different spatial arrangements of atoms or groups of atoms due to the rotation or twisting of carbon or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair conformation and boat conformation in the cyclohexane structure. "Stereoisomers" refer to compounds of this invention containing one or more asymmetric centers, thus allowing them to exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The compounds of this invention have asymmetric centers, each of which produces two optical isomers. The scope of this invention includes all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds. The compounds of this invention can exist as tautomers, which have different hydrogen bonding sites through one or more double bond shifts. For example, ketones and their enol forms are ketone-enol tautomers. All tautomers and mixtures thereof are included in the compounds of this invention. All enantiomers, diastereomers, racemates, mesomates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of all compounds of formulas (I) to (IV) are included within the scope of this invention.

[0065] The term "isotope derivative" in this invention refers to molecules in which the compounds described herein are isotopically labeled. Commonly used isotopes for isotopic labeling are hydrogen isotopes. 2 H and 3 H; Carbon isotopes: 11 C, 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially deuterium. 3 H and carbon 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby reducing the dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0066] The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

[0067] Furthermore, the present invention provides pharmaceutical compositions for the prevention and / or treatment of cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising compounds of the present invention as active ingredients. The pharmaceutical compositions may optionally comprise a pharmaceutically acceptable carrier.

[0068] Furthermore, the present invention provides a method for preventing and / or treating cancer, tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, attention-related diseases, or immune-mediated diseases, comprising administering the compound of the present invention to a mammal in need of such treatment.

[0069] Representative examples of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other inflammatory joint conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung diseases, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic inflammatory lung disease, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjögren's syndrome, and autoimmune thyroid diseases. Diseases, urticaria (rubella), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0070] Representative examples of cancers or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral thyroid cancer. Neuroectodermal tumors, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0071] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with other anticancer agents or immune checkpoint inhibitors used to treat cancer or tumors, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced anticancer effects.

[0072] Representative examples of anticancer agents used to treat cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dextrin, doxorubicin, epirubicin, doxorubicin, mitoxantrone, bleomycin, mitomycin C, and ixabi. Tamoxifen, Flutamide, Gonarelin analogues, Medroxyprogesterone acetate, Prednisone, Dexamethasone, Methylprednisolone, Thalidomide, Interferon Alpha, Leucovorin, Sirolimus, Sirolimus esters, Everolimus, Afatinib, Alisertib, Amuvatinib, Apatinib, Axitinib, Bortezomib, Bosutinib, Brinib, Cabozantinib, Sildenafil, Crenolanib, Crizotinib, Dabrafenib, Dacomitinib, Danusertinib, Dasatinib, Dovitinib, Erlotinib, Foretinib, Ganetespib, Gefitinib, Ibrutinib, Icotinib, Imatinib Iniparib, Lapatinib, Lenvatinib, Linifanib, Linsitinib, Macitinib, Momelotinib, Motishanib, Lenatinib, Niraparib, Oprozomib, Olaparib, Pazopanib, Pictilisib, Ponatinib, Quizartinib, Regorafenib, Rigosertib, Rucaparib, Ruxolitinib, Secatinib, Saridegib, Sorafenib, Sunitinib, Tiratitinib, Vtivantinib Tivozani, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vemodega, volasertib, alenmab, bevacizumab, belentoumab, vedotin, caputuzumab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, oflamumab, panitumab, rituximab, tosimomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0073] When the compounds of the present invention or their pharmaceutically acceptable salts are administered in combination with other therapeutic agents for treating inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced therapeutic effects.

[0074] Representative examples of therapeutic agents for treating inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, prednisolone hydrochloride, prednisolone methylhydrochloride, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα agents (e.g., etanercept, infliximab, adalimumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one or more of these therapeutic agents may be included in the pharmaceutical compositions of the present invention.

[0075] In addition, the present invention provides a method for preventing and / or treating tumors, cancer, viral infections, organ transplant rejection, neurodegenerative diseases, attention-related diseases, or autoimmune diseases, comprising administering the compounds of the present invention or the pharmaceutical compositions of the present invention to mammals in need of such treatment.

[0076] The pharmaceutical compositions of the present invention can be formulated into dosage forms for oral or parenteral administration (including intramuscular, intravenous, and subcutaneous routes, and intratumoral injection) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0077] The pharmaceutical compositions of the present invention for oral administration can be prepared by mixing the active ingredient with, for example, a carrier including: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier, and diluent.

[0078] Examples of carriers used in the injectable pharmaceutical compositions of the present invention may be water, salt solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerol ester, surfactant, suspending agent, and emulsifier.

[0079] Other features of the invention will become apparent as the exemplary embodiments are described. The embodiments are given to illustrate the invention and are not intended to be limiting. The following examples use the methods disclosed in the invention to prepare, separate, and characterize.

[0080] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. They can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for the kit materials used and suitable for the transformation achieved. Those skilled in the art of organic synthesis will understand that the functionalities present on the molecule are consistent with the proposed transformation. This sometimes necessitates determining whether to change the order of synthetic steps or the starting materials to obtain the desired compound of the present invention. Detailed Implementation

[0081] the term

[0082] Unless otherwise specified, the terms used in this application, including those in the specification and claims, are defined as follows. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0083] In the specification and claims, the given chemical formula or name shall encompass all its stereoisomers and optical isomers, as well as racemic forms containing such isomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of this invention. Various geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are covered within this invention. This invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of this invention, which can be separated into mixtures of isomers or separate isomeric forms. The compounds of this invention can be separated in optically active or racemic forms. All methods used to prepare the compounds of this invention and the intermediates prepared therein are considered part of this invention. In the preparation of enantiomers or diastereomers, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). Depending on the method conditions, the final products of this invention are obtained in free (neutral) or salt form. The free forms of these end products and their salts are all within the scope of this invention. If desired, one form of the compound can be converted to another. A free base or acid can be converted to a salt; a salt can be converted to a free compound or another salt; a mixture of isomers of the present invention can be separated into individual isomers. The compounds of the present invention, their free forms, and their salts can exist in a variety of tautomeric forms, wherein hydrogen atoms are transposed to other parts of the molecule and thereby the chemical bonds between the atoms of the molecule are rearranged. It should be understood that all possible tautomeric forms are included within the scope of this invention.

[0084] In the present invention, when the listed linking groups do not specify their linking directions, the linking directions are arbitrary. For example in , L is -C(O)NH-, and at this time, -C(O)NH- can link the phenyl group and the cyclohexyl group either in the reading order from left to right to form or link the phenyl group and the cyclohexyl group in the reading order opposite to that from left to right to form The combination of the linking group and the group to be linked is allowed only when such a stable compound will be produced. In some preferred embodiments of the present invention, in the reading order from left to right.

[0085] Unless otherwise defined, the definitions of the substituents of the present invention are independent of each other rather than related to each other. For example (by way of illustration but not limitation), in one aspect, for the substituent R a (or R a ’), it is independent in the definitions of different substituents. Specifically, for R a (or R a ’), when a definition is selected in one substituent, it does not mean that this R a (or R a ’) has the same definition in other substituents. More specifically, for example (by way of illustration but not limitation) for NR a R a ’, when the definition of R a (or R a ’) is selected from hydrogen, it does not mean that in -C(O)-NR a R a ’, R a (or R a ’) must be hydrogen. In another aspect, when there are more than one R a (or R a ’) in a certain substituent, these R a (or R a ’) are also independent of each other. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, when m + n is greater than or equal to 2, the m + n R a (or R a ’) are independent of each other, and they can have the same or different meanings.

[0086] Unless otherwise defined, when a substituent is labeled "optionally substituted," the substituent is selected from, for example, alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxyl, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (where the two amino substituents are selected from alkyl, aryl, or arylalkyl), alkanoylamino, arylanoylamino, arylalkylamino, substituted alkanoylamino, substituted arylamino, substituted arylalkylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, Alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl (e.g., -SO2NH2), substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl (e.g., -CONH2), substituted carbamoyl (e.g., -CONHalkyl, -CONHaryl, -CONHarylalkyl or having two substituents selected from alkyl, aryl or arylalkyl on nitrogen), alkoxycarbonyl, aryl, substituted aryl, guanidine, heterocyclic groups (e.g., indolyl, imidazolyl, furanyl, thiophene, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine, homopiperazine, etc.) and substituted heterocyclic groups.

[0087] As used herein, the term "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). Alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable linking point, preferably from one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In this document, alkyl groups are preferably alkyl groups having 1 to 6, more preferably 1 to 4 carbon atoms.

[0088] As used herein, the term "alkylene" is intended to include branched, straight-chain, saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, comprising or not comprising cyclic alkyl groups, which are residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, "C0-C6 alkylene" means an alkylene group having 0 (i.e., bond), 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -(CHCH2CH)-), butylene (e.g., -(CH2)4-, -CH2CH(CH2CH3)-, -CH2(CHCH2CH)-, etc.), pentylene (e.g., -(CH2)5-, -CH2CH(CH(CH3)2)-, -CH2(CHCH2CH)CH2-, etc.), and hexylene (e.g., -(CH2)6-, -CH2CH2CH(CH(CH3)2)-, -CH2(CHCH(CH3)CH)CH2-, etc.). In this document, alkylene groups are preferably alkylene groups having 0-6, 0-4, 0-3, 1-6, 1-4, or 1-3 carbon atoms. In this document, alkylene groups are preferably alkylene groups that do not contain cyclic alkyl groups.

