Tricyclic compounds and their applications

Abstract

A series of tricyclic compounds and their applications, specifically compounds represented by formula (II) and pharmaceutically acceptable salts thereof are disclosed.

Description

[0001] This application claims the following priority

[0002] CN202110134377.6, application date: January 29, 2021;

[0003] CN202210020761.8, application date: January 7, 2022. Technical Field

[0004] The present invention relates to a series of tricyclic compounds and applications thereof, and specifically discloses a compound represented by formula (II) and a pharmaceutically acceptable salt thereof. Background Art

[0005] Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase composed of regulatory subunits p85 or p101 and catalytic subunit p110 (divided into four isoforms: p110a, p110b, p110g, and p110d). PI3K catalyzes the phosphorylation of the 3'-OH group of the inositol ring of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby activating downstream proteins such as Akt, thereby playing a key role in cell proliferation, survival, and metabolism. In tumor cells, PI3K is overexpressed, leading to rapid proliferation and growth.

[0006] There are four PI3K isoforms, of which PI3Kα is widely distributed throughout the body. Aberrant activation of PI3Kα has also been found in various solid tumors. Mutations in the PIK3CA gene are also found in different solid tumors, contributing to tumor development and progression. In its normal physiological function, PI3Kα primarily regulates insulin-related blood sugar regulation pathways. Therefore, inhibition of wild-type PI3Kα has been clinically shown to cause side effects such as hyperglycemia. Therefore, inhibitors targeting mutant PI3Kα are crucial for clinical safety.

[0007] GDC-0077 is a highly selective PI3Kα inhibitor developed by Roche. It also has the function of degrading mutant PI3Kα protein, which brings new hope for the clinical development of safer PI3K inhibitors.

[0008] Summary of the Invention

[0009] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0010]

[0011] in,

[0012] T is selected from O and S;

[0013] L is selected from -C 1-3 Alkyl- and -C 1-3 Alkyl-cyclopropyl-;

[0014] R1 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0015] R2 is selected from H, F, Cl, Br, I, OH and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0016] X and Y are independently selected from O and NR3, and X and Y are not selected from O at the same time;

[0017] R3 is independently selected from H, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 The cycloalkyl group is optionally substituted with 1, 2 or 3 R c replace;

[0018] R4 and R5 are selected from H, F, Cl, Br, I, OH and C 1-3 alkyl;

[0019] R6 is selected from H and C 1-3 alkyl;

[0020] R7 is selected from C 1-3 Alkyl, C 1-3 Alkoxy and 3-5 membered heterocycloalkyl;

[0021] Alternatively, R6, R7 and the carbon atom they share form a 3-5 membered heterocycloalkyl group;

[0022] Alternatively, R1, R7 and the atoms to which they are attached form a 3-5 membered heterocycloalkyl group;

[0023] Ring B is selected from 4-8 membered heterocycloalkyl, said 4-8 membered heterocycloalkyl being optionally substituted by 1, 2 or 3 R d replace;

[0024] R a 、R b 、R c and R d are independently selected from F, Cl, Br and I.

[0025] In some embodiments of the present invention, the above R1 is selected from H and CH3, and the CH3 is optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, the above R1 is selected from H, CH3, CH2F, CHF2 and CF3, and other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH and CH3, and the CH3 is optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, the above-mentioned R2 is selected from H, F, Cl, Br, I, OH, CH3, CH2F, CHF2 and CF3, and the other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, the above R3 is independently selected from H, OH, CN, CH3, CH2CH3, OCH3, OCH2CH3, -OCH(CH3)2, -O-cyclopropyl and -O-cyclobutyl, and the CH3, CH2CH3, OCH3, OCH2CH3, -OCH(CH3)2, -O-cyclopropyl and -O-cyclobutyl are optionally replaced by 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above-mentioned R3 is independently selected from H, OH, CN, CH3, CH2CH3, OCH3, OCH2CH3, -OCH(CH3)2, -O-cyclopropyl and -O-cyclobutyl, and other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above-mentioned X and Y are independently selected from O, NH, NOH, NCN, N-CH3, N-OCH3, N-OCH2CH3, N-OCH(CH3)2, NO-cyclopropyl and NO-cyclobutyl, and other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, R4 and R5 are selected from H, F, Cl, Br, I, OH and CH3, and other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above R4 is selected from H, F, Cl, Br, I, OH and CH3, and other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the above R5 is selected from H, F, Cl, Br, I, OH and CH3, and other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the above R7 is selected from CH3, CH(CH3)2, OCH3 and oxetanyl, and other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, R6, R7 and the carbon atom they share form an oxetane group, and other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the above R1, R7 and the atoms to which they are attached form azetidinyl and pyrrolidinyl, and other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above L is selected from -CH2CH2-, -CH(CH3)CH2- and Other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the ring B is selected from described Optional 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the ring B is selected from Other variables are as defined in the present invention.

[0041] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0042]

[0043] in,

[0044] R1 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0045] R2 is selected from H, F, Cl, Br, I, OH and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;;

[0046] X and Y are independently selected from O and NR3, and X and Y are not selected from O at the same time;

[0047] R3 is independently selected from H, OH, CN, C 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 The cycloalkyl group is optionally substituted with 1, 2 or 3 R c replace;

[0048] R a 、R b and R c are independently selected from F, Cl, Br and I.

[0049] In some embodiments of the present invention, the above R1 is selected from H and CH3, wherein the CH3 is optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the above R1 is selected from H, CH3, CH2F, CHF2 and CF3, and other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH and CH3, wherein the CH3 is optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above-mentioned R2 is selected from H, F, Cl, Br, I, OH, CH3, CH2F, CHF2 and CF3, and the other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the above R3 is independently selected from H, OH, CN, CH3, CH2CH3, OCH3, OCH2CH3, -OCH(CH3)2, -O-cyclopropyl and -O-cyclobutyl, and the CH3, CH2CH3, OCH3, OCH2CH3, -OCH(CH3)2, -O-cyclopropyl and -O-cyclobutyl are optionally replaced by 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above-mentioned R3 is independently selected from H, OH, CN, CH3, CH2CH3, OCH3, OCH2CH3, -OCH(CH3)2, -O-cyclopropyl and -O-cyclobutyl, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above-mentioned X and Y are independently selected from O, NH, NOH, NCN, N-CH3, N-OCH3, N-OCH2CH3, N-OCH(CH3)2, NO-cyclopropyl and NO-cyclobutyl, and other variables are as defined in the present invention.

[0056] Some other solutions of the present invention are obtained by any combination of the above variables.

[0057] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:

[0058]

[0059] in,

[0060] R1, R2 and R3 are as defined herein.

[0061] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:

[0062]

[0063] in,

[0064] R1, R2 and R3 are as defined herein.

[0065] The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0066]

[0067]

[0068]

[0069] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:

[0070]

[0071]

[0072]

[0073] Technical Effects

[0074] The compounds of the present invention effectively inhibit PI3Kα kinase activity while exhibiting high isoform selectivity for PI3Kβ / γ / δ. Furthermore, they effectively inhibit cell proliferation in HCC1954 cells harboring PIK3CA mutations. The compounds of the present invention exhibit high permeability and low efflux, as well as excellent pharmacokinetic properties.

[0075] Definition and Description

[0076] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0077] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0078] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0079] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0080] Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0081] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0082] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0083] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0084] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0085] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0086] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0087] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).

[0088]

[0089] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0090] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0091] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0092] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0093] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0094] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0095] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0096] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0097] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0098] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0099] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0100] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0101] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0102] Unless otherwise specified, “C 3-5 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic system. 3-5 Cycloalkyl groups include C 3-4 and C 4-5 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0103] Unless otherwise specified, the term "3-5 membered heterocycloalkyl" by itself or in combination with other terms means a saturated monocyclic radical consisting of 3 to 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). In addition, with respect to such "3-5 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. Such 3-5 membered heterocycloalkyls include 4-5 membered, 4 membered, and 5 membered heterocycloalkyls. Examples of 3-5 membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.).

[0104] Unless otherwise specified, the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). This includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "4-8 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 4-8 membered heterocycloalkyl includes 4-6 membered, 4-5 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyls, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0105] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0106] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0107] The solvent used in the present invention is commercially available.

