Polycyclic azacyclo-ketone compound and application thereof

Abstract

The invention discloses a polycyclic azacyclo-ketone compound and application thereof, and particularly discloses a compound as shown in a formula (I) and pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Polycyclic nitrogen heterocyclic ketone compounds and their applications

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on September 20, 2022, with application number 202211146951.0 and invention name “Polycyclic nitrogen heterocyclic ketone compounds and their applications”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present invention relates to a polycyclic nitrogen heterocyclic ketone compound and application thereof, and specifically to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Background Art

[0003] Among viruses, human immunodeficiency virus (HIV), a retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). Therapeutic agents for AIDS are primarily selected from a group of reverse transcriptase inhibitors (such as AZT and 3TC) and protease inhibitors (such as indinavir), but these have been shown to be associated with side effects such as kidney disease and the emergence of drug-resistant viruses. Therefore, there is a desire to develop anti-HIV drugs with alternative mechanisms of action.

[0004] On the other hand, due to the frequent emergence of drug-resistant mutants, reports suggest that combination therapy can effectively treat AIDS. Reverse transcriptase inhibitors and protease inhibitors have been clinically used as anti-HIV drugs. However, drugs with the same mechanism of action often exhibit cross-resistance or only have additive activity. Therefore, based on this situation, the development of anti-HIV drugs focuses on novel mechanisms of action. HIV integrase inhibitors are anti-HIV drugs with such novel mechanisms of action. After extensive research, the present inventors have discovered polycyclic azacycloketone derivatives with effective HIV integrase inhibitory activity.

[0005] Summary of the Invention

[0006] The present invention provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0007] in, Is a single bond or a double bond;

[0008] Each R1 is independently selected from H, halogen, CN, OH, NH2, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Each alkoxy group is independently optionally substituted by 1, 2 or 3 R a replace;

[0009] Each R a independently selected from H, halogen, CN, OH, NH2 and -COOH;

[0010] Each R2 is independently selected from H, halogen, CN, OH, NH2, -C(=O)N(R 1a )2、-S(=O)2N(R 1a )2、-N(R 1a )C(=O)N(R 1a )2、C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy group is independently optionally substituted by 1, 2 or 3 R b replace;

[0011] Each R 1a Independently selected from H, C 1-3 Alkyl and C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2 or 3 H, halogen, CN, OH or NH2;

[0012] Each R b independently selected from H, halogen, CN, OH and NH2;

[0013] Each R3 is independently selected from H, halogen, CN, OH, NH2, 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 replace;

[0014] Each R c independently selected from H, halogen, CN, OH and NH2;

[0015] L1 is selected from -(C(R 1b )2) p - and C 3-5 Cycloalkyl, the C 3-5 Cycloalkyl is optionally substituted with 1, 2, 3 or 4 Rd;

[0016] Each R 1b Selected from H, F, CI, Br, I, OH, NH2, 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 substituents selected from H, F, CI, Br, I, OH and NH2;

[0017] Each Rd is independently selected from H, halogen, CN, OH and NH2;

[0018] T1 is selected from CH, N, O and S;

[0019] T2 is selected from CH and N;

[0020] m, n and q are independently selected from 0, 1, 2, 3 and 4;

[0021] p is selected from 1 and 2;

[0022] Ring A is selected from 3-10 membered heterocycloalkyl;

[0023] Ring B is selected from 5-6 membered heteroaryl;

[0024] The 3-10 membered heterocycloalkyl and 5-6 membered heteroaryl each independently contain 1, 2 or 3 heteroatoms or heteroatom groups each independently selected from N, O, S and NH.

[0025] In some embodiments of the present invention, each R1 is independently selected from H, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Each alkoxy group is independently optionally substituted by 1, 2 or 3 R a Replacement, R a and other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, each R1 is independently selected from H and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R a Replacement, R a and other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, each of the above R1 is independently selected from H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)2CH3, and the -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)2CH3 are optionally replaced by 1, 2 or 3 R a Replacement, R a and other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, each R2 is independently selected from H, F, Cl, Br, I, CN, -C(=O)NH2, -S(=O)2NH2, -NHC(=O)NH and C 1-3 Alkoxy, the C 1-3Alkoxy is optionally substituted independently by 1, 2 or 3 R b Replacement, R b and other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, each R2 is independently selected from H, F, Cl, CN, -C(=O)NH2, -S(=O)2NH2, -NHC(=O)NH2, -OCH3, -OCH2CH3 and -OCH2CH2CH3, and other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above L1 is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(OCH3)-, -C(OCH3)2- and Other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the ring A is selected from 3-8 membered heterocycloalkyl, and other variables are as defined herein.

[0032] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above structural unit Selected from wherein T1, R1, R3, m, q and ring B are as defined in the present invention.

[0034] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof has a structure represented by formula (IA):

[0035] wherein T1 is selected from CH and N;

[0036] R1, R2, R3, L1, T2, m, n, q, Ring A and Ring B are as defined herein.

[0037] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof has a structure represented by formula (I-1), (I-2), (I-3) or (I-4):

[0038] wherein R1, R2, R3, L1, q and n are as defined in the present invention;

[0039] T1 is selected from CH and N;

[0040] T3 is selected from CH and N;

[0041] T4 is selected from N and CH;

[0042] T5 is selected from CH2, NH, O and S.

[0043] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof has a structure represented by formula (IB):

[0044] wherein T1 is selected from O and S;

[0045] R1, R2, R3, L1, T2, m, n, q, Ring A and Ring B are as defined herein.

[0046] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof has a structure shown in formula (I-5):

[0047] wherein R1, R2, R3, L1, q and n are as defined in the present invention;

[0048] T1 is selected from O and S;

[0049] T6 is selected from CH and N.

[0050] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof has the structure represented by Formula (I-1A), (I-1B), (I-1C), (I-1D), (I-2A), (I-3A), (I-4A) and (I-5A):

[0051] wherein R1, R2, R3, L1, q and n are as defined in the present invention;

[0052] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0053] The present invention also provides the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0054] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt is selected from:

[0055] The present invention further provides a pharmaceutical composition comprising a therapeutically effective dose of the compound of the present invention or a pharmaceutically acceptable salt thereof; optionally, the composition further comprises a pharmaceutically acceptable excipient, auxiliary agent or carrier.

[0056] On the other hand, the present application also provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing and / or treating HIV infection.

[0057] Technical Effects

[0058] The compound of the present invention has a significant inhibitory effect on HIV integrase activity, and simultaneously exhibits a positive effect in a test of inhibiting HIV pseudovirus or mutant pseudovirus gene replication at the cellular level, and has good pharmacokinetic properties.

[0059] Definition and Description

[0060] 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.

[0061] 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.

[0062] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or 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 neutral form of such compounds with a sufficient amount of acid in neat solution or a suitable inert solvent. 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.

[0063] 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.

[0064] Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0065] 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.

[0066] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0067] 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.

[0068] 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.

[0069] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0070] 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 key 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 and straight dashed key

[0071] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert to each other. If tautomers are possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

[0072] 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%.

[0073] 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%. 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), diastereomeric salts are formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods well known in the art, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually achieved by using chromatography using a chiral stationary phase and optionally combined with a chemical derivatization method (such as the formation of carbamates from amines).

[0074] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium (3H), iodine-125 (125I), or C-14 (14C). As another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and extended drug biological half-life. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0075] 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.

[0076] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 2-3 and C 3-4 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0077] Unless otherwise specified, the term “C 1-4 "Alkoxy" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-4 Alkoxy groups include C 1-2 、C 2-3 、C 3-4 , C4 and C3, C2 alkoxy, etc. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0078] 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.

[0079] 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 , and C3, 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.

[0080]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0081] Unless otherwise specified, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 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). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-10 membered heterocycloalkyl includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-10 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.

[0082] Unless otherwise specified, "C3-5 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system. Such C3-5 cycloalkyl groups include C3-4 and C4-5 cycloalkyl groups, and may be monovalent, divalent, or polyvalent. Examples of C3-5 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0083] Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 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). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-8 membered heterocycloalkyl includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-8 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.

[0084] Unless otherwise specified, the term "5-6 membered heteroaryl" is used interchangeably herein and refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, 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, where p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule via a heteroatom or carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0085] 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.

[0086] 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.

[0087] The solvents used in the present invention are commercially available. The following abbreviations are used in the present invention: aq represents water; eq represents equivalent; M represents mol / L; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; rt represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; ACN represents acetonitrile; and mp represents melting point.

[0088] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0089] 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.

[0090] Example 1

[0091] Synthesis route:

[0092] Step 1: Synthesis of compound 1b

[0093] Compound 1a (1 g, 693.64 mmol) and N,N-dimethylformamide (10 mL) were added to a single-necked flask, followed by aminoacetaldehyde dimethyl acetal (911.58 mg, 1.04 mol, 113.36 mL) and triethylamine (140.38 g, 1.39 mol, 193.09 mL). The reaction was incubated at 25°C for 5 hours. 30 mL of water was added to the reaction solution. Extraction was performed with 2 × 50 mL of ethyl acetate, and the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 1b.

[0094] 1 H NMR (400MHz, CDCl3) δ = 8.11 (d, J = 6.1Hz, 1H), 6.54 (d, J = 6.4Hz, 1H), 4.55 (t, J = 5.2Hz, 1H), 3.45 (s, 6H), 3.40 (t, J = 5.4Hz, 2H).

[0095] Step 2: Synthesis of compound 1c

[0096] Compound 1b (1 g, 4.14 mmol) and methanol (12 mL) were added to a pre-dried single-necked flask, followed by sodium methoxide (447.08 mg, 8.28 mmol). The reaction was incubated at 60°C for 12 hours. The reaction was quenched with 100 mL of saturated ammonium chloride solution, extracted with 2 × 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated to afford compound 1c.

[0097] Step 3: Synthesis of compound 1d

[0098] Compound 1c (1 g, 4.21 mmol) and tetrahydrofuran (10 mL) were added to a dry, single-necked flask. Methylmagnesium bromide (3 M, 5.62 mL) was then added at 0°C. The reaction was incubated at 60°C for 12 hours. The reaction mixture was stirred with 3N citric acid for 5 hours. Upon completion of the intermediate reaction, the pH was adjusted to 7-8 with 50 mL of saturated sodium bicarbonate solution. The mixture was extracted with 3 × 50 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated to yield compound 1d.

[0099] 1 H NMR (400MHz, CDCl3) δ = 7.84 (d, J = 6.4Hz, 1H), 6.28 (d, J = 6.1Hz, 1H), 4.57 (t, J=5.5Hz,1H),3.99(s,3H),3.44(s,6H),3.36(t,J=5.5Hz,2H),2.61(s,3H).

[0100] Step 4: Synthesis of Compound 1f

[0101] Compound 1d (0.7 g, 2.75 mmol) and tetrahydrofuran (20 mL) were added to a pre-dried single-necked flask. Dimethyl oxalate (698.92 mg, 5.92 mmol) was then added, followed by potassium tert-butoxide (1 M, 4.90 mL) at 0°C. The reaction was incubated at 0°C for 1 hour. LCMS showed that the starting material signal disappeared, while the intermediate 1e signal was generated. The reaction solution was then slowly added to citric acid (3 M, 27.53 mL) at 0°C, and the temperature was slowly raised to 25°C for 12 hours. The reaction solution was adjusted to pH 7-8 with 100 mL of saturated sodium bicarbonate solution at low temperature, extracted with 2 × 50 mL of ethyl acetate, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 1f.

[0102] 1H NMR (400MHz, CDCl3) δ = 8.21 (d, J = 6.4Hz, 1H), 7.02 (d, J = 6.4Hz, 1H), 6.74 (s, 1H), 4.53 (br s,2H),4.49-4.45(m,1H),4.13(s,3H),3.95(s,3H),3.35(s,6H).

[0103] Step 5: Synthesis of Compound 1g

[0104] 1f (3.3 g, 10.24 mmol) was dissolved in acetonitrile (70 mL), followed by the addition of acetic acid (2.93 mL) and methanesulfonic acid (295.19 mg). The reaction was incubated at 65°C for 36 hours. The reaction mixture was then cooled and used directly in the next step.

[0105] Step 6: Synthesis of compound 1h

[0106] L-aminopropanol (3.36 g, 44.80 mmol) was added to the reaction mixture of compound 1g and the reaction was incubated at 65°C for 12 h. The reaction mixture was cooled, and 50 mL of water was added to a conical flask. Extraction was performed with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 1h.

[0107] 1 H NMR (400MHz, DMSO-d6) δ = 8.24 (d, J = 6.3Hz, 1H), 7.48-7.37 (m, 1H), 6.67 (s, 1H), 5.42 (dd, J = 4.3, 9.9Hz, 1H), 5 .10-5.01(m,1H),4.44-4.40(m,1H),4.35-4.29(m,1H),3.94(s,3H),3.78-3.66(m,2H),1.34(d,J=6.3Hz,3H).

[0108] Step 7: Synthesis of Compound 1i

[0109] Compound 1h (0.2 g, 663.80 μmol) was dissolved in acetonitrile (3 mL), followed by the addition of 1,4-diazabicyclo[2,2,2]octane (3.72 mg, 33.19 μmol, 3.65 μL) and trichloroisocyanuric acid (72.51 mg, 311.98 μmol). The reaction was incubated at 40°C for 12 h. A conical flask was added, 20 mL of water was added, and the reaction mixture was poured into it. Extraction was performed with 20 mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1i.

[0110] 1 H NMR (400MHz, DMSO-d6) δ=8.29-8.18(m,1H),7.36(d,J=6.6Hz,1H),5.42(dd,J=3.8,9.8Hz,1H),4.91(br dd,J=3.6,12.4Hz,1H),4.40-4.26(m,2H),3.92(s,3H),3.86-3.78(m,1H),3.67(dd,J=6.4,7.9Hz,1H),1.29(d,J=6.1Hz,3H).

[0111] Step 8: Synthesis of Compound 1j

[0112] Compound 1i (0.5 g, 1.49 mmol) was dissolved in acetonitrile (12 mL), followed by the addition of sodium iodide (669.68 mg, 4.47 mmol) and cerium chloride heptahydrate (1.66 g, 4.47 mmol, 424.64 μL). The reaction was incubated at 100°C for 12 h. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to yield a residue. The methanol solution was filtered through a syringe filter to obtain the crude product. The crude product was then separated by preparative reverse-phase liquid chromatography (Phenomenex Luna column, 80 × 30 mm × 3 μm; mobile phase: [H₂O(HCl)-ACN]; ACN %: 1%-25%, 8 min) to afford compound 1j.