[0089] The term "cycloalkyl" refers to monocyclic, polycyclic, or branched cycloalkyl groups. For example, C3-C 12 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Polycyclic cycloalkyl groups, such as bicyclic and tricyclic cycloalkyl groups, include bridged, spirocyclic, or fused cycloalkyl groups. Cycloalkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable connection point, wherein the substituent is preferably one or more of halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl. In the invention, the cycloalkyl group is preferably C3-C6. 12 Cycloalkyl, more preferably C3-C8 cycloalkyl.

[0090] Similarly, the term "heterocyclic alkyl" refers to a member-ring structure in which at least one carbon atom in a cycloalkyl ring is replaced by a heteroatom selected from N, O, S, and P. The N atom may optionally be quaternized, and the N and S atoms may optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic heterocyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, fused, and bridged heterocyclic rings. Heterocyclic alkyl groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable junction. The substituents are preferably one or more selected from halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, alkyl groups, alkoxy groups, haloalkyl groups, cycloalkyl groups, heterocyclic alkyl groups, aryl groups, and heteroaryl groups. In this invention, the heterocyclic alkyl group is preferably a 4-12 membered heterocyclic alkyl group, more preferably a 4-8 membered heterocyclic alkyl group.

[0091] In this invention, the term "cyclic" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms.

[0092] In this invention, the term "bridged ring" refers to a polycyclic group in which two rings in the system share two or more ring atoms.

[0093] In this invention, the term "spirocyclic" refers to a polycyclic group in which single rings share a single carbon atom (called a spiro atom).

[0094] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this document, C2-C6 alkenyl groups are preferred.

[0095] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl groups refer to C3-C8 cyclic alkenyl groups, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norcamphenyl. Branched cyclic alkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl." Bicyclic cyclic alkenyl groups include bridged, spiro, or fused ring cyclic alkenyl groups.

[0096] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms. For example, "C2-C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, etc. In this document, the alkynyl group is preferably C2-C6 alkynyl.

[0097] The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C1-C6 alkoxy" (or alkyloxy) is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. In this document, alkoxy groups are preferably alkoxy groups having 1 to 6, more preferably 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above, connected by a sulfur bridge, having a specified number of carbon atoms; for example, methyl-S- and ethyl-S-. Alkoxy groups can be unsubstituted or substituted, and when substituted, they can be substituted at any usable connection point, wherein the substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0098] The term "carbonyl" refers to an organic functional group (C=O) formed by carbon and oxygen atoms linked by a double bond.

[0099] The term "aryl," alone or as part of a larger group such as "aralkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. In some embodiments of the invention, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring, non-limiting examples of which include benzyl, phenethyl, etc. Fused aryl groups may be attached to another group at a suitable position on a cycloalkyl or aromatic ring. Dashed lines drawn from the ring system indicate that the bond may be attached to any suitable ring atom. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0100] The term "heteroaryl" refers to a stable 5-, 6-, or 7-membered aromatic monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polycyclic heterocycle that is fully or partially unsaturated and contains a carbon atom and one, two, three, or four heteroatoms independently selected from N, O, and S; it includes structures fused with cycloalkanes or heterocyclic alkanes to aromatic rings such as benzene or heterocyclic rings such as pyridine, where the substituent site can be located on the cycloalkane, heterocyclic alkane, aromatic ring, or heterocyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom to obtain a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted at the carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. The heteroaryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. When the term "heterocycle" is used, it is intended to include heteroaryl groups.Examples of aromatic heteroyl groups include, but are not limited to, acridine, aziridine, acridine, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophene, benzooxazolyl, benzooxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-diathiazinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, imidazopyridyl, indolenyl, and dihydroindolenyl. Indazinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochoryl, isoindazoleyl, isodihydroindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, diazanaphthyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolopyridyl, naphthalene-intercalated diazaphenyl, hydroxyindolyl, pyrimidinyl, phenanthidyl, phenanthrololinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl Phthalasinyl, Piperazinyl, Piperidinyl, Piperidinoneyl, 4-Piperidinoneyl, Piperinyl, Pteridinyl, Puryl, Pyranyl, Pyrazinyl, Pyrazoloalkyl, Pyrazolinyl, Pyrazolopyridyl, Pyrazolyl, Pyridazinyl, Pyridoxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridinyl, Pyrimidinyl, Pyrrolylyl, Pyrrololinyl, 2-Pyrrolidoneyl, 2H-Pyrrolyl, Pyrrolyl, Quinazolinyl, Quinolinyl, 4H-Quinazinyl, Quinoxalinyl, Quinoxalinyl, Quininecycloyl, Tetrazolyl, Tetrahydrofuranyl, Tetrahydroisoquinolinyl, Tetrahydroquinolinyl, 6H-1,2,5-Thiadiazinyl, 1,2,3-Thiadiazinyl, 1,2,4-Thiadiazinyl, 1,2,5-Thiadiazinyl, 1,3,4-Thiadiazinyl Thianyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl-pyridyl, thiazolyl-thiazolyl, thiazolyl-oxazolyl, thiazolyl-imidazolyl, thiazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indoleyl, isoindoleyl, dihydroindoleyl, 1H-inzolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl.The term "heteroaryl" may also include biaryl structures formed by an "aryl" as defined above and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridinyl-", "-phenylbipyrimidinyl", "-pyridylbiphenyl", "-pyridylbipyrimidinyl-", and "-pyrimidinylbiphenyl-"; wherein the present invention also includes fused-ring and spirocyclic compounds containing, for example, the heterocycles described above.

[0101] As used herein, the term "substitution" means the replacement of at least one hydrogen atom with a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound. The cyclic double bond used herein refers to a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0102] In this disclosure, one or more halogens may be independently selected from fluorine, chlorine, bromine and iodine.

[0103] "Halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" / "halogenated alkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having a specified number of carbon atoms and substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of halogenated alkyl groups also include "fluoroalkyl" groups intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms. "Halogenated cycloalkyl" / "halogenated heterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having a specified number of carbon atoms and substituted with one or more halogens. In this invention, the halogen atom is preferably fluorine or chlorine, more preferably fluorine.

[0104] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above that is oxygen-bridged and has a specified number of carbon atoms. For example, "haloC1-C6 alkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above that is sulfur-bridged and has a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0105] In this disclosure, C is used when referring to certain substituent groups. x1 -C x2The expression indicates that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0106] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0107] In cases where nitrogen atoms (e.g., amines) are present on the compounds of the present invention, these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the present invention. Therefore, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxides to obtain derivatives of the present invention.

[0108] When any variable appears more than once in any composition or formula of a compound, its definition for each occurrence is independent of its definition for each other occurrence. Thus, for example, if a substituent group is shown to have 0-3 R groups, the substituent group may optionally be substituted with up to three R groups, and each occurrence of R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce a stable compound.

[0109] As used herein, the term "patient" refers to an organism treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, apes, monkeys, horses, cattle, pigs, dogs, cats, etc.), and most preferably, humans.

[0110] As used herein, the term "effective amount" means the amount of a drug or agent (i.e., the compound of the present invention) that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, a researcher or clinician. Furthermore, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who has not received the aforementioned amount, results in improved treatment, cure, prevention, or reduction of a disease, symptom, or side effect, or a slower rate of progression of a disease or symptom. Effective amounts may be administered, applied, or dosed in one or more ways and are not intended to be limited to a particular formulation or route of administration. The term also includes effective amounts within its scope that enhance normal physiological function.

[0111] The term “treatment” as used in this article includes any effect that results in improvement of a condition, disease, disorder, etc., such as reducing, decreasing, regulating, improving or eliminating, or improving its symptoms.

[0112] The term "pharmaceutical" as used herein refers to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0113] As used herein, the phrase "pharmaceutically acceptable carrier" or "medicinal carrier" refers to a pharmaceutical substance, composition, or medium, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulation substance, relating to the transport or delivery of a subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmlessness to the patient.

[0114] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of a bioactive agent to an animal (specifically a mammal), including (i) adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.

[0115] Specific pharmaceutical and medical terminology

[0116] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0117] The term "cancer," as used in this article, refers to an uncontrolled abnormal growth of cells that, under certain conditions, can metastasize (spread). This type of cancer includes, but is not limited to, solid tumors (such as those of the bladder, intestines, brain, chest, uterus, heart, kidneys, lungs, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as the thyroid), prostate, skin (melanoma), or hematologic malignancies (such as nonleukemic leukemia).

[0118] The term “combined administration” or similar terms, as used herein, refers to the administration of several selected therapeutic agents to a patient in the same or different manners of administration at the same or different times.

[0119] The terms “enhancement” or “potential enhancement,” as used herein, refer to the expected increase or prolongation of either efficacy or duration of effect. Therefore, in the context of enhancing the therapeutic effect of a drug, the term “potential enhancement” refers to the ability of a drug in a system to increase or prolong its efficacy or duration. The term “synergistic value,” as used herein, refers to the ability of an ideal system to maximally enhance the efficacy of another therapeutic agent.

[0120] The term "immune disease" refers to a disease or symptom that results from an adverse or harmful reaction to endogenous or exogenous antigens. The result is often impaired cell function, or damage to cells leading to dysfunction, or damage to organs or tissues that may produce immune symptoms.

[0121] The terms "reagent kit" and "product packaging" are synonyms.

[0122] The terms "subject" or "patient" include both mammals and non-mammals. Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes, and monkeys; agricultural animals such as cattle, horses, goats, sheep, and pigs; livestock such as rabbits and dogs; and laboratory animals including rodents such as rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In a preferred aspect, the selected mammal is a human.

[0123] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndrome; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; mitigating a disease or symptom; reducing complications arising from a disease or symptom, or preventing and / or treating signs arising from a disease or symptom.

[0124] As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. This may be attributable to or related to the administration, whether the administration is fixed or intermittent, continuous or discontinuous.