[0108] The present invention uses the following abbreviations: aq represents water; eq represents equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; DMF represents N,N-dimethylformamide; Cbz represents benzyloxycarbonyl, which is an amine protecting group; Boc represents tert-butyloxycarbonyl, which is an amine protecting group; rt represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; HCl represents hydrochloric acid; iPrOH represents 2-propanol; mp represents melting point ; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; DIBAL-H represents diisobutylaluminum hydride; NIS represents N-iodosuccinimide; Dess-Martin represents Dess-Martin; BAST represents bis(2-methoxy)ethylsulfur trifluoride; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOSu represents N-hydroxysuccinimide; EDCI represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride.

[0109] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0110] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0111] Reference Example 1: Fragment BB-1

[0112]

[0113] Synthesis route:

[0114]

[0115] Step 1: Synthesis of compound BB-1-2

[0116] Dissolve BB-1-1 (50 g, 321.38 mmol, 1 eq, HCl) in dichloromethane (500 mL). Add triethylamine (65.04 g, 642.76 mmol, 89.46 mL, 2 eq). After replacing the nitrogen atmosphere, cool the mixture to 0°C and then dropwise add a solution of triphenylmethane (89.59 g, 321.38 mmol, 1 eq) in dichloromethane (300 mL). Slowly warm the reaction mixture to 20°C and stir for 10 hours. After completion, pour the reaction mixture into saturated sodium chloride (200 mL) and slowly quench at 0°C. Extract the mixture with dichloromethane (200 mL x 3). Combine the organic phases, wash with saturated sodium chloride (100 mL), dry over anhydrous sodium sulfate, filter, and finally evaporate to dryness under reduced pressure to obtain compound BB-1-2, which was used directly in the next reaction. 1 H NMR (400MHz, CDCl3) δ7.41 (d, J=7.5Hz, 6H), 7.22-7.17 (m, 6H), 7.16-7.08 (m, 3H), 3.62 (br d, J=3.9Hz, 1H), 3.54-3.43 (m, 2H), 3.22 (s, 3H).

[0117] Step 2: Synthesis of compound BB-1-3

[0118] Compound BB-1-2 (55 g, 152.17 mmol, 1 eq), toluene (390 mL), and triethylamine (39.57 g, 391.08 mmol, 54.43 mL, 2.57 eq) were added to a dry reaction flask. After nitrogen was replaced, the temperature was lowered to 0°C, and a solution of triphosgene (76.77 g, 258.69 mmol, 1.7 eq) in toluene (165 mL) was slowly added. After nitrogen was replaced, the reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, 600 mL of saturated sodium carbonate solution was slowly added to the reaction mixture at 0°C to quench the reaction. The mixture was then extracted with 50 mL of ethyl acetate (3 times). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was filtered and dried under reduced pressure to dryness. The product was then slurried with 400 mL of a mixture of petroleum ether and ethyl acetate (3:1) for 0.5 hr, filtered, and the filter cake was dried under reduced pressure to obtain compound BB-1-3. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.26-7.40 (m, 15H), 4.51-4.63 (m, 1H), 4.41-4.50 (m, 1H), 4.21 (dd, J = 8.8, 3.2Hz, 1H), 3.49 (s, 3H).

[0119] Step 3: Synthesis of compound BB-1-4

[0120] Dissolve BB-1-3 (45 g, 116.15 mmol, 1 eq) in tetrahydrofuran (450 mL). After replacing the nitrogen atmosphere, cool to -30°C and slowly add lithium aluminum tetrahydride (5.29 g, 139.38 mmol, 1.2 eq). The reaction mixture is stirred at -30°C for 2 hours. The same amount is added to two parallel pots. After the reaction is complete, warm the reaction mixture to -10-0°C and slowly quench with ethyl acetate (5.3 mL). Water (5.3 mL), 20% sodium hydroxide (5.3 mL), and water (21.2 mL) are then added in sequence. Stir for 0.5 hour, then add anhydrous magnesium sulfate (10.6 g). Stir for 0.5 hour, filter, and wash the filter cake with ethyl acetate (500 mL). The filtrates are combined and concentrated to yield compound BB-1-4, which is carried on to the next step without purification. 1 H NMR (400MHz, CDCl3) δ7.39-7.28(m,15H), 4.50-4.29(m,2H), 3.89-3.77(m,1H), 3.43-3.31(m,1H), 3.30-3.18(m,1H).

[0121] Step 4: Synthesis of compound BB-1-5

[0122] Compound BB-1-4 (30 g, 83.47 mmol, 1 eq) and Dess-Martin (42.48 g, 100.16 mmol, 31.01 mL, 1.2 eq) were added to a dry reaction flask. After nitrogen was replaced with dichloromethane (600 mL), the mixture was stirred at 20°C for 16 hours. After the reaction was completed, saturated sodium thiosulfate solution (300 mL) was added to the reaction solution, stirred for 1 hour, and then extracted with dichloromethane (300 mL*2). The organic phases were combined and washed with saturated sodium carbonate (300 mL*2) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was slurried with 500 mL of petroleum ether, filtered, and the filter cake was spin-dried to obtain compound BB-1-5. 1 H NMR (400MHz, CDCl3) δ (ppm) 9.24 (d, J = 3.1 Hz, 1H), 7.32-7.36 (m, 15H), 4.49-4.55 (m, 1H), 4.38 (dt, J = 9.6, 3.8Hz, 1H), 4.23 (dd, J = 9.3, 4.5Hz, 1H).

[0123] Step 5: Synthesis of compound BB-1-6

[0124] Dissolve BB-1-5 (17 g, 47.57 mmol, 1 eq) in dichloromethane (170 mL). After replacing the nitrogen atmosphere, cool the mixture to 0°C and slowly add BAST (26.31 g, 118.91 mmol, 26.05 mL, 2.5 eq). The reaction mixture is slowly heated to 20°C and stirred for 10 hours, then heated to 35°C and stirred for 2 hours. The same amount is added to two parallel batches. After completion of the reaction, the combined reaction mixtures are slowly quenched with saturated sodium bicarbonate (500 mL) at 0-10°C. The mixture is then extracted with dichloromethane (200 mL x 3). The combined organic phases are washed with saturated sodium chloride (100 mL) and dried over anhydrous sodium sulfate. The organic phase is filtered and evaporated to dryness under reduced pressure. The crude product is purified by silica gel column chromatography (100-200 mesh; petroleum ether:ethyl acetate = 5:1 to 1:1) to yield compound BB-1-6. 1 H NMR (400MHz, CDCl3) δ7.42-7.34(m,9H),7.33-7.28(m,6H),4.91-4.56(m,2H),4.46(t,J=9.2Hz,1H),4.21-4.06(m,1H).

[0125] Step 6: Synthesis of compound BB-1

[0126] BB-1-6 (8 g, 21.09 mmol, 1 eq) was dissolved in methanolic hydrochloric acid (4 M, 160.00 mL, 30.35 eq) and methanol (2 mL). After replacing the nitrogen atmosphere, the mixture was heated to 50°C and stirred for 10 hours. After completion of the reaction, the reaction solution was cooled to 20°C and then spin-dried. The crude product was purified by silica gel column chromatography (silica gel mesh size: 100-200 mesh; dichloromethane:methanol = 100:0.1 to 100:2) to obtain compound BB-1. 1 H NMR (400MHz, CDCl3) δ6.07(br dd,J=5.3,6.7Hz,1H),5.94-5.60(m,1H),4.59-4.51(m,1H),4.43(dd,J=4.1,9.5Hz,1H),4.12(tt,J=4.4,8.9Hz,1H).

[0127] Reference Example 2: Fragment BB-2

[0128]

[0129] Synthesis route:

[0130]

[0131] Step 1: Synthesis of compound BB-2-3

[0132] Compound BB-2-2 (23.52 g, 384.99 mmol, 23.28 mL, 1.1 eq) was added to a dry reaction flask. After complete dissolution in tetrahydrofuran (70 mL), potassium tert-butoxide (47.13 g, 419.98 mmol, 1.2 eq) was added at 5°C. After nitrogen was replaced, the mixture was stirred and reacted for 40 minutes. A solution of compound BB-2-1 (70 g, 349.99 mmol, 1 eq) in tetrahydrofuran (210 mL) was added. After nitrogen was replaced, the mixture was stirred and reacted at 5°C for 16 hours. After completion of the reaction, 200 mL of water was added to the reaction solution to quench the mixture. Ethyl acetate (250 mL*2) was added for extraction. The organic phases were combined, saturated brine (250 mL) was added to the organic phases, dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain the crude product. The crude product was dissolved in 280 mL of tetrahydrofuran and then added with 180 mL of 3 mol / L hydrochloric acid propanol (prepared). After stirring at 70°C for 3 hours, the mixture was naturally cooled to room temperature, filtered and dried under reduced pressure to obtain the hydrochloride of compound BB-2-3. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.41 (br s, 3H), 7.72 (d, J = 8.3Hz, 1H), 7.60 (d, J = 1.4Hz, 1H), 7.36 (dd, J = 8.3, 1.4Hz, 1H), 4.44 (t, J = 5.1Hz, 2H), 3.22 (br d,J=4.5Hz,2H).

