Tricyclic compounds and their uses

Abstract

A series of tricyclic compounds and uses thereof are disclosed, specifically compounds represented by formula (II) and pharma- ceutically acceptable salts thereof. [Formula 1] JPEG2024504811000061.jpg36170

Description

[Technical field]

[0001] This application claims priority to: CN202110134377.6, filing date: January 29, 2021; CN202210020761.8, application date: January 7, 2022.

[0002] The present invention relates to a series of tricyclic compounds and uses thereof, and in particular discloses compounds represented by formula (II) and pharma- ceutically acceptable salts thereof. [Background technology]

[0003] Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase composed of regulatory subunits p85 or p101 and catalytic subunit p110 (further subdivided into four subtypes p110a, p110b, p110g, and p110d). It catalyzes the phosphorylation of the 3'-OH of the inositol ring of phosphatidylinositol 4,5-bisphosphate (PIP2) and activates downstream Akt such as phosphatidylinositol 3,4,5-trisphosphate (PIP3), thereby playing an important role in cell proliferation, survival, and metabolism. In tumor cells, PI3K is overexpressed, causing rapid proliferation and growth of tumor cells.

[0004] There are four subtypes of PI3K, among which PI3Kα is widely distributed in the body. Abnormal activation of PI3Kα is also found in many solid tumors. PIK3CA gene mutations also exist in different solid tumors, all of which lead to tumor development and progression. In normal physiological functions, PI3Kα mainly regulates insulin and other related blood glucose regulation pathways. Therefore, it has been clinically verified that inhibition of wild-type PI3Kα causes side effects such as hyperglycemia. Therefore, inhibitors targeting mutant PI3Kα play an important role in clinical safety.

[0005] GDC-0077 is a highly selective PI3Kα inhibitor developed by Roche that also has the ability to degrade mutant PI3Kα protein, raising new hopes for the development of safer PI3Kα inhibitors for clinical use. [ka] Summary of the Invention

[0006] The present invention provides a compound represented by formula (II) or a pharma- ceutically acceptable salt thereof. [ka] however, T is selected from O and S; L is -C 1-3 Alkyl- and -C 1-3 alkyl-cyclopropyl-; R 1 H and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R a is replaced by R 2 are H, F, Cl, Br, I, OH and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R b is replaced by X and Y are each independently O or NR 3 and X and Y are not simultaneously selected from O; R 3 are independently H, OH, CN, and C 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 cycloalkyl, 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 Cycloalkyl optionally has one, two or three R c is replaced by R 4 and R 5 are H, F, Cl, Br, I, OH and C 1-3 alkyl, R 6 H and C 1-3 alkyl, R 7 is C 1-3 Alkyl, C 1-3 selected from alkoxy and 3- to 5-membered heterocycloalkyl; Or, R 6 , R 7 form a 3- to 5-membered heterocycloalkyl with the carbon atoms they share; Or, R 1 , R 7 form a 3- to 5-membered heterocycloalkyl with the atom to which they are linked; Ring B is selected from 4-8 membered heterocycloalkyl, which optionally has one, two or three R d is replaced by R a , R b , R c and R d are each independently selected from F, Cl, Br, and I.

[0007] In some embodiments of the present invention, the R 1 H and CH 3 wherein CH is selected from 3 Optionally, 1, 2 or 3 Ra and other variables are as defined herein.

[0008] In some embodiments of the present invention, the R 1 H, CH 3 , C.H. 2 F, CHF 2 and CF 3 and the other variables are as defined herein.

[0009] In some embodiments of the present invention, the R 2 are H, F, Cl, Br, I, OH and CH 3 wherein CH is selected from 3 Optionally, 1, 2 or 3 R b and other variables are as defined herein.

[0010] In some embodiments of the present invention, the R 2 are H, F, Cl, Br, I, OH, CH 3 , C.H. 2 F, CHF 2 and CF 3 and the other variables are as defined herein.

[0011] In some embodiments of the present invention, the R 3 are independently H, OH, CN, and CH 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , -OCH(CH 3 ) 2 , -O-cyclopropyl and -O-cyclobutyl, 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , -OCH(CH 3 ) 2 , -O-cyclopropyl and -O-cyclobutyl are optionally represented by one, two or three R cand other variables are as defined herein.

[0012] In some embodiments of the present invention, the R 3 are independently H, OH, CN, and CH 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , -OCH(CH 3 ) 2 , -O-cyclopropyl and -O-cyclobutyl, the other variables being as defined herein.

[0013] In some embodiments of the invention, X and Y are each independently O, NH, NOH, NCN, N-CH 3 , N-OCH 3 , N-OCH 2 CH 3 , N-OCH(CH 3 ) 2 , NO-cyclopropyl and NO-cyclobutyl, the other variables being as defined herein.

[0014] In some embodiments of the present invention, the R 4 and R 5 are H, F, Cl, Br, I, OH and CH 3 and the other variables are as defined herein.

[0015] In some embodiments of the present invention, the R 4 are H, F, Cl, Br, I, OH and CH 3 and the other variables are as defined herein.

[0016] In some embodiments of the present invention, the R 5 are H, F, Cl, Br, I, OH and CH 3 and the other variables are as defined herein.

[0017] In some embodiments of the present invention, the R 7is CH 3 , CH(CH 3 ) 2 , O.C.H. 3 and oxetanyl, the other variables being as defined herein.

[0018] In some embodiments of the present invention, the R 6 , R 7 together with the carbon atom they share form an oxetanyl, and the other variables are as defined herein.

[0019] In some embodiments of the present invention, the R 1 , R 7 with the atom to which they are attached form azetidinyl and pyrrolidinyl, and other variables are as defined herein.

[0020] In some embodiments of the invention, L is -CH 2 CH 2 -, -CH(CH 3 )CH 2 - and [ka] and the other variables are as defined herein.

[0021] In some embodiments of the present invention, Ring B is [ka] is selected from [ka] Optionally, 1, 2 or 3 R d and other variables are as defined herein.

[0022] In some embodiments of the present invention, Ring B is [ka] and the other variables are as defined herein.

[0023] The present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof. [ka] however, R 1 H and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R a is replaced by R 2 are H, F, Cl, Br, I, OH and C 1-3 alkyl, 1-3 Alkyl is optionally one, two or three R b is replaced by X and Y are each independently O or NR 3 and X and Y are not simultaneously selected from O; R 3 are independently H, OH, CN, and C 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 cycloalkyl, 1-3 Alkyl, C 1-3 Alkoxy and -OC 3-5 Cycloalkyl optionally has one, two or three R c is replaced by R a , R b and R c are each independently selected from F, Cl, Br, and I. In some embodiments of the present invention, the R 1 H and CH 3 wherein said CH 3 Optionally, 1, 2 or 3 R a and other variables are as defined herein. In some embodiments of the present invention, the R 1 , H, CH 3, C.H. 2 F, CHF 2 and CF 3 and the other variables are as defined herein.

[0024] In some embodiments of the present invention, the R 2 are H, F, Cl, Br, I, OH and CH 3 wherein said CH 3 Optionally, 1, 2 or 3 R b and other variables are as defined herein.

[0025] In some embodiments of the present invention, the R 2 are H, F, Cl, Br, I, OH, CH 3 , C.H. 2 F, CHF 2 and CF 3 and the other variables are as defined herein.

[0026] In some embodiments of the present invention, the R 3 are independently H, OH, CN, and CH 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , -OCH(CH 3 ) 2 , -O-cyclopropyl and -O-cyclobutyl, 3 , C.H. 2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , -OCH(CH 3 ) 2 , -O-cyclopropyl and -O-cyclobutyl are optionally represented by one, two or three R c and other variables are as defined herein.