[0125] Drug composition and dosage

[0126] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of the present invention formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the other therapeutic agents described above. The compounds of the present invention can be administered in any suitable manner for any of the above-described uses, such as orally, in tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; sublingually; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to a nasal membrane, such as by inhalation sprays; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories; or intratumorally. They can be administered alone, but are typically administered using a pharmaceutical carrier chosen based on the selected route of administration and standard pharmaceutical practice.

[0127] Pharmaceutical carriers include aqueous and non-aqueous liquid media as well as various solid and semi-solid pharmaceutical carriers. These carriers may include a variety of different components and additives besides active agents, which are included in formulations for various reasons known to those skilled in the art, such as stabilizers, binders, etc. Descriptions of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen LV Jr. et al. Remington: The Science and Practice of PharmaCy1 (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0128] Of course, the dosage regimen of the compounds of the present invention varies depending on known factors, such as the pharmacodynamic properties of the specific pharmaceutical agent and its administration mode and route; the recipient's species, age, sex, health status, medical condition, and weight; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect. According to general guidelines, when used for a specified effect, the daily oral dose of each active ingredient should be from about 0.001 mg / day to about 10-5000 mg / day, preferably from about 0.01 mg / day to about 1000 mg / day, and most preferably from about 0.1 mg / day to about 250 mg / day. During constant-rate infusion, the most preferred intravenous dose should be from about 0.01 mg / kg / min to about 10 mg / kg / min. The compounds of the present invention can be administered as a single daily dose, or as a total daily dose administered in two, three, or four separate doses daily.

[0129] The compound is typically administered in the form of a mixture with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier) appropriately selected according to the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and consistent with routine pharmaceutical practice.

[0130] Suitable dosage forms (pharmaceutical compositions) may contain from about 1 mg to about 2000 mg of active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

[0131] The scope of this invention includes (alone or in combination with a drug carrier) pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of the invention as an active ingredient. Optionally, the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0132] Regardless of the chosen route of administration, the compounds of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0133] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be altered to obtain an amount of active ingredient that is effective and non-toxic to patients in achieving the desired therapeutic response, composition, and administration mode for a particular patient.

[0134] The selected dose level will depend on a variety of factors, including the activity of the specific compound of the present invention or its ester, salt or amide; route of administration; time of administration; excretion rate of the specific compound; absorption rate and extent; duration of treatment; other drugs, compounds and / or substances used in combination with the specific compound; and medically known factors such as the age, sex, weight, condition, general health and prior medical history of the patient being treated.

[0135] A physician or veterinarian with ordinary skill in the art can determine and prescribe an effective amount of the desired pharmaceutical composition. Generally, the appropriate daily dose of the compound of the invention will be the amount of the lowest dose of the compound that effectively produces a therapeutic effect. This effective dose generally depends on the factors described above. Typically, the oral, intravenous, intraventricular, and subcutaneous doses of the compound of the invention for a patient range from about 0.01 to about 50 mg / kg body weight / day. If desired, an effective daily dose of the active compound may be administered in two, three, four, five, six, or more sub-dose at appropriate intervals throughout the day, optionally in unit dosage form. In some aspects of the invention, the medication is administered once daily.

[0136] Although the compounds of the present invention can be administered alone, they are preferably administered in the form of pharmaceutical formulations (compositions).

[0137] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0138] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0139] The units used in weight-volume percentages in this invention are well known to those skilled in the art, for example, referring to the weight (g) of the solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as known to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0140] Example

[0141] General process

[0142] When the preparation method is not specified, all raw materials and reagents used in this invention are known products that can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents used require further purification.

[0143] Room temperature refers to 20-30℃.

[0144] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere. A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon of approximately 1L.

[0145] Hydrogenation reactions are typically carried out under vacuum, filled with hydrogen gas, and repeated three times. A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon of approximately 1L.

[0146] Microwave reaction use Initiator + Microwave Reactor.

[0147] The structure of the compounds of this invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The measurements are given in units of (ppm). NMR determinations are performed using (Bruker Ascend) TM A Model 500 NMR spectrometer was used. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). The following abbreviations are used for NMR signal multiplicity: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values ​​and measured in Hz.

[0148] Reversed-phase preparative chromatography was performed using a Thermo (UltiMate 3000) reversed-phase preparative chromatograph. Rapid column chromatography was performed using an Agilent (FS-9200T) automated column press, and pre-packed silica gel columns were obtained from Sante. Pre-packed column. Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The thickness used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.

[0149] The LC-MS analysis method is as follows:

[0150] 1) Mass spectrometry method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameter settings: drying gas temperature 350℃; drying gas flow rate 10L / min; MS range: 120-1000.

[0151] 2) Liquid chromatography conditions: Column: Waters XBridge (3.5 μm, 50 mm × 4.6 mm); Mobile phase A is an aqueous solution containing 0.1% ammonium bicarbonate, and mobile phase B is an acetonitrile solution, with linear gradient elution according to Table 1; Flow rate: 2 mL / min; Column temperature: 30 ℃; UV detection wavelength: 214 nm, 254 nm, 280 nm; Injection volume: 2 μL.

[0152] Table 1. Gradient elution conditions

[0153]

[0154] The HPLC analysis method is as follows:

[0155] Chromatographic column: Waters XBridge phenyl (3.5 μm, 150 mm × 4.6 mm); mobile phase A was an aqueous solution containing 0.1% ammonium bicarbonate, and mobile phase B was an acetonitrile solution, with linear gradient elution performed according to Table 2; flow rate: 1 mL / min; column temperature: 30 ℃; UV detection wavelengths: 214 nm, 254 nm, 280 nm; injection volume: 2 μL.

[0156] Table 2. Gradient elution conditions

[0157]

[0158] The synthesis methods of some intermediates in the invention are as follows:

[0159] Intermediate 1

[0160]

[0161] Intermediate 1 is prepared by the following steps:

[0162]

[0163] Step 1: 100 g (756.7 mmol) of methyl 2,2-dimethyl-3-hydroxypropionate (INT-1a) was dissolved in 1 L of N,N-dimethylformamide. Imidazole (128.8 g, 1.89 mol) was added, and the mixture was stirred until dissolved. Tert-butyldiphenylchlorosilane (228.8 g, 832.3 mmol) was added dropwise at room temperature. After the addition was complete, stirring was continued for 4 hours. After the reaction was complete, the reaction solution was poured into 3 L of ice water. The suspension was extracted with ethyl acetate (1 L * 2). The organic phase was washed three times with water and concentrated under reduced pressure to obtain a colorless oily substance, INT-1b. No purification was required; it was used directly in the next step. ESI-MS (m / z): 371.2 [M+H] + .

[0164] Step 2: Add the residual INT-1b obtained in the previous step to 2L of methanol, then add 360g of a prepared 33% sodium hydroxide aqueous solution, and stir at room temperature for 17 hours. After the reaction is complete, add 1L of water, remove methanol under reduced pressure, and extract the residual liquid with petroleum ether (1L*5). After extraction, adjust the pH of the aqueous phase to 4-5 with hydrochloric acid, continue stirring for 30 minutes, filter, and dry to obtain a white solid INT-1c (269g, yield 90%). ESI-MS (m / z): 357.8 [M+H] + .

[0165] Step 3: Dissolve INT-1c (130g, 364.6mmol) in 500mL of dichloromethane, add thionyl chloride (130.1g, 1.09mol, 79.4mL) at room temperature, stir at 60℃ for 3 hours. After the reaction is complete, remove dichloromethane and the remaining thionyl chloride under reduced pressure to obtain a pale yellow oily substance INT-1d. Without purification, add 200mL of dichloromethane for later use.

[0166] Step 4: Dissolve INT-1e (64.8 g, 331 mmol) in 400 mL of dichloromethane. Add 198 mL of diethylaluminum chloride solution (2 M in hexanes) dropwise at 0 °C, controlling the temperature to not exceed 5 °C during the addition. Stir for 30 minutes after the addition is complete. Add the resulting dichloromethane solution of INT-1d dropwise to the reaction flask. Control the temperature to not exceed 10 °C during the addition. Continue stirring for 2 hours after the addition is complete. After the reaction is complete, pour the reaction solution into 1 L of ice water, stir for 30 minutes, and then concentrate under reduced pressure to remove dichloromethane. Extract the residue with ethyl acetate (1 L * 2), wash with water, and concentrate the organic phase under reduced pressure to obtain a brown oily substance. Add the oily substance to 2 L of a 10 / 1 mixture of petroleum ether and ethyl acetate, stir to precipitate a solid, filter, and obtain a yellow solid INT-1f (139 g, yield 78%). ESI-MS (m / z): 534.8 [M + H] + .

[0167] Step 5: Dissolve INT-1f (100g, 187.1mmol) in 500mL of tetrahydrofuran, add lithium borohydride (12.2g, 561.2mmol), stir overnight at 60°C. After the starting material disappears, quench the reaction mixture in 200mL of ice water, extract with ethyl acetate (500mL*3), wash the organic phase with water, dry, concentrate under reduced pressure, dissolve the residue in 500mL of dichloromethane, and add 2,6-dimethyl-1,4- Diethyl dihydro-3,5-pyridinedicarboxylate (28.4 g, 112.2 mmol) and p-toluenesulfonic acid (21.4 g, 112.2 mmol) were stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove dichloromethane. The residue was dissolved in 500 mL of methanol, and 100 mL of a pre-prepared 14% lithium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 3 hours and filtered to give a yellow solid INT-1 g (84 g, yield 86.3%). ESI-MS (m / z): 520.2 [M+H] + .