[0133] Step 2: Synthesis of compound BB-2-4

[0134] Compound BB-2-3 (80 g, 288.24 mmol, 1 eq, HCl), methanol (280 mL), diethoxymagnesium (79.16 g, 691.78 mmol, 2.4 eq), and 2-methyltetrahydrofuran (640 mL) were added to a dry reaction flask. After replacing the nitrogen atmosphere, the mixture was stirred at 70°C for 60 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was decompressed and spun off approximately 300 mL of liquid at 40°C. To the remaining reaction mixture were added 700 mL of 2-methyltetrahydrofuran and 560 mL of 3 mol / L hydrochloric acid in propanol. The mixture was stirred at room temperature for 3 hours and filtered. The filter cake was rinsed with 100 mL of 2-methyltetrahydrofuran and dried under reduced pressure to obtain the hydrochloride salt of compound BB-2-4. 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.49(br s,1H),9.49-9.71(m,2H),7.59-7.68(m,2H),7.50(d,J=1.5Hz,1H),4.45(t,J=5.3Hz,2H),3.52(q,J=4.9Hz,2H).

[0135] Step 3: Synthesis of compound BB-2-5

[0136] To a dry reaction flask, compound BB-2-4 (50 g, 180.15 mmol, 1 eq, HCl) was added, along with 2-methyltetrahydrofuran (400 mL), chloroacetaldehyde (45.96 g, 234.20 mmol, 37.67 mL, 40% purity, 1.3 eq), and water (25 mL). After replacing the nitrogen atmosphere, the temperature was raised to 40°C. Saturated potassium bicarbonate solution (3.37 M, 267.29 mL, 5 eq) was added. After replacing the nitrogen atmosphere, the temperature was raised to 45°C and the reaction was stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with saturated sodium bisulfite solution. Saturated sodium carbonate solution was then added to the reaction mixture, and the pH was adjusted to 9-10. The mixture was extracted with ethyl acetate (400 mL x 3). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to yield compound BB-2-5. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.32 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 7.22-7.28 (m, 2H), 7.06 (d, J = 0.9 Hz, 1H), 4.42-4.46 (m, 4H).

[0137] Step 4: Synthesis of compound BB-2-6

[0138] Compound BB-2-5 (50 g, 188.60 mmol, 1 eq), DMF (250 mL), and NIS (91.23 g, 405.50 mmol, 2.15 eq) were added to a dry reaction flask. After nitrogen was replaced, the temperature was raised to 70°C and the reaction was stirred for 16 hours. After the reaction was completed, 5% glacial acetic acid solution (200 mL) was slowly added to the reaction mixture to quench it. Dichloromethane (250 mL x 3) was added to the quenched reaction mixture. The organic phases were combined, washed with saturated brine (250 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and dried under reduced pressure to obtain the crude product. The crude product was slurried with methyl tert-butyl ether (500 mL) for 0.5 hour, filtered, and the filter cake was rinsed with methyl tert-butyl ether (300 mL). The filter cake was then dried under reduced pressure to obtain compound BB-2-6. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.20 (d, J = 8.6Hz, 1H), 7.16-7.36 (m, 2H), 4.42-4.54 (m, 2H), 4.31-4.40 (m, 2H).

[0139] Step 5: Synthesis of compound BB-2

[0140] Compound BB-2-6 (52 g, 100.60 mmol, 1 eq) and tetrahydrofuran (25 mL) were added to a dry reaction flask. After nitrogen was replaced, the temperature was lowered to 10°C and ethylmagnesium bromide (3 M, 40.24 mL, 1.2 eq) was slowly added. After nitrogen was replaced again, the reaction was stirred at 10°C for 2 hours. After the reaction was completed, 5% glacial acetic acid solution (200 mL) was slowly added to the reaction solution to quench it. Ethyl acetate (250 mL*3) was added to the quenched reaction solution. The organic phases were combined and washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) with a gradient elution to obtain compound BB-2. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.21 (d, J = 8.6Hz, 1H), 7.54 (s, 1H), 7.23-7.30 (m, 2H), 4.40-4.46 (m, 4H).

[0141] Example 1

[0142]

[0143] Synthesis route:

[0144]

[0145] Step 1: Synthesis of Compound 001-2

[0146] To a dry reaction flask were added BB-1 (1.6 g, 11.67 mmol, 1 eq), hydrated copper acetate (2.10 g, 10.50 mmol, 2.10 mL, 0.9 eq), BB-2 (4.56 g, 11.67 mmol, 1 eq), cesium carbonate (7.23 g, 22.18 mmol, 1.9 eq), 001-1 (664.08 mg, 4.67 mmol, 0.4 eq), and dioxane (40 mL). After nitrogen displacement, the reaction was stirred at 110°C for 5 hours. After completion of the reaction, the reaction solution was cooled to 20°C and dried under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel mesh size: 100-200 mesh; petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound 001-2. 1H NMR (400MHz, CDCl3) δ8.21 (d, J = 9.2Hz, 1H), 7.30 (s, 1H), 7.25-7.16 (m, 2H), 6.86-6.48 (m, 1H), 4.97 -4.82(m,1H),4.74(dd,J=4.0,9.4Hz,1H),4.61-4.51(m,1H),4.49-4.42(m,2H),4.39-4.31(m,2H).

[0147] Step 2: Synthesis of Compound 001-3

[0148] To a dry reaction flask, 001-2 (1 g, 2.50 mmol, 1 eq), Lawesson's reagent (5.05 g, 12.49 mmol, 5 eq), and toluene (50 mL) were added. After replacing the nitrogen atmosphere, the reaction was stirred at 130°C for 10 hours. After completion, the reaction solution was cooled and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh; mobile phase: petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain compound 001-3. 1 H NMR (400MHz, CDCl3) δ7.33 (d, J = 9.2Hz, 1H), 6.61-6.26 (m, 3H), 5.94-5.57 (m, 1H), 4.44-4 .30(m,1H),4.09(dd,J=3.9,9.7Hz,1H),3.84(t,J=9.6Hz,1H),3.68-3.59(m,2H),3.55(br dd,J=3.0,4.9Hz,2H).

[0149] Step 3: Synthesis of Compound 001-4

[0150] To a dry reaction flask, 001-3 (2.8 g, 6.73 mmol, 1 eq), O-methylhydroxylamine hydrochloride (1.80 g, 21.53 mmol, 3.2 eq), triethylamine (4.08 g, 40.36 mmol, 5.62 mL, 6 eq), and mercuric oxide (14.57 g, 67.27 mmol, 10 eq) were added. DMF (56 mL) was then added, the atmosphere was replaced with nitrogen, and the mixture was heated to 60°C and stirred for 10 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane (100 mL), filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and finally dried under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh; petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain compound 001-4. 1H NMR (400MHz, CDCl3) δ8.41-7.96(m,1H),7.47-7.38(m,1H),7.25-7.16(m,2H),6.80-6.38(m,1H),5.03-4.8 7(m,1H),4.82(dd,J=3.5,9.2Hz,1H),4.64-4.54(m,1H),4.50-4.41(m,2H),4.39-4.32(m,2H),3.82(s,3H).

[0151] Step 4: Synthesis of Compound 001-6

[0152] 001-4 (0.5 g, 1.16 mmol, 1 eq), 001-5 (415.14 mg, 4.66 mmol, 4 eq), and potassium phosphate (1.24 g, 5.82 mmol, 5 eq) were dissolved in DMSO (11 mL). After nitrogen displacement, cuprous iodide (66.56 mg, 349.47 μmol, 0.3 eq) was added. The reaction solution was heated to 120°C with microwave stirring for 1.5 hours. After completion of the reaction, the reaction solution was cooled to 20°C and filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; acetonitrile: 8%-38%; 8 min) to obtain compound 001-6. 1 H NMR(400MHz, CDCl3)δ8.13(br d,J=8.6Hz,1H),7.15-6.95(m,1H),6.82-6.04(m,3H),5.08-4.84(m,1H),4.80(dd,J=3.2,9.4Hz,1H),4.65-4.51(m,1H),4.41(br s,3H),4.31(br s,3H),3.81(s,3H),1.64-1.59(m,3H).