[0113] 1 HNMR (400MHz, DMSO-d6) δ = 7.64 (br d, J = 7.7Hz, 1H), 6.64 (br d, J = 7.7Hz, 1H), 5.43 (dd, J = 3.5, 9.6Hz, 1H), 4.83 (br dd,J=3.6,12.2Hz,1H),4.38-4.30(m,2H),3.84-3.67(m,3H),1.31(d,J=5.9Hz,3H).

[0114] Step 9: Synthesis of Compound 1k

[0115] Compound 1j (0.74 g, 2.30 mmol) was dissolved in N,N-dimethylformamide (7 mL) and 1,4-dioxane (7 mL). 1,8-diazabicycloundec-7-ene (525.27 mg, 3.45 mmol) and benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (1.32 g, 2.99 mmol) were added and stirred for 0.5 h. 2,4-Difluorobenzylamine (987.70 mg, 6.90 mmol) was added and stirred at 80°C for 6 h. A conical flask was added, 20 mL of water was added, and the reaction mixture was poured into it. Extraction was performed with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1k.

[0116] 1 H NMR (400MHz, DMSO-d6) δ = 10.45 (t, J = 5.8Hz, 1H), 8.12 (d, J = 6.3Hz, 1H), 7.52 -7.40(m,1H),7.33-7.18(m,1H),7.10-7.04(m,1H),6.88(d,J=6.4Hz,1H),5. 44(dd,J=3.8,9.7Hz,1H),4.89(dd,J=4.0,12.3Hz,1H),4.82-4.71(m,2H),4. 42-4.26(m,2H),3.89-3.80(m,1H),3.75-3.68(m,1H),1.33(d,J=6.0Hz,3H).

[0117] Step 10: Synthesis of Compound 1

[0118] Compound 1k (50 mg, 111.90 μmol) was dissolved in anhydrous ethanol (1 mL), followed by the addition of sodium hydroxide (22.38 mg, 559.49 μmol). The reaction was incubated at 65°C for 16 hours. The reaction mixture was poured into an Erlenmeyer flask, and 1N citric acid solution was added to adjust the pH to 4. Then, 10 mL of ethyl acetate was added, followed by the addition of 10 mL of saturated sodium bicarbonate solution to wash the organic phase. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was dissolved in methanol and filtered through a syringe filter to obtain the crude product. The crude product was separated by preparative reverse-phase liquid chromatography (Separation conditions: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [H2O(NH3H2O+NH4HCO3)-ACN]; ACN%: 45%-65%, 8 min) to obtain compound 1. MS (ESI, m / z): 429.2 [M+1].

[0119] 1 H NMR (400MHz, DMSO-d6) δ = 11.84-11.67 (m, 1H), 10.56 (br t,J=5.7Hz,1H),7.98(d,J=6.4Hz,1H),7.43-7.35(m,1H),7.27-7.21(m,1H),7.06-7.00(m,1H),6.84(d,J=6.6Hz,1H),5.36(dd,J=4.2,9.8Hz, 1H),5.10(br dd,J=4.2,12.4Hz,1H),4.74(br d,J=5.3Hz,2H),4.47-4.32(m,2H),3.73-3.60(m,2H),1.37(d,J=6.2Hz,3H).

[0120] Example 2

[0121] Synthesis route:

[0122] Step 1: Synthesis of compound 2a

[0123] To a pre-dried three-necked flask, 4,6-dichloro-5-pyrimidinecarboxaldehyde (2 g, 11.30 mmol) and tetrahydrofuran (20 mL) were added, followed by the addition of methylmagnesium bromide (3 M, 15.07 mL) at 0°C. The reaction was stirred at 25°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide compound 2a.

[0124] Step 2: Synthesis of compound 2b

[0125] To a pre-dried, single-necked flask, 2a (1.5 g, 7.77 mmol) was added, along with dichloromethane (20 mL) and Dess-Martin (3.63 g, 8.55 mmol). The reaction was stirred at 20°C for 12 hours. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was then separated by silica gel column chromatography (ethyl acetate:petroleum ether = 100:0 to 90:10) to afford 2b.

[0126] Step 3: Synthesis of compound 2c

[0127] To a pre-dried single-necked flask, 2b (0.950 g, 4.97 mmol) and N,N-dimethylformamide (10 mL) were added and stirred. Aminoacetaldehyde dimethyl acetal (522.88 mg, 4.97 mmol) and triethylamine (1.01 g, 9.95 mmol) were then added. The reaction was stirred at 0°C for 5 hours. 20 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was isolated by silica gel column chromatography (ethyl acetate:petroleum ether = 100:0 to 80:20) to afford 2c.

[0128] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (d, J = 1.6Hz, 1H), 8.14 (br s, 1H), 4.58-4.52 (m, 1H), 3.52 (br t, J = 4.6Hz, 2H), 3.31-3.24 (m, 6H), 2.62-2.55 (m, 3H).

[0129] Step 4: Synthesis of compound 2d

[0130] To a pre-dried single-necked flask, 2c (10.24 g, 39.43 mmol) and methanol (50 mL) were added, followed by sodium methoxide (4.26 g, 78.86 mmol). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 60°C for 2 hours. The reaction was quenched with 50 mL of saturated ammonium chloride solution and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with 150 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated by silica gel column chromatography (ethyl acetate:petroleum ether = 100:0 to 90:10) to afford 2d.

[0131] 1 H NMR (400MHz, CDCl3) δ = 9.82 (br s, 1H), 8.23 ​​(s, 1H), 4.50 (t, J = 5.4Hz, 1H), 4.00 (s, 3H), 3.68 (t, J = 5.6Hz, 2H), 3.39 (s, 6H), 2.55 (s, 3H).

[0132] Step 5: Synthesis of compound 2f

[0133] To a pre-dried three-necked flask, 2d (0.7 g, 2.74 mmol) and tetrahydrofuran (10 mL) were added, followed by dimethyl oxalate (696.23 mg, 5.90 mmol). Potassium tert-butoxide (1 M, 4.88 mL) was then added at 0°C, and the reaction was continued at 0°C for 5 min. Compound 2e was obtained. Citric acid (3 M, 27.42 mL) was slowly added at 0°C, the nitrogen atmosphere was replaced three times, and the temperature was raised to 20°C and stirred for 24 hours. The reaction mixture was adjusted to pH 7-8 with saturated sodium bicarbonate solution at low temperature and extracted with dichloromethane:methanol (10:1) (20 mL x 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate:petroleum ether = 100:0 to 0:100) to obtain 2f.

[0134] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (s, 1H), 6.59 (s, 1H), 4.92-4.80 (m, 2H), 4.46 (t, J = 4.8Hz, 1H), 4.11 (s, 3H), 3.95 (s, 3H), 3.38 (s, 3H), 3.31 (s, 3H).

[0135] Step 6: Synthesis of compound 2g

[0136] To a pre-dried single-necked flask, 2f (0.1 g, 309.31 μmol) and N,N-dimethylformamide (2 mL) were added, followed by 2,4-difluorobenzylamine (66.41 mg, 463.96 μmol) and triethylamine (31.30 mg, 309.31 μmol). The mixture was stirred at 35°C for 12 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated by silica gel column chromatography (ethyl acetate:petroleum ether = 100:0 to 75:25) to yield 2 g.

[0137] 1 H NMR (400MHz, CDCl3) δ=10.78-10.69(m,1H),8.49-8.44(m,1H),7.43-7.35(m,1H),6.88-6.79(m,2H),6.68-6.63(m,1H),4.96(br d,J=2.9Hz,2H),4.83(d,J=6.0Hz,2H),4.34(t,J=5.1Hz,1H),3.95(s,3H),3.35(s,6H).

[0138] Step 7: Synthesis of compound 2i

[0139] To a pre-dried single-necked flask, 2g (0.7g, 1.61mmol) was added acetic acid (1mL) and methanesulfonic acid (92.93mg, 966.87μmol, 68.83μL). The mixture was stirred at 35°C for one hour to yield 2h. The temperature was then lowered to 20°C, and acetonitrile (5mL) and L-aminopropanol (181.55mg, 2.42mmol) were added. The mixture was stirred at 65°C for 20 hours. 10mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10mL x 3). The combined organic phases were washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was isolated by silica gel column chromatography (ethyl acetate:petroleum ether = 100:0 to 50:50) to yield 2i.

[0140] 1 H NMR (400MHz, CDCl3) δ = 10.74 (br s, 1H), 8.47 (s, 1H), 7.46-7.31 (m, 1H), 7.12 (s, 1H), 6.83 (br t,J=8.4Hz,2H),5.86(dd,J=4.1,13.0Hz,1H),5.30-5.19(m,1H),4.88-4.79(m,2 H),4.53-4.42(m,2H),3.78-3.65(m,1H),3.32(dd,J=10.1,12.9Hz,1H),1.46(br d,J=5.9Hz,3H).

[0141] Step 8: Synthesis of compound 2j

[0142] To a pre-dried single-necked flask, 2i (0.07 g, 169.34 μmol) and acetonitrile (5 mL) were added, followed by trichloroisocyanuric acid (18.89 mg, 81.28 μmol) and 1,4-diazabicyclo[2,2,2]octane (949.75 μg, 8.47 μmol). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 40°C for 1 hour. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane:methanol (10:1) (10 mL x 3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 2j, which was used directly in the next step without purification.

[0143] 1H NMR (400MHz, CDCl3) δ=10.69-10.58(m,1H),8.48(s,1H),7.44-7.32(m,1H),6.84(br t,J=8.4Hz,2H),5.94(br d,J=1.5Hz,1H),5.31-5.20(m,1H),4.84(br d,J=5.7Hz,2H),4.47-4.41(m,1H),4.39-4.27(m,1H),3.72(t,J=8.0Hz,1H),3.32(dd,J=11.0,12.3Hz,1H),1.46(d,J=5.9Hz,3H).

[0144] Step 9: Synthesis of Compound 2

[0145] Prepare a dry single-necked flask, add 2j (115.00 mg, 256.80 μmol) and tetrahydrofuran (2 mL) solvent, then add sodium hydroxide (51.36 mg, 1.28 mmol), replace the atmosphere with nitrogen three times, and react at 60°C for 1 hour. The reaction solution is concentrated under reduced pressure, dissolved with N,N-dimethylformamide, and the insoluble matter is filtered off. Methanol (approximately 0.2 mL) is added to the reaction solution, and a solid precipitates from the reaction solution. After filtration, the solid is washed with water and lyophilized. The filter cake is slurried with methanol (0.2 mL) for 1 hour, filtered, washed with water, and lyophilized to obtain compound 2.

[0146] MS (ESI, m / z): 430.1 [M+1].

[0147] 1 H NMR (400MHz, CDCl3) δ = 11.72 (s, 1H), 10.78-10.72 (m, 1H), 8.40 (s, 1H), 7.43-7.35 (m, 1H), 6.89-6.79 (m, 2H), 6.05-5.96 (m, 1H), 5.25 (br d,J=0.9Hz,1H),4.91-4.81(m,2H),4.53-4.43(m,2H),3.80-3.70(m,2H),1.52-1.48(m,3H).

[0148] Example 3

[0149] Synthesis route:

[0150] Step 1: Synthesis of compound 3a

[0151] To a dry three-necked flask, add (S)-2-(Boc-amino)-N-methoxy-N-methylpropionamide (25 g, 182.33 mmol) and tetrahydrofuran (50 mL). Cool to -15°C in a dry ice-ethanol bath and stir for 10 minutes. Replace the atmosphere with nitrogen three times, then add a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 14.85 mL, 44.56 mmol). Stir the reaction at -15°C for 10 minutes. Slowly add a solution of 3-butenylmagnesium bromide in tetrahydrofuran (0.5 M, 396.08 mL) over 30 minutes and stir at 25°C for 3 hours. Quench the reaction slowly with 2M dilute hydrochloric acid (30 mL) until bubbling ceases. Extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1-10:1) to obtain 3a.

[0152] 1 H NMR(400MHz, CDCl3)δ=5.88-5.68(m,1H),5.08-4.92(m,2H),4.38-4.23(m,1H) ),2.68-2.50(m,2H),2.39-2.26(m,2H),1.47-1.39(m,9H),1.33-1.28(m,3H).

[0153] Step 2: Synthesis of compound 3b

[0154] A pre-dried three-necked flask was charged with 9-borabicyclo[3.3.1]nonane (0.5M, 270mL, 135mmol). The mixture was purged with nitrogen three times and cooled to 0°C in an ice-water bath. 3a (9.6g, 42.24mmol) was dissolved in tetrahydrofuran (60mL) and slowly added dropwise to the reaction mixture. The temperature was raised to 25°C and stirred for 4 hours. After completion, the reaction mixture was cooled to 0°C in an ice-water bath. Sodium hydroxide solution (6M, 60mL, 360mmol) and hydrogen peroxide solution (30%, 60mL, 624mmol) were slowly added to the reaction mixture in sequence. The temperature was raised to 25°C and stirred for 1 hour. The insoluble material was filtered, quenched with saturated aqueous sodium sulfite solution (150mL), and extracted with ethyl acetate (150mL x 3). The organic phases were combined, washed with saturated brine (300mL), dried over anhydrous sodium sulfate, and filtered. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1-1:1) to obtain 3b.

[0155] 1H NMR (400MHz, CDCl3) δ=5.05-4.91(m,1H),3.72-3.55(m,4H),3.11(br s,2H),1.64-1.49(m,3H),1.36(br s,12H),1.10-1.01(m,3H).

[0156] Step 3: Synthesis of compound 3c

[0157] To a dry three-necked flask, 3b (9 g, 36.39 mmol) was added, followed by dichloromethane (150 mL) and trifluoroacetic acid (49.79 g, 436.66 mmol). The atmosphere was replaced with nitrogen three times and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethanol (90 mL), and the pH was adjusted to alkaline by adding fine solid sodium hydroxide. The excess sodium hydroxide solid was removed by filtration, and the ethanol was concentrated under reduced pressure to yield 3c, which was used directly in the next step without purification.

[0158] 1 H NMR (400MHz, D2O) δ=3.66-3.57(m,2H),3.52-3.43(m,1H),2.88-2.78(m,1H),1.69-1.32(m,6H),1.08-0.99(m,3H).

[0159] Step 4: Synthesis of compound 3d

[0160] To a pre-dried three-necked flask, 1d (4.78 g, 17.30 mmol) and acetonitrile (100 mL) were added and stirred. Acetic acid (5.20 g, 86.52 mmol) and methanesulfonic acid (0.499 g, 5.19 mmol) were then added. The temperature was raised to 65°C and stirred for 72 hours. 3c (5.63 g, 38.24 mmol) was added and stirred at 65°C for another 24 hours. Water (150 mL) was added to the reaction solution, followed by extraction with dichloromethane (150 mL x 5). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 50:1 to 20:1) to yield 3d.