[0168] Step 6: Dissolve INT-1 g (50 g, 96 mmol) in 250 mL of tetrahydrofuran, add tetrabutylammonium fluoride (1 M inTHF, 197 mL), stir overnight at 60 °C. After the reaction is complete, add the reaction solution to 300 mL of water, extract with ethyl acetate (200 mL * 3), wash with water, concentrate under reduced pressure to obtain a brown oil. Dissolve the residue in 40 mL of methanol, add 20 mL of water, wash the mixture with petroleum ether (40 mL * 5), concentrate under reduced pressure to remove methanol, extract the residue with ethyl acetate (50 mL * 2), wash the organic phase with water, dry to obtain a pale yellow oil INT-1h (25 g, yield 90.4%). ESI-MS (m / z): 282.8 [M + H] + .

[0169] Step 7: Dissolve compound INT-1h (22 g, 77 mmol) in 100 mL of dichloromethane. Add 4-dimethylaminopyridine (467 mg, 3.82 mmol) and triethylamine (23.2 g, 230 mmol). Add acetic anhydride (7.9 g, 77 mmol) dropwise at 0 °C. After the addition is complete, allow the mixture to heat naturally and stir overnight. Once the reaction is complete, wash the reaction solution with water, dry it, and concentrate it to obtain a brown oil. Purify the oil by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain a pale yellow oil INT-1i (22.5 g, yield 90.7%). ESI-MS (m / z): 324.2 [M+H] + .

[0170] Step 8: Compound INT-1i (40 g, 123.4 mmol) was dissolved in dioxane (400 mL), and potassium acetate (30.3 g, 308.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (10 g, 12.3 mmol), and pinacol diboronate (78.3 g, 308.4 mmol) were added. The reaction was carried out at 90 °C for 3 hours under nitrogen protection. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (300 mL). The solution was washed with water and brine. The organic phase was purified by silica gel column chromatography to obtain a white solid compound INT-1j (35 g, yield 76.4%). ESI-MS (m / z): 372.5 [M+H] + .

[0171] Step 9: Compound INT-1j (35 g, 94.3 mmol) and compound INT-1k (37.9 g, 103.7 mmol) were dissolved in dioxane (300 mL) and water (30 mL). Potassium phosphate (50 g, 235.7 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6.89 g, 9.43 mmol) were added. The reaction was carried out overnight at 90 °C under nitrogen protection. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water and brine, and the organic phase was purified by silica gel column chromatography to give a yellow oily compound INT-1l (28 g, yield 56.08%). ESI-MS (m / z): 530.7 [M+H] + .

[0172] Step 10: Compound INT-1l (28 g, 52.9 mmol) was dissolved in N,N-dimethylformamide (280 mL), and N-iodosuccinimide (11.9 g, 52.9 mmol) was added. The reaction was carried out at 50 °C for 2 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was poured into water (800 mL), extracted with ethyl acetate (200 mL * 2), washed with saturated brine, dried, filtered, and purified by silica gel column chromatography to obtain a yellow solid compound INT-1m (22 g, yield 63.5%). ESI-MS (m / z): 656.6 [M + H] + .

[0173] Step 11: Compound INT-1m (5 g, 7.63 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (939.4 mg, 2.29 mmol), tris(dibenzylacetone)dipalladium (838.1 mg, 0.915 mmol), and potassium acetate (2.6 g, 26.7 mmol) were dissolved in toluene (100 mL). Pinara-borane (4.9 g, 38.1 mmol) was added dropwise under nitrogen protection. After the addition was complete, the reaction was carried out at 50 °C for 5 hours under nitrogen protection. The reaction mixture was monitored by LC-MS to ensure complete reaction. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow oily compound INT-1 (4.5 g, 90% yield). ESI-MS (m / z): 656.5 [M+H] + .

[0174] Intermediate 2

[0175]

[0176] Intermediate 2 is prepared by the following steps:

[0177]

[0178] Step 1: Compound INT-1m (12 g, 18.3 mmol) was dissolved in tetrahydrofuran (120 mL) and water (20 mL). Lithium hydroxide monohydrate (3.84 g, 91.5 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in water (100 mL), and the pH was adjusted to 4–5 with 4 M hydrochloric acid. The mixture was extracted with dichloromethane (100 mL * 3), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid compound INT-2a (10.6 g, yield 96.6%). ESI-MS (m / z): 600.7 [M + H] + .

[0179] Step 2: Compounds INT-2a (9.5 g, 15.9 mmol) and INT-2b (11.7 g, 31.7 mmol) were dissolved in acetonitrile (190 mL). N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (6.67 g, 23.8 mmol) and 1-methylimidazole (6.51 g, 79.2 mmol) were added at 0 °C. The reaction was carried out at 0 °C for 1 hour. LC-MS was used to monitor the reaction until complete. The reaction solution was poured into water (200 mL), extracted with dichloromethane (100 mL x 3), and the organic phase was washed with water. The solution was purified by silica gel column chromatography to obtain a yellow solid compound INT-2c (9.6 g, yield 83.5%). ESI-MS (m / z): 726.3 [M+H] + .

[0180] Step 3: Compound INT-2c (9.6 g, 13.2 mmol) was dissolved in tetrahydrofuran (100 mL) and water (10 mL). Lithium hydroxide monohydrate (1.39 g, 33.1 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly concentrated under reduced pressure, and the residue was dissolved in water (100 mL). The pH was adjusted to 4-5 with 4 M hydrochloric acid, and a white solid precipitated. The solid was filtered, washed with water, and dried to obtain a white solid compound INT-2d (8.3 g, yield 88.2%). ESI-MS (m / z): 712.6 [M+H] + .

[0181] Step 4: Compound INT-2d (3.5 g, 4.9 mmol), 1-hydroxybenzotriazole (1.99 g, 14.8 mmol), and 4-dimethylaminopyridine (1.8 g, 14.8 mmol) were dissolved in dichloromethane (170 mL). N,N-diisopropylethylamine (6 mL, 34.4 mmol) was added at 0 °C, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.71 g, 24.6 mmol). The reaction was carried out overnight at room temperature. The reaction mixture was monitored by LCMS to ensure complete reaction. The reaction solution was washed with saturated ammonium chloride aqueous solution, dried over sodium sulfate, and purified by silica gel column chromatography to obtain a yellow solid compound INT-2e (2 g, yield 58.6%). ESI-MS (m / z): 694.6 [M+H] + .

[0182] Step 5: Compound INT-2e (500 mg, 0.721 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (88.8 mg, 0.216 mmol), tris(dibenzylacetone)dipalladium (79 mg, 0.086 mmol), and potassium acetate (247 mg, 2.52 mmol) were dissolved in tetrahydrofuran (20 mL). Pinara-borane (461 mg, 3.6 mmol) was added dropwise under nitrogen protection. After the addition was complete, the reaction was carried out at 50 °C for 3 hours under nitrogen protection. LC-MS was used to monitor the reaction until complete. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-2 (400 mg, 80% yield). ESI-MS (m / z): 694.6 [M+H] + .

[0183] Intermediate 3

[0184]

[0185] Intermediate 3 is prepared by the following steps:

[0186]

[0187] Step 1: Compound INT-2e (1.7 g, 2.45 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 2 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), washed twice with saturated NaHCO3 aqueous solution, washed with water with the organic phase, dried over sodium sulfate, filtered, and concentrated to give a yellow solid compound INT-3a (1.3 g, yield 89.4%). ESI-MS (m / z): 594.7 [M+H] + .

[0188] Step 2: Compounds INT-3a (1.3 g, 2.19 mmol) and INT-3b (0.24 g, 2.41 mmol) were dissolved in acetonitrile (30 mL). N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (921.9 mg, 3.29 mmol) and 1-methylimidazole (414 mg, 5.04 mmol) were added at 0 °C. The reaction was carried out at 0 °C for 1 hour. LC-MS was used to monitor the reaction until complete. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was washed with water. The mixture was then purified by column chromatography to obtain a white solid compound INT-3c (1.3 g, yield 87.9%). ESI-MS (m / z): 675.7 [M+H] + .

[0189] Step 3: Compound INT-3c (1.1 g, 1.63 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (200.5 mg, 0.188 mmol), tris(dibenzylacetone)dipalladium (179 mg, 0.195 mmol), and potassium acetate (559 mg, 5.7 mmol) were dissolved in toluene (30 mL). Pinara-borane (1.04 g, 8.14 mmol) was added dropwise under nitrogen protection. After the addition was complete, the reaction was carried out at 50 °C for 3 hours under nitrogen protection. LC-MS was used to monitor the reaction until complete. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-3 (990 mg, 90% yield). ESI-MS (m / z): 676.9 [M+H] + .

[0190] Intermediate 4

[0191]

[0192] Intermediate 4 is prepared by the following steps:

[0193]

[0194] Step 1: Compounds INT-3a (2.2 g, 3.71 mmol) and INT-4a (0.47 g, 4.08 mmol) were dissolved in dichloromethane (50 mL). N,N,N',N'-tetramethylchloromethanesulfonyl hexafluorophosphate (1.56 g, 5.56 mmol) and 1-methylimidazole (0.70 g, 8.53 mmol) were added at 0 °C. The reaction was carried out at 0 °C for 1 hour. LC-MS was used to monitor the reaction until complete. The reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 3), and the organic phase was washed with water. The mixture was then purified by column chromatography to obtain a white solid compound INT-4b (2.3 g, yield 90.0%). ESI-MS (m / z): 690.2 [M+H] + .