[0027] In some embodiments of the present invention, the R 3 are independently H, OH, CN, and CH 3 , C.H.2 CH 3 , O.C.H. 3 , O.C.H. 2 CH 3 , -OCH(CH 3 ) 2 , -O-cyclopropyl and -O-cyclobutyl, the other variables being as defined herein.

[0028] In some embodiments of the invention, X and Y are each independently O, NH, NOH, NCN, N-CH 3 , N-OCH 3 , N-OCH 2 CH 3 , N-OCH(CH 3 ) 2 , NO-cyclopropyl and NO-cyclobutyl, the other variables being as defined herein.

[0029] Some aspects of the invention are further formed by any combination of the above variables.

[0030] In some aspects of the invention, the compound, or a pharma- ceutically acceptable salt thereof, is selected from the formula: [ka] however, R 1 , R 2 and R 3 is as defined in the present invention.

[0031] In some aspects of the invention, the compound, or a pharma- ceutically acceptable salt thereof, is selected from the formula: [ka] however, R 1 , R 2 and R 3 is as defined in the present invention.

[0032] The present invention provides a compound represented by the formula: or a pharma- ceutically acceptable salt thereof. [ka] [ka]

[0033] In some aspects of the invention, the compound, or a pharma- ceutically acceptable salt thereof, is selected from the formula: [ka] [ka] [ka] Effect of the Invention

[0034] The compound of the present invention can sufficiently inhibit the activity of PI3Kα kinase, and at the same time has high subtype selectivity for PI3Kβ / γ / δ.It can also effectively inhibit the cell proliferation activity of PIK3CA mutation HCC1954 cells, and the compound of the present invention has the properties of high permeability and low excretion, and the compound of the present invention has excellent pharmacokinetic properties. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] [Definitions and Explanations] Unless otherwise stated, the following terms and phrases used herein have the following meanings: A particular term or phrase, unless otherwise defined, should be understood to have its ordinary definition, not to be indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0036] As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0037] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents discovered in this invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a separate 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 these compounds with a sufficient amount of acid in a separate solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, 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, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any suitable base or acid addition salt.

[0038] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0039] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, enantiomers and tautomers.

[0040] 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 and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both within the scope of the present invention.

[0041] Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.

[0042] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0043] Unless otherwise explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.

[0044] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0045] Unless otherwise stated, [ka]

[0046] Unless otherwise defined, when a compound has a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom in the double bond has two different substituents bonded to it (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered to be one substituent bonded to it), the atoms on the double bond of the compound and their substituents are [ka] When the formula (A) is linked to the formula (A-1) or (A-2), it means the (Z) isomer, the (E) isomer, or a mixture of the two isomers of the compound. For example, the formula (A) below means that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2), or in the form of two isomers of formula (A-1) and formula (A-2); the formula (B) below means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2), or in the form of two isomers of formula (B-1) and formula (B-2). The formula (C) below means that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2), or in the form of two isomers of formula (C-1) and formula (C-2). [ka]

[0047] Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and can be rapidly interconverted at room temperature. Tautomers can reach chemical equilibrium of tautomers when possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0048] Unless otherwise explained, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of such isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0049] Unless otherwise stated, 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%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0050] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. A single enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is decomposed to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with a suitable optically active acid or salt, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to provide the isolated enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic techniques using chiral stationary phases and any chemical derivatization techniques (e.g., carbamate formation from amines).

[0051] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms constituting the compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioisotopes such as radioisotopes C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life of the drug. Conversion of the isotopic composition of the compounds of the invention, whether radioactive or not, is within the scope of the invention.

[0052] The terms "optionally" and "optionally" mean that the following event or circumstance is possible but not necessarily occurring, and that the description includes the case where the described event or circumstance does not occur, if that event or circumstance occurs.

[0053] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, which may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound is stable after the replacement. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto group substitution does not occur in aromatic groups. The term "optionally substituted" refers to either substituted or unsubstituted, and unless otherwise defined, the type and number of substituents are any that are chemically stable and can be realized.

[0054] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0055] If the listed linking group does not specify another linking direction, then the linking direction is arbitrary, for example: [ka] In the formula, the linking group L is -MW-, and -MW- is connected between ring A and ring B in the same direction as reading from left to right. [ka] and you can read ring A and ring B in the reverse order from left to right. [ka] Combinations of the above linking groups, substituents and / or variables are permissible only if such combinations result in stable compounds.

[0056] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, the number of H atoms at the site is reduced to a group with a corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is: [ka] For example, -OCH 3 A straight solid bond means that the group is bonded to another group via an oxygen atom of the group. [ka] A straight dashed bond within a group means that a nitrogen atom within the group is bonded at both ends to other groups. [ka] The wavy line in the middle means that the phenyl group is bonded to another group via carbon atoms at positions 1 and 2. [ka] means that any available site on the piperidinyl group can be bonded to another group by one chemical bond, and at least [ka] It includes the four bond forms, and even if the H atom is drawn as -N-, [ka] for [ka] Groups of this bond type are included, but when one chemical bond is attached, one H is removed at that site to become the corresponding monovalent piperidine group.

[0057] Unless otherwise stated, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "5- to 7-membered ring" refers to a "ring" of 5 to 7 atoms arranged around it.

[0058] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl has C 1-2 and C. 2-3 Alkyl groups and the like are included, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).

[0059] Unless otherwise defined, the term "C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 Alkoxy and the like are included. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like.

[0060] Unless otherwise defined, "C 3-5 "Cycloalkyl" means a cyclic saturated hydrocarbon group consisting of 3 to 5 carbon atoms, which represents a monocyclic ring system, and is defined as C 3-5 Cycloalkyl has C 3-4 Or C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. C 3-5 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0061] Unless otherwise defined, the term "3- to 5-membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated monocyclic group composed of 3 to 5 ring atoms, of which 1, 2, 3, and 4 ring atoms are independently selected from O, S, and N heteroatoms, and the remainder are carbon atoms. 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). Additionally, with respect to "3- to 5-membered heterocycloalkyl," a heteroatom can occupy the position of attachment of the heterocycloalkyl to the rest of the molecule. Said 3- to 5-membered heterocycloalkyl includes 4- to 5-membered, 4-membered, and 5-membered heterocycloalkyl, and the like. Illustrative examples of 3- to 5-membered heteroaryl groups include, but are not limited to, heterobutyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like) or tetrahydropyran (including tetrahydrofuran-2-yl, and the like).

[0062] Unless otherwise defined, the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group composed of 4 to 8 ring atoms, in which 1, 2, 3, and 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which 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). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Additionally, for "4-8 membered heterocycloalkyl", a heteroatom can occupy the position of attachment of the heterocycloalkyl to the rest of the molecule. The 4-8 membered heteroaryl includes 4-6 membered, 4-5 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heteroaryl, etc. Illustrative examples of 4-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-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, or homopiperidinyl.

[0063] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, after collecting the relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis. The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments given below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0064] All solvents used in this invention can be obtained commercially.

[0065] The present invention uses the following abbreviations: aq stands for water; eq stands for equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DMSO stands for dimethylsulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; DMF stands for N,N-dimethylformamide; CBz stands for the amine protecting group benzoxycarbonyl; Boc stands for the amine protecting group tert-butoxycarbonyl; rt stands for room temperature; O / N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; HCl stands for hydrochloric acid; iPrOH stands for 2-propanol; mp stands for melting point; Pd(PPh 3 ) 4 stands for tetrakis(triphenylphosphine)palladium; Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); DIBAL-H represents diisobutylaluminum hydride; NIS represents N-iodosuccinimide; Dess-Martin represents Dess-Martin; BAST represents bis(2-methoxyethyl)aminosulfur 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.