[0161] 1H NMR (400MHz, CDCl3) δ=8.29-8.20(m,1H),7.14-7.05(m,1H),6.89-6.81(m,1H),5.51-5.40(m,1H),4.67-4.55(m,2H),4.30-4 .22(m,1H),4.16-4.08(m,3H),3.78-3.70(m,2H),3.64-3.54(m,1H),1.77-1.59(m,6H),1.39-1.34(m,1H),1.32-1.22(m,3H).

[0162] Step 5: Synthesis of compound 3e

[0163] To a pre-dried single-necked flask, 3d (2.73 g, 7.31 mmol) and acetonitrile (54 mL) were added, followed by trichloroisocyanuric acid (0.578 g, 2.49 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (41.01 g, 0.365 mmol). The reaction was incubated at 40°C for 4 hours. Water (150 mL) was added to the reaction solution, followed by extraction with dichloromethane (150 mL x 5). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 50:1-20:1) to afford compound 3e.

[0164] 1 H NMR (400MHz, CDCl3) δ=8.18-8.12(m,1H),6.78-6.71(m,1H),5.66-5.56(m,1H),4.66-4.57(m,1H),4.54-4.4 4(m,1H),4.35-4.25(m,1H),4.05-3.98(m,3H),3.76-3.69(m,3H),1.76-1.58(m,6H),1.27(d,J=6.5Hz,4H).

[0165] Step 6: Synthesis of compound 3f

[0166] To a pre-dried single-necked flask, 3e (1 g, 2.45 mmol) and acetonitrile (20 mL) were added, followed by sodium iodide (1.10 g, 7.36 mmol) and cerium chloride heptahydrate (2.74 g, 7.36 mmol). The reaction was incubated at 90°C for 18 hours. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative reverse-phase liquid chromatography (Phenomenex C18 150 x 40 mm x 5 μm; mobile phase: [H2O(HCl)-ACN]; ACN%: 1%-30%, 10 min) to afford compound 3f.

[0167] 1 H NMR (400MHz, CD3OD) δ = 8.09-7.92 (m, 1H), 7.17-7.03 (m, 1H), 5.71-5.59 (m, 1H), 5.13-4.98 (m, 1H), 4.71-4.56 (m, 1H) ),4.45-4.33(m,1H),4.27-4.12(m,1H),3.68-3.55(m,2H),1.82-1.60(m,5H),1.58-1.43(m,1H),1.38-1.22(m,3H).

[0168] Step 7: Synthesis of compound 3g

[0169] To a pre-dried single-necked flask, 3f (650 mg, 1.65 mmol, 1 eq) was added and dissolved in 1,4-dioxane (6 mL) and N,N-dimethylformamide (6 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (376.90 mg, 2.48 mmol, 1.5 eq) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (948.98 mg, 2.15 mmol, 1.3 eq) were then added. The reaction was stirred at 25°C for 0.5 h. 2,4-Difluorobenzylamine (708.73 mg, 4.95 mmol, 3 eq) was added and the mixture was allowed to react at 80°C for 16 h. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1-1:9) to obtain 3 g of compound.

[0170] 1H NMR (400MHz, CDCl3) δ = 10.64-10.49 (m, 1H), 8.27-8.12 (m, 1H), 7.44-7.3 4(m,1H),6.90-6.75(m,3H),6.42-6.30(m,1H),5.35-5.24(m,1H),4.85- 4.78(m,2H),4.77-4.67(m,1H),3.98-3.90(m,1H),3.90-3.82(m,1H),3. 76-3.68(m,2H),3.66-3.55(m,1H),1.87-1.54(m,7H),1.52-1.41(m,3H).

[0171] Step 8: Synthesis of compound 3

[0172] To a pre-dried single-necked flask, 3 g (50 mg, 0.097 mmol) of the compound and tetrahydrofuran (1.5 mL) were added, followed by ground sodium hydroxide (19.27 mg, 0.49 mmol). The reaction was incubated at 65°C for 4 hours. The reaction mixture was adjusted to pH 4-5 with 1 M citric acid solution and then to pH 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (5 mL x 5). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography (Xtimate C18 150 x 40 mm x 5 μm; mobile phase: [H2O(HCl)-ACN]; ACN%: 5%-35%, 10 min) to yield compound 3.

[0173] MS (ESI, m / z): 501.1 [M+1].

[0174] 1 H NMR (400MHz, CD3OD) δ=7.90-7.80(m,1H),7.62-7.48(m,1H),7.33-7.21(m,1H),7.20-7.02(m,2H),5.62-5.51(m,1H),5.21-5.08(m,1H),4.95-4 .75(m,2H),4.71-4.58(m,1H),4.44-4.27(m,1H),3.95-3.78(m,1H),3.6 8-3.56(m,2H),1.82-1.58(m,5H),1.57-1.45(m,1H),1.40-1.26(m,3H).

[0175] Example 4

[0176] Synthesis route:

[0177] Step 1: Synthesis of compound 4a

[0178] To a pre-dried single-necked flask, add 3g (250mg, 0.48mmol) and dichloromethane (5mL). Cool to 0°C in an ice-water bath. Then, add Dess-Martin periodinane (306.5mg, 0.722mmol) and incubate at 25°C for 2 hours. The reaction mixture is diluted with dichloromethane (10mL) and extracted with saturated sodium bicarbonate (10mL x 3). The organic phase is concentrated under reduced pressure. The crude product is separated by silica gel column chromatography (dichloromethane / methanol = 30:1-10:1) to obtain compound 4a.

[0179] Step 2: Synthesis of compound 4b

[0180] To a pre-dried single-necked flask, 4a (160 mg, 0.309 mmol) and dimethyl sulfoxide (6.4 mL) were added, along with a solution of 2-methyl-2-butene (451.52 mg, 6.44 mmol) in tetrahydrofuran (3.2 mL). A solution of sodium dihydrogen phosphate (308.23 mg, 2.57 mmol) and sodium chlorite (44.79 mg, 0.495 mmol) in water (1.6 mL) was then added. The reaction was incubated at 25°C for 16 hours. The remaining sodium hypochlorite was quenched by the slow addition of dilute sodium sulfite solution (6.4 mL). The crude filtrate was then directly purified by preparative reverse-phase liquid chromatography (Xtimate C18 150*40 mm*5 μm; mobile phase: [H2O(HCl)-ACN]; ACN%: 15%-45%, 10 min) to afford compound 4b.

[0181] 1 H NMR (400MHz, CD3OD) δ=8.06-7.94(m,1H),7.61-7.49(m,1H),7.30-7.20(m,1H),7.17-6.99(m,2H),5.67-5.36(m,1H),4.95-4.80(m,3H) ),4.70-4.58(m,1H),4.47-4.32(m,1H),4.18-3.89(m,1H),2.49-2.38(m,2H),1.95-1.81(m,1H),1.80-1.66(m,3H),1.34-1.24(m,3H).

[0182] Step 3: Synthesis of compound 4

[0183] To a pre-dried single-necked flask, 4b (60 mg, 0.112 mmol) and tetrahydrofuran (1.5 mL) were added, followed by the addition of finely ground sodium hydroxide (45.03 mg, 1.13 mmol). The reaction was incubated at 65°C for 12 hours. The reaction mixture was adjusted to pH 4-5 with 1 M citric acid solution and then to pH 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (5 mL x 5). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography (Xtimate C18 150 x 40 mm x 5 μm; mobile phase: [H2O(HCl)-ACN]; ACN%: 15%-35%, 10 min) to yield compound 4.

[0184] MS (ESI, m / z): 515.1 [M+1].

[0185] 1 H NMR (400MHz, CD3OD) δ=7.90-7.80(m,1H),7.61-7.49(m,1H),7.29-7.21(m,1H),7.18-7.01(m,2H),5.63-5.51(m,1H),5.20-5.08(m,1H) ),5.07-4.75(m,2H),4.69-4.58(m,1H),4.42-4.30(m,1H),3.93-3.80(m,1H),2.48-2.37(m,2H),1.92-1.64(m,4H),1.34-1.30(m,3H).

[0186] Example 5

[0187] Synthesis route:

[0188] Step 1: Synthesis of compound 5a

[0189] To a pre-dried, single-necked flask, 2f (1 g, 3.09 mmol) and N,N-dimethylformamide (10 mL) were added, followed by 2,4,6-trifluorobenzylamine (747.56 mg, 4.64 mmol) and triethylamine (469.49 mg, 4.64 mmol, 645.78 μL). The mixture was stirred at 35°C for 12 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 75:25), and the fractions were concentrated under reduced pressure to obtain 5a.

[0190] 1H NMR (400MHz, CDCl3) δ = 10.64 (br s, 1H), 8.50 (s, 1H), 6.69 (t, J = 8.1Hz, 2H), 6.62 (s, 1H), 4.95 (br s, 2H), 4.86 (d, J = 5.5Hz, 2H), 4.33 (t, J = 5.1Hz, 1H), 3.94 (s, 3H), 3.35 (s, 6H).

[0191] Step 2: Synthesis of compound 5c

[0192] To a pre-dried single-necked vial, 5a (0.1 g, 221.05 μmol) was added acetic acid (1 mL) and methanesulfonic acid (12.75 mg, 132.63 μmol, 9.44 μL). The mixture was stirred at 35°C for 1 hour to yield 5b. The temperature was then lowered to 20°C, and acetonitrile (5 mL) and L-aminopropanol (24.25 mg, 331.58 μmol, 33.17 μL) were added. The mixture was stirred at 65°C for 72 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 50:50), and the fractions were concentrated under reduced pressure to yield 5c.

[0193] 1 H NMR (400MHz, CDCl3) δ = 10.64 (br d,J=5.0Hz,1H),8.49(s,1H),7.09(s,1H),6.74-6.65(m,2H),5.86(dd,J=4.3,13.0Hz,1H),5.25(dd,J=4.2,10.1Hz,1 H),4.87(d,J=5.6Hz,2H),4.53-4.42(m,2H),3.77-3.68(m,1H),3.32(dd,J=10.1,12.9Hz,1H),1.46(d,J=6.0Hz,3H).

[0194] Step 3: Synthesis of compound 5d

[0195] To a pre-dried single-necked flask, 5c (0.07 g, 162.27 μmol) and acetonitrile (1 mL) were added, followed by trichloroisocyanuric acid (18.10 mg, 77.89 μmol) and 1,4-diazabicyclo[2,2,2]octane (910.12 μg, 8.11 μmol, 0.89 μL). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 40°C for 1 hour. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane / methanol (10:1, 10 mL x 3). The combined organic phases were washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5d, which was used directly in the next step without purification. 1 H NMR(400MHz, CDCl3)δ=10.58-10.52(m,1H),8.53-8.49(m,1H),6.75-6.66(m,2H),6.04-5.96(m,1H),5.28-5.1 6(m,1H),4.92-4.86(m,2H),4.54-4.38(m,2H),3.72(t,J=8.0Hz,1H),3.36-3.24(m,1H),1.46(d,J=6.1Hz,3H).

[0196] Step 4: Synthesis of compound 5

[0197] Prepare a dry, single-necked flask and add 5d (0.06 g, 128.81 μmol) and tetrahydrofuran (1 mL). Then, add sodium hydroxide (25.76 mg, 644.04 μmol). Replace the atmosphere with nitrogen three times and incubate at 60°C for 1 hour. The reaction mixture is concentrated under reduced pressure and slurried with methanol (1 mL) for 1 hour. After filtration, the filter cake is washed with water and lyophilized to yield 5.

[0198] MS (ESI, m / z): 447.1 [M+1].

[0199] 1 H NMR (400MHz, DMSO-d6) δ = 11.81 (s, 1H), 10.67-10.59 (m, 1H), 8.52-8.37 (m, 1H), 7.35-7.15 (m, 2H), 5.74-5.58 (m, 1H),5.38-5.29(m,1H),4.90(s,2H),4.49-4.28(m,2H),3.74-3.57(m,1H),3.20-3.13(m,1H),1.44-1.28(m,3H).

[0200] Example 6

[0201] Synthesis route:

[0202] Step 1: Synthesis of compound 6a

[0203] To a round-bottom flask, 2f (358.86 mg, 1.11 mmol), N,N-dimethylformamide (4 mL), 2,6-difluorobenzylamine (238.11 mg, 1.67 mmol, 198.43 μL), and triethylamine (168.34 mg, 1.67 mmol, 231.55 μL) were added and reacted at 35°C for 12 hours. The reaction mixture was poured into the conical flask after adding 20 mL of water. Extraction was performed with 20 mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 10:1), and the fraction was concentrated under reduced pressure to obtain 6a.

[0204] 1 H NMR (400MHz, DMSO-d6) δ = 10.73 (t, J = 5.7Hz, 1H), 8.59 (s, 1H), 7.61-7.43 (m, 1H),7.20(t,J=8.0Hz,2H),6.67-6.49(m,1H),4.93(d,J=5.8Hz,2H),4.84(br s,2H),4.45-4.39(m,1H),3.94(s,3H),3.30(s,6H).

[0205] Step 2: Synthesis of compound 6c

[0206] 6a (0.37 g, 851.76 μmol) was dissolved in acetic acid (4 mL), and methanesulfonic acid (24.56 mg, 255.53 μmol, 18.19 μL) was added. The mixture was stirred at 65°C for 48 hours. The reaction mixture was concentrated to obtain crude product 6b. 6b was dissolved in 1,2-dichloroethane (4 mL), and L-aminopropanol (23.80 mg, 316.89 μmol, 24.66 μL) was added. The mixture was heated to 90°C in an oil bath and stirred for 24 hours. The reaction mixture was cooled, and 20 mL of water was added to a conical flask. The mixture was then extracted three times with 20 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. 6c was then purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain 6c.

[0207] Step 4: Synthesis of compound 6d

[0208] To a dried round-bottom flask, 6c (70 mg, 169.34 μmol) and acetonitrile (1 mL) were added, followed by trichloroisocyanuric acid (18.89 mg, 81.28 μmol) and 1,4-diazabicyclo[2,2,2]octane (949.75 μg, 8.47 μmol, 0.93 μL). The reaction was stirred at 40°C for 2 hours. The reaction mixture was cooled, and 20 mL of water was added to the conical flask. The mixture was then poured into the flask and extracted with 20 mL of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to afford 6d.

[0209] Step 5: Synthesis of compound 6

[0210] 6d (40 mg, 89.32 μmol) was dissolved in tetrahydrofuran (1 mL), and sodium hydroxide (17.86 mg, 446.61 μmol) was added. The mixture was stirred at 60°C for 12 hours. 20 mL of water was added to a conical flask, and the reaction mixture was poured into the flask. The mixture was then extracted with 20 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with methanol (1 mL) and filtered to obtain 6.

[0211] MS (ESI, m / z): 429.1 [M+1].