[0195] Step 2: Compound INT-4b (2.1 g, 3.05 mmol), 2-dicyclohexylphosphine-2′,6′-dimethylbiphenyl (375.0 mg, 0.91 mmol), tris(dibenzylacetone)dipalladium (334.6 mg, 0.365 mmol), and potassium acetate (1.05 g, 10.7 mmol) were dissolved in toluene (30 mL). Pinara-borane (1.95 g, 15.2 mmol) was added dropwise under nitrogen protection. After the addition was complete, the reaction was carried out at 50 °C for 3 hours under nitrogen protection. LC-MS was used to monitor the reaction until complete. The reaction solution was filtered and purified by silica gel column chromatography to obtain a yellow solid compound INT-4 (1.8 g, yield 85.7%). ESI-MS (m / z): 690.3 [M+H] + .

[0196] Intermediate 5

[0197]

[0198] Intermediate 5 is prepared by the following steps:

[0199]

[0200] Step 1: Compound INT-5a (2 g, 19.42 mmol) and benzyl chloroformate (3.3 g, 19.42 mmol) were dissolved in tetrahydrofuran (20 mL). N,N-diisopropylethylamine (5.0 g, 38.76 mmol) was added at room temperature, and the reaction was carried out for 16 hours at room temperature. The reaction mixture was monitored by LCMS until the starting material was completely reacted. The reaction solution was diluted with ethyl acetate (60 mL), washed three times with saturated ammonium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain a yellow oily compound INT-5b (3.9 g, yield 84.7%). ESI-MS (m / z): 238.2 [M+H] + .

[0201] Step 2: Compound INT-5b (3.9 g, 16.45 mmol) was dissolved in methanol (30 mL), and ammonium carbamate (1.9 g, 24.35 mmol) and iodobenzene acetate (10.6 g, 32.91 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound INT-5c (3.5 g, yield 79.5%). ESI-MS (m / z): 269.3 [M+H] + .

[0202] Step 3: Compounds INT-5c (600 mg, 2.24 mmol) and INT-5d (761 mg, 2.24 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cuprous iodide (85 mg, 0.45 mmol), N,N-dimethylethylenediamine (40 mg, 0.45 mmol), and potassium phosphate (1.42 g, 6.72 mmol) were added. The reaction system was purged with nitrogen and heated to 80 °C with stirring for 16 hours. After the reaction was complete, water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL * 2). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-5 (615 mg, yield 57.1%). ESI-MS (m / z): 482.6 [M+H] + .

[0203] Intermediate 6

[0204]

[0205] Intermediate 6 is prepared by the following steps:

[0206]

[0207] Step 1: Compounds INT-5d (500 mg, 1.46 mmol) and INT-6a (150 mg, 1.61 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (56 mg, 0.29 mmol), N,N-dimethylethylenediamine (26 mg, 0.29 mmol), and potassium phosphate (931 mg, 4.4 mmol) were added. The reaction system was purged with nitrogen and heated to 85 °C with stirring for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-6 (360 mg, yield 80.2%). ESI-MS (m / z): 307.4 [M+H] + .

[0208] Intermediate 7

[0209]

[0210] Intermediate 7 is prepared by the following steps:

[0211]

[0212] Step 1: Compound INT-7a (500 mg, 5.67 mmol) and morpholine (989 mg, 11.35 mmol) were dissolved in 1,2-dichloroethane (5 mL), and acetic acid (34 mg, 0.57 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (2.4 g, 11.35 mmol) was added, and stirring was continued for 3 h. After the reaction was complete, saturated sodium bicarbonate (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give compound INT-7b (650 mg, yield 71.9%). ESI-MS (m / z): 159.9 [M+H] + .

[0213] Step 2: Compound INT-7b (600 mg, 3.77 mmol) was dissolved in methanol (10 mL), and ammonium carbamate (441 mg, 5.65 mmol) and iodobenzene acetate (2.43 g, 7.54 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-7c (670 mg, yield 93.5%). ESI-MS (m / z): 191.3 [M+H] +. 1 H NMR (500MHz, DMSO-d6) δ4.65(s,1H),4.05–3.94(m,2H),3.91–3.82(m,2H),3.60–3.55(m,4H),3.14–3.06(m,1H),2.35–2.29(m,4H).

[0214] Step 3: Compounds INT-7c (55.6 mg, 0.29 mmol) and INT-5d (100 mg, 0.29 mmol) were dissolved in N,N-dimethylformamide (5 mL), and cuprous iodide (11 mg, 0.058 mmol), N,N-dimethylethylenediamine (5 mg, 0.058 mmol), and potassium phosphate (186 mg, 0.87 mmol) were added. The reaction system was purged with nitrogen and heated to 80 °C with stirring for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-7 (65 mg, yield 55%). ESI-MS (m / z): 404.6 [M+H] + .

[0215] Intermediate 8

[0216]

[0217] Intermediate 8 is prepared by the following steps:

[0218]

[0219] By replacing benzyl chloroformate in the first step of the synthesis of intermediate INT-5 with di-tert-butyl dicarbonate, compound INT-8 can be obtained using a similar method and reaction steps. ESI-MS (m / z): 448.6 [M+H] + .

[0220] Intermediate 9

[0221]

[0222] Intermediate 9 is prepared by the following steps:

[0223]

[0224] By replacing INT-5a in intermediate INT-5 with INT-9a, and using a similar method and reaction steps, compound INT-9 can be obtained. ESI-MS (m / z): 494.4 [M+H] + .

[0225] Intermediate 10

[0226]

[0227] Intermediate 10 is prepared by the following steps:

[0228]

[0229] Step 1: Compound INT-10a (1.3 g, 11.19 mmol) and morpholine (974.8 mg, 11.19 mmol) were dissolved in dichloromethane (10 mL), and acetic acid (67 mg, 1.12 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (4.74 g, 22.38 mmol) was added, and stirring continued for 3 h. After the reaction was complete, saturated sodium bicarbonate (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give compound INT-10b (1.8 g, yield 85.9%). ESI-MS (m / z): 188.6 [M+H] + .

[0230] Step 2: Compound INT-10b (1.8 g, 9.61 mmol) was dissolved in methanol (15 mL), and ammonium carbamate (1.88 g, 24.03 mmol) and iodobenzene acetate (7.74 g, 24.03 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-10c (1.5 g, yield 71.5%). ESI-MS (m / z): 219.4 [M+H] + .

[0231] Step 3: Compound INT-10c (127.7 mg, 0.58 mmol) and compound INT-5d (200 mg, 0.58 mmol) were dissolved in 1,4-dioxane (5 mL), and tris(dibenzylacetone)dipalladium (53.6 mg, 0.058 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (33.8 mg, 0.058 mmol), and cesium carbonate (381.1 mg, 1.17 mmol) were added. The reaction system was purged with nitrogen and heated to 80 °C with stirring for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL * 2). The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound INT-10 (180 mg, yield 71.2%). ESI-MS(m / z): 432.6[M+H]+.

[0232] Intermediate 11

[0233]

[0234] Intermediate 11 is prepared by the following steps:

[0235]

[0236] By replacing INT-10a in intermediate INT-10 with INT-11a, and using a similar method and reaction steps, compound INT-11 can be obtained. ESI-MS (m / z): 446.4 [M+H] + .

[0237] The synthesis method of the compounds in the embodiments of this invention is as follows:

[0238] Example 1

[0239] (1S,2S)-N-((63R,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((4-methyl-1-oxido-1l6-thiomorpholin-1-ylidene)amino)pyridin-3-yl)-10,10-dimethyl-5,7-d ioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacyclodecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0240]

[0241] Example 1 was prepared by the following steps:

[0242]

[0243] Step 1: Intermediates INT-3 (60 mg, 13.4 μmol) and INT-8 (99 mg, 14.7 μmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (19 mg, 0.26 mmol) and potassium phosphate (57 mg, 0.54 mmol) were added. The reaction mixture was purged with nitrogen and heated to 70 °C with stirring for 12 hours. The reaction was monitored by LCMS until completion. The solvent was removed by vacuum distillation, the mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and the filtrate was concentrated and purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 1a (88 mg, 71% yield). ESI-MS (m / z): 917.5 [M+H] + .

[0244] Step 2: Compound 1a (88 mg, 96 μmol) was dissolved in DMF (3 mL), and cesium carbonate (94 mg, 288 μmol) was added. Then, iodoethane (75 mg, 0.48 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete as determined by LCMS, saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 1b. ESI-MS (m / z): 945.5 [M+H] + .

[0245] Step 3: Trifluoroacetic acid (1 mL) was added dropwise to dichloromethane (3 mL) of the crude product 1b. The reaction mixture was stirred at room temperature for 30 minutes, and the reaction was monitored by LCMS until completion. The reaction mixture was concentrated by vacuum distillation, saturated sodium carbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 1c. ESI-MS (m / z): 845.5 [M+H] + .

[0246] Step 4: Formaldehyde aqueous solution (0.05 mL, 37%) was added dropwise to compound 1c (67 mg, 79 μmol) and 1,2-dichloroethane (2 mL). After stirring the reaction solution at room temperature for 20 minutes, sodium triacetoxyborohydride (101 mg, 476 μmol) was added, and the reaction solution was stirred at room temperature for another 30 minutes. After the reaction was completed by LCMS monitoring, saturated ammonium chloride aqueous solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to obtain a white solid compound 1 (5 mg, 7% yield) and an epimer compound 1' (9 mg, 13% yield). The absolute configurations of the two compounds are assumed based on experience; compound 1 is the isomer with a longer retention time in LCMS or HPLC, while 1' is the isomer with a shorter retention time in LCMS or HPLC.

[0247] Compound 1:

[0248] ESI-MS (m / z): 859.6 [M+H] + LC-MS retention time RT = 1.60 min. HPLC retention time RT = 10.04 min.