[0066] Compounds are identified by their common names in the field or by ChemDraw (R) The compounds are named by the software, and commercially available compounds use the names from the manufacturer's catalogue.

[0067] [Specific implementation method] The present invention will be specifically described below by way of examples, but is not intended to be an adverse restriction of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0068] [Reference Example 1: Fragment BB-1] [ka]

[0069] Step 1: Synthesis of compound BB-1-2 BB-1-1 (50 g, 321.38 mmol, 1 eq, HCl) was dissolved in dichloromethane (500 mL), triethylamine (65.04 g, 642.76 mmol, 89.46 mL, 2 eq) was added, and the mixture was replaced with nitrogen gas and cooled to 0 ° C., and then a solution of triphenylchloromethane (89.59 g, 321.38 mmol, 1 eq) in dichloromethane (300 mL) was added dropwise. The reaction solution was slowly warmed to 20 ° C. and stirred for 10 hours. After the reaction was completed, the reaction solution was poured into saturated sodium chloride (200 mL), slowly quenched at 0 ° C., and then extracted with dichloromethane (200 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (100 mL), further dried over anhydrous sodium sulfate, filtered, and finally spin-dried under reduced pressure to obtain compound BB-1-2, which was directly used in the next step reaction. 1 H NMR (400 MHz, CDCl 3 ) δ 7.41(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).

[0070] Step 2: Synthesis of compound BB-1-3 Compound BB-1-2 (55 g, 152.17 mmol, 1 eq), toluene (390 mL), triethylamine (39.57 g, 391.08 mmol, 54.43 mL, 2.57 eq) were added to a dried reaction flask, and the flask was replaced with nitrogen gas. The flask was then cooled to 0 ° C., and a solution of triphosgene (76.77 g, 258.69 mmol, 1.7 eq) in toluene (165 mL) was slowly added, and the mixture was replaced with nitrogen gas. The mixture was then stirred at 25 ° C. for 16 hours to react. After the reaction was completed, the reaction solution was quenched by slowly adding 600 mL of saturated sodium carbonate solution at 0 ° C., and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed successively with saturated saline (50 mL), and dried over anhydrous sodium sulfate. The crude product was filtered and spun dry under reduced pressure to obtain the crude product, which was then slurried in 400 mL of a mixture of petroleum ether and ethyl acetate (3:1) for 0.5 hours, filtered, and the cake was spun dry under reduced pressure to obtain compound BB-1-3. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0071] Step 3: Synthesis of compound BB-1-4 BB-1-3 (45 g, 116.15 mmol, 1 eq) was dissolved in tetrahydrofuran (450 mL), purged with nitrogen gas, and cooled to -30 ° C. Lithium aluminum hydride (5.29 g, 139.38 mmol, 1.2 eq) was slowly added, and the reaction solution was stirred at -30 ° C. for 2 hours. The same amount of two pots were added in parallel. After the reaction was completed, the reaction solution was warmed to -10 to 0 ° C. and slowly quenched with ethyl acetate (5.3 mL). Then, water (5.3 mL), 20% sodium hydroxide (5.3 mL), and water (21.2 mL) were added in sequence, and the mixture was stirred for 0.5 hours. After that, anhydrous magnesium sulfate (10.6 g) was added, and the mixture was stirred for 0.5 hours and then filtered. The cake was washed with ethyl acetate (500 mL), and the filtrate was combined and concentrated to obtain compound BB-1-4, which was used directly in the next step reaction without purification. 1H NMR (400 MHz, CDCl 3 ) δ 7.39-7.28(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).

[0072] Step 4: Synthesis of compound BB-1-5 Compound BB-1-4 (30 g, 83.47 mmol, 1 eq), Dess-Martin (42.48 g, 100.16 mmol, 31.01 mL, 1.2 eq), and dichloromethane (600 mL) were added to a dried reaction flask, and the mixture was replaced with nitrogen gas and stirred at 20 ° C for 16 hours to react. After the reaction was completed, a saturated sodium thiosulfate solution (300 mL) was added to the reaction solution, and the mixture was stirred for 1 hour, and then extracted with dichloromethane (300 mL × 2), and the organic phases were combined, and the organic phases were washed successively with saturated sodium carbonate (300 mL × 2), saturated saline (300 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was slurried in 500 mL of petroleum ether, filtered, and the cake was spin-dried to obtain compound BB-1-5. 1 H NMR (400MHz, CDCl 3 ) δ(ppm) 9.24(d,J=3.1Hz,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).

[0073] Step 5: Synthesis of compound BB-1-6 BB-1-5 (17 g, 47.57 mmol, 1 eq) was dissolved in dichloromethane (170 mL), purged with nitrogen gas, cooled to 0 ° C, and BAST (26.31 g, 118.91 mmol, 26.05 mL, 2.5 eq) was slowly added. The reaction solution was slowly warmed to 20 ° C and stirred for 10 h, then warmed to 35 ° C and stirred for 2 h. The two pots were charged in parallel with the same amount. After the reaction was completed, the reaction solutions were combined and then slowly quenched with saturated sodium bicarbonate (500 mL) at 0-10 ° C, then extracted with dichloromethane (200 mL × 3), the organic phases were combined, washed with saturated sodium chloride (100 mL), and further dried over anhydrous sodium sulfate. After filtration, the organic phase was spin-dried under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; petroleum ether: ethyl acetate = 5:1-1:1) to obtain compound BB-1-6. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.34(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).

[0074] Step 6: Synthesis of compound BB-1 BB-1-6 (8 g, 21.09 mmol, 1 eq) was dissolved in hydrochloric acid methanol (4 M, 160.00 mL, 30.35 eq) and methanol (2 mL), and the mixture was replaced with nitrogen gas, then heated to 50°C and stirred for 10 hours. After completion of the reaction, the reaction solution was cooled to 20°C and spin-dried. The crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; dichloromethane:methanol = 100:0.1-100:2) to obtain compound BB-1. 1 H NMR (400 MHz, CDCl 3 ) δ 6.07(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).

[0075] [Reference Example 2: Fragment BB-2] [ka]

[0076] Step 1: Synthesis of compound BB-2-3 Compound BB-2-2 (23.52 g, 384.99 mmol, 23.28 mL, 1.1 eq) was added to a dried reaction flask, and tetrahydrofuran (70 mL) was added to completely dissolve the compound. Potassium tert-butoxide (47.13 g, 419.98 mmol, 1.2 eq) was added at 5 ° C., and the mixture was replaced with nitrogen gas, and the mixture was stirred for 40 minutes to react. Next, a tetrahydrofuran (210 mL) solution containing compound BB-2-1 (70 g, 349.99 mmol, 1 eq) was added, and the mixture was stirred for 16 hours at 5 ° C. after replacing with nitrogen gas. After the reaction was completed, the reaction solution was quenched by adding 200 mL of water, and ethyl acetate (250 mL × 2) was added for extraction, and the organic phase was combined, and the organic phase was dried by adding saturated saline (250 ml) and anhydrous sodium sulfate in sequence, and the crude product was obtained by spin drying under reduced pressure. The crude product was dissolved in 280 mL of tetrahydrofuran, and then (180 mL) of 3 mol / L propanol hydrochloride (self-made) was added, stirred at 70° C. for 3 hours, then naturally cooled to room temperature, filtered, and spin-dried under reduced pressure to obtain the hydrochloride salt of compound BB-2-3. 1 H NMR (400MHz, DMSO-d 6 ) 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).