[0212] 1 H NMR (400MHz, DMSO-d6) δ = 11.04-10.31 (m, 1H), 8.30 (br s,1H),7.61-7.32(m,1H),7.25-6.96(m,2H),5.96-5.68(m,1H),5.43-5.12(m,1H),4.85(br d,J=2.9Hz,2H),4.44-4.29(m,1H),4.15(q,J=5.3Hz,2H),3.72-3.56(m,1H),3.17(d,J=5.1Hz,3H).

[0213] Example 7

[0214] Synthesis route:

[0215] Step 1: Synthesis of compound 7b

[0216] 7a (1 g, 6.33 mmol) was dissolved in acetonitrile (10 mL), and anhydrous potassium carbonate (961.57 mg, 6.96 mmol) and dimethyl sulfate (877.56 mg, 6.96 mmol, 659.82 μL) were added. The mixture was stirred at 25°C for 12 hours. 50 mL of water was added to a conical flask, and the reaction mixture was poured into the flask. Extraction was then performed with 50 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 7b, which was used directly in the next step without purification.

[0217] Step 2: Synthesis of compound 7c

[0218] Dissolve 7b (1 g, 5.81 mmol) in anhydrous ethanol (10 mL), add hydroxylamine hydrochloride (1.21 g, 17.43 mmol) and sodium acetate (1.91 g, 23.24 mmol), and heat to 80°C with stirring for 2 hours. Pour the reaction mixture into a conical flask, add 50 mL of water, and extract with 50 mL of ethyl acetate. Separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 7c, which was used directly in the next step without purification.

[0219] Step 3: Synthesis of compound 7d

[0220] Palladium on carbon (0.4 g, containing 10% palladium) and anhydrous ethanol (100 mL) were added to a hydrogenation flask, followed by 7c (4 g, 23.11 mmol) and hydrochloric acid (12 M, 11.34 mL). The reaction was stirred at 25°C and 50 psi for 16 hours. The reaction mixture was cooled, filtered through celite, and concentrated under reduced pressure to afford 7d, which was used directly in the next step without purification.

[0221] Step 4: Synthesis of compound 7e

[0222] 2f (310 mg, 0.96 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 7d (249.05 mg, 1.44 mmol) and triethylamine (145.54 mg, 1.44 mmol, 200.19 μL) were added. The mixture was stirred at 35°C for 12 hours. 50 mL of water was added to a conical flask, and the reaction mixture was then extracted with 50 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50:50), and the fraction was concentrated under reduced pressure to obtain 7e.

[0223] Step 5: Synthesis of compound 7g

[0224] 7e (0.2 g, 430.65 μmol) was dissolved in acetic acid (5 mL), and methanesulfonic acid (12.42 mg, 129.19 μmol, 9.20 μL) was added. The mixture was stirred at 65°C for 12 hours, and the reaction solution was concentrated to obtain crude 7f. 7f was dissolved in 1,2-dichloroethane (2 mL), and L-aminopropanol (52.11 mg, 693.84 μmol, 54.00 μL) was added. The mixture was heated to 90°C in an oil bath and stirred for 12 hours. The reaction solution was cooled, and 20 mL of water was added to a conical flask. The reaction solution was then extracted three times with 20 mL of dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50:50), and the fraction was concentrated under reduced pressure to obtain 7g.

[0225] 1 H NMR (400MHz, DMSO-d6) δ = 10.63 (t, J = 5.5Hz, 1H), 8.50 (s, 1H), 6.97-6.81 (m, 2H), 6.70 (s, 1H), 5.49 (dd, J = 4.3, 12.4Hz, 1H), 5.35 (dd, J = 4. 3,10.0Hz,1H),4.76-4.68(m,2H),4.39(dd,J=6.8,8.6Hz,1H),4.30-4.20(m,1H),3.91-3.86(m,3H),3.66-3.51(m,2H),1.34-1.27(m,3H).

[0226] Step 6: Synthesis of compound 7h

[0227] 7g (0.1g, 225.53μmol) was dissolved in acetonitrile (2mL), and trichloroisocyanuric acid (25.16mg, 108.25μmol) and 1,4-diazabicyclo[2,2,2]octane (1.26mg, 11.28μmol, 1.24μL) were added. The mixture was heated to 40°C in an oil bath and stirred for 2 hours. The reaction mixture was cooled, and 20mL of water was added to a conical flask. The mixture was then extracted with 20mL of ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50:50) to obtain 7h.

[0228] 1H NMR (400MHz, DMSO-d6) δ=6.98-6.79(m,2H),5.74(s,1H),5.62-5.54(m,1H),5.40-5.30(m,1H),4.75(d,J=5.5Hz,1H),4.37(dd,J=6.6 ,8.6Hz,1H),4.33-4.24(m,1H),3.93-3.87(m,3H),3.65(dd,J=7.0,8.3Hz,1H),3.61-3.51(m,1H),3.32(s,2H),1.29(d,J=6.1Hz,3H)

[0229] Step 7: Synthesis of compound 7

[0230] 7h (80 mg, 167.42 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and sodium hydroxide (33.48 mg, 837.09 μmol) was added. The mixture was heated to 60°C in an oil bath and stirred for 12 hours. A conical flask was added with 20 mL of water, and the reaction mixture was then extracted with 20 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and dissolved in methanol. The crude product was filtered through a syringe filter to obtain the crude product. The crude product was separated by preparative reverse-phase liquid chromatography (Phenomenex Luna 80 × 30 mm × 3 μm; mobile phase: [H₂O(HCl)-ACN]; ACN%: 30%-60%, 8 min) to obtain compound 7.

[0231] MS (ESI, m / z): 459.1 [M+1].

[0232] 1 H NMR (400MHz, DMSO-d6) δ=12.00-11.57(m,1H),10.61(t,J=5.5Hz,1H),8.42(s,1H),7.01-6.85(m,2H),5.66(dd,J=4.3,12.4Hz,1H),5.34(dd,J=4.2 ,10.0Hz,1H),4.76(d,J=5.5Hz,2H),4.44(dd,J=7.0,8.5Hz,1H),4.37-4. 30(m,1H),3.92(s,3H),3.68(dd,J=6.8,8.5Hz,2H),1.37(d,J=6.3Hz,3H).

[0233] Example 8

[0234] Synthesis route:

[0235] Step 1: Synthesis of compound 8b

[0236] 5a (0.4 g, 884.21 μmol) was dissolved in acetic acid (3 mL), and methanesulfonic acid (25.49 mg, 265.26 μmol, 18.88 μL) was added. The mixture was stirred at 65°C for 48 hours to yield 5b. The reaction mixture was concentrated, and 1,2-dichloroethane (3.5 mL) and 8a (144.38 mg, 1.43 mmol) were added. The mixture was heated to 90°C in an oil bath and stirred for 24 hours. The reaction mixture was cooled to room temperature, and then 20 mL of water was added to a conical flask. Extraction was performed with 20 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to yield 8b.

[0237] MS (ESI, m / z): 458.1 [M+1].

[0238] Step 2: Synthesis of compound 8c

[0239] 8b (30 mg, 65.59 μmol) was dissolved in acetonitrile (1 mL), and trichloroisocyanuric acid (7.16 mg, 30.83 μmol) and 1,4-diazabicyclo[2,2,2]octane (367.86 μg, 3.28 μmol, 0.36 μL) were added. The mixture was stirred at 40°C for 2 hours. The reaction mixture was cooled, and 20 mL of water was added to a conical flask. The mixture was then extracted three times with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain 8c.

[0240] MS (ESI, m / z): 492.0 [M+1].

[0241] 1 H NMR (400MHz, CDCl3) δ=10.56-10.41(m,1H),8.43(s,1H),6.68-6.53(m,3H),5.71(dd,J=3.9,13.5Hz,1H),5.27(t,J=4.0Hz,1H),5 .23(s,1H),5.18(dd,J=3.9,9.7Hz,1H),4.80(d,J=5.5Hz,2H),4.62-4.57(m,1H),3.36(dd,J=9.7,13.4Hz,1H),2.09-1.97(m,4H).

[0242] Step 3: Synthesis of compound 8

[0243] 8c (33 mg, 67.09 μmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and sodium hydroxide (13.42 mg, 335.47 μmol) was added. The mixture was stirred at 60°C for 12 hours. The reaction mixture was cooled, and then 20 mL of water was added to a conical flask. The mixture was then extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by preparative reverse-phase liquid chromatography (Separation conditions: Waters Xbridge BEH C18 100*30 mm*10 μm; Mobile phase: [water (NH4HCO3)-ACN]; ACN%: 45%-75%, 8 min) to obtain 8.

[0244] MS (ESI, m / z): 474.0 [M+1].

[0245] 1 H NMR (400MHz, DMSO-d6) δ = 12.71-12.38 (m, 1H), 10.65 (t, J = 5.7Hz, 1H), 8.40 (s, 1H), 7 .31-7.19(m,2H),5.42(dd,J=4.2,9.3Hz,1H),5.28(dd,J=4.2,12.9Hz,1H),5.11(br s,1H),4.83(t,J=6.1Hz,2H),4.62(br s,1H),3.61(dd,J=9.3,12.9Hz,1H),2.01-1.86(m,5H),1.62-1.55(m,1H).

[0246] Example 9

[0247] Synthesis route:

[0248] Step 1: Synthesis of compound 9a

[0249] Dissolve 7g (0.1g, 225.53μmol) in acetonitrile (2mL), add trichloroisocyanuric acid (25.16mg, 108.25μmol) and 1,4-diazabicyclo[2,2,2]octane (1.26mg, 11.28μmol, 1.24μL), and stir in an oil bath at 40°C for 2 hours. Cool the reaction mixture, pour 20mL of water into a conical flask, and extract three times with 20mL of ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product is purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1), and the fraction is concentrated under reduced pressure to obtain compound 9a.

[0250] MS (ESI, m / z): 512.1 [M+1].

[0251] Step 2: Synthesis of compound 9

[0252] 9a (80 mg, 167.42 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and sodium hydroxide (33.48 mg, 837.09 μmol) was added. The mixture was heated to 60°C in an oil bath and stirred for 12 hours. The reaction mixture was cooled, and then 20 mL of water was added to a conical flask. The mixture was then extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by preparative reverse-phase liquid chromatography (Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; ACN%: 30%-60%, 8 min) to obtain compound 9.

[0253] MS (ESI, m / z): 494.0 [M+1].

[0254] 1 H NMR (400MHz, CDCl3) δ = 11.63 (s, 1H), 10.75-10.57 (m, 1H), 8.34 (s, 1H), 6.50 (br d,J=10.6Hz,1H),5.90(dd,J=4.2,12.8Hz,1H),5.13(dd,J=4.3,9.9Hz,1H),4.84-4.74(m,2H),4.4 2-4.35(m,2H),3.87(s,3H),3.66-3.60(m,1H),3.16(dd,J=9.9,12.7Hz,1H),1.41(d,J=5.8Hz,3H).

[0255] Example 10

[0256] Synthesis route:

[0257] Step 1: Synthesis of compound 10b

[0258] In a single-necked flask, 10a (5 g, 28.9 mmol) and N,N-dimethylformamide (25 mL) were added, followed by aminoacetaldehyde dimethyl acetal (3.34 g, 31.79 mmol) and diisopropylethylamine (3.74 g, 28.9 mmol). The reaction was incubated at 50°C for 12 hours. 30 mL of water was added to the reaction solution. Extraction was performed with 2 × 50 mL of ethyl acetate, and the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 10b.

[0259] MS (ESI, m / z): 242.0 [M+1].

[0260] 1 H NMR (600MHz, DMSO-d6) δ8.31(s,1H),7.95(s,1H),6.67(s,1H),4.54(t,J=5.1Hz,1H),3.45(t,J=5.6Hz,2H),3.32(s,6H).

[0261] Step 2: Synthesis of compound 10c

[0262] To a pre-dried single-necked flask, 10b (1 g, 4.14 mmol) and methanol (12 mL) were added, followed by sodium methoxide (670.9 mg, 12.42 mmol). The reaction was incubated at 60°C for 12 hours. The reaction was quenched with 100 mL of saturated ammonium chloride solution, extracted with 2 × 100 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The crude product was purified by silica gel column chromatography to afford compound 10c.

[0263] MS (ESI, m / z): 238.0 [M+1].

[0264] 1 H NMR (600MHz, DMSO-d6) δ7.97(d,J=2.8Hz,1H),7.75(d,J=2.8Hz,1H),6.16(d,J=6.2Hz,1H ),4.53(d,J=2.5Hz,1H),3.93(d,J=2.9Hz,3H),3.46–3.38(m,2H),3.31(d,J=2.9Hz,6H).

[0265] Step 3: Synthesis of compound 10d

[0266] To a dry, single-necked flask, 10c (3.88 g, 16.35 mmol) and tetrahydrofuran (25 mL) were added, followed by the addition of methylmagnesium bromide (1 M, 49.05 mL) at -20°C. The reaction was allowed to proceed at room temperature for 12 hours. The pH of the reaction solution was adjusted to 3 with hydrochloric acid and stirred for 0.5 hours. Upon completion of the intermediate reaction, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The product was extracted with 3 × 50 mL of ethyl acetate, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated to yield compound 10d.

[0267] MS (ESI, m / z): 255.0 [M+1].

[0268] 1H NMR (600MHz, CDCl3) δ8.08(t,J=5.7Hz,1H),7.92(s,1H),7.70(s,1H),4.58(t,J=5.6Hz,1H) ,3.95(d,J=1.8Hz,3H),3.43(d,J=2.0Hz,6H),3.38(t,J=5.6Hz,2H),2.59(d,J=2.0Hz,3H).

[0269] Step 4: Synthesis of compound 10f

[0270] To a pre-dried, single-necked flask, 10d (2 g, 7.9 mmol) and tetrahydrofuran (20 mL) were added, along with dimethyl oxalate (1.4 g, 11.85 mmol). Potassium tert-butoxide (1.6 g) was then added at 0°C, and the reaction was incubated at 0°C for 1 hour. TLC indicated the disappearance of the starting material signal, while the signal for intermediate 10e was generated. The reaction solution was then slowly added to citric acid (45.5 g, 237 mmol) at 0°C, and the temperature was slowly raised to 25°C before continuing for 12 hours. The reaction solution was adjusted to pH 7-8 with 100 mL of saturated sodium bicarbonate solution at low temperature, extracted with 2 × 50 mL of ethyl acetate, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography to yield compound 10f.

[0271] MS (ESI, m / z): 323.1 [M+1].

[0272] 1 H NMR (600MHz, CDCl3) δ8.82(s,1H),8.19(s,1H),6.67(d,J=2.2Hz,1H),4.65(d,J=5.0Hz ,2H),4.53(t,J=4.9Hz,1H),4.08(s,3H),3.96(d,J=2.2Hz,3H),3.36(d,J=2.2Hz,6H).