[0249] 1 H NMR (500MHz, DMSO-d6) δ8.49-8.38(m,2H),8.31(d,J=2.6Hz,1H),7.72(s,1H),7.69-7.63(m,1H),7.49(d,J=8.7Hz ,1H),7.17(d,J=2.6Hz,1H),5.50(t,J=9.1Hz,1H),5.03-4.98(m,1H),4.28-4.06(m,5H),3.55-3.47(m,3H),3.16(s ,3H),3.11-3.05(m,1H),2.93-2.63(m,7H),2.37-2.32(m,1H),2.23(s,3H),2.01(d,J=9.6Hz,1H),1.76-1.64(m,2 H),1.49-1.40(m,2H),1.26(d,J=6.0Hz,3H),1.03-0.95(m,4H),0.86-0.77(m,7H),0.51-0.44(m,1H),0.28(s,3H).

[0250] Compound 1':

[0251] ESI-MS (m / z): 859.5 [M+H] +LC-MS retention time RT = 1.59 min. HPLC retention time RT = 10.03 min.

[0252] 1 H NMR (500MHz, DMSO-d6) δ8.56-8.49(m,2H),8.38(d,J=2.5Hz,1H),7.80(s,1H),7.72(dd,J=8.7,1.7Hz,1H),7.51(d,J=8.7Hz,1H),7.38(d,J=2.6Hz,1 H),5.54(t,J=9.2Hz,1H),5.08-5.02(m,1H),4.22(t,J=12.2Hz,2H),3.93 -3.88(m,1H),3.66(d,J=10.9Hz,1H),3.54(d,J=10.9Hz,1H),3.38(d,J=4. 8Hz,1H),3.18-3.11(m,1H),3.08(s,3H),3.02(d,J=14.4Hz,1H),2.93-2. 85(m,2H),2.84-2.71(m,3H),2.45-2.40(m,1H),2.30(s,3H),2.15-2.08(m ,1H),1.84-1.77(m,2H),1.55-1.48(m,2H),1.21(d,J=6.2Hz,3H),1.14-1. 05(m,6H),0.94(s,3H),0.89-0.83(m,1H),0.59-0.53(m,1H),0.51(s,3H).

[0253] Example 2

[0254] (1S,2S)-N-((63S,4S,Z)-12-(5-((dimethyl(oxo)-l6-sulfaneylidene)amino)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-he xahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0255]

[0256] Example 2 was prepared by the following steps:

[0257]

[0258] Step 1: Compound INT-2 (108.4 mg, 0.16 mmol) was dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL). INT-6 (40 mg, 0.13 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9.5 mg, 0.013 mmol), and potassium phosphate (82.9 mg, 0.39 mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20:1) to give a pale yellow solid compound 2a (55 mg, yield 53.2%). ESI-MS (m / z): 794.5 [M+H] + .

[0259] Step 2: Compound 2a (55 mg, 0.069 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (45.1 mg, 0.138 mmol) and iodoethane (16.2 mg, 0.104 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give a pale yellow solid compound 2b (45 mg, yield 79.0%). ESI-MS (m / z): 822.4 [M+H] + .

[0260] Step 3: Compound 2b (45 mg, 0.055 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (30 mL) was added to the reaction system under ice bath conditions, and the mixture was extracted with dichloromethane (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid, compound 2c (40 mg, 100% yield). ESI-MS (m / z): 722.4 [M + H] + .

[0261] Step 4: Compound 2c (40 mg, 0.055 mmol) was dissolved in N,N-dimethylformamide (2 mL), and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (11.1 mg, 0.11 mmol), N,N-diisopropylethylamine (21.5 mg, 0.166 mmol), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (47.5 mg, 0.11 mmol) were added. The reaction mixture was stirred in an ice bath for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography to give a white solid compound 2 (5 mg, yield 11.2%) and epimer 2' (8 mg, yield 18.0%). The absolute configurations drawn for the two compounds are assumptions based on experience. Compound 2 is the isomer with a longer retention time in LCMS or HPLC, while 2' is the isomer with a shorter retention time in LCMS or HPLC.

[0262] Compound 2:

[0263] ESI-MS (m / z): 804.5 [M+H] + LC-MS retention time RT = 1.56 min. HPLC retention time RT = 11.12 min.

[0264] 1H NMR(500MHz,DMSO-d6)δ8.53–8.50(m,1H),8.49-8.47(m,1H),8.33(d,J=2.5Hz,1H),7.80(s,1H),7.75-7.71(m,1H),7.59-7.54(m,1 H),7.20(d,J=2.5Hz,1H),5.60-5.53(m,1H),5.11-5.05(m,1H),4.33-4.17(m,5H),3.61-3.54(m,2H),3.32-3.31(m,3H),3.29(s,3H) ,3.22(s,3H),3.17-3.12(m,1H),2.98-2.92(m,1H),2.79-2.73(m,1H),2.44-2.40(m,1H),2.10-2.05(m,1H),1.82-1.75(m,2H),1.5 3-1.48(m,2H),1.33(d,J=6.0Hz,3H),1.24-1.19(m,1H),1.14-1.06(m,5H),0.94-0.85(m,6H),0.57-0.52(m,1H),0.39-0.33(m,3H).

[0265] Compound 2':

[0266] ESI-MS (m / z): 804.5 [M+H] + LC-MS retention time RT = 1.56 min. HPLC retention time RT = 11.09 min.

[0267] 1 H NMR (500MHz, DMSO-d6) δ8.55-8.51(m,2H),8.34(d,J=2.5Hz,1H),7.80(s,1H),7.74-7.70(m,1H),7.53-7.49(m,1H),7.34(d,J=2.5Hz,1H ),5.54(t,J=9.0Hz,1H),5.05(d,J=12.0Hz,1H),4.29-4.18(m,2H),3.99-3.91(m,1H),3.88-3.80(m,2H),3.70-3.64(m,1H),3.59-3.51( m,1H),3.31(s,3H),3.28(s,3H),3.18-3.12(m,1H),3.07(s,3H),3.04-3.00(m,1H),2.80-2.74(m,1H),2.43(d,J=14.0Hz,1H),2.16-2.1 1(m,1H),1.85-1.78(m,2H),1.55-1.47(m,2H),1.25-1.17(m,4H),1.13-1.05(m,7H),0.94(s,3H),0.90-0.85(m,1H),0.60-0.48(m,4H).

[0268] Example 3

[0269] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((6-methyl-2-oxido-2l6-thia-6-azaspiro[3.3]heptan-2-ylidene)amino)pyridin-3-yl)-10,10-dimethy l-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacyclodecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0270]

[0271] Example 3 was prepared by the following steps:

[0272]

[0273] By replacing INT-8 in the synthesis step of compound 1 with INT-9, and using a similar method and reaction steps, compound 3 can be obtained. Compound 3 and its epimer 3' cannot be purified by reverse preparative liquid chromatography and normal-phase column chromatography. The two epimers have the same retention time in both LC-MS and HPLC.

[0274] Compound 3+3':

[0275] ESI-MS (m / z): 871.5 [M+H] + LC-MS retention time RT = 1.58 min. HPLC retention time RT = 11.23 min.

[0276] Example 4

[0277] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((4-(2-methoxyethyl)-1-oxido-1l6-thiomorpholin-1-ylidene)amino)pyridin-3-yl)-10,10-dimethyl- 5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacyclodecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0278]

[0279] Example 4 was prepared by the following steps:

[0280]

[0281]

[0282] Step 1: Compound INT-2 (155.9 mg, 0.225 mmol) was dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL). INT-5 (108.2 mg, 0.225 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (16.8 mg, 0.023 mmol), and potassium phosphate (95.4 mg, 0.45 mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20:1) to give a pale yellow solid compound 4a (130.5 mg, yield 60.0%). ESI-MS (m / z): 969.5 [M+H] + .

[0283] Step 2: Compound 4a (130.5 mg, 0.135 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (88 mg, 0.27 mmol) and iodoethane (42.1 mg, 0.27 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give a pale yellow solid compound 4b (116.6 mg, yield 86.8%). ESI-MS (m / z): 997.5 [M+H] + .

[0284] Step 3: Compound 4b (116.6 mg, 0.117 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (30 mL) was added to the reaction system under ice bath conditions, and the mixture was extracted with dichloromethane (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid, compound 4c (105.5 mg, 100% yield). ESI-MS (m / z): 897.5 [M + H] + .

[0285] Step 4: Compound 4c (105.5 mg, 0.117 mmol) was dissolved in N,N-dimethylformamide (3 mL), and (1S,2S)-2-methylcyclopropanecarboxylic acid INT-3b (17.6 mg, 0.176 mmol), N,N-diisopropylethylamine (30.2 mg, 0.234 mmol), and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphate (75.4 mg, 0.176 mmol) were added. The reaction mixture was stirred in an ice bath for 1 hour. After the reaction was complete, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography to give a pale yellow solid compound 4d (100 mg, 85% yield). ESI-MS (m / z): 979.6 [M+H] + .

[0286] Step 5: Compound 4d (100 mg, 0.10 mmol) was dissolved in tetrahydrofuran (6 mL), and palladium hydroxide / carbon (15 mg) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness to give a yellow oily compound 4e (80 mg, 93% yield). ESI-MS (m / z): 845.3 [M+H] + .

[0287] Step 6: Compound 4e (30 mg, 0.04 mmol) was dissolved in DMF (2 mL), and 1-iodo-2-methoxyethane (13 mg, 0.07 mmol), cesium carbonate (23 mg, 0.07 mmol), and potassium iodide (1.4 mg, 0.008 mmol) were added. The mixture was stirred at 60°C for 16 hours. After the reaction was complete, the mixture was filtered and concentrated. The residue was purified by preparative liquid chromatography to give a white solid compound 4 (6 mg, yield 18.7%) and its epimer 4' (9 mg, yield 28.1%). The absolute configurations of the two compounds are assumptions based on experience. Compound 4 is the isomer with a longer retention time in LCMS or HPLC, while 4' is the isomer with a shorter retention time in LCMS or HPLC.