[0153] Step 5: Synthesis of Compound 001

[0154] Dissolve 001-6 (0.02 g, 45.73 μmol, 1 eq) in DMSO (2 mL). Then add triethylamine (69.40 mg, 685.88 μmol, 95.47 μL, 15 eq), HATU (156.47 mg, 411.53 μmol, 9 eq), and ammonium chloride (36.69 mg, 685.88 μmol, 15 eq). After replacing the nitrogen atmosphere, stir at 25°C for 2 hours. Three parallel reactions were set up. After completion, the reaction mixtures were combined and slowly quenched with saturated sodium carbonate (50 mL). The mixture was then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and finally dried under reduced pressure. The crude product was purified by preparative HPLC (Phenomenex Gemini-NX 80*40mm*3μm column; mobile phase: [water (10mM NH4HCO3)-ACN]; acetonitrile: 15%-45%, 8min) to afford compound 001-7, which was detected as a racemate. Compound 001-7 was then purified by preparative supercritical fluid chromatography (REGIS(s,s)WHELK-O1 (250mm*30mm, 5μm column); mobile phase: A: CO2, B: [0.1% NH3H2O ​​EtOH]; B%: 45%-45%, 15min) to afford compounds 001 (Rt=1.663min) and 002 (Rt=1.861min).

[0155] Compound 001: 1 H NMR (400MHz, CD3OD) δ8.05(d,J=8.8Hz,1H),7.16(s,1H),6.81-6.39(m,2H),6.18(d,J=2.4Hz,1H),4.76-4.52(m,3H),4.43-4.38(m,2H),4.34(br s,2H),3.82(q,J=7.0Hz,1H),3.31(s,3H),1.46(d,J=7.1Hz,3H); MS:m / z=437[M+1] + ;ee%=98.8%.

[0156] Compound 002: 1H NMR (400MHz, CD3OD) δ8.04(d,J=8.8Hz,1H),7.06(s,1H),6.62-6.34(m,2H),6.17(d,J=2.4Hz,1H),5.01-4.91(m,1H),4.71(dd,J=3.3,9.3Hz,1 H),4.65-4.56(m,1H),4.42-4.36(m,2H),4.31(dt,J=1.8,4.0Hz,2H),3 .84-3.79(m,1H),3.68(s,3H),1.46(d,J=7.1Hz,3H); MS:m / z=437[M+1] + ;ee%=98.7%.

[0157] Example 2

[0158]

[0159] Synthesis route:

[0160]

[0161] Step 1: Synthesis of Compound 003-1

[0162] 001-3 (0.2 g, 480.49 μmol, 1 eq), 001-5 (171.23 mg, 1.92 mmol, 4 eq), and potassium phosphate (815.95 mg, 3.84 mmol, 8 eq) were dissolved in DMSO (10 mL). After nitrogen displacement, cuprous iodide (118.96 mg, 624.64 μmol, 1.3 eq) was added. The reaction mixture was heated to 90°C and stirred for 0.5 h in a microwave oven. Ten reactions were performed in parallel. After completion, the ten reaction mixtures were combined and diluted in 200 mL of ice water in an ice-water bath. The filtrate was filtered and extracted with ethyl acetate (100 mL). After separation, the aqueous phase was collected, adjusted to pH ≈ 6 with 10% sodium bisulfate, and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield compound 003-1, which was used directly in the next reaction.

[0163] Step 2: Synthesis of Compound 003-2

[0164] 003-1 (1.2 g, 2.83 mmol, 1 eq) was dissolved in tetrahydrofuran (120 mL), followed by the addition of HOSu (1.95 g, 16.96 mmol, 6 eq). After stirring at 25°C for 0.5 h, EDCI (5.42 g, 28.27 mmol, 10 eq) and NH3 / MeOH (7 M, 6.06 mL, 15 eq) were added sequentially. After replacing the nitrogen atmosphere, the mixture was stirred at 25°C for 9.5 h. After completion of the reaction, the reaction system was diluted with 100 mL of water / 100 mL of ethyl acetate. After separation, the organic phase was collected and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh; dichloromethane:methanol = 100:0 to 100:3) to obtain compound 003-2. 1 H NMR (400MHz, CDCl3) δ8.17-8.10(m,1H),8.00(s,1H),6.85-6.45(m,2H),6.30-6.20(m,1H),5.28-5.16(m,1H),4.93(dd ,J=3.9,9.7Hz,1H),4.74-4.66(m,1H),4.48-4.43(m,2H),4.38-4.34(m,2H),3.94-3.84(m,1H),1.57(d,J=7.0Hz,3H).

[0165] Step 3: Synthesis of Compound 003

[0166] To a dry reaction flask, 003-2 (0.1 g, 236.16 μmol, 1 eq), silver acetate (78.84 mg, 472.33 μmol, 24.18 μL, 2 eq), and methanolic ammonia (7 M, 4.00 mL, 118.56 eq) were added. The reaction mixture was stirred at 60°C for 2 hours. After completion, the reaction mixture was filtered and finally evaporated under reduced pressure. The crude product was purified by preparative HPLC (Phenomenexluna C18 100*40 mm*5 μm column; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 1%-20%, 8 min) to obtain compound 003. 1H NMR (400MHz, CD3OD) δ8.08(d,J=8.8Hz,1H),7.31(s,1H),6.67-6.24(m,2H),6.20(d,J=2.3Hz,1H),5 .14-4.95(m,3H),4.51-4.34(m,4H),3.84(d,J=7.0Hz,1H),1.47(d,J=7.0Hz,3H); MS:m / z=407[M+1] + ;ee%=95.5% (SFC Rt=1.142min).

[0167] Example 3

[0168]

[0169] Synthesis route:

[0170]

[0171] Step 1: Synthesis of Compound 006

[0172] To a dry reaction flask, 003-2 (0.2 g, 472.33 μmol, 1 eq) and silver acetate (157.67 mg, 944.65 μmol, 48.37 μL, 2 eq) were added, followed by DMF (5 mL). After nitrogen displacement, methylamine hydrochloride (63.78 mg, 944.65 μmol, 2 eq) and triethylamine (191.18 mg, 1.89 mmol, 262.97 μL, 4 eq) were added. The reaction mixture was stirred at 25°C for 10 hours. After completion of the reaction, the reaction mixture was filtered and finally dried under reduced pressure. The crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenexluna CN 5μm 100*30mm; mobile phase: [n-heptane-EtOH]; ethanol: 40%-95%, 10 min) to obtain compound 005-1, which was further separated and purified by preparative supercritical fluid chromatography (chromatographic column: REGIS (S,S) WHELK-O1 (250mm*25mm, 10μm); mobile phase: A is CO2, B is [neutral-IPA]; B%: 50%-50%, 15 min) to obtain compound 005 (Rt=1.646min) or 006 (Rt=1.844min).

[0173] Compound 006: 1H NMR (400MHz, CD3OD) δ8.01(d,J=8.8Hz,1H),7.10(s,1H),6.57-6.22(m,2H),6.18(d,J=2.1Hz,1H),4.74-4.55 (m,3H),4.43-4.37(m,2H),4.33-4.28(m,2H),3.82(q,J=7.0Hz,1H),2.88(s,3H),1.46(d,J=6.9Hz,3H); LCMS m / z=421[M+1] + .

[0174] Example 4

[0175]

[0176] Synthesis route:

[0177]

[0178] Step 1: Synthesis of Compound 007-2

[0179] 007-1 (250 mg, 613.69 μmol, 1 eq) and Lawesson's reagent (744.66 mg, 1.84 mmol, 3 eq) were added to a pre-dried reaction flask, followed by tetrahydrofuran (1 mL). The reaction was stirred at 20°C for 1 hour. After completion of the reaction, the reaction solution was directly spin-dried to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel mesh size 100-200 mesh; petroleum ether:ethyl acetate = 20:1 elution for 30 min, and then the eluent was changed to dichloromethane:methanol = 1:0 to 50:1) to obtain compound 007-2. 1 H NMR (400MHz, CDCl3) δ8.18 (d, J = 8.77Hz, 1H), 8.10 (br s, 1H), 7.43 (br s,1H),7.18(s,1H),6.48-6.79(m,1H),6.44(dd,J=2.41,8.77Hz,1H),6.23(d,J=2.41Hz,1H),4.94(br d,J=13.59Hz,1H),4.71(dd,J=3.84,9.32Hz,1H),4.51-4.59(m,1H),4.42(brd,J=7.02Hz,2H),4.23-4.33(m,4H),1.68(s,3H).