[0077] Step 2: Synthesis of compound BB-2-4 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 dried reaction flask, and the mixture was replaced with nitrogen gas, followed by stirring at 70 ° C for 60 hours to react. After the reaction was completed, the reaction system was cooled to room temperature, and the reaction solution was reduced in pressure to 300 mL of liquid at 40 ° C and spin-dried, and 2-methyltetrahydrofuran (700 mL) and a 3 mol / L hydrochloric acid propanol solution (560 mL) were further added to the remaining reaction solution, and the mixture was stirred at room temperature for 3 hours and then filtered. The cake was rinsed with 2-methyltetrahydrofuran (100 mL), and the rinsed cake was reduced in pressure and spin-dried to obtain the hydrochloride salt of compound BB-2-4. 1 H NMR (400MHz, DMSO-d 6 ) 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).

[0078] Step 3: Synthesis of compound BB-2-5 Compound BB-2-4 (50 g, 180.15 mmol, 1 eq, HCl), 2-methyltetrahydrofuran (400 mL), chloroacetaldehyde (45.96 g, 234.20 mmol, 37.67 mL, 40% purity, 1.3 eq) and water (25 mL) were added to a dried reaction flask, and the flask was replaced with nitrogen gas, and then heated to 40° C. Saturated potassium bicarbonate solution (3.37 M, 267.29 mL, 5 eq) was added, and the flask was replaced with nitrogen gas, and then heated to 45° C. and reacted with stirring for 16 hours. After the reaction was completed, the reaction was cooled to room temperature, and a saturated sodium bisulfite solution was added to wash the reaction solution. A saturated sodium carbonate solution was further added to the reaction solution to adjust the pH to 9-10, and the reaction solution was extracted with ethyl acetate (400 mL x 3). The organic phases were combined, and the organic phase was dried sequentially with saturated brine (500 mL) and anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain compound BB-2-5. 1 H NMR (400MHz, DMSO-d 6) δ(ppm) 8.32(d,J=8.6Hz,1H), 7.33(s,1H), 7.22-7.28(m,2H), 7.06(d,J=0.9Hz,1H), 4.42-4.46(m,4H).

[0079] Step 4: Synthesis of compound BB-2-6 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 dried reaction flask, and the flask was replaced with nitrogen gas. The temperature was raised to 70 ° C. and the reaction was allowed to proceed with stirring for 16 hours. After completion of the reaction, the reaction solution was quenched by slowly adding 5% glacial acetic acid solution (200 mL), and dichloromethane (250 mL x 3) was added to the quenched reaction solution. The organic phases were combined, washed with saturated saline (250 mL) in sequence, and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was spin-dried under reduced pressure to obtain the crude product. The crude product was slurried with methyl tert-butyl ether (500 mL) for 0.5 hours, filtered, the cake was rinsed with methyl tert-butyl ether (300 mL), and the cake was spin-dried under reduced pressure to obtain compound BB-2-6. 1 H NMR (400MHz, DMSO-d 6 ) 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).

[0080] Step 5: Synthesis of compound BB-2 Compound BB-2-6 (52 g, 100.60 mmol, 1 eq) and tetrahydrofuran (25 mL) were added to a dried reaction flask, and the flask was replaced with nitrogen gas. The flask was then cooled to 10°C, and ethyl magnesium bromide (3 M, 40.24 mL, 1.2 eq) was slowly added. The flask was then replaced with nitrogen gas, and the mixture was stirred at 10°C for 2 hours to react. After the reaction was completed, the reaction solution was quenched by slowly adding 5% glacial acetic acid solution (200 mL), and ethyl acetate (250 mL x 3) was added to the quenched reaction solution. The organic phases were combined, and the organic phase was washed successively with saturated saline (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 3:1) and gradient eluted to obtain compound BB-2. 1 H NMR (400MHz, DMSO-d 6 ) 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).

[0081] [Example 1] [ka]

[0082] Step 1: Synthesis of compound 001-2 A dried reaction flask was charged with BB-1 (1.6 g, 11.67 mmol, 1 eq), copper acetate hydrate (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 replacing with nitrogen gas, the reaction was stirred at 110 °C for 5 hours. After the reaction was completed, the reaction solution was cooled to 20 °C, decompressed and spin-dried. The crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; petroleum ether: ethyl acetate = 10:1-5:1) to obtain compound 001-2.1 H NMR (400 MHz, CDCl 3 ) δ 8.21(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).

[0083] Step 2: Synthesis of compound 001-3 001-2 (1 g, 2.50 mmol, 1 eq), Lawesson's reagent (5.05 g, 12.49 mmol, 5 eq) and toluene (50 mL) were added to a dried reaction flask, and the mixture was replaced with nitrogen gas, followed by stirring at 130°C for 10 hours. After completion of the reaction, the reaction solution was cooled, reduced pressure and spin-evaporated. The crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; mobile phase petroleum ether: mobile phase ethyl acetate = 100:1-20:1) to obtain compound 001-3. 1 H NMR (400 MHz, CDCl 3 ) δ 7.33(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).

[0084] Step 3: Synthesis of compound 001-4 A dried reaction flask was charged with 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), then DMF (56 mL) was added, and the mixture was replaced with nitrogen gas, heated to 60° C., and stirred for 10 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (100 mL), filtered, and the filtrate was extracted with ethyl acetate (100 mL×3), and the organic phases were combined, washed with saturated sodium chloride (10 mL), further dried over anhydrous sodium sulfate, filtered, and finally spun dry under reduced pressure. The crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; petroleum ether: ethyl acetate = 5:1-3:1) to obtain compound 001-4. 1 H NMR (400 MHz, CDCl 3 ) δ 8.41-7.96(m,1H), 7.47-7.38(m,1H), 7.25-7.16(m,2H), 6.80-6.38(m,1H), 5.03-4.87(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).

[0085] Step 4: Synthesis of compound 001-6 001-4 (0.5 g, 1.16 mmol, 1 eq), 001-5 (415.14 mg, 4.66 mmol, 4 eq), potassium phosphate (1.24 g, 5.82 mmol, 5 eq) were dissolved in DMSO (11 mL) and substituted with nitrogen gas. After that, copper(I) iodide (66.56 mg, 349.47 μmol, 0.3 eq) was added, and the reaction solution was heated to 120 °C in a microwave and stirred for 1.5 hours. After the reaction was completed, the reaction solution was cooled to 20 °C, then filtered, and the filtrate was analyzed by preparative high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3)-ACN]; acetonitrile: 8% to 38%, 8 min) to obtain compound 001-6. 1 H NMR (400 MHz, CDCl 3 ) δ 8.13(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).

[0086] Step 5: Synthesis of Compound 001 001-6 (0.02 g, 45.73 μmol, 1 eq) was dissolved in DMSO (2 mL), then 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) were added, and the mixture was purged with nitrogen gas and stirred at 25° C. for 2 hours. Three reactions were carried out in parallel. After the reaction was completed, the reaction solutions were combined and then slowly quenched with saturated sodium carbonate (50 mL), then extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride (30 mL), further dried over anhydrous sodium sulfate, filtered, and finally spun dry under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH 4 HCO 3 Compound 001-7 was purified and separated by preparative supercritical fluid chromatography (column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm, 5 μm); mobile phase: A is CO 2 , B is [0.1% NH 3 H 2O EtOH]; B%: 45% - 45%, 15 minutes) for separation and purification to obtain Compound 001 (Rt = 1.663 minutes) and 002 (Rt = 1.861 minutes).

[0087] Compound 001: 1 H NMR(400MHz, CD 3 OD) δ 8.05(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%.

[0088] Compound 002: 1 H NMR(400MHz, CD 3 OD) δ 8.04(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, 1H), 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%.