[0288] Compound 4:

[0289] ESI-MS (m / z): 903.5 [M+H] + LC-MS retention time RT = 1.63 min. HPLC retention time RT = 11.69 min.

[0290] 1H NMR (500MHz, DMSO-d6) δ8.54-8.47(m,2H),8.37(d,J=2.6Hz,1H),7.79(s,1H),7.73(dd,J=8.7,1.6Hz,1H),7.56(d,J=8.7Hz,1H),7.2 4(d,J=2.6Hz,1H),5.56(t,J=9.1Hz,1H),5.10-5.05(m,1H),4.35-4.12(m,6H),3.27(s,3H),3.22(s,3H),3.18-3.12(m,2H),3.06-2. 92(m,6H),2.82-2.74(m,2H),,2.69(t,J=5.5Hz,2H),2.66-2.62(m,1H),2.44-2.35(m,2H),2.11-2.04(m,1H),1.82-1.74(m,2H),1.5 5-1.46(m,2H),1.33(d,J=6.0Hz,3H),1.31-1.25(m,2H),1.24(s,3H),1.06(s,3H),0.91-0.84(m,6H),0.57-0.53(m,1H),0.35(s,3H).

[0291] Compound 4':

[0292] ESI-MS (m / z): 903.6 [M+H] + LC-MS retention time RT = 1.62 min. HPLC retention time RT = 11.67 min.

[0293] 1H NMR (500MHz, DMSO-d6) δ8.57-8.49(m,2H),8.38(d,J=2.6Hz,1H),7.79(s,1H),7.72(dd,J=8.7,1.7Hz,1H),7.51(d,J=8.7Hz,1H),7.37 (d,J=2.6Hz,1H),5.54(t,J=9.2Hz,1H),5.07-5.01(m,1H),4.27-4.18(m,2H),3.97-3.79(m,5H),3.23(s,3H),3.07(s,3H),3.05-2.92 (m,5H),2.81-2.73(m,2H),2.69(t,J=5.5Hz,3H),2.42(d,J=14.3Hz,1H),2.16-2.09(m,1H),1.83-1.77(m,2H),1.57-1.48(m,2H),1.2 4(s,2H),1.21(d,J=6.2Hz,3H),1.11(t,J=7.1Hz,3H),1.07(s,3H),0.94(s,3H),0.90-0.85(m,2H),0.56(d,J=6.6Hz,1H),0.51(s,3H).

[0294] Example 5

[0295] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((3-morpholino-1-ox ido-1l6-thietan-1-ylidene)amino)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-o xa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0296]

[0297] Example 5 was prepared by the following steps:

[0298]

[0299] By replacing INT-6 in the synthesis step of compound 2 with INT-7, and using a similar method and reaction steps, compound 5 and its epimer 5' can be obtained. The absolute configurations drawn for both compounds are assumptions based on experience. Compound 5 is the isomer with a longer retention time in LCMS or HPLC, while 5' is the isomer with a shorter retention time in LCMS or HPLC.

[0300] Compound 5:

[0301] ESI-MS (m / z): 901.8 [M+H] + LC-MS retention time RT = 1.62 min. HPLC retention time RT = 11.78 min.

[0302] 1 H NMR(500MHz,DMSO-d6)δ8.52-8.47(m,2H),8.35-8.30(m,1H),7.81-7.79(m,1H),7.75-7.71(m,1H),7.58-7.54(m,1H),7.19-7.1 5(m,1H),5.57(t,J=9.5Hz,1H),5.10-5.05(m,1H),4.46-4.40(m,2H),4.33-4.15(m,7H),3.61-3.54(m,6H),3.31-3.27(m,1H),3 .23(s,3H),3.18-3.11(m,1H),2.96-2.91(m,1H),2.79-2.72(m,1H),2.42-2.35(m,5H),2.10-2.05(m,1H),1.83-1.74(m,2H),1. 53-1.47(m,2H),1.33(d,J=6.0Hz,3H),1.25-1.20(m,1H),1.08-1.04(m,4H),0.95-0.85(m,7H),0.56-0.52(m,1H),0.36(s,3H).

[0303] Compound 5':

[0304] ESI-MS (m / z): 901.9 [M+H] + LC-MS retention time RT = 1.62 min. HPLC retention time RT = 11.76 min.

[0305] 1H NMR(500MHz,DMSO-d6)δ8.55-8.50(m,2H),8.36-8.31(m,1H),7.80(s,1H),7.74-7.70(m,1H),7.54-7.48(m,1H),7.36-7.28(m,1 H),5.55(t,J=9.5Hz,1H),5.07-5.02(m,1H),4.47-4.32(m,3H),4.29-4.20(m,3H),3.99-3.92(m,1H),3.88-3.79(m,2H),3.70-3. 65(m,1H),3.61-3.48(m,6H),3.19-3.11(m,1H),3.09-3.06(m,3H),3.05-3.00(m,1H),2.80-2.73(m,1H),2.43-2.35(m,5H),2.1 5-2.10(m,1H),1.83-1.77(m,2H),1.56-1.48(m,2H),1.24-1.20(m,3H),1.13-1.05(m,7H),0.97-0.85(m,5H),0.59-0.50(m,4H).

[0306] Example 6

[0307] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((4-morpholino-1-ox idotetrahydro-2H-1l6-thiopyran-1-ylidene)amino)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,

[0308] 3)-pyridazinacyclodecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0309]

[0310] Example 6 was prepared by the following steps:

[0311]

[0312] By replacing INT-8 in the synthesis step of compound 1 with INT-10, and using a similar method and reaction steps, compound 6 can be obtained. Compound 6 and its epimer 6' cannot be purified by reverse preparative liquid chromatography and normal-phase column chromatography. The two epimers have the same retention time in both LC-MS and HPLC.

[0313] Compound 6+6':

[0314] ESI-MS (m / z): 929.8 [M+H] + LC-MS retention time RT = 1.58 min. HPLC retention time RT = 11.28 min.

[0315] Example 7

[0316] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((4-(morpholinomet hyl)-1-oxidotetrahydro-2H-1l6-thiopyran-1-ylidene)amino)pyridin-3-yl)-10,10-di methyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacyclodecaphane-4-yl)-2-methylcyclopropane-1-carbox

[0317] amide

[0318]

[0319] Example 7 was prepared by the following steps:

[0320]

[0321]

[0322] By replacing INT-6 in the synthesis step of Example 2 with INT-11, and using similar methods and reaction steps, compound 7 and its epimer 7' can be obtained. The absolute configurations drawn for both compounds are assumptions based on experience. Compound 7 is the isomer with a longer retention time in LCMS or HPLC, while 7' is the isomer with a shorter retention time in LCMS or HPLC.

[0323] Compound 7:

[0324] ESI-MS (m / z): 943.8 [M+H] + LC-MS retention time RT = 1.66 min. HPLC retention time RT = 11.92 min.

[0325] 1 H NMR(500MHz,DMSO-d6)δ8.55-8.44(m,2H),8.39-8.33(m,1H),7.81-7.76(m, 1H),7.75-7.69(m,1H),7.60-7.49(m,1H),7.25-7.19(m,1H),5.60-5.51(m,1 H),5.11-5.01(m,1H),4.34-4.12(m,4H),3.99-3.79(m,1H),3.60-3.51(m,6 H),3.49-3.42(m,2H),3.26-3.19(m,3H),3.18-3.10(m,1H),3.10-3.05(m,1H ),3.00-2.89(m,1H),2.82-2.70(m,1H),2.43-2.26(m,6H),2.21-2.16(m,2H ),2.14-1.98(m,4H),1.97-1.89(m,1H),1.83-1.71(m,2H),1.63-1.47(m,4H) ,1.36-1.30(m,2H),1.25-1.19(m,1H),1.14-1.08(m,1H),1.08-1.03(m,4H) ,0.97-0.93(m,1H),0.91-0.84(m,5H),0.58-0.47(m,2H),0.41-0.29(m,2H).

[0326] Compound 7':

[0327] ESI-MS (m / z): 943.9 [M+H] + LC-MS retention time RT = 1.66 min. HPLC retention time RT = 11.84 min.

[0328] 1H NMR(500MHz,DMSO-d6)δ8.57-8.47(m,2H),8.39-8.33(m,1H),7.80(s,1H),7 .72(dd,J=8.7,1.7Hz,1H),7.54-7.46(m,1H),7.39-7.32(m,1H),5.61-5.48 (m,1H),5.10-4.99(m,1H),4.30-4.15(m,2H),3.99-3.89(m,1H),3.89-3.76 (m,2H),3.71-3.63(m,1H),3.60-3.52(m,5H),3.49-3.41(m,2H),3.18-3.12( m,1H),3.09-3.05(m,3H),3.04-2.99(m,1H),2.81-2.72(m,1H),2.48-2.39( m,2H),2.36-2.28(m,4H),2.20-2.17(m,1H),2.16-2.01(m,4H),1.96-1.89( m,1H),1.84-1.75(m,2H),1.62-1.48(m,4H),1.24-1.19(m,3H),1.12-1.04( m,7H),0.94(s,3H),0.90-0.86(m,1H),0.58-0.54(m,1H),0.54-0.48(m,3H).