[0180] Step 2: Synthesis of compounds 007 and 008

[0181] To a pre-dried reaction flask, add 007-2 (30.00 mg, 70.85 μmol, 1 eq) and dichloromethane (2 mL). The reaction mixture was cooled to 0°C and methyl trifluoromethanesulfonate (69.76 mg, 425.09 μmol, 46.51 μL, 6 eq) was added. The temperature was raised to 20°C and stirred for 2 hours. The reaction system was cooled to 0°C and O-methylhydroxylamine hydrochloride (16.67 mg, 199.59 μmol, 3.97 μL, 2.82 eq) and DIEA (54.94 mg, 425.09 μmol, 74.04 μL, 6 eq) were added. The reaction was stirred at 20°C for 10 hours. After the reaction was completed, the reaction solution was dried by rotary evaporation, and the crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 5%-35%, 9 min), and then separated by preparative supercritical fluid chromatography (chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: A is CO2, B is [0.1% NH3H2O ​​MeOH]; B%: 45%-45%, 10 min) to obtain Compound 007 (Rt = 1.231 min) and Compound 008 (Rt = 1.428 min). Compound 007: 1 H NMR (400MHz, CDCl3) δ8.14(d,J=8.78Hz,1H),7.17(s,1H),6.53-6.84(m,1H),6.48(dd,J=2.32,8.85Hz,1H),6. 34(d,J=2.26Hz,1H),4.82-4.93(m,1H),4.72(dd,J=3.95,9.35Hz,1H),4.67(s,2H),4.49-4.55(m,1H),4.42(br d,J=4.89Hz,2H),4.30(br d,J=5.40Hz,2H),3.98(br dd,J=3.14,6.65Hz,1H),3.92(br s,1H),3.84(s,3H),1.54(d,J=6.78Hz,3H); MS:m / z=437.2[M+1] + ;ee%=99.24%.

[0182] Compound 008: 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.78 Hz, 1H), 7.16 (s, 1H), 6.53-6.87 (m, 1H), 6.48 (dd, J = 2.20, 8.72 Hz, 1H), 6.34 (d, J = 2.26 Hz, 1H), 4.79-4.95 (m, 1H), 4.72 (dd, J = 4.02, 9.41 Hz, 1H), 4.68 (s, 2H), 4.48-4.56 (m, 1H), 4.38-4.45 (m, 2H), 4.26-4.32 (m, 2H), 3.95-4.04 (m, 1H), 3.93 (br d,J=3.64Hz,1H),3.83(s,3H),1.53(d,J=6.65Hz,3H); MS:m / z=437.2[M+1] + ;ee%=100%.

[0183] The ee% values ​​of compounds 007 and 008 were analyzed by supercritical fluid chromatography as follows: (Chromatographic column: DAICELCHIRALCEL OJ (150 mm*4.6 mm, 5 μm); mobile phase: A: CO2, B: [0.05% DEA EtOH]; B%: 5%-40%, 10 min)

[0184] Example 5

[0185]

[0186] Synthesis route:

[0187]

[0188] Step 1: Synthesis of compounds 009-1 and 010-1

[0189] 007-2 (100 mg, 236.16 μmol, 1 eq) was separated by preparative supercritical fluid chromatography (chromatographic column: DAICELCHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: A is CO2, B is [0.1% NH3H2O ​​EtOH]; B%: 50%-50%, 8 min) to give compounds 009-1 (RT = 1.425 min) and 010-1 (RT = 1.584 min).

[0190] Step 2: Synthesis of Compound 009

[0191] To a pre-dried reaction flask, add 009-1 (50 mg, 118.08 μmol, 1 eq) and dichloromethane (2 mL). The reaction was cooled to 0°C, and methyl trifluoromethanesulfonate (38.75 mg, 236.16 μmol, 25.84 μL, 2 eq) was added. The temperature was raised to 20°C and stirred for 2 hours. The reaction system was cooled to 0°C and 004-1 (24.82 mg, 590.41 μmol, 24.82 μL, 5 eq) and DIEA (30.52 mg, 236.16 μmol, 41.13 μL, 2 eq) were added. The reaction was stirred at 20°C for 10 hours. After the reaction was completed, the reaction solution was directly spin-dried and separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 12%-27%, 9 min) to obtain trifluoroacetate salt of compound 009. 1H NMR (400MHz, CD3OD) δ8.54(d,J=8.50Hz,1H),7.37(s,1H),7.10-7.21(m,2H),6.49-6.85(m,1H),5.19(q,J=7.00Hz,1H),4.94-5.05(m, 1H),4.68-4.75(m,1H),4.61-4.67(m,1H),4.53-4.58(m,2H),4.46-4.52(m,2H),1.48(d,J=7.00Hz,3H).MS(1.5min); m / z=432.2[M+1] + ;SFC Rt=1.254min;ee%=100%.

[0192] Step 3: Synthesis of Compound 010

[0193] To a pre-dried reaction flask, add 010-1 (20.00 mg, 47.23 μmol, 1 eq) and dichloromethane (2 mL). The reaction mixture was cooled to 0°C, and methyl trifluoromethanesulfonate (15.50 mg, 94.47 μmol, 10.33 μL, 2 eq) was added. The temperature was then raised to 20°C and stirred for 2 hours. The reaction system was cooled to 0°C and 004-1 (9.93 mg, 236.16 μmol, 9.93 μL, 5 eq) and DIEA (12.21 mg, 94.47 μmol, 16.45 μL, 2 eq) were added. The reaction mixture was stirred at 20°C for 10 hours. After completion, the reaction solution was directly spin-dried. The crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 12%-27%, 9min) to obtain trifluoroacetate salt of compound 010.1 HNMR (400MHz, CD3OD) δ8.52(d,J=8.60Hz,1H),7.35(s,1H),7.06-7.18(m,2H),6.48- 6.81(m,1H),5.15(q,J=6.91Hz,1H),4.99(br d,J=9.26Hz,1H),4.66-4.70(m,1H),4.59-4.64(m,1H),4.51-4.57(m,2H),4.45-4.49(m,2H),1.45(d,J=7.06Hz,3H); m / z=432.0[M+1] + ; SFC Rt=1.197min.

[0194] Example 6

[0195]

[0196] Synthesis route:

[0197]

[0198] Step 1: Synthesis of compound 011-2

[0199] Prepare three 20 mL microwave tubes and run three reactions in parallel as follows: Dissolve 001-3 (0.2 g, 480.49 μmol, 1 eq), 011-1 (198.19 mg, 1.92 mmol, 4 eq), and potassium phosphate (815.95 mg, 3.84 mmol, 8 eq) in DMSO (10 mL). After replacing the nitrogen atmosphere, add cuprous iodide (118.96 mg, 624.64 μmol, 1.3 eq). Heat the reaction mixture in a microwave oven at 90°C and stir for 80 minutes. After completion, combine the three reactions. Pour the reaction mixture into 20 mL of ice water in an ice-water bath, dilute, filter, and extract the filtrate with ethyl acetate (100 mL). After separation, collect the aqueous phase, adjust the pH to ≈ 6 with 10% sodium bisulfate, and extract with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 011-2, which was directly used in the next reaction.

[0200] Step 2: Synthesis of compound 011-3

[0201] 011-2 (0.6 g, 1.37 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), followed by the addition of HOSu (944.96 mg, 8.21 mmol, 6 eq). After stirring at 25°C for 0.5 h, EDCI (2.62 g, 13.68 mmol, 10 eq) and a 7 M methanolic ammonia solution (2.93 mL, 15 eq) were added sequentially. After nitrogen displacement, the mixture was stirred at 25°C for 9.5 h. After completion of the reaction, water (5 mL) was added to quench the reaction mixture, which was then extracted with ethyl acetate (100 mL x 2). The organic phases were collected, combined, and dried under reduced pressure. The crude product was isolated and purified by preparative HPLC (Phenomenex Gemini-NX 80 x 40 mm x 3 μm column; mobile phase: water (0.05% NH₃H₂O)-ACN; acetonitrile: 32%-62%; 8 min) to afford compound 011-3. 1 H NMR (400MHz, CD3OD) δppm1.41 (d, J=7.03Hz, 3H), 2.91 (s, 3H), 4.35-4.40 (m, 2H), 4.41-4.45 (m, 2H), 4.49 (q, J=7.03Hz, 1H), 4.69-4. 79(m,1H),4.85(d,J=3.76Hz,1H),5.21-5.35(m,1H),6.42(d,J=2.51Hz,1H),6.45-6.78(m,2H),7.89(s,1H),8.15(d,J=9.03Hz,1H).