[0089] [Example 2]

Chemical formula

[0090] Step 1: Synthesis of Compound 003 - 1 001-3 (0.2 g, 480.49 μmol, 1 eq), 001-5 (171.23 mg, 1.92 mmol, 4 eq), potassium phosphate (815.95 mg, 3.84 mmol, 8 eq) were dissolved in DMSO (10 mL) and replaced with nitrogen gas. Then, copper(I) iodide (118.96 mg, 624.64 μmol, 1.3 eq) was added, and the reaction solution was heated to 90 °C in a microwave and stirred for 0.5 h. Ten reactions were carried out in parallel. After the reaction was completed, the ten reaction solutions were combined, then diluted with 200 mL of ice water in an ice-water bath, filtered, and the filtrate was extracted with ethyl acetate (100 mL). The aqueous phase was separated and collected, and the aqueous phase was adjusted to pH ≒ 6 with 10% sodium hydrogen sulfate, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 003-1, which was used directly in the next step reaction.

[0091] Step 2: Synthesis of compound 003-2 003-1 (1.2 g, 2.83 mmol, 1 eq) was dissolved in tetrahydrofuran (120 mL), and then HOSu (1.95 g, 16.96 mmol, 6 eq) was added. After stirring at 25° C. for 0.5 h, EDCI (5.42 g, 28.27 mmol, 10 eq), NH 3 / MeOH (7M, 6.06mL, 15eq) were added in sequence, and the atmosphere was replaced with nitrogen gas, followed by stirring at 25°C for 9.5 hours. After completion of the reaction, the reaction system was diluted with 100mL water / 100mL ethyl acetate, separated, and the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50mL x 3). The organic phases were combined, washed with saturated saline (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; dichloromethane:methanol = 100:0-100:3) to obtain compound 003-2. 1 H NMR (400 MHz, CDCl 3) δ 8.17-8.10(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).

[0092] Step 3: Synthesis of compound 003 A dried reaction flask was charged with 003-2 (0.1 g, 236.16 μmol, 1 eq), silver acetate (78.84 mg, 472.33 μmol, 24.18 μL, 2 eq), and ammonia-methanol solution (7 M, 4.00 mL, 118.56 eq). The reaction solution was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was filtered, and finally, the reaction solution was spin-evaporated under reduced pressure, and the crude product was separated and purified by preparative high-performance liquid chromatography (column: Phenomenex luna C18 100 × 40 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 1%-20%, 8 min) to obtain compound 003. 1 H NMR (400MHz, CD 3 OD) δ 8.08(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).

[0093] [Example 3] [ka]

[0094] Step 1: Synthesis of compound 006 003-2 (0.2 g, 472.33 μmol, 1 eq), silver acetate (157.67 mg, 944.65 μmol, 48.37 μL, 2 eq) were added to a dried reaction flask, then DMF (5 mL) was added, and after replacing with nitrogen gas, 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 solution was stirred at 25° C. for 10 hours. After the reaction was completed, the reaction solution was filtered and finally spun dry under reduced pressure. The crude product was separated and purified by preparative high-performance liquid chromatography (column: Phenomenex luna CN 5 μm 100 × 30 mm; mobile phase: [n-heptane-EtOH]; ethanol: 40% to 95%, 10 min) to obtain compound 005-1, which was then purified by preparative supercritical fluid chromatography (column: REGIS (S,S) WHELK-O1 (250 mm × 25 mm, 10 μm); mobile phase: A is CO 2 Compound B was separated and purified using [neutral-IPA]; B%: 50% to 50%, 15 min) to obtain compounds 005 (Rt = 1.646 min) or 006 (Rt = 1.844 min).

[0095] Compound 006: 1 H NMR (400MHz, CD 3 OD) δ 8.01(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] + .

[0096] [Example 4] [ka]

[0097] Step 1: Synthesis of compound 007-2 007-1 (250 mg, 613.69 μmol, 1 eq), Lawesson's reagent (744.66 mg, 1.84 mmol, 3 eq), and then tetrahydrofuran solvent (1 mL) were added to a pre-dried reaction flask. The reaction system was stirred at 20°C for 1 h. After the reaction was completed, the reaction solution was directly spin-dried to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (silica gel mesh: 100-200 mesh; petroleum ether: ethyl acetate = 20: 1, eluted for 30 min, eluent was changed to dichloromethane: methanol = 1: 0-50: 1) to obtain compound 007-2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.18(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(br d,J=7.02Hz,2H), 4.23-4.33(m,4H), 1.68(s,3H).

[0098] Step 2: Synthesis of Compounds 007 and 008 007-2 (30.00 mg, 70.85 μmol, 1 eq) was added to a pre-dried reaction flask, dichloromethane solvent (2 mL) was added, cooled to 0° C., methyl trifluoromethanesulfonate (69.76 mg, 425.09 μmol, 46.51 μL, 6 eq) was added, and the mixture was warmed to 20° C. and stirred for 2 hours. The reaction 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 spin-dried, and the crude product was separated and purified by high-performance liquid chromatography (column: Phenomenex Gemini-NX 150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 5% to 35%, 9 min), and then further purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); mobile phase: A is CO 2 , B is [0.1% NH 3 H 2 O MeOH; B%: 45% to 45%, 10 min) to give compound 007 (Rt = 1.231 min) and compound 008 (Rt = 1.428 min).

[0099] Compound 007: 1 H NMR (400 MHz, CDCl 3 ) δ 8.14(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(brs,1H), 3.84(s,3H), 1.54(d,J=6.78Hz,3H); MS:m / z=437.2[M+1] +;ee%=99.24%.

[0100] Compound 008: 1 H NMR (400 MHz, CDCl 3 ) δ 8.13(d,J=8.78Hz, 1H), 7.16(s,1H), 6.53-6.87(m,1H), 6.48(dd,J=2.20,8.72Hz,1H), 6.34(d,J=2.26Hz,1H), 4.79-4.95(m,1H), 4.72(dd,J=4.02, 9.41Hz,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%.

[0101] The ee% values ​​of the above compounds 007 and 008 were analyzed by supercritical fluid chromatography (detection method) as follows: (Column: DAICEL CHIRALCEL OJ (150 mm×4.6 mm, 5 μm); Mobile phase: A is CO 2 , B is [0.05% DEA EtOH]; B%: 5%-40%, 10 min)

[0102] [Example 5] [ka]

[0103] Step 1: Synthesis of compounds 009-1 and 010-1 007-2 (100 mg, 236.16 μmol, 1 eq) was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); mobile phase: A is CO 2 , B is [0.1% NH 3 H 2O / EtOH; B%: 50% to 50%, 8 min) to give compounds 009-1 (RT = 1.425 min) and 010-1 (RT = 1.584 min).

[0104] Step 2: Synthesis of compound 009 A pre-dried reaction flask was charged with 009-1 (50 mg, 118.08 μmol, 1 eq), dichloromethane (2 mL), cooled to 0° C., methyl trifluoromethanesulfonate (38.75 mg, 236.16 μmol, 25.84 μL, 2 eq), warmed to 20° C. and stirred for 2 hours. The reaction 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 (column: Phenomenex Gemini-NX 150×30 mm×5 μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 12%-27%, 9 min) to obtain the trifluoroacetate salt of compound 009. 1 H NMR (400MHz, CD 3 OD) δ 8.54(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%.