[0273] Step 5: Synthesis of compound 10g

[0274] 10f (1.5 g, 4.7 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of acetic acid (2.8 g, 23.5 mmol) and methanesulfonic acid (406.54 mg, 4.23 mmol). The reaction mixture was then cooled and used directly in the next step. L-aminopropanol (0.78 g, 10.4 mmol) was added to the reaction mixture and the reaction mixture was allowed to react at 65°C for 12 hours. The reaction mixture was cooled, and 50 mL of water was added to a conical flask. The reaction mixture was then poured into the flask and extracted with 20 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column to obtain compound 10 g.

[0275] MS (ESI, m / z): 302.0 [M+1].

[0276] 1 H NMR(600MHz, CDCl3)δ8.65(dt,J=9.4,2.8Hz,1H),8.26–8.08(m,1H),7.09–6.90(m, 1H),5.40(ddd,J=11.8,3.9,1.6Hz,1H),4.94(dt,J=12.0,3.7Hz,1H),4.50(dt,J=15 .3, 6.2Hz, 1H), 4.45 (ddd, J=8.5, 6.9, 1.6Hz, 1H), 4.05 (dt, J=7.4, 2.1Hz, 3H), 3.76 (ddd,J=8.5,6.4,1.4Hz,1H),3.70(ddd,J=12.0,9.8,2.5Hz,1H),1.51–1.43(m,3H).

[0277] Step 6: Synthesis of compound 10h

[0278] Compound 10g (0.72g, 2.4mol) was dissolved in acetonitrile (3mL) and then 1,4-diazabicyclo[2,2,2]octane (13.5mg, 0.12mol) and trichloroisocyanuric acid (195mg, 0.84mol) were added. The reaction was allowed to react at room temperature for 12 hours. A conical flask was added with 20mL of water, and the reaction solution was poured into it. Extraction was performed with 20mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified on a silica gel column, and the fraction was concentrated under reduced pressure to obtain compound 10h.

[0279] MS (ESI, m / z): 336.0 [M+1].

[0280] 1H NMR (600MHz, CDCl3) δ8.63(s,1H),8.21(s,1H),5.46(dd,J=9.6,4.0Hz,1H),4.89(dd,J=12.0,4.0Hz,1H), 4.53(q,J=6.5Hz,1H),4.43(dd,J=8.8,6.6Hz,1H),4.07(s,3H),3.81–3.75(m,2H),1.49(d,J=6.2Hz,3H).

[0281] Step 7: Synthesis of compound 10i

[0282] 10h (0.31 g, 0.92 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of sodium iodide (0.41 g, 2.76 mmol) and cerium chloride (0.68 g, 2.76 mmol). The reaction was incubated at 100°C for 12 hours. A conical flask was then filled with 20 mL of water, and the reaction mixture was poured into it. Extraction was then performed with 20 mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column, and the fraction was concentrated under reduced pressure to obtain compound 10i.

[0283] MS (ESI, m / z): 322.0 [M+1].

[0284] Step 8: Synthesis of compound 10j

[0285] 10i (0.021 g, 0.06 mmol) was dissolved in 0.2 mL of pyridine, the nitrogen atmosphere was replaced, and the reaction was placed in an ice bath. Trifluoromethanesulfonic anhydride was then added and the reaction was allowed to react at room temperature for 12 hours. 10 mL of water was added to a conical flask, and the reaction solution was poured into the flask. Ethyl acetate (3 × 10 mL) was added for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified on a silica gel column, and the fraction was concentrated under reduced pressure to obtain compound 10j.

[0286] MS (ESI, m / z): 454.0 [M+1].

[0287] Step 9: Synthesis of compound 10k

[0288] 10j (0.12 g, 0.26 mmol) was weighed into a reaction tube, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (9.4 mg, 0.013 mmol), potassium phosphate (82 mg, 0.39 mmol), 1,1'-bis(diphenylphosphino)ferrocene (14 mg, 0.002 mmol), and 2,4-difluorobenzylamine (74 mg, 0.52 mmol). After nitrogen displacement, 3 mL of toluene was added and the reaction was incubated at 90°C for 12 hours. A conical flask was then filled with 10 mL of water and the reaction mixture. The mixture was extracted with 3 × 10 mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified on a silica gel column, and the fraction was concentrated under reduced pressure to obtain compound 10k.

[0289] MS (ESI, m / z): 447.0 [M+1].

[0290] Step 10: Synthesis of compound 10

[0291] Compound 10h (0.02 g, 0.04 mmol) was dissolved in 3 mL of tetrahydrofuran, followed by the addition of sodium hydroxide (0.2 g, 5 mmol). The reaction was incubated at 65°C for 12 hours. A conical flask was then filled with 10 mL of water, and the reaction mixture was poured into the flask. Extraction was then performed with 3 × 10 mL of ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column, and the fraction was concentrated under reduced pressure to obtain compound 10.

[0292] MS (ESI, m / z): 447.0 [M+1].

[0293] 1 H NMR (600MHz, DMSO-d6) δ9.87 (t, J=6.2Hz, 1H), 8.44 (s, 1H), 7.69 (s, 1H), 7.48 (q, J= 8.1Hz,1H),7.30–7.24(m,1H),7.07(td,J=8.7,2.6Hz,1H),6.08–5.96(m,1H),5.39( dd,J=9.9,4.3Hz,1H),5.31(dd,J=12.1,4.4Hz,1H),4.57(d,J=6.1Hz,2H),4.44(dd ,J=8.5,6.8Hz,1H),4.37(q,J=6.5Hz,1H),3.75–3.68(m,2H),1.38(d,J=6.3Hz,3H).

[0294] Example 11

[0295] Synthesis route:

[0296] Step 1: Synthesis of compound 11a

[0297] Boc-L-alanine aldehyde (8.5 g, 49.07 mmol) and tetrahydrofuran (160 mL) were added to a dry three-necked flask and dissolved into a colorless solution. The solution was cooled to 0°C and stirred. A solution of 3-butene magnesium bromide in tetrahydrofuran (1 M, 98.15 mL, 98.15 mmol) was slowly added and stirred at 25°C for 3 hours. The reaction solution was slowly quenched with saturated aqueous ammonium chloride (200 mL) until bubbling ceased. Ethyl acetate (150 mL x 3) was added for extraction. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1-10:1). The fraction was concentrated under reduced pressure to yield 11a, which showed the presence of isomers in a 3.5:1 ratio.

[0298] 1 H NMR (400MHz, CDCl3) δ=5.93-5.77(m,1H),5.12-4.92(m,2H),4.84-4.68(m,1H),3.75-3.59(m,1H) ,3.57-3.45(m,1H),2.35-2.08(m,3H),1.50-1.42(m,11H),1.23-1.16(m,3H),1.13-1.08(m,1H).

[0299] Step 2: Synthesis of compound 11b

[0300] To a pre-dried three-necked flask, add 9-borabicyclo[3.3.1]nonane (0.5M, 217.69 mL, 108.85 mmol), purge with nitrogen three times, and cool to 0°C in an ice-water bath. Dissolve 11a (3.9 g, 17.01 mmol) in tetrahydrofuran (24 mL) and slowly add dropwise to the reaction mixture. Warm to 25°C and stir for 21 hours. After completion, cool to 0°C in an ice-water bath. Slowly add sodium hydroxide solution (6M, 24.16 mL, 144.92 mmol) and hydrogen peroxide solution (30%, 24.15 mL, 251.37 mmol) to the reaction mixture. Warm to 25°C and stir for 1 hour. Filter the insoluble material, quench with saturated sodium sulfite solution (150 mL), and extract with ethyl acetate (150 mL x 3). Combine the organic phases, wash with saturated brine (300 mL), dry over anhydrous sodium sulfate, and filter. The organic phase was tested for hydrogen peroxide content using potassium iodide test paper. The organic phase was concentrated under reduced pressure until half to one-quarter of the volume remained, and then tested again using potassium iodide test paper. The remaining aqueous phase was quenched with saturated sodium sulfite solution (100 mL). The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1 to 1:1), and the fractions were concentrated under reduced pressure to obtain 11b, which showed the presence of isomers in a 3:1 ratio.

[0301] 1 H NMR(400MHz, CDCl3)δ=4.99-4.77(m,1H),3.88-3.72(m,3H),3.71-3.58(m,3H) ,1.67-1.55(m,8H),1.53-1.38(m,15H),1.21-1.13(m,2H),1.12-1.05(m,1H).

[0302] Step 3: Synthesis of compound 11c

[0303] To a dry three-necked flask, 11b (6.6 g, 26.68 mmol) was added, followed by dichloromethane (230 mL) and trifluoroacetic acid (36.51 g, 320.22 mmol). The atmosphere was replaced with nitrogen three times and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethanol (50 mL), and the pH was adjusted to alkaline by adding fine solid sodium hydroxide. The excess sodium hydroxide solid was removed by filtration, and the ethanol was concentrated under reduced pressure to yield 11c, which was used directly in the next step without purification.

[0304] Step 4: Synthesis of compound 11e

[0305] To a pre-dried three-necked flask, 1d (4 g, 12.41 mmol) and acetonitrile (100 mL) were added and stirred. Acetic acid (3.73 g, 62.05 mmol) and methanesulfonic acid (0.357 g, 3.72 mmol) were then added. The temperature was raised to 65°C and stirred for 72 hours. 11c (3.93 g, 26.7 mmol) was added and stirred at 65°C for another 24 hours. Water (150 mL) was added to the reaction solution, followed by extraction with dichloromethane (150 mL x 5). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 50:1 to 20:1) to afford 11e, which contained isomers in an 8.5:1 ratio.

[0306] 1 H NMR (400MHz, CDCl3) δ=8.31-8.07(m,1H),7.13(s,1H),6.87(d,J=6.5Hz,1H),5.44-5.21(m,1H),4.78(dd,J=4.3,12.0Hz,1H),4.16-4.06(m ,3H),4.02-3.82(m,2H),3.77-3.67(m,2H),3.66-3.53(m,1H),1.85- 1.74(m,4H),1.70-1.65(m,2H),1.51-1.45(m,3H),1.33-1.24(m,1H).

[0307] Step 6: Synthesis of compound 11f

[0308] To a pre-dried single-necked flask, 11e (2.12 g, 5.68 mmol) and acetonitrile (42 mL) were added, followed by trichloroisocyanuric acid (0.448 g, 1.93 mmol) and 1,4-diazabicyclo[2,2,2]octane (31.84 g, 0.283 mmol, 0.03 mL). The reaction was incubated at 40°C for 4 hours. Water (150 mL) was added to the reaction solution, followed by extraction with dichloromethane (150 mL x 5). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 50:1-20:1) to afford compound 11f, with an isomer ratio of 8.5:1.

[0309] 1H NMR (400MHz, CDCl3)δ=8.34-8.18(m,1H),6.90-6.75(m,1H),5.47-5.39(m,1H),4.80-4.71(m,1H), 4.13-4.08(m,3H),4.00-3.83(m,2H),3.78-3.68(m,2H),3.68-3.60(m,1H),1.77(br s,2H),1.74-1.64(m,4H),1.52-1.47(m,3H),1.33-1.28(m,1H).

[0310] Step 7: Synthesis of compound 11g

[0311] To a pre-dried single-necked flask, 11f (1.15 g, 2.82 mmol) and acetonitrile (20 mL) were added, followed by sodium iodide (1.27 g, 8.46 mmol) and cerium chloride heptahydrate (3.15 g, 8.46 mmol). The reaction was incubated at 90°C for 18 hours. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative reverse-phase liquid chromatography (Phenomenex C18 150 x 40 mm x 5 μm; mobile phase: [water (HCl)-ACN]; ACN%: 1%-30%, 10 min) to yield compound 11g, with a 9:1 isomer ratio.

[0312] 1 H NMR (400MHz, METHANOL-d4)δ=8.15-8.04(m,1H),7.34-7.26(m,1H),5.61-5.49(m,1H),5.44-5.31(m,1H),4.2 3-4.11(m,1H),4.05-3.90(m,2H),3.68-3.55(m,2H),1.95-1.55(m,6H),1.53-1.44(m,3H),1.34-1.28(m,1H).

[0313] Step 8: Synthesis of compound 11h

[0314] To a pre-dried single-necked flask, 11 g (650 mg, 1.65 mmol) of the compound was added and dissolved in 1,4-dioxane (6 mL) and N,N-dimethylformamide (6 mL). 1,8-diazabicycloundec-7-ene (376.90 mg, 2.48 mmol) and benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate (948.98 mg, 2.15 mmol) were then added. The reaction was stirred at 25°C for 0.5 hours. 2,4-Difluorobenzylamine (708.73 mg, 4.95 mmol) was added and the reaction was allowed to react at 80°C for 16 hours. Water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1-1:9) to obtain compound 11h in a single configuration.

[0315] 1 H NMR (400MHz, CD3OD) δ = 10.64-10.49 (m, 1H), 8.27-8.12 (m, 1H), 7.44-7.3 4(m,1H),6.90-6.75(m,3H),6.42-6.30(m,1H),5.35-5.24(m,1H),4.85- 4.78(m,2H),4.77-4.67(m,1H),3.98-3.90(m,1H),3.90-3.82(m,1H),3. 76-3.68(m,2H),3.66-3.55(m,1H),1.87-1.54(m,7H),1.52-1.41(m,3H).

[0316] Step 9: Synthesis of compound 11

[0317] To a pre-dried single-necked flask, 11h (150 mg, 0.287 mmol) and tetrahydrofuran (2 mL) were added, followed by ground sodium hydroxide (57.81 mg, 1.45 mmol). The reaction was incubated at 65°C for 4 hours. The reaction solution was adjusted to pH 4-5 with 1 M citric acid solution and then to pH 7-8 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (5 mL x 5). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography (Xtimate C18 150 x 40 mm x 5 μm; mobile phase: [water (HCl)-ACN]; ACN%: 5%-35%, 10 min) to yield compound 11.

[0318] MS (ESI, m / z): 501.1 [M+1].

[0319] 1 H NMR(400MHz, CD3OD)δ=7.95-7.83(m,1H),7.61-7.47(m,1H),7.35-7.21(m,2H),7.16-7.02(m,1H),5.50 -5.26(m,2H),4.00-3.89(m,2H),3.87-3.73(m,1H),3.59-3.40(m,2H),1.87-1.51(m,6H),1.50-1.43(m, 3H).