[0202] Step 3: Synthesis of Compound 011

[0203] To a dry reaction flask, add 011-3 (0.2 g, 457.18 μmol, 1 eq), silver acetate (152.62 mg, 914.36 μmol, 46.82 μL, 2 eq), and methanolic ammonia (10 mL). Heat to 60°C and react for 2 hours. After the reaction is complete, filter and collect the filtrate. Rinse the filter cake with methanol (10 mL), and the combined organic phases are spin-dried. The crude product was separated and purified by preparative high-performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% FA)-ACN]; acetonitrile: 5%-35%, 7 min) to obtain compound 011-4, which was further separated and purified by preparative supercritical fluid chromatography (chromatographic column: DAICELCHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: A: CO2, B: [0.1% NH3H2O ​​EtOH]; B%: 35%-35%, 8 min) to obtain compound 011 (Rt=3.405 min). 1H NMR(400MHz,CD3OD)δppm 1.40(d,J=7.03Hz,3H),2.91(s,3H),4.32-4.39(m,2H),4.40-4.45(m,2H),4.48(q,J=7.03Hz,1H),4.52-4.62(m,2H),4.67-4 .79(m,1H),6.19-6.52(m,2H),6.65(dd,J=9.03,2.51Hz,1H),7.06-7.20(m,1H),8.11(d,J=9.03Hz,1H); MS:m / z=421.0[M+1] + ;ee%=100%.

[0204] Example 7

[0205]

[0206] Synthesis route:

[0207]

[0208] Step 1: Synthesis of compound 013

[0209] To a pre-dried reaction flask, 003-2 (50 mg, 118.08 μmol, 1 eq) and DMF (3 mL) were added, followed by 004-2 (15.36 mg, 236.16 μmol, 9.93 μL, 2 eq), 004-1 (9.93 mg, 236.16 μmol, 9.93 μL, 2 eq), and silver acetate (39.42 mg, 236.16 μmol, 12.09 μL, 2 eq). The reaction was stirred at 20°C for 1 hour. After completion, the reaction solution was filtered and diluted with 10 mL of water and 10 mL of ethyl acetate. The organic phase was separated and collected, and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; acetonitrile: 10%-40%, 8min), and then separated by preparative supercritical fluid chromatography (chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: A is CO2, B is neutral MeOH]; B%: 50%-50%, 10min) to give compound 013 (Rt=1.598min). 1H NMR (400MHz, DMSO-d6) δ7.94 (d, J = 8.82Hz, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 6. 95(s,1H),6.51-6.84(m,1H),6.35(dd,J=2.43,8.82Hz,1H),6.15(d,J=7.06H z,1H),6.03(d,J=2.43Hz,1H),5.12-5.25(m,1H),4.83-4.90(m,2H),4.30(s ,4H),3.71(quin,J=6.84Hz,1H),1.25(d,J=6.84Hz,3H); MS:m / z=432.1[M+1] + .

[0210] Example 8

[0211]

[0212] Synthesis route:

[0213]

[0214] Step 1: Synthesis of Compound 015

[0215]

[0216] Compound 009-1 (30.00 mg, 70.85 μmol, 1 eq) was added to a pre-dried reaction flask, followed by dichloromethane (3.5 mL). The temperature was cooled to 0°C, and methyl trifluoromethanesulfonate (58.13 mg, 354.25 μmol, 38.75 μL, 5 eq) was added. The temperature was then raised to 20°C and stirred for 2 hours. The reaction system was then cooled to 0°C, and 015-1 (HCl, 14.89 μL, 5 eq) and DIEA (45.78 mg, 354.25 μmol, 61.70 μL, 5 eq) were added. The reaction was stirred at 20°C for 10 hours. After completion, the reaction solution was quenched with methanol and dried to obtain the crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150*30mm*5μm; mobile phase: [water (0.1% TFA)-ACN]; B (acetonitrile)%: 1%-35%, 9 min), and then separated by preparative supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: [0.1% NH3H2OMeOH]; B%: 50%-50%, 10 min) to give compound 015 (Rt=1.375 min). 1 H NMR (400 MHz, CD3OD) δ ppm 1.22-1.30(m,3H)1.49(d,J=6.88Hz,3H)3.83-3.93(m,1H)3.94-4.04 (m,2H)4.30-4.36(m,2H)4.38-4.46(m,2H)4.59-4.64(m,1H)4.66-4.7 3(m,1H)4.93-5.01(m,1H)5.47-5.48(m,1H)6.34(d,J=2.38Hz,1H)6.43-6.79(m,2H)7.17(s,1H)8.04(d,J=8.75Hz,1H); MS:m / z=451.1[M+1] + .

[0217] Example 9

[0218]

[0219] Synthesis old route:

[0220]

[0221] Step 1: Synthesis of Compound 016-1

[0222] Compound 003-1 (0.13 g, 306.30 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL). HATU (1.75 g, 4.59 mmol, 15 eq), triethylamine (619.88 mg, 6.13 mmol, 852.66 μL, 20 eq), and ammonium chloride (245.77 mg, 4.59 mmol, 15 eq) were added at 0°C. The mixture was stirred at 15°C for 16 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain 016-1. MS: m / z = 424 [M+1] + .

[0223] Step 2: Synthesis of Compound 016

[0224] Compound 016-1 (130.00 mg, 307.01 μmol, 1 eq) was dissolved in methanol (10 mL). Triethylamine (155.33 mg, 1.54 mmol, 213.66 μL, 5 eq) and hydroxylamine hydrochloride (50.70 mg, 1.54 mmol, 5 eq) were added at 20°C. The mixture was heated to 80°C for 22 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was then isolated and purified by preparative HPLC (column: Boston Prime C18 150*30 mm*5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; 15%-45% over 7 min) to yield compound 016. 1 H NMR (400MHz, CD3OD) δ=8.06(d,J=9.0Hz,1H),6.65-6.31(m,2H),6.19(d,J=2.3Hz,1H),4.73(dd,J=3.1,9.2Hz,1H),4.67-4.57(m,2H),4.40(br d,J=2.8Hz,2H),4.32(br d,J=3.3Hz,2H),3.84(q,J=6.8Hz,1H),1.48(d,J=7.0Hz,3H); MS:m / z=423[M+1] + .

[0225] Example 10

[0226]

[0227] Synthesis route:

[0228]

[0229] Step 1: Synthesis of Compound 017

[0230]

[0231] Under nitrogen, hydroxylamine hydrochloride (66 mg, 949.76 μmol, 5.03 eq) was added to a reaction flask containing compound 009-1 (80 mg, 188.93 μmol, 1 eq), TEA (98.15 mg, 969.92 μmol, 135 μL, 5.13 eq), and methanol (5 mL). The mixture was heated to 80°C and stirred for 10 hours. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, 20 mL of water was added, and the mixture was extracted three times with dichloromethane (20 mL × 3). The organic phase was collected, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The reaction solution was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1), and then resolved by preparative supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 50%-50%, 10min) to obtain compound 017. 1 H NMR (400MHz, CDCl3) δppm 1.53 (br d, J=6.53Hz, 3H) 3.87-4.06 (m, 2H) 4.29 (br d, J=4.52Hz, 2H) 4.40 (br s,2H)4.47-4.60(m,1H)4.68-4.77(m,3H)4.79-4.92(m,1H)6.33(s,1H)6.47(br d,J=8.78Hz,1H)6.52-6.87(m,1H)7.17(s,1H)8.13(d,J=8.78Hz,1H). MS: m / z=423[M+1] + .