[0105] Step 3: Synthesis of compound 010 010-1 (20.00 mg, 47.23 μmol, 1 eq) was added to a pre-dried reaction flask, dichloromethane solvent (2 mL) was added, cooled to 0° C., methyl trifluoromethanesulfonate (15.50 mg, 94.47 μmol, 10.33 μL, 2 eq) was added, and the mixture was warmed to 20° C. and stirred for 2 hours. The reaction 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 was stirred at 20° C. for 10 hours. After the reaction was completed, the reaction solution was directly spun dry. The crude product was separated and purified by high performance liquid chromatography (column: Phenomenex Gemini-NX 150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; acetonitrile: 12% to 27%, 9 min) to obtain the trifluoroacetate salt of compound 010. 1 H NMR (400MHz, CD 3 OD) δ 8.52(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.

[0106] [Example 6] [ka]

[0107] Step 1: Synthesis of compound 011-2 Three 20 mL microwave tubes were taken and three reactions were carried out in parallel according to the steps below. 001-3 (0.2 g, 480.49 μmol, 1 eq), 011-1 (198.19 mg, 1.92 mmol, 4 eq), potassium phosphate (815.95 mg, 3.84 mmol, 8 eq) were dissolved in DMSO (10 mL). After replacing with nitrogen gas, copper(I) iodide (118.96 mg, 624.64 μmol, 1.3 eq) was added and the reaction solution was heated to 90 °C in a microwave and stirred at 90 °C for 80 min. After the reaction was completed, the three reactions were combined and processed. The reaction solution was diluted by pouring into 20 mL of ice water in an ice bath, filtered, and the filtrate was extracted with ethyl acetate (100 mL), separated, and the aqueous phase was collected, adjusted to pH ≒ 6 with 10% sodium hydrogen sulfate, and extracted with ethyl acetate (200 mL × 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 step reaction.

[0108] Step 2: Synthesis of compound 011-3 011-2 (0.6 g, 1.37 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), then HOSu (944.96 mg, 8.21 mmol, 6 eq) was added, and the mixture was stirred at 25 ° C for 0.5 hours, after which EDCI (2.62 g, 13.68 mmol, 10 eq) and ammonia in methanol (7 M, 2.93 mL, 15 eq) were added in sequence. After replacing with nitrogen gas, the mixture was stirred at 25 ° C for 9.5 hours. After the reaction was completed, the reaction solution was quenched by adding water (5 mL), and then extracted with ethyl acetate (100 mL × 2), and the organic phase was collected, combined, and spin-dried under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (0.05% NH 3 H 2 Compound 011-3 was obtained by separation and purification using a 1:1 mixture of 011-1, 011-2, 011-3, and 011-4 (-ACN; acetonitrile: 32% to 62%, 8 min). 1 H NMR (400 MHz, CD 3OD) δ ppm 1.41 (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).

[0109] Step 3: Synthesis of compound 011 In a dried reaction flask, 011-3 (0.2 g, 457.18 μmol, 1 eq), silver acetate (152.62 mg, 914.36 μmol, 46.82 μL, 2 eq) and ammonia-methanol solution (10 mL) were added, and the mixture was heated to 60° C. and reacted for 2 h. After completion of the reaction, the mixture was filtered and the filtrate was collected. The cake was rinsed with methanol (10 mL), and the organic phase was combined and spun dry. The crude product was separated and purified by preparative high-performance liquid chromatography (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.225% FA)-ACN]; acetonitrile: 5%-35%, 7 min) to obtain compound 011-4, which was further purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 μm); mobile phase: A is CO 2 , B is [0.1% NH 3 H 2 The compound was isolated and purified using a 2×1000 sachette (O / EtOH; B%: 35%–35%, 8 min) to obtain compound 011 (Rt = 3.405 min). 1 H NMR (400MHz, CD 3OD) δ ppm 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%.

[0110] [Example 7] [ka]

[0111] Step 1: Synthesis of compound 013 A pre-dried reaction flask was charged with 003-2 (50 mg, 118.08 μmol, 1 eq), DMF solvent (3 mL), followed by 004-2 (15.36 mg, 236.16 μmol, 9.93e-1 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 h. After completion of the reaction, the reaction solution was filtered, the filtrate was diluted with 10 mL water / 10 mL ethyl acetate, separated and the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL×3). The organic phases were combined, 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 purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 The product was separated and purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm); mobile phase: A is CO 2, B is neutral MeOH]; B%: 50% to 50%, 10 min) to obtain compound 013 (Rt = 1.598 min). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.94(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=7.06Hz,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] + .

[0112] [Example 8] [ka]

[0113] Step 1: Synthesis of compound 015 [ka]

[0114] Compound 009-1 (30.00 mg, 70.85 μmol, 1 eq) was added to a pre-dried reaction flask, dichloromethane solvent (3.5 mL) was added, cooled to 0° C., methyl trifluoromethanesulfonate (58.13 mg, 354.25 μmol, 38.75 μL, 5 eq) was added, and the mixture was warmed to 20° C. and stirred for 2 hours. The reaction was 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 the reaction was completed, the reaction solution was quenched with methanol and then spin-dried to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B (acetonitrile)%: 1% to 35%, 9 min) and further separated by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O MeOH]; B%: 50% to 50%, 10 min) to obtain compound 015 (Rt = 1.375 min). 1 H NMR (400 MHz, CD 3 OD) 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) 4.66-4.73(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] + .

[0115] [Example 9] [ka]

[0116] Step 1: Synthesis of compound 016-1 Compound 003-1 (0.13 g, 306.30 μmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), and 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., and the mixture was stirred at 15° C. for 16 hours to react. After the reaction was completed, water (20 mL) was added to the reaction solution, and it was extracted three times with ethyl acetate (3×10 mL), and 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] + .

[0117] Step 2: Synthesis of compound 016 Compound 016-1 (130.00 mg, 307.01 μmol, 1 eq) was dissolved in methanol (10 mL), and 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, and the mixture was heated to 80°C and reacted for 22 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (3 × 10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then subjected to preparative high performance liquid chromatography (column: Boston Prime C18 150 × 30 mm × 5 μm; mobile phase: [water (NH 3 H 2 O+NH 4 HCO 3 )-ACN]; 15%~45%, 7 min) to obtain compound 016. 1 H NMR (400MHz, CD 3OD) 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 MS:m / z=423[M+1] + .

[0118] [Example 10] [ka]

[0119] Step 1: Synthesis of compound 017 [ka]

[0120] Under the protection of nitrogen gas, 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), and the temperature was raised to 80 °C and stirred for 10 hours. After the reaction was completed, the reaction solution was spin-dried under reduced pressure, 20 mL of water was added, and the mixture was extracted three times with dichloromethane (20 mL × 3), and the organic phase was combined and dried with saturated saline (20 mL) and anhydrous sodium sulfate. The reaction solution was separated and purified by preparative thin layer chromatography (dichloromethane:methanol = 20:1), and further purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O / MeOH; B%: 50% to 50%, 10 min) to obtain compound 017. 1 H NMR (400 MHz, CDCl 3) δ ppm 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] + .

[0121] [Example 11] [ka]

[0122] Step 1: Synthesis of compound 018-1 Compound 001-3 (0.87g, 1.88mmol, 1eq) was dissolved in toluene (10mL), dichloro(p-cymene)ruthenium(II) dimer (345.94mg, 564.90μmol, 3.01e-1eq) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (233.62mg, 569.07μmol, 3.03e-1eq) were added, and the mixture was heated to 110℃ under nitrogen gas protection and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature (25℃), 10mL of ethyl acetate and 10mL of saturated saline were added, and the organic phase was collected and dried with anhydrous sodium sulfate. After spin drying under reduced pressure, compound 018-1 was obtained by separation and purification using column chromatography (petroleum ether:ethyl acetate=1:0~21:4). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 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).