[0320] Example 12

[0321] Synthesis route:

[0322] Step 1: Synthesis of compound 12a

[0323] In a dry three-necked flask, 1d (500 mg, 1.55 mmol) and N,N-dimethylformamide (8 mL) were added and dissolved into a solution. Triethylamine (1.10 g, 10.83 mmol, 1.51 mL) and 1-(2,4-difluorophenyl)cyclopropylamine (954.06 mg, 4.64 mmol) were added and stirred at 80°C for 15 hours. The reaction mixture was diluted with water (10 mL). Dichloromethane (10 mL x 3) was added for extraction. The organic phases were combined, washed with saturated sodium bicarbonate solution (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0-10:1), and the fraction was concentrated under reduced pressure to yield 12a.

[0324] 1 H NMR (400MHz, DMSO-d6) δ = 10.98 (s, 1H), 8.51 (s, 1H), 7.81-7.66 (m, 1H), 7.17 (d dd,J=2.5,9.2,11.2Hz,1H),7.02(dt,J=2.1,8.6Hz,1H),6.56(s,1H),4.76(br s,1H),4.33(t,J=4.9Hz,1H),3.88(s,3H),3.22(s,6H),1.34-1.28(m,2H),1.27-1.21(m,2H).

[0325] Step 2: Synthesis of compound 12b

[0326] To a pre-dried three-necked flask, 12a (220 mg, 477.81 μmol) and acetic acid (3.7 mL) were added and stirred. Methanesulfonic acid (18.37 mg, 191.13 μmol, 13.61 μL) was then added and the mixture was heated to 35°C and stirred for 20 hours. 1,2-Dichloroethane (2 mL) and L-aminopropanol (140.26 mg, 1.87 mmol, 145.35 μL) were then added and the mixture was heated to 90°C and stirred for 12 hours. Water (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0-1:1), and the fraction was concentrated under reduced pressure to yield 12b.

[0327] 1 H NMR (400MHz, DMSO-d6) δ = 11.03 (s, 1H), 8.51 (s, 1H), 7.78-7.69 (m, 1H), 7.22-7.14 (m, 1H), 7.05-6.99 (m, 1H), 6.74 (s, 1H), 5.48 (dd, J = 4.3, 12.3Hz, 1H), 5.34 (dd, J=4.3, 10.1Hz, 1H), 4.40 (dd, J=6.8, 8.4Hz, 1H), 4.29 (td, J=6.6, 13.1Hz, 1H), 1.35-1.30 (m, 3H), 1.29-1.22 (m, 4H).

[0328] Step 3: Synthesis of compound 12c

[0329] To a dry three-necked flask, 12b (6.6 g, 26.68 mmol) and acetonitrile (2 mL) were added, followed by trichloroisocyanuric acid (25.39 mg, 109.24 μmol) and 1,4-diazabicyclo[2,2,2]octane (1.28 mg, 11.38 μmol, 1.25 μL). The reaction was stirred at 40°C for 2 hours. Water (5 mL) was added to the reaction solution, followed by extraction with dichloromethane / methanol (10:1 v / v, 5 mL x 3). The combined organic phases were washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography (Phenomenex C1880 x 40 mm x 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-ACN]; ACN %: 48%-78%, 8 min) to afford 12c.

[0330] 1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 8.53 (s, 1H), 7.78-7.69 (m, 1H), 7.22-7.14 (m, 1H), 7.06-6.98 (m, 1H), 5.57 (dd, J = 3.9, 12.7 Hz, 1H), 5.34 (dd, J = 3.8, 9.8 Hz, 1H), 4.41-4.34 (m, 1H), 4.33-4.28 (m, 1H), 3.67 (dd, J = 6.8, 8.0 Hz, 1H), 3.61 (dd, J = 10.0, 12.3 Hz, 1H), 1.35-1.30 (m, 3H), 1.29-1.25 (m, 4H). Step 4: Synthesis of compound 12

[0331] To a dry three-necked flask, 12c (75 mg, 0.158 mmol) and tetrahydrofuran (0.8 mL) were added, followed by sodium hydroxide (31.65 mg, 791.37 μmol). The reaction was stirred at 60°C for 6 hours. The tetrahydrofuran was concentrated and dissolved in 2 mL of water, and the pH was adjusted to 5 by adding 1 M citric acid solution. The crude product was purified by preparative reverse-phase liquid chromatography (Phenomenex C18 150*40 mm*5 μm; mobile phase: [water (hydrochloric acid)-ACN]; ACN%: 40%-70%, 10 min) to afford 12.

[0332] MS (ESI, m / z): 456.3 [M+1].

[0333] 1 H NMR(400MHz, DMSO-d6)δ=11.09-10.79(m,1H),8.45-8.27(m,1H),7.80-7.62(m,1H),7.28-7.09(m,1H),7.08 -6.87(m,1H),5.74-5.49(m,1H),5.41-5.16(m,1H),4.53-4.21(m,2H),3.75-3.60(m,3H),1.43-1.19(m,7H).

[0334] Example 13

[0335] Synthesis route:

[0336] Step 1: Synthesis of compound 13b

[0337] To a pre-dried, single-necked flask, 1d (2 g, 6.19 mmol) and N,N-dimethylformamide (10 mL) were added, along with triethylamine (2.19 g, 21.65 mmol, 3.01 mL) and 13a (2.01 g, 9.28 mmol). The reaction was incubated at 35°C for 16 hours. 20 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1), and the fractions were concentrated to yield 13b.

[0338] 1 HNMR (400MHz, CDCl3) δ=11.34-10.96(m,1H),8.47-8.26(m,1H),7.25(ddd,J=2.4,8.1,9.1Hz,1H ),6.79-6.56(m,1H),5.15-4.83(m,4H),4.43-4.26(m,1H),4.07-3.90(m,3H),3.45-3.26(m,6H).

[0339] Step 2: Synthesis of compound 13c

[0340] 13b (2.5 g, 5.74 mmol) was dissolved in acetic acid (31 mL), and methanesulfonic acid (441.5 mg, 4.60 mmol, 327.04 μL) was added. The mixture was stirred at 35°C for 16 hours. Methanesulfonic acid (357.41 mg, 3.72 mmol, 264.75 μL) was added to the reaction solution, and the reaction was continued at 90°C for 16 hours. L-aminopropanol (279.33 mg, 3.72 mmol, 289.46 μL) was added, and the reaction system was continued at 90°C for another 16 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0-10:1) to obtain 13c.

[0341] Step 3: Synthesis of compound 13d

[0342] 13c (0.15 g, 362.00 μmol) was added to acetonitrile (1.5 mL), followed by the addition of trichloroisocyanuric acid (40.38 mg, 173.76 μmol) and 1,4-diazabicyclo[2,2,2]octane (2.03 mg, 18.10 μmol, 1.99 μL). The atmosphere was purged with nitrogen three times, and the reaction system was incubated at 40°C for 1 hour. Water (5 mL) was added, and the mixture was extracted three times with dichloromethane / methanol (10:1 v / v, 10 mL × 3). The organic phases were combined and concentrated, and the crude product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 1:0-20:1) to obtain 13d.

[0343] Step 4: Synthesis of compound 13

[0344] 13d was added to tetrahydrofuran (7 mL), followed by sodium hydroxide (30.30 mg, 757.56 μmol). The reaction system was incubated at 60°C for 2 hours, and the reaction solution was concentrated. The crude product was purified by preparative reverse-phase liquid chromatography (Welch Xtimate C18 100*40mm*3μm; mobile phase: [water (TFA)-ACN]; ACN%: 19%-49%, 8 min) to obtain 13.

[0345] MS (ESI, m / z): 431.0 [M+1].

[0346] 1 H NMR (400MHz, CDCl3) δ = 11.67 (br s, 1H), 11.28 (br s,1H),8.38(s,1H),8.31(d,J=2.4Hz,1H),6.93(s,1H),5.94(dd,J=4.3,12.9Hz,1H),5.19-5.14(m,1H),4.97(br s,1H),4.98-4.95(m,1H),4.41(br d,J=6.0Hz,2H),3.67(s,1H),3.22(dd,J=9.8,12.7Hz,1H),1.42-1.42(m,3H).

[0347] Example 14

[0348] Synthesis route:

[0349] Step 1: Synthesis of compound 14b

[0350] To a pre-dried three-necked flask, 2,4,6-trichloro-5-pyrimidinecarboxaldehyde (14a, 10 g, 47.30 mmol, 1 eq) and tetrahydrofuran (100 mL) were added. Stirring was initiated and the nitrogen atmosphere was replaced three times. Methylmagnesium bromide solution (3 M, 63.06 mL, 4 eq) was then added at -60°C and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted three times with ethyl acetate (150 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0-90:10), and the fraction was concentrated under reduced pressure to yield 14b.

[0351] MS (ESI, m / z): 226.8 [M+1].

[0352] 1 H NMR (400MHz, CDCl3) δ = 5.58-5.41 (m, 1H), 2.61 (br s, 1H), 1.66 (d, J = 6.9Hz, 3H).

[0353] Step 2: Synthesis of compound 14c

[0354] To a pre-dried single-necked flask, 14b (8.3 g, 36.49 mmol, 1 eq) was added dichloromethane (83 mL). The temperature was lowered to 0°C, and Dess-Martin reagent (20.12 g, 47.43 mmol, 14.69 mL, 1.3 eq) was added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 20°C for 1 hour. The reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0-95:5), and the fraction was concentrated under reduced pressure to obtain 14c.

[0355] MS (ESI, m / z): 224.8 [M+1].

[0356] 1 H NMR (400MHz, CDCl3) δ = 2.63 (s, 3H).

[0357] Step 3: Synthesis of compound 14d

[0358] To a pre-dried single-necked flask, 14c (6.2 g, 27.50 mmol, 1 eq) and N,N-dimethylformamide (62 mL) were added and stirred. Aminoacetaldehyde dimethyl acetal (2.89 g, 27.50 mmol, 3.00 mL, 1 eq) and triethylamine (5.57 g, 55.00 mmol, 7.66 mL, 2 eq) were then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 0°C for 2 hours. 60 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 90:10), and the fraction was concentrated under reduced pressure to obtain 14d.

[0359] MS (ESI, m / z): 293.9 [M+1].

[0360] 1H NMR (400MHz, CDCl3) δ = 9.25-9.13 (m, 1H), 4.50 (t, J = 5.1Hz, 1H), 3.69 (t, J = 5.4Hz, 2H), 3.46-3.40 (m, 6H), 2.77-2.72 (m, 3H).

[0361] Step 4: Synthesis of compound 14e

[0362] To a pre-dried single-necked flask, 14d (6.77 g, 23.02 mmol, 1 eq) and methanol (70 mL) were added, followed by sodium methoxide (4.35 g, 80.56 mmol, 3.5 eq). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 25°C for 1 hour. The reaction was quenched with 50 mL of saturated ammonium chloride solution and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with 150 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0-90:10), and the fractions were concentrated under reduced pressure to obtain 14e.

[0363] MS (ESI, m / z): 285.9 [M+1].

[0364] 1 H NMR (400MHz, DMSO-d6)δ=10.09-9.93(m,1H),4.53-4.37(m,1H),3.96-3.86(m,6H),3.66-3.52(m,2H),3.40-3.25(m,6H),2.51-2.34(m,3H).

[0365] Step 5: Synthesis of compound 14g

[0366] To a pre-dried three-necked flask, 14e (6.8 g, 23.83 mmol, 1 eq) and tetrahydrofuran (70 mL) were added. Dimethyl oxalate (5.63 g, 47.67 mmol, 2 eq) and potassium tert-butoxide (1 M, 42.43 mL, 1.78 eq) were then added. The reaction was allowed to proceed at 20°C for 0.5 h to yield 14f. Citric acid (3 M, 119.17 mL, 15 eq) was added at 20°C, the atmosphere was purged with nitrogen three times, and the temperature was raised to 35°C and stirred for 12 h. The reaction mixture was adjusted to pH 7-8 at 0°C with saturated sodium bicarbonate solution and extracted with dichloromethane (70 mL x 3). The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 0:100), and the fractions were concentrated under reduced pressure to yield 14 g.

[0367] MS (ESI, m / z): 353.9 [M+1].

[0368] 1 H NMR (400MHz, CDCl3) δ = 6.72 (s, 1H), 4.95 (br d, J = 4.3Hz, 2H), 4.34 (t, J = 4.7Hz, 1H), 4.21 (s, 3H), 4.00 (s, 3H), 3.95 (s, 3H), 3.37 (s, 6H).

[0369] Step 6: Synthesis of compound 14h

[0370] To a pre-dried single-necked flask, 14 g (3 g, 8.49 mmol, 1 eq) and N,N-dimethylformamide (30 mL) were added, followed by 2,4-difluorobenzylamine (1.82 g, 12.74 mmol, 1.5 eq) and triethylamine (1.72 g, 16.98 mmol, 2.36 mL, 2 eq). The atmosphere was purged with nitrogen three times and stirred at 35°C for 12 hours. 20 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 40:60), and the fractions were concentrated under reduced pressure to obtain 14h.

[0371] MS (ESI, m / z): 465.1[M+1].

[0372] 1 H NMR (400MHz, CDCl3) δ = 10.78 (br t, J = 5.5Hz, 1H), 7.47-7.30 (m, 1H), 6.91-6.76 (m, 2H), 6.60 (s, 1H), 4.90 (br d,J=4.5Hz,2H),4.81(d,J=5.9Hz,2H),4.36(t,J=5.3Hz,1H),4.00(s,3H),3.94(s,3H),3.35(s,6H).

[0373] Step 7: Synthesis of compound 14j

[0374] To a pre-dried single-necked flask, 14h (0.5 g, 1.08 mmol, 1 eq), acetic acid (0.5 mL), and methanesulfonic acid (620.84 mg, 6.46 mmol, 459.88 μL, 6 eq) were added. The atmosphere was purged with nitrogen three times and stirred at 35°C for one hour to yield 14i. The temperature was then lowered to 20°C, and 1,2-dichloroethane (5 mL) and L-aminopropanol (521.14 mg, 6.94 mmol, 540.04 μL, 6 eq) were added. The atmosphere was purged with nitrogen three times and stirred at 90°C for 12 hours. The reaction mixture was added with 10 mL of water and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 50:50), and the fractions were concentrated under reduced pressure to yield 14j.

[0375] MS (ESI, m / z): 444.0 [M+1].

[0376] 1 H NMR (400MHz, CDCl3) δ = 10.87-10.72 (m, 1H), 7.44-7.32 (m, 1H), 7.05 (s, 1H), 6.89-6.76 (m, 2H), 5.73 (dd, J = 4.3, 13.0Hz, 1H), 5.37-5 .11(m,1H),4.81(d,J=5.8Hz,2H),4.55-4.38(m,2H),4.05-3.95(m,3H),3.79-3.64(m,1H),3.40-3.17(m,1H),1.46(d,J=6.1Hz,3H).