[0329] Example 8

[0330] (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-((4-(oxetan-3-yl)-1-oxido-1l6-thiomorpholin-1-ylidene)amino)pyridin-3-yl)-10,10-dimethyl-5 ,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacyclodecaphane-4-yl)-2-methylcyclopropane-1-carboxamide

[0331]

[0332] Example 8 was prepared by the following steps:

[0333]

[0334] Step 1: Compound 4e (30 mg, 0.04 mmol) was dissolved in DCM (5 mL), and 3-oxetane (13 mg, 0.18 mmol), sodium triacetoxyborohydride (23 mg, 0.11 mmol), and glacial acetic acid (2 mg, 0.04 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, DCM (15 mL) was added to the reaction solution, the organic phase was washed twice with water, the organic phase was concentrated, and the residue was purified by preparative liquid chromatography to obtain a white solid compound 8 (4 mg, yield 12.9%) and its epimer 8' (6 mg, yield 18.7%). The absolute configurations of the two compounds are assumptions based on experience. Compound 8 is the isomer with a longer retention time in LCMS or HPLC, while 8' is the isomer with a shorter retention time in LCMS or HPLC.

[0335] Compound 8:

[0336] ESI-MS (m / z): 901.9 [M+H] + LC-MS retention time RT = 1.58 min. HPLC retention time RT = 11.19 min.

[0337] 1H NMR (500MHz, DMSO-d6) δ8.51(d,J=9.0Hz,1H),8.48(d,J=1.6Hz,1H),8.38(d,J=2.6Hz,1H),7.79(s,1H),7.73(dd,J=8.7,1.7Hz,1H),7.56(d,J=8 .6Hz,1H),7.25(d,J=2.6Hz,1H),5.57(t,J=9.2Hz,1H),5.11-5.05(m,1H ),4.54(t,J=6.6Hz,2H),4.42(t,J=6.1Hz,2H),4.36-4.11(m,5H),3.76- 3.68(m,1H),3.61-3.54(m,2H),3.49-3.38(m,4H),3.22(s,3H),3.18-3. 11(m,1H),2.97-2.93(m,1H),2.87-2.73(m,5H),2.44-2.35(m,1H),2.10 -2.05(m,1H),1.84-1.72(m,2H),1.57-1.43(m,2H),1.33(d,J=6.1Hz,3H ),1.09-1.01(m,4H),0.92-0.83(m,6H),0.57-0.52(m,1H),0.35(s,3H).

[0338] Compound 8':

[0339] ESI-MS (m / z): 901.9 [M+H] + LC-MS retention time RT = 1.58 min. HPLC retention time RT = 11.19 min.

[0340] 1 H NMR(500MHz,DMSO-d6)δ8.56-8.50(m,2H),8.38(d,J=2.6Hz,1H),7.80(s,1H),7.72(dd,J=8.6,1.7Hz,1H),7.51(d,J=8.6Hz,1H),7.38(d,J=2.7Hz ,1H),5.54(t,J=9.2Hz,1H),5.08-5.04(m,1H),4.54(t,J=6.6Hz,2H),4. 42(t,J=6.2Hz,2H),4.28-4.17(m,2H),3.98-3.78(m,3H),3.75-3.63(m,2 H),3.58-3.52(m,1H),3.45-3.38(m,4H),3.19-3.11(m,1H),3.08(s,3H) ,3.05-3.00(m,1H),2.87-2.69(m,5H),2.45-2.40(m,1H),2.15-2.10(m,1 H),1.86-1.76(m,2H),1.59-1.45(m,2H),1.21(d,J=6.3Hz,3H),1.13-1.0 4(m,6H),0.94(s,3H),0.90-0.84(m,1H),0.58-0.53(m,1H),0.51(s,3H).

[0341] Biological screening and results of RAS inhibitors

[0342] Experimental Example 1: In vitro cell proliferation inhibition assay

[0343] Due to the diversity of RAS mutations, and in order to evaluate the activity of compounds in different RAS mutant cell lines, we selected KRAS. WT KRAS G12C KRAS G12D KRAS G12V In vitro activity assessment and screening of compounds were performed using BRAF-mutant cell lines (see table below).

[0344] NCI-H358 Lung;Bronchiole KRAS(p.G12C) MIA PaCa-2 Pancreas KRAS(p.G12C) LS513 Large intestine;Cecum KRAS(p.G12D) AsPC-1 Pancreas KRAS(p.G12D) HCC1588 Lung KRAS(p.G12D);BRAF(p.E204L) SW480 Large intestine;Colon KRAS(p.G12V) NCI-H727 Lung;Bronchus KRAS(p.G12V) NCI-H520 Lung <![CDATA[KRAS WT ;]]> HT-29 Colon <![CDATA[KRAS WT ;BRAF(p.V600E)]]>

[0345] Experimental protocol: CellTiter- Cell Luminescent Viability Assay(Promega)

[0346] Depending on the doubling time of different cell lines, varying numbers of cells (1000-5000 cells / well) were seeded into 96-well plates containing 180 μl of the corresponding culture medium and cultured overnight in a 37°C cell culture incubator containing 5% CO2. The next day, the test compound was pre-diluted 3-fold serially with the culture medium, with a maximum concentration of 100 μM, for a total of 10 concentration gradients. Then, 20 μl of culture medium containing different concentrations of the compound was added to the cells in the 96-well plates, ensuring the final concentration of the compound was at a maximum of 10 μM, representing 10 concentration gradients of 3-fold dilutions. After co-incubating the cells and compound for 72 h, the 96-well plates were removed from the incubator and equilibrated at room temperature for 30 min. Then, 25 μl of CellTiter- (the culture medium was added to each well) was added. Mix the Reagent thoroughly and incubate at room temperature for 10 min. Then transfer 100 μl of sample to a white 96-well plate (OptiPlate). TM -96, PerkinElmer), using a multi-functional microplate reader ( The i3x (Molecular Devices) were used to read the fluorescence signal values. The signal values ​​were then standardized, and a four-parameter regression equation was used to fit a curve to calculate the half maximal inhibitory concentration (IC50) of the compound on the cell line.

[0347] Table 3: Antiproliferative activity of the compounds of this invention against KRAS cell mutants

[0348]

[0349] *NT indicates that no detection was performed.

Claims

1. A compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt or stereoisomer thereof: (I) or (II) in: Compound (I) has the structure of formula (III), and compound (II) has the structure of formula (IV): Formula (III) Formula (IV) R1 indicates a C1-C3 alkyl group; R2 indicates ;in, This indicates the location where R2 connects to the part of equation (I) that is connected to it; R3 represents hydrogen; Cy1 represents C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl groups; R4 can independently represent hydrogen, halogen, oxo, C1-C6 alkyl, -(C0-C6 alkylene)(C3-C6)cycloalkyl, -(C0-C6 alkylene)(4-8-membered)heterocyclic alkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CORa, -(C0-C6 alkylene)COORa, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene)OCONRaRa', -(C0-C6 alkylene) NRaCONRaRa', -(C0-C6 alkylene)SORa, -(C0-C6 alkylene)S(O)2Ra, -(C0-C6 alkylene)NRaS(O)2Ra', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(C6-C10 aromatic) or -(C0-C6 alkylene)(5-12 heteroaryl); wherein, the R4 atoms on the two C atoms of Cy1, together with the C atoms attached thereto and the atoms between the two C atoms, can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or the two R4 atoms on the same C atom of Cy1, together with the C atoms attached thereto, can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; R6 and R6' each independently represent hydrogen or methyl; Among them, the structure in equation (I) Selected from the following: ; in, express The site connected to the part in equation (I); Among them, the structure in equation (II) Selected from the following: in, express The site connected to the part in equation (II); Where p represents 0, 1, 2, 3 or 4; Ra and Ra' each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, and 4-8 membered heterocyclic alkyl; wherein, when Ra and Ra' are attached to the same N atom, Ra and Ra' and the commonly attached N atom can form a 4-8 membered ring, and the 4-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; The alkyl, cycloalkyl, heterocycloalkyl, and alkylene groups can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

2. The compound having the structure of formula (I) or formula (II) as described in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, Cy1 represents C3-C8 cycloalkyl or 4-8 heterocyclic alkyl.

3. The compound having the structure of formula (I) or formula (II) as described in claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of R4 independently represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)ORa, -(C0-C6 alkylene)SRa, -(C0-C6 alkylene)NRaRa', -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)NRaCORa', -(C0-C6 alkylene) OCONRaRa', -(C0-C6 alkylene)CN, -(C0-C6 alkylene)(5-12 heteroaryl), or the R4 atoms on two C atoms of Cy1 together with the C atoms attached thereto and the atoms between the two C atoms can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; or the two R4 atoms on the same C atom of Cy1 together with the C atoms attached thereto can form a 3-8 membered ring, wherein the 3-8 membered ring may optionally contain 0, 1, 2 or 3 heteroatoms selected from N, O or S.

4. The compound having the structure of formula (I) or formula (II) as described in claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each of R4 independently represents hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)CONRaRa', -(C0-C6 alkylene)(5-12-membered heteroaryl), or R4 on two C atoms of Cy1 together with the C atom attached thereto and the atom between the two C atoms can form a 3-8 membered ring, the 3-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S; or two R4 on the same C atom of Cy1 together with the C atom attached thereto can form a 3-8 membered ring, the 3-8 membered ring optionally containing 0, 1, 2 or 3 heteroatoms selected from N, O or S.

5. The compound having the structure of formula (I) or formula (II) as described in claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein, In equation (I), the structure of -Cy1-(R4)p is selected from the following: in, This indicates the site where -Cy1-(R4)p is connected to the part of Equation (I) that is connected to it.

6. A compound having the following structure: 。 7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or a pharmaceutically acceptable salt or stereoisomer thereof.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention and / or treatment of tumors, inflammatory diseases, autoimmune diseases, or immune-mediated diseases.

9. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer thereof, or the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention and / or treatment of cancer.

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