[0123] Step 2: Synthesis of compound 018-2 Compound 018-1 (670 mg, 1.45 mmol, 1 eq), 001-5 (520 mg, 5.84 mmol, 4.04 eq), potassium phosphate (1.58 g, 7.46 mmol, 5.16 eq) were dissolved in DMSO (20 mL), and copper (I) iodide (365.45 mg, 1.92 mmol, 1.33 eq) was added under the protection of nitrogen gas, and the mixture was heated to 125 ° C and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, the cake was washed with 10 mL of DMSO, and the filtrate was collected to obtain a DMSO solution of the crude product compound 018-2. The reaction system was not further purified and was directly used in the next step reaction.

[0124] Step 3: Synthesis of compound 018-3 Compound 018-2 (600 mg, 1.41 mmol, 1 eq) was added to a pre-dried reaction flask, followed by DMSO solvent (30 mL) and tetrahydrofuran (15 mL), the temperature was cooled to 0°C, HATU (3.25 g, 8.55 mmol, 6.05 eq) was added, followed by ammonia-methanol solution (7 M, 4.5 mL, 22.28 eq), and the reaction system was stirred at 20°C for 12 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure. An additional 100 mL of water was added, and the mixture was extracted three times with dichloromethane (50 mL x 3). The organic phase was collected, washed four times with water (100 mL x 4), and dried over anhydrous sodium sulfate. Compound 018-3 was obtained by separation and purification using column chromatography (dichloromethane:methanol = 1:0 to 9:1), and it was speculated that racemization occurred during the reaction process. 1 H NMR (400MHz, CD 3 OD) δ ppm 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).

[0125] Step 4: Synthesis of compound 018-4 Compound 018-3 (100 mg, 236.16 μmol, 1 eq), Lawesson's reagent (190 mg, 469.75 μmol, 1.99 eq) were added to a pre-dried reaction flask, followed by the addition of tetrahydrofuran solvent (4 mL). The reaction system was stirred at 20°C for 2 hours. After completion of the reaction, the reaction solution was spun dry under reduced pressure. The crude product was separated and purified by preparative thin layer chromatography (dichloromethane:methanol=20:1) to obtain compound 018-4. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 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).

[0126] Step 5: Synthesis of compound 018 Compound 018-4 (60 mg, 136.52 μmol, 1 eq) was added to a pre-dried reaction flask, dichloromethane (3 mL) was added, cooled to 0° C., methyl trifluoromethanesulfonate (50.58 mg, 308.22 μmol, 33.72 μL, 2.26 eq) was added, and the mixture was warmed to 20° C. and stirred for 2 hours. The reaction 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 kept stirring at 20° C. for 10 hours. After the reaction was completed, 50 mL of water was added to the reaction, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, decanted to discard the solution, concentrated under reduced pressure, and further separated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1), and purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O EtOH]; B%:CO 2 , 35%-35%, 10 min) to give compound 018 (Rt = 2.041 min). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 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=2.26Hz,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] + .

[0127] [Experimental Example 1: In vitro evaluation] 1. In vitro enzyme activity test The lipid kinase reaction is carried out in the presence of appropriate substrates and ATP, followed by the catalysis of ADP-Glo ​​in two steps. TM The kinase activity was measured using the kit. Step 1: The kinase reaction was terminated and the remaining ATP was completely removed, leaving only ADP; Step 2: Kinase detection reagent was added to convert ADP to ATP, which was accompanied by a luciferin / luciferase reaction. Finally, the output value of the fluorescence value was converted into kinase activity. The conditions for measuring PI3K enzyme activity are shown in Table 1.

[0128] [Table 1]

[0129] Experimental materials and equipment: a) Enzyme: PI3K α Millipore #14-602-K PI3K β Promega #V1751 PI3K δ Millipore #14-604-K PI3K γ Millipore #14-558-K b) Kit: ADP-Glo TM Lipid Kinase and PIP2:3PS Kit (Promega #V1792) The kit contained: 1 mM PIP2:3PS, 10x lipid dilution buffer, 1 M magnesium chloride, 10 mM ATP, 10 mM ADP, ADP-Glo ​​reagent, detection buffer and detection substrate. c) Reaction well plate: OptiPlate-384, clear white (PerkinElmer #6007299)

[0130] Preparation of reagents: a) 10x reaction buffer: 500mM HEPES, pH 7.5, 500mM NaCl, 9mM MgCl 2 ;BSA: 10% stock solution, self-made. b) Final test reaction conditions: 1x reaction: 50 mM HEPES, 50 mM NaCl, 3 mM MgCl 2, 0.01% BSA (freshly prepared on the day of the experiment), 1% DMSO (v / v) + / - compound c) Reaction system: 3 μL of enzyme and substrate mixture (1:1) + 2 μL of ATP / MgCl 2 Mixture of + 5 μL ADP-Glo ​​Reagent + 10 μL Detection Reagent.

[0131] The specific experimental procedures are as follows: a) Compound dilution: 50 nL of 100× compound / DMSO was transferred to the test well plate using the Echo. For -PI3Kα, compounds were diluted 3-fold from a top concentration of 0.111 mM to give a total of 10 concentrations. -For PI3Kβ / PI3Kδ / PI3Kβ, compounds were diluted 3-fold from a top concentration of 1.11 mM to give a total of 10 concentrations.

[0132] b) Kinase reaction: (1) Test compounds were prepared and 50 nL of 100 plus compound solution or DMSO was added to the corresponding well plate. (2) A 3.33x reaction buffer solution was prepared. (3) Prepare 3.33×PIP2:3PS and thaw the PIP2:3PS by vortexing for at least 1 minute before use. (4) 5.25 mM MgCl 2 An ATP solution containing: (5) A 3.33×PI3Kα / PI3Kβ / PI3Kδ / PI3Kγ solution was prepared. (6) The lipid kinase solution and the PIP2:3PS solution were mixed in a 1:1 volume ratio. (7) 3.33× lipid kinase buffer was mixed with PIP2:3PS solution in a 1:1 volume ratio. (8) 3 μL of the buffer and PIP2:3PS mixture was added to the first and second rows of the well plate. (9) 3 μL of the mixture of enzyme and PIP2:3PS was added to the wells of the well plate except for the first and second rows, and centrifuged (1000 rpm) for 10 seconds. The plates were then incubated at 23° C. for 20 minutes. (10) 2 μL of ATP solution was added and shaken uniformly at 1,000 rpm. (11) The well plate was covered and shaken vigorously for about 30 seconds, and then the well plate was incubated at 23°C for 2 hours. (12) 10 mM MgCl 2 5 μL of ADP-Glo ​​reagent containing (13) Centrifuge at 1,000 rpm for 10 seconds, cover the well plate, shake for about 30 seconds, and incubate at 23°C for 60 minutes. (14) 10 μL of kinase detection reagent was added. (15) The mixture was centrifuged at 1,000 rpm for 10 seconds and then incubated at 23°C for 60 minutes. (16) Fluorescence values ​​were measured using an Envision instrument.

[0133] 2. In vitro cell activity test The effect of the test compounds on the cellular antiproliferative activity was measured in two cell lines, HCC1954 and HDQ-P1, by the CTG method. Cell culture medium: Cell complete culture medium (RPMI 1640 + 10% serum + 1% L-glutamine + 1% double antibody)

[0134] The specific work steps are as follows: (1) HCC1954 and HDQ-P1 cells (ATCC (R) HTB-22 TM ) were seeded into a 96-well plate with 100 μL of cell complete medium per well (4000 cells / well / HDQ-P1, 3500 cells / well / HCC1954) and incubated at 37 °C in 5% CO 2 The cells were cultured under the conditions for 24 hours. (2) The cells were starved overnight by replacing the complete medium with 100 μL of serum-free medium. (3) Compounds (the starting compound concentration was 10 μM and was diluted 3-fold into 8 concentrations. Then, each concentration of compound was further diluted 100-fold with serum-free medium) were prepared, and 25 μL of the diluted compounds were added to the well plate containing the cells. (4) 37°C, 5% CO 2The cells were cultured under these conditions for 72 hours (HCC1954) or 120 hours (HDQ-P1). (5) For subsequent procedures, we referred to the instructions in the Promega CTG kit.