[0232] Example 11

[0233]

[0234] Synthesis route:

[0235]

[0236] Step 1: Synthesis of Compound 018-1

[0237] Compound 001-3 (0.87 g, 1.88 mmol, 1 eq) was dissolved in toluene (10 mL). Dichloro(p-methylisopropylbenzene)ruthenium(II) dimer (345.94 mg, 564.90 μmol, 3.01 e-1 eq) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (233.62 mg, 569.07 μmol, 3.03 e-1 eq) were added. The mixture was heated to 110°C and stirred for 12 hours under nitrogen. After completion of the reaction, the reaction solution was cooled to room temperature (25°C), and 10 mL of ethyl acetate and 10 mL of saturated brine were added. The organic phase was collected and dried over anhydrous sodium sulfate. The residue was then dried under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:0-21:4) to obtain compound 018-1. 1 H NMR (400MHz, CDCl3) δppm 3.59 (br d, J=11.80Hz,1H)3.69-3.80(m,1H)4.33-4.54(m,6H)5.18-5.34(m,1H)6.26-6.63(m,1H)7.38-7.50(m,3H)8.06-8.15(m,1H).

[0238] Step 2: Synthesis of Compound 018-2

[0239] Compound 018-1 (670 mg, 1.45 mmol, 1 eq), 001-5 (520 mg, 5.84 mmol, 4.04 eq), and potassium phosphate (1.58 g, 7.46 mmol, 5.16 eq) were dissolved in DMSO (20 mL). Under nitrogen, cuprous iodide (365.45 mg, 1.92 mmol, 1.33 eq) was added, and the mixture was heated to 125°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with 10 mL of DMSO, and the filtrate was collected to obtain a DMSO solution of crude compound 018-2. The reaction was carried on to the next step without further purification.

[0240] Step 3: Synthesis of Compound 018-3

[0241] Compound 018-2 (600 mg, 1.41 mmol, 1 eq) was added to a pre-dried reaction flask, followed by the solvents DMSO (30 mL) and tetrahydrofuran (15 mL). The temperature was lowered to 0°C, and HATU (3.25 g, 8.55 mmol, 6.05 eq) was added, followed by a 7M ammonia methanol solution (4.5 mL, 22.28 eq). The reaction was stirred at 20°C for 12 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure. 100 mL of water was added, and the mixture was extracted three times with dichloromethane (50 mL*3). The organic phase was collected, washed four times with water (100 mL*4), and dried over anhydrous sodium sulfate. Compound 018-3 was then isolated and purified by column chromatography (dichloromethane:methanol = 1:0-9:1), presumably during the reaction, to obtain compound 018-3. Racemization was presumed to occur during the reaction. 1 H NMR(400MHz,CD3OD)δppm 2.12(d,J=7.03Hz,3H)4.22(dd,J=12.05,2.26Hz,1H)4.38-4.51(m,2H)4.92-5.08(m,4H)5.24(s, 3H)5.73-5.86(m,1H)6.82(d,J=2.26Hz,1H)6.94-7.27(m,2H)7.92(s,1H)8.69(d,J=9.03Hz,1H).

[0242] Step 4: Synthesis of Compound 018-4

[0243] Compound 018-3 (100 mg, 236.16 μmol, 1 eq) and Lawesson's reagent (190 mg, 469.75 μmol, 1.99 eq) were added to a pre-dried reaction flask, followed by tetrahydrofuran (4 mL). The reaction was stirred at 20°C for 2 hours. After completion, the reaction solution was vacuum-dried to dryness. The crude product was isolated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain compound 018-4. 1 H NMR(400MHz,CDCl3)δppm 1.67(br d,J=6.53Hz,3H)3.06(q,J=7.19Hz,1H)3.54-3.73(m,2H)4.26-4.31(m,3H)4.39-4.46 (m,2H)5.06-5.23(m,1H)6.23(d,J=2.51Hz,1H)6.34-6.66(m,2H)7.32(s,1H)7.44(br s,1H)8.11(br s,1H)8.17(d,J=8.53Hz,1H).

[0244] Step 5: Synthesis of Compound 018

[0245] Compound 018-4 (60 mg, 136.52 μmol, 1 eq) and dichloromethane (3 mL) were added to a pre-dried reaction flask. The temperature was cooled to 0°C, and methyl trifluoromethanesulfonate (50.58 mg, 308.22 μmol, 33.72 μL, 2.26 eq) was added. The temperature was raised to 20°C and stirred for 2 hours. The reaction system was cooled to 0°C and O-methylhydroxylamine hydrochloride (120.40 mg, 1.44 mmol, 109.46 μL, 10.56 eq) and DIEA (221.61 mg, 1.71 mmol, 298.66 μL, 12.56 eq) were added. The reaction was stirred at 20°C for 10 minutes. After completion of the reaction, 50 mL of water was added to the reaction system, and the organic phase was collected and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure. The product was then separated and purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1) and then separated by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​EtOH]; B%: CO2, 35%-35%, 10 min) to give compound 018 (Rt=2.041 min). 1 H NMR (400MHz, CDCl3) δppm 1.53 (d, J = 6.78Hz, 3H) 3.58-3.71 (m, 2H) 3.83 (s, 3H) 3.90-4.01 (m, 2H) 4.30 (br d,J=4.27Hz,2H)4.38-4.45(m,2H)4.68(s,2H)5.10-5.21(m,1H)6.33(d,J=2.26 Hz,1H)6.37-6.66(m,2H)7.31(s,1H)8.14(d,J=8.78Hz,1H); MS:m / z=453.1[M+1] + .

[0246] Experimental Example 1: In vitro evaluation

[0247] 1. In vitro enzyme activity test

[0248] The lipid kinase reaction is carried out in the presence of appropriate substrates and ATP, followed by two steps of ADP-Glo TM The kinase activity is detected using a luciferase assay kit. The first step is to terminate the kinase reaction, completely eliminating any residual ATP and leaving only ADP. The second step is to add a kinase assay reagent to convert ADP into ATP, accompanied by a luciferin / luciferase reaction. Finally, the fluorescence output is converted to kinase activity. The conditions for testing PI3K enzyme activity are shown in Table 1.

[0249] Table 1 Conditions for testing PI3K enzyme activity

[0250]

[0251]

[0252] Experimental materials and equipment:

[0253] a) Enzyme: PI3KαMillipore#14-602-K

[0254] PI3Kβ Promega#V1751

[0255] PI3Kδ Millipore#14-604-K

[0256] PI3Kγ Millipore#14-558-K

[0257] b) Kit: ADP-Glo TM Lipid kinase and PIP2:3PS kit (Promega #V1792)

[0258] The kit contains: 1mM PIP2:3PS, 10× lipid dilution buffer, 1M magnesium chloride, 10mM ATP, 10mM ADP, ADP-Glo ​​reagent, detection buffer and detection substrate.

[0259] c) Reaction plate: OptiPlate-384, white and transparent (PerkinElmer #6007299)

[0260] Reagent preparation:

[0261] a) 10× reaction buffer: 500 mM HEPES, pH 7.5, 500 mM NaCl, 9 mM MgCl2; BSA: 10% stock solution, homemade

[0262] b) Final test system conditions: 1× reaction system: 50 mM HEPES, 50 mM NaCl, 3 mM MgCl2, 0.01% BSA (freshly prepared on the day of the experiment), 1% DMSO (v / v) + / - compound

[0263] c) Reaction system: 3 μL enzyme and substrate mixture (1:1) + 2 μL ATP / MgCl2 mixture + 5 μL ADP-Glo ​​reagent + 10 μL detection reagent.

[0264] The specific experimental operations are as follows:

[0265] a) Compound dilution: Use Echo to transfer 50 nL of 100× compound / DMSO to the test wells.

[0266] - For PI3Kα, compounds were diluted three-fold from the highest concentration of 0.111 mM for a total of 10 concentrations.

[0267] - For PI3Kβ / PI3Kδ / PI3Kγ, compounds were diluted three-fold from the highest concentration of 1.11 mM for a total of 10 concentrations.

[0268] b) Kinase reaction:

[0269] (1) Prepare the test compound and add 50nL of 100mg compound solution or DMSO to the corresponding well plate.

[0270] (2) Prepare 3.33× reaction buffer

[0271] (3) Prepare 3.33× PIP2:3PS and vortex thaw PIP2:3PS for at least 1 minute before use

[0272] (4) Prepare ATP solution containing 5.25mM MgCl2

[0273] (5) Prepare 3.33×PI3Kα / PI3Kβ / PI3Kδ / PI3Kγ solution

[0274] (6) Mix the lipid kinase solution and PIP2:3PS solution in a volume ratio of 1:1

[0275] (7) Mix 3.33× lipid kinase buffer and PIP2:3PS solution in a volume ratio of 1:1

[0276] (8) Add 3 μL of the mixed solution of buffer and PIP2:3PS to the first and second columns of the well plate.