[0377] Step 8: Synthesis of compound 14k

[0378] To a pre-dried single-necked flask, 14j (0.06 g, 135.32 μmol, 1 eq) and acetonitrile (1 mL) were added, followed by trichloroisocyanuric acid (15.10 mg, 64.95 μmol, 0.48 eq) and 1,4-diazabicyclo[2,2,2]octane (758.93 μg, 6.77 μmol, 7.44 e-1 μL, 0.05 eq). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 40°C for 1 hour. 10 mL of water was added to the reaction solution, which was then extracted with dichloromethane / methanol (10:1 v / v, 10 mL x 3). The combined organic phases were washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was separated by silica gel column chromatography (ethyl acetate / petroleum ether = 100:0 to 40:60), and the fraction was concentrated under reduced pressure to yield 14k.

[0379] MS (ESI, m / z): 478.0 [M+1].

[0380] 1 H NMR (400MHz, CDCl3) δ = 10.70 (br t,J=4.8Hz,1H),7.41-7.31(m,1H),6.88-6.79(m,2H),5.90-5.83(m,1H),5.25-5.19(m,1H),4.84-4.79( m,2H),4.53-4.38(m,2H),4.04-3.99(m,3H),3.74-3.68(m,1H),3.34-3.23(m,1H),1.46(d,J=6.1Hz,3H).

[0381] Step 9: Synthesis of compound 14

[0382] In a dry, single-necked flask, 14k (0.035 g, 73.25 μmol, 1 eq) and tetrahydrofuran (2 mL) were added, followed by sodium hydroxide (14.65 mg, 366.23 μmol, 5 eq). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 60°C for 12 hours. The reaction mixture was adjusted to pH 3 with 1 M hydrochloric acid and concentrated under reduced pressure. The concentrated solution was dissolved in methanol and filtered through a syringe filter to obtain the crude product. The crude product was separated by reverse-phase preparative liquid chromatography (Phenomenex Luna C18 80 x 40 mm x 3 μm; mobile phase: [water (HCl)-ACN]; ACN%: 30%-60%, 8 min). The fraction was concentrated under reduced pressure to yield 14.

[0383] MS (ESI, m / z): 460.0 [M+1].

[0384] 1 H NMR (400MHz, CDCl3) δ = 11.66 (s, 1H), 10.79 (br t,J=4.6Hz,1H),7.43(s,1H),6.88-6.79(m,2H),5.91-5.81(m,1H),5.23-5.14(m,1H),4.88-4.79 (m,2H),4.53-4.42(m,2H),4.00(s,3H),3.79-3.69(m,1H),3.28-3.19(m,1H),1.51-1.45(m,3H).

[0385] Example 15A

[0386] Synthesis route:

[0387] Step 1: Synthesis of compound 15a

[0388] Compound 1d (1 g, 3.09 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). 2,4-Difluoromethylbenzylamine (729.17 mg, 4.64 mmol, 1.5 eq) and triethylamine (469.48 mg, 4.64 mmol, 645.78 μL, 1.5 eq) were added and stirred at 80°C for 12 hours. A conical flask was added, 50 mL of water was added, and the reaction mixture was poured into it. Extraction was performed with 50 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1). The fraction was concentrated under reduced pressure to obtain compound 15a (0.5 g, 36.05% yield). MS (ESI, m / z): 449.0 [M+1].

[0389] Step 2: Synthesis of compound 15b

[0390] Compound 15a (0.5 g, 1.115 mmol, 1 eq) was dissolved in glacial acetic acid (4 mL), and methanesulfonic acid (32.14 mg, 334.5 μmol, 23.9 μL, 0.3 eq) was added. The mixture was heated to 65°C in an oil bath and stirred for 12 hours to obtain compound 15b (0.46 g, crude product). The reaction mixture was directly used in the next reaction. MS (ESI, m / z): 417.0 [M+1].

[0391] Step 3: Synthesis of compound 15c

[0392] Compound 15b (0.5 g, 1.20 mmol, 1 eq) was dissolved in 1,2-dichloroethane (5 mL), and L-aminopropanol (180.39 mg, 2.40 mmol, 186.93 μL, 2 eq) was added. The mixture was stirred at 90°C for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1). The fraction was concentrated under reduced pressure to obtain compound 15c (0.2 g, 38.97% yield). MS (ESI, m / z): 427.40 [M+1].

[0393] Step 4: Synthesis of compound 15d

[0394] Compound 15c (0.2 g, 467.94 μmol, 1 eq) was dissolved in acetonitrile (1 mL), and 1,4-diazabicyclo[2.2.2]octane (2.62 mg, 23.40 μmol, 2.57 μL, 0.05 eq) and trichloroisocyanuric acid (51.11 mg, 219.93 μmol, 0.47 eq) were added. The mixture was heated to 40°C in an oil bath and stirred for 2 hours. A conical flask was added, 20 mL of water was added, and the reaction mixture was poured into the flask. The mixture was extracted with 20 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to obtain compound 15d (0.14 g, 67.78% yield).

[0395] Step 5: Synthesis of compounds 15e-1 and 15e-2

[0396] Compound 15d was subjected to SFC separation (separation conditions: DAICEL CHIRALCEL OJ 250mm*30mm*10μm; mobile phase: [Neu-EtOH (0.1% NH3·H2O)]%: 42%-42%, 6min). The separated fractions were concentrated under reduced pressure to give compounds 15e-1 (30 mg, 10.71% yield) and 15e-2 (40 mg, 14.29% yield).

[0397] Analytical method: Column type: Chiralcel OD-3 50mm*4.6mm*3μm; Mobile phase: [A: CO2; B: EtOH (0.1% IPAm, v / v)]; B%: 5%, 0.2min; 5%-50%, 1min; 50%, 1min; 50%-5%, 0.4min; 5%, 0.4min; Retention time: 1.574min (15e-1), 1.716min (15e-2).

[0398] 15e-1: 1H NMR (400MHz, CDCl3) δ = 10.74 (br d,J=7.5Hz,1H),8.34(s,1H),7.31-7.23(m,1H),6.80-6.67(m,2H),5.92(dd,J=3.7,13.1Hz,1H),5.64(quin,J=7.1Hz,1H),5.17(dd,J=3.7,10.0Hz ,1H),4.45-4.38(m,1H),4.35(dd,J=6.8,8.6Hz,1H),3.69-3.60(m,1H),3 .21(dd,J=9.9,13.1Hz,1H),1.55(d,J=7.0Hz,3H),1.39(d,J=6.1Hz,3H).

[0399] 15e-2: 1 H NMR (400MHz, CDCl3) δ = 10.74 (br d,J=8.0Hz,1H),8.34(s,1H),7.37-7.24(m,1H),6.81-6.69(m,2H),5.90(dd,J=3.8,13.1Hz,1H),5.64(quin,J=7.2Hz,1H),5.14(dd,J =3.8,9.9Hz,1H),4.47-4.31(m,2H),3.64(t,J=8.0Hz,1H),3.23(dd,J=9.9,13.1Hz,1H),1.55(d,J=6.9Hz,3H),1.39(d,J=6.1Hz,3H).

[0400] Step 6: Synthesis of compound 15A

[0401] Compound 15e-1 (30 mg, 64.96 μmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (2 mL), and sodium hydroxide (12.99 mg, 324.78 μmol, 5 eq) was added. The mixture was stirred at 60°C for 12 hours. A conical flask was added, 10 mL of water was added, and the reaction mixture was then extracted with 10 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was separated by reverse-phase preparative liquid chromatography (Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [H2O (0.04% HCl)-ACN]; ACN: 40%-80%, 8.0 min). The fraction was lyophilized to obtain compound 15A (7 mg, 12.03% yield, obtained from two parallel reactions). MS (ESI, m / z): 444.0 [M+1].

[0402] 1H NMR (400MHz, CDCl3) δ = 12.00 (s, 1H), 11.91-11.81 (m, 1H), 8.60-8.30 (m, 1H), 7.76-7.63 (m, 1H), 6.88-6.77 (m ,2H),6.02-5.93(m,2H),5.28-5.15(m,1H),4.55-4.39(m,2H),3.80-3.65(m,1H),3.39-3.27(m,1H),1.72(br d,J=6.4Hz,3H),1.48(d,J=5.7Hz,3H)

[0403] Example 15B

[0404] Synthesis route:

[0405] Compound 15B was prepared by referring to the synthesis of Example 15A using 15e-2 as the starting material. MS (ESI, m / z): 444.0 [M+1]. 1 H NMR (400MHz, CDCl3) δ=11.67(s,1H),10.99-10.83(m,1H),8.34-8.28(m,1H),7.39-7.27(m,1H),6.84-6.76(m,2H),5.95(dd,J=4.3,12.8Hz,1H ),5.75-5.65(m,1H),5.20-5.12(m,1H),4.48-4.41(m,2H),3.73-3.68( m,1H),3.29-3.17(m,1H),1.60(d,J=6.8Hz,3H),1.47(d,J=5.7Hz,3H).

[0406] Example 16

[0407] Synthesis route:

[0408] Step 1: Synthesis of compound 16b

[0409] To a pre-dried three-necked flask, the raw material 1-bromo-3,5-difluoro-2-iodobenzene (16a, 15 g, 47.04 mmol, 1 eq) and the solvent tetrahydrofuran (150 mL) were added. A solution of isopropylmagnesium chloride lithium complex (1.3 M, 37.98 mL, 1.05 eq) was then added at 0°C. The mixture was stirred for 0.5 hours, and N-formylmorpholine (1.97 g, 51.27 mmol, 5.13 mL, 1.09 eq) was added. The temperature was raised to 25°C and stirred for 2 hours. The reaction mixture was quenched with hydrochloric acid (1 M aqueous solution), diluted with 60 mL of water, and extracted with 100 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. This yielded the crude product 16b (8 g).

[0410] MS (ESI, m / z): 221.0 [M+1].

[0411] Step 2: Synthesis of compound 16c

[0412] To a pre-dried single-necked flask, 16b (6 g, 27.14 mmol, 1 eq) was added, along with ethanol (100 mL) as solvent, followed by the reagents hydroxylamine hydrochloride (5.66 g, 81.44 mmol, 3 eq) and anhydrous sodium acetate (8.9 g, 108.6 mmol, 4 eq). The reaction was stirred at 80°C for 2 hours. 200 mL of water was added to the conical flask, and the reaction mixture was poured into it. Extraction was performed with 200 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was isolated by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to afford 16c (2.9 g, 45.26% yield, obtained from two parallel reactions). MS (ESI, m / z): 236.01 [M+1].

[0413] Step 3: Synthesis of compound 16d

[0414] To a pre-dried, single-necked flask, 16c (3.4 g, 14.4 mmol, 1 eq) was added and dissolved in a mixture of ethanol (40 mL) and acetic acid (30 mL). Stirring was initiated, followed by the addition of zinc powder (3.76 g, 57.62 mmol, 4 eq). The reaction was stirred at 25°C for 2 hours. The reaction solution was filtered, and the filtered zinc powder must be quenched with 0.1-1 M hydrochloric acid. Any weighing paper or spoon that had been contaminated with zinc powder can be washed with very dilute hydrochloric acid. The filtrate was adjusted to pH 8 with saturated sodium bicarbonate solution and then extracted three times with 150 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1), and the fraction was concentrated under reduced pressure to yield 16d (2.4 g, 75.03% yield, obtained from two parallel reactions).

[0415] MS (ESI, m / z): 221.8 [M+1].

[0416] Step 4: Synthesis of compound 16e

[0417] In a pre-dried single-necked flask, 2f (1.54 g, 4.75 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL). 16d (1.586 g, 7.14 mmol, 1.5 eq) and triethylamine (1.446 g, 14.3 mmol, 1.989 mL, 3 eq) were added and stirred at 35°C for 12 hours. The reaction mixture was poured into the conical flask, 100 mL of water was added, and the mixture was extracted three times with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1), and the fraction was concentrated under reduced pressure to obtain 16e (2.1 g, 85.89% yield). MS (ESI, m / z): 512.9 [M+1].

[0418] Step 5: Synthesis of compound 16g

[0419] In a pre-dried three-necked flask, 16e (1.2 g, 2.338 mmol, 1 eq) was dissolved in acetic acid (2 mL). Methanesulfonic acid (67.4 mg, 701.36 μmol, 49.92 μL, 0.3 eq) was added and the reaction was incubated at 65°C for 24 hours to yield 16f. The solution was cooled to 20°C and 1,2-dichloroethane (6 mL) and L-aminopropanol (346.47 mg, 4.62 mmol, 359.04 μL, 2 eq) were added. The reaction mixture was poured into the conical flask, 20 mL of water was added, and 20 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1). The fraction was concentrated under reduced pressure to yield 16g (0.5 g was obtained from three parallel reactions, yield 44.04%). MS (ESI, m / z): 491.9 [M+1].

[0420] Step 6: Synthesis of compound 16h

[0421] To a pre-dried single-necked flask, 16 g (37 mg, 75.16 μmol, 1 eq) and acetonitrile (1 mL) were added, followed by trichloroisocyanuric acid (8.21 mg, 35.33 μmol, 0.47 eq) and 1,4-diazabicyclo[2,2,2]octane (421.54 μg, 3.76 μmol, 4.13e-1 μL, 0.05 eq). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 40°C for 1 hour. The reaction mixture was then poured into the conical flask, 20 mL of water was added, and 20 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1), and the fraction was concentrated under reduced pressure to yield 16h (28 mg, 70.73% yield). MS (ESI, m / z): 525.9 [M+1].

[0422] Step 9: Synthesis of compound 16

[0423] A dry, single-necked flask was prepared, and 16h (28 mg, 53.16 μmol, 1 eq) and tetrahydrofuran (1 mL) were added. Subsequently, sodium hydroxide (10.63 mg, 265.80 μmol, 5 eq) was added. The atmosphere was purged with nitrogen three times, and the mixture was allowed to react at 60°C for 12 hours. The reaction mixture was then poured into the conical flask, with 20 mL of water added. Extraction was then performed with 20 mL of dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative reverse-phase liquid chromatography (Phenomenex Luna 80*30 mm*3 μm; mobile phase: [H₂O(HCl)-ACN]; B%: 35%-65%, 8 min) to yield 16 (0.003 g, 11.1% yield). MS (ESI, m / z): 507.9 [M+1].

[0424] Example 17

[0425] Synthesis route:

[0426] Step 1: Synthesis of compound 17a

[0427] Under nitrogen, add 2,4,6-trifluorobenzonitrile (10 g, 63.66 mmol, 1 eq) and 2-methyltetrahydrofuran (160 mL) to a dry three-necked flask. Stirring is initiated, followed by the addition of tetraisopropyl titanate (19.90 g, 70.02 mmol, 20.67 mL, 1.1 eq). Stir at 25°C for 7 minutes. Slowly add ethylmagnesium bromide (3 M, 46.05 mL, 2.17 eq) dropwise, and stir at 25°C for 55 minutes. Slowly add boron trifluoride etherate (18.07 g, 127.31 mmol, 15.71 mL, 2 eq) dropwise, and stir at 25°C for 55 minutes. Ammonium chloride (30 mL) is added to quench the reaction, and hydrogen chloride (1 M) is added to adjust the pH to 1. Methyl tert-butyl ether (40 mL x 3) was added for extraction. The combined organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford crude product 17a (1.55 g, 13.01% yield). MS (ESI, m / z): 187.9 [M+1].

[0428] 1 H NMR (400MHz, DMSO-d6)δ=7.16-7.03(m,2H),2.28(br s,2H),0.94-0.83(m,2H),0.77-0.72(m,2H).

[0429] Step 2: Synthesis of compound 17b

[0430] To a dry three-necked flask, 1d (500 mg, 1.55 mmol, 1 eq) and DMF (2 mL) were added and stirred. Triethylamine (999.38 mg, 7.73 mmol, 1.35 mL, 5 eq) and 17a (1.16 g, 6.19 mmol, 4 eq) were added and stirred at 80°C for 20 hours. The reaction mixture was diluted with water (10 mL). Dichloromethane (10 mL × 3) was added for extraction. The combined organic phases were washed with saturated sodium bicarbonate (10 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0-1:1), and the fraction was concentrated under reduced pressure to yield 17b (274 mg, 37.03% yield). MS (ESI, m / z): 479.1 [M+1].

[0431] 1 H NMR (400MHz, DMSO-d6) δ = 10.96 (br s, 1H), 8.50 (d, J = 3.3Hz, 1H), 7.13 (br t, J = 8.7Hz, 2H), 6.56 (d, J = 3.5Hz, 1H), 4.76 (br s, 2H), 4.34 (br d,J=3.5Hz,1H),3.89(br s,3H),3.22(br s,6H),1.33(br s,4H).

[0432] Step 3: Synthesis of compound 17c

[0433] To a pre-dried three-necked flask, 17b (509 mg, 1.06 mmol, 1 eq) and acetic acid (5 mL) were added and stirred. Methanesulfonic acid (71.57 mg, 744.74 μmol, 53.21 μL, 0.7 eq) was then added and stirred at 65°C for 16 hours. Methanesulfonic acid (40.90 mg, 425.57 μmol, 30.41 μL, 0.4 eq) was then added and stirred at 65°C for 16 hours. 1,2-Dichloroethane (4 mL) and L-aminopropanol (474.50 mg, 6.32 mmol, 491.71 μL, 6 eq) were then added and the temperature was raised to 90°C with stirring for 6 hours. L-aminopropanol (316.34 mg, 4.21 mmol, 327.81 μL, 4 eq) was then added and stirred at 90°C for 16 hours. The reaction mixture was added with hydrochloric acid (1 M, 10 mL), followed by extraction with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0-4:1), and the fractions were concentrated under reduced pressure to afford 17c (137 mg, 28.45% yield). MS (ESI, m / z): 458.1 [M+1].

[0434] 1 H NMR (400MHz, DMSO-d6) δ=11.00(s,1H),8.49(s,1H),7.12(t,J=8.9Hz,2H),6.74(s,1H),5.48(dd,J=4.4,12.4Hz,1H),5.34(dd,J=4.3,10.0H z,1H),4.40(dd,J=6.8,8.5Hz,1H),4.36-4.23(m,1H),3.65(dd,J=6.8,8.5Hz,1H),3.55(dd,J=10.0,12.3Hz,1H),1.33(s,4H),1.32(s,3H).

[0435] Step 4: Synthesis of compound 17d

[0436] To a dry three-necked flask, 17c (130 mg, 284.21 μmol, 1 eq) and acetonitrile (1 mL) were added, followed by trichloroisocyanuric acid (31.71 mg, 136.42 μmol, 0.48 eq) and triethylenediamine (1.59 mg, 14.21 μmol, 1.56 μL, 0.05 eq). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 40°C for 1.5 hours. Water (5 mL) was added to the reaction solution, followed by extraction with dichloromethane:methanol (10:1, 5 mL × 3). The organic phases were combined, washed with saturated brine (2 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative reversed-phase liquid chromatography (Xtimate C18 150*25mm*5μm; mobile phase: water (0.05% NH3·H2O + 10mM NH4HCO3)-ACN); B%: 44%-74%, 11 min) to afford compound 17d (91 mg, 65.10% yield). MS (ESI, m / z): 492.1 [M+1].

[0437] 1 H NMR (400MHz, DMSO-d6) δ = 10.87 (s, 1H), 8.52 (s, 1H), 7.12 (br t,J=8.8Hz,2H),5.57(dd,J=3.6,12.2Hz,1H),5.34(dd,J=3.9,9.9Hz,1H),4.42-4.35(m,1H),4.35 -4.27(m,1H),3.71-3.64(m,1H),3.61(dd,J=10.0,12.5Hz,1H),1.36(s,3H),1.31(d,J=6.3Hz,4H).

[0438] Step 5: Synthesis of compound 17

[0439] To a dry three-necked flask, 17d (64 mg, 130.12 μmol, 1 eq) and tetrahydrofuran (2 mL) were added, followed by sodium hydroxide (26.02 mg, 650.61 μmol, 5 eq). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 60°C for 16 hours. Water (5 mL) was added to the reaction solution, followed by extraction with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative reverse-phase liquid chromatography (Xtimate C18 150*40 mm×5 μm; mobile phase: [water (HCl)-ACN]; B%: 40%-80%, 10 min) to afford compound 17 (10 mg, 16.23% yield).

[0440] MS (ESI, m / z): 474.2 [M+1].

[0441] 1 H NMR (400MHz, CD3OD) δ = 8.39 (s, 1H), 6.86 (t, J = 8.7Hz, 2H), 5.86 (dd, J = 4.3, 12.8Hz, 1H), 5.32 (dd, J = 4.1, 9.9Hz, 1 H),4.58-4.40(m,2H),3.76(dd,J=6.8,8.3Hz,1H),3.43(dd,J=10.0,12.8Hz,1H),1.48(d,J=6.0Hz,4H),1.45(br s,3H).

[0442] Example 18

[0443] Synthesis route:

[0444] Step 1: Synthesis of compound 18b

[0445] Compound 18a (10 g, 120.35 mmol, 1 eq) and potassium carbonate (18.30 g, 132.39 mmol, 1.1 eq) were added to N,N-dimethylformamide (100 mL). The system was cooled to 0°C, and carbon disulfide (10.08 g, 132.39 mmol, 8.00 mL, 1.1 eq) was added dropwise. The reaction was stirred at 25°C for 2 hours. The reaction solution was filtered, and iodomethane (34.18 g, 240.71 mmol, 14.98 mL, 2 eq) was added to the filtrate. The reaction was stirred at 20°C for 2 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic phase was washed with saturated sodium chloride solution (200 mL × 2) and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-70:30) to give compound 18b (14.3 g, 63.44% yield). MS (ESI, m / z): 187.8 [M+1].

[0446] 1 H NMR (400MHz, CDCl3) δ = 2.79 (s, 3H), 2.59 (s, 3H), 2.48 (s, 3H).

[0447] Step 2: Synthesis of compound 18c

[0448] Compound 18b (14 g, 74.75 mmol, 1 eq) and aminoacetal dimethanol (4.72 g, 44.85 mmol, 4.89 mL, 0.6 eq) were added to methanol (150 mL) and the reaction was stirred at 25°C for 10 minutes. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL x 2). The organic phase was washed with saturated sodium chloride solution (200 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-70:30) to obtain compound 18c (11 g, 59.87% yield). MS (ESI, m / z): 245.0 [M+1].

[0449] 1 H NMR (400MHz, CDCl3) δ = 4.47 (t, J = 5.1Hz, 1H), 3.75 (t, J = 5.5Hz, 2H), 3.45 (s, 6H), 2.70 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H).

[0450] Step 3: Synthesis of compound 18d

[0451] Compound 18c (10 g, 40.93 mmol, 1 eq) was added to ethanol (50 mL) and water (50 mL). The system was cooled to 0°C, and a 50% aqueous hydroxylamine solution (2.70 g, 40.93 mmol, 1 eq) was added. The reaction was stirred at 25°C for 2 hours. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL x 2). The organic phase was washed with saturated sodium chloride solution (200 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-50:50) to obtain compound 18d (6 g, 56.46% yield). MS (ESI, m / z): 251.9 [M+23].

[0452] 1 H NMR (400MHz, DMSO-d6) δ = 7.76 (s, 2H), 6.26 (br t, J = 5.8Hz, 1H), 4.52 (t, J = 5.4Hz, 1H), 3.28 (s, 6H), 3.15 (t, J = 5.8Hz, 2H), 2.23 (s, 3H).

[0453] Step 4: Synthesis of compound 18e

[0454] Compound 18d (14.2 g, 61.95 mmol, 1 eq) and 4-dimethylaminopyridine (2.27 g, 18.58 mmol, 0.3 eq) were added to tetrahydrofuran (150 mL), followed by di-tert-butyl dicarbonate (20.28 g, 92.92 mmol, 21.35 mL, 1.5 eq). The reaction mixture was stirred at -30°C for 1 hour. The pH of the reaction mixture was adjusted to 5-6 with aqueous citric acid solution and extracted with ethyl acetate (200 mL x 2). The organic phase was washed with saturated sodium chloride solution (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-50:50) to obtain compound 18e (4 g, 19.12% yield). MS (ESI, m / z): 351.9 [M+23].

[0455] 1 H NMR (400MHz, DMSO-d6) δ = 10.56 (s, 1H), 6.26 (t, J = 6.0Hz, 1H), 4.56 (t, J = 5.4Hz, 1H), 3.29 (s, 6H), 3.22 (t, J = 5.8Hz, 2H), 2.31 (s, 3H), 1.47 (s, 9H).

[0456] Step 5: Synthesis of compound 18f

[0457] Compound 18e (4.5 g, 13.66 mmol, 1 eq) was dissolved in tetrahydrofuran (35 mL), and dimethyl oxalate (3.23 g, 27.33 mmol, 2 eq) and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (27.33 mL, 2 eq) were added. The reaction was stirred at 20°C for 0.5 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-70:30) to obtain compound 18f (two parallel reactions yielded 7 g, 61.48% yield). MS (ESI, m / z): 438.1 [M+23].

[0458] 1 H NMR (400MHz, DMSO-d6) δ = 10.67 (s, 1H), 7.30 (s, 1H), 4.60 (t, J = 5.3Hz, 1H), 3.67 ( s,3H),3.28(d,J=6.5Hz,6H),2.95-2.89(m,1H),2.85-2.78(m,1H),1.44(s,9H).

[0459] Step 6: Synthesis of compound 18g

[0460] Compound 18f (7 g, 18.85 mmol, 1 eq) was added to tetrahydrofuran (70 mL), followed by trifluoroacetic acid (48.84 g, 428.34 mmol, 31.82 mL, 25.42 eq). The reaction was stirred at 20°C for 1 hour. The reaction mixture was adjusted to pH 7-8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-50:50) to obtain compound 18g (5.7 g, 85.12% yield). MS (ESI, m / z): 420.0 [M+23].

[0461] Step 7: Synthesis of compound 18h

[0462] Compound 18g (4.5g, 11.32mmol, 1eq) was added to acetonitrile (35mL), followed by acetic acid (35mL) and methanesulfonic acid (544.18mg, 5.66mmol, 404.60μL, 0.5eq). The reaction was stirred at 65°C for 1 hour. The reaction mixture was cooled to 20°C, and a solution of L-aminopropanol (8.51g, 113.24mmol, 8.81mL, 10eq) in acetonitrile (10mL) was added. The reaction mixture was stirred at 20°C for another 1 hour. The pH of the reaction mixture was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50mL x 2). The organic phase was washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0-70:30) to give compound 18h ​​(2.5 g, yield 72.92%). MS (ESI, m / z): 276.9 [M+1].

[0463] 1 HNMR(400MHz,DMSO-d6)δ=8.50(br s,2H),6.12(s,1H),5.38(dd,J=4.6,9.8Hz,1H),4.39-4.30(m,2H),4.29-4.23(m,1H),3.65-3.56(m,2H),1.30(d,J=6.3Hz,3H).

[0464] Step 8: Synthesis of compound 18i

[0465] Compound 18h ​​(500 mg, 1.81 mmol, 1 eq) was dissolved in tetrahydrofuran (7.5 mL). After nitrogen purging, the system was cooled to 0°C and sodium hydride (108.60 mg, 2.71 mmol, 60% content, 1.5 eq) was added. The reaction was stirred at 0°C for 0.5 hours. A solution of 2,4-difluorobenzyl bromide (374.69 mg, 1.81 mmol, 1 eq) in tetrahydrofuran (1 mL) was then added. The reaction was stirred at 20°C for 12 hours. The reaction solution was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was extracted with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated by silica gel column chromatography (petroleum ether / ethyl acetate = 100:0 to 50:50) to obtain compound 18i (300 mg, 41.20% yield). MS (ESI, m / z): 402.9 [M+1].

[0466] 1H NMR(400MHz,DMSO-d6)δ=9.32(br s,1H),7.43(dt,J=6.8,8.7Hz,1H),7.25(ddd,J=2.6,9.5,10.5Hz,1H),7.0 9(tt,J=1.4,8.5Hz,1H),6.15(s,1H),5.37(dd,J=4.5,9.8Hz,1H),4.66(br s,2H),4.40-4.30(m,2H),4.29-4.24(m,1H),3.64-3.56(m,2H),1.30(d,J=6.3Hz,3H).

[0467] Step 9: Synthesis of compound 18j

[0468] Compound 18i (300 mg, 745.62 μmol, 1 eq) was dissolved in acetonitrile (6 mL), followed by the addition of trichloroisocyanuric acid (58.92 mg, 253.51 μmol, 0.34 eq) and triethylenediamine (4.18 mg, 37.28 μmol, 4.10 μL, 0.05 eq). The reaction was stirred at 20°C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 100:0-90:10) to afford compound 18j (350 mg, 43.69% yield, obtained from two parallel reactions). MS (ESI, m / z): 436.8 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ=9.56(t,J=6.1Hz,1H),7.49-7.41(m,1H),7.30-7.23(m,1H),7.10(dt,J=1.6,8.6Hz,1H),5.40(dd,J=4.0,9.8Hz,1H),4.66(br s,2H),4.38-4.25(m,3H),3.69-3.60(m,2H),1.30(d,J=6.0Hz,3H).

[0469] Step 10: Synthesis of Compound 18

[0470] Compound 18