[0135] The experimental results are shown in Table 2. [Table 2]

[0136] Conclusion: The compounds of the present invention can effectively inhibit the activity of PI3Kα kinase, and at the same time, show high subtype selectivity against PI3Kβ / γ / δ. Moreover, they can effectively inhibit the cell proliferation activity of HCC1954 cells with PIK3CA mutation.

[0137] [Experimental Example 2: Permeability test] The permeability of the compounds of the present invention was measured through MDCK cell membranes that highly express MDR1. The specific work steps are as follows: Compounds in DMSO stock solutions were diluted to 2 μM (DMSO<1%) using transport buffer (HBSS with 10 mM Hepes, pH 7.4) and applied to the apical or basolateral side of the cell monolayer. Permeability of compounds in the A to B or B to A directions was measured in duplicate. Plates were incubated for 2 h at 4 °C for 1 h at 2 °C. 2 The cells were then cultured for 2.5 hours in an incubator at 37 ± 1 °C and 5% CO 2 The mixture was saturated with humidity and was not shaken. In addition, the flux rate of each compound was measured. Compounds were quantified by LC-MS / MS analysis based on the peak area ratio of analyte / IS.

[0138] After the transport test, the integrity of the cell monolayer was measured using a fluorescent yellow exclusion test. The buffer was removed from the apical and basal chambers, and then 75 μL of 100 μM fluorescent yellow transport buffer and 250 μL of transport buffer were added to the apical and basal chambers. The plates were incubated at 37° C., 5% CO without shaking.2 The cells were incubated for 30 min under conditions of pH 7.0 and saturated humidity. After 30 min incubation, 20 μL of fluorescent yellow sample was collected from the apical side, and then 60 μL of transport buffer was added. Then, 80 μL of fluorescent yellow sample was collected from the basolateral side. The relative fluorescence units (RFU) of fluorescent yellow at 425 / 528 nm (excitation / emission) were measured using an Envision microplate reader. The measurement results are shown in Table 3.

[0139] [Table 3]

[0140] Conclusion: The compounds of the present invention exhibited high permeability and low efflux properties in MDCK-MDR1 permeability experiments.

[0141] [Experimental Example 3: In vivo study] 1. In vivo DMPK study Experimental Objective: Male CD-1 mice were selected as test animals to measure the blood concentration of the compound after a single administration and evaluate its pharmacokinetic behavior.

[0142] Experimental procedure: Eight healthy adult male CD-1 mice were selected, four for the intravenous injection group and four for the oral administration group. The test compound was mixed with an appropriate amount of the intravenous injection group solvent (DMSO / solvent / water (10:10:80 v / v / v)), vortexed and sonicated to obtain a clear solution of 1.0 mg / mL, which was filtered through a microporous membrane for use; the oral administration group solvent was DMSO / solvent / water (10:10:80 v / v / v), the test compound was mixed with the solvent, vortexed and sonicated, and adjusted to a homogeneously mixed suspension of 1.0 mg / mL for use. After intravenous injection at 1 mg / kg or oral administration at 3 mg / kg to the mice, whole blood was collected at a designated time and processed to prepare plasma, and the drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 4.

[0143] [Table 4]

[0144] Conclusion: The compounds of the present invention exhibited high exposure, low clearance rate, and good oral bioavailability in mice.

[0145] 2. In vivo plasma / brain tissue distribution study Experimental objective: Male SD rats were selected as test animals, and the blood concentration of the compound, as well as the drug concentrations in brain tissue and cerebrospinal fluid after a single administration, were measured to evaluate the brain penetration of the compound of the present invention. Experimental work: Two healthy adult male SD rats were selected. The test compound was mixed with an appropriate amount of oral administration group solvent (DMSO / solvent / water (10:10:80 v / v / v)), vortexed and sonicated to obtain a clear solution of 1.0 mg / mL. After oral administration of 10 mg / kg to the rats, whole blood, brain tissue and cerebrospinal fluid were collected at a predetermined time to prepare plasma, brain tissue homogenate and cerebrospinal fluid. Drug concentration was analyzed by LC-MS / MS method, and pharmacokinetic parameters were calculated by Phoenix WinNonlin software (Pharsight, USA). The experimental results are shown in Table 5.

[0146] [Table 5]

[0147] 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 pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (however, T is selected from O; L is selected from -CH2CH2-; R １ is H and C １－３ alkyl, １－３ Alkyl is optionally one, two or three R ａ is replaced by R ２ is H, F, Cl, Br, I, and C １－３ alkyl, １－３ Alkyl is optionally one, two or three R ｂ is replaced by X and Y are each independently O and NR ３ and X and Y are not simultaneously selected from O; R ３ are independently H, C １－３ Alkyl and C １－３ alkoxy, １－３ Alkyl and C １－３ Alkoxy optionally has one, two or three R ｃ is replaced by R ４ and R ５ is H, F, Cl, Br, I and C １－３ alkyl, R ６ is H and C １－３ alkyl, R ７ is C １－３ Alkyl and C １－３ alkoxy; Ring B is selected from the following groups: 【Chemistry 2】 【Chemistry 3】 optionally one or two R ｄ is replaced by R ａ , R ｂ , R ｃ and R ｄ are each independently selected from F, Cl, Br and I.

2. R １ is H and CH ３ wherein said CH ３ optionally 1, 2 or 3 R ａ is replaced by And / or R ２ is H, F, Cl, Br, I and CH ３ wherein said CH ３ optionally 1, 2 or 3 R ｂ is replaced by And / or R ３ are independently H, CH ３ , C.H. ２ CH ３ , O.C.H. ３ , O.C.H. ２ CH ３ and -OCH(CH ３ ) 2, wherein said CH ３ , C.H. ２ CH ３ , O.C.H. ３ , O.C.H. ２ CH ３ and -OCH(CH ３ ) 2 optionally has 1, 2 or 3 R ｃ is replaced by And / or R ４ and R ５ is H, F, Cl, Br, I and CH ３ 2. The compound of claim 1, selected from:

3. R １ is H, CH ３ , C.H. ２ F, C.H.F. ２ and C.F. ３ is selected from And / or R ２ is H, F, Cl, Br, I, CH ３ , C.H. ２ F, C.H.F. ２ and C.F. ３ is selected from And / or R ３ are independently H, CH ３ , C.H. ２ CH ３ , O.C.H. ３ , O.C.H. ２ CH ３ and -OCH(CH ３ ) 2 is selected from and / or ring B is selected from the following groups: 【Chemistry 4】 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

4. X and Y are each independently O, NH, or N—CH ３ , N-OCH ３ , N-OCH ２ CH ３ , and N-OCH(CH ３ 4. The compound according to claim 1 or 3, or a pharma- ceutically acceptable salt thereof, selected from:

5. R ７ is CH ３ , CH(CH ３ ) ２ and OCH3; or a pharma- ceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound selected from the following formulas: 【Chemistry 5】 (however, R １ , R ２ and R ３ is as defined in any one of claims 1 to 3.

7. The compound of claim 6, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound selected from the following formulas: 【Chemistry 6】 (however, R １ , R ２ and R ３ is as defined in claim 6.

8. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 7】 【Chemistry 8】 9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, wherein the compound is a compound selected from the following formula: 【Chemistry 9】 【Chemistry 10】

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