[0277] (9) Add 3 μL of the enzyme and PIP2:3PS mixed solution to the wells of the plate except for the first and second columns, centrifuge for 10 seconds (1000 rpm), and incubate at 23°C for 20 minutes.

[0278] (10) Add 2 μL of ATP solution and shake at 1000 rpm.

[0279] (11) Cover the plate and shake for about 30 seconds, then incubate the plate at 23°C for 2 hours.

[0280] (12) Add 5 μL of ADP-Glo ​​reagent containing 10 mM MgCl2

[0281] (13) Centrifuge at 1000 rpm for 10 seconds, cover the plate and shake for about 30 seconds, and incubate at 23°C for 60 minutes.

[0282] (14) Add 10 μL kinase detection reagent

[0283] (15) Centrifuge at 1000 rpm for 10 seconds and then incubate at 23°C for 60 minutes.

[0284] (16) Fluorescence values ​​were measured on an Envision instrument.

[0285] 2. In vitro cell activity test

[0286] The effects of the test compounds on the anti-proliferative activity of cells were determined in HCC1954 and HDQ-P1 cell lines using the CTG method.

[0287] Cell culture medium: complete cell culture medium (RPMI 1640 + 10% serum + 1% L-glutamine + 1% double antibody)

[0288] The specific steps are as follows:

[0289] (1) HCC1954 and HDQ-P1 cells ( HTB-22 TM ) were seeded into 96-well plates, with 100 μL of complete cell culture medium per well (4000 cells per well / HDQ-P1, 3500 cells per well / HCC1954), and the cells were incubated at 37°C, 5% CO2 for 24 h.

[0290] (2) Replace the complete cell culture medium with 100 μL serum-free culture medium and starve the cells overnight.

[0291] (3) Prepare the compound (the initial concentration of the compound is 10 μM, and it is diluted threefold into 8 concentrations. Each concentration of the compound is then diluted 100-fold in serum-free medium) and add 25 μL of the diluted compound to the well plate containing the cells.

[0292] (4) Incubate at 37°C, 5% CO2 for 72 h (HCC1954) or 120 h (HDQ-P1)

[0293] (5) Subsequent operations were performed according to the instructions of the Promega CTG kit.

[0294] The results are shown in Table 2.

[0295] Table 2 Results of in vitro screening tests of compounds of the present invention

[0296]

[0297] “NA”: Indicates that the IC cannot be calculated 50 value

[0298] Conclusion: The compound of the present invention can effectively inhibit the activity of PI3Kα kinase and has high selectivity for PI3Kβ / γ / δ. In addition, it can also effectively inhibit the proliferation of HCC1954 cells with PIK3CA mutation.

[0299] Experimental Example 2: Penetration Test

[0300] The permeability of the compounds of the present invention was determined through the membrane of MDCK cells overexpressing MDR1.

[0301] The specific steps are as follows:

[0302] Compounds were diluted from DMSO stocks to 2 μM (DMSO <1%) in transport buffer (HBSS containing 10 mM Hepes, pH 7.4) and applied to the apical or basolateral side of the cell monolayer. Compound permeation from A to B or B to A was determined in duplicate. Plates were incubated for 2.5 hours in a CO2 incubator at 37 ± 1°C, 5% CO2, and saturated humidity without shaking. The efflux rate of each compound was also determined. Compounds were quantified by LC-MS / MS analysis based on the analyte / IS peak area ratio.

[0303] After the transport test, the integrity of the cell monolayer was determined by the Lucifer Yellow exclusion test. The buffer was removed from the apical and basolateral chambers, and 75 μL of 100 μM Lucifer Yellow transport buffer and 250 μL of transport buffer were added to the apical and basolateral chambers, respectively. The plates were incubated at 37°C, 5% CO2, and saturated humidity for 30 minutes without shaking. After 30 minutes of incubation, 20 μL of Lucifer Yellow sample was collected from the apical side, and 60 μL of transport buffer was added. Then 80 μL of Lucifer Yellow sample was collected from the basolateral side. The relative fluorescence units (RFU) of Lucifer Yellow were measured at 425 / 528 nm (excitation / emission) using an Envision microplate reader. The test results are shown in Table 3.

[0304] Table 3 Permeability study results of the compounds of the present invention

[0305]

[0306] Conclusion: The compounds of the present invention showed high permeability and low efflux properties in the MDCK-MDR1 permeability experiment.

[0307] Experimental Example 3: In vivo studies

[0308] 1. In vivo DMPK studies

[0309] Experimental purpose: Male CD-1 mice were used as test animals to determine the blood concentration of the compound and evaluate the pharmacokinetic behavior after a single dose.

[0310] Experimental Procedure: Eight healthy adult male CD-1 mice were enrolled, with four receiving intravenous injection and four receiving oral administration. The test compound was mixed with an appropriate amount of the intravenous vehicle (DMSO / vehicle / water (10:10:80 v / v / v)), vortexed, and sonicated to produce a 1.0 mg / mL clear solution, which was then filtered through a microporous filter and used for later use. For the oral administration, the test compound was mixed with the vehicle (DMSO / vehicle / water (10:10:80 v / v / v)), vortexed, and sonicated to produce a 1.0 mg / mL homogeneous suspension. Following intravenous administration of 1 mg / kg or oral administration of 3 mg / kg to mice, whole blood was collected at defined intervals to prepare plasma. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The results are shown in Table 4.

[0311] Table 4 Results of the pharmacokinetic study of the compounds of the present invention in mice

[0312]

[0313] Conclusion: The compounds of the present invention showed high exposure, low clearance, and good oral bioavailability in mice.

[0314] 2. In vivo plasma / brain tissue distribution studies

[0315] Experimental purpose: Male SD rats were used as test animals. After a single administration, the blood concentration of the compound and the drug concentrations in brain tissue and cerebrospinal fluid were measured and the brain penetration of the compound of the present invention was evaluated.

[0316] Experimental Procedure: Twelve healthy adult male Sprague-Dawley rats were used. The test compound was mixed with an appropriate amount of oral vehicle (DMSO / vehicle / water (10:10:80 v / v / v)), vortexed, and sonicated to prepare a 1.0 mg / mL clear solution for later use. Following oral administration of 10 mg / kg, whole blood, brain tissue, and cerebrospinal fluid were collected over time to prepare plasma, brain tissue homogenates, and cerebrospinal fluid. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The results are shown in Table 5.

[0317] Table 5 Results of the study on the distribution of the compounds of the present invention in rat plasma / brain tissue

[0318]

[0319] Note: ND means not calculable.

[0320] Conclusion: The compounds of the present invention showed higher brain drug exposure levels in rats.

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof, in, T is O; L is -CH2CH2-; R1 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace; R2 is selected from H, F, Cl, Br, I and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace; X is O and Y is NR3, or X is NR3 and Y is O; R3 is independently selected from H, OH, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R c Substituted; R4 and R5 are selected from H, F, Cl, Br, I and C 1-3 alkyl; R6 is selected from H and C 1-3 alkyl; R7 is selected from C 1-3 Alkyl and C 1-3 alkoxy; Ring B is described Optional 1, 2 or 3 R d replace; R a 、R b 、R c and R d are independently selected from F, Cl, Br and I.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H and CH3, said CH3 optionally being replaced by 1, 2 or 3 R a replace.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, CH3, CH2F, CHF2 and CF3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, F, Cl, Br, I and CH3, wherein CH3 is optionally replaced by 1, 2 or 3 R b replace.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, F, Cl, Br, I, CH3, CH2F, CHF2 and CF3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is independently selected from H, OH, CH3, CH2CH3, OCH3, OCH2CH3 and -OCH(CH3)2, wherein CH3, CH2CH3, OCH3, OCH2CH3 and -OCH(CH3)2 are optionally replaced by 1, 2 or 3 R c replace.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein: R3 is independently selected from H, OH, CH3, CH2CH3, OCH3, OCH2CH3 and -OCH(CH3)2.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O and Y is selected from NH, NOH, N—CH 3 , N—OCH 3 , N—OCH 2 CH 3 and N—OCH (CH 3 ) 2 , or X is selected from NH, NOH, N—CH 3 , N—OCH 3 , N—OCH 2 CH 3 and N—OCH (CH 3 ) 2 and Y is O.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are selected from H, F, Cl, Br, I and CH3.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is selected from CH3, CH(CH3)2 and OCH3.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is 12. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from 14. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein: The compound is a compound represented by the following formula (I):

15. A compound or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from 16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from 17. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein: The compound is 18. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein: The compound is 19. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein: The compound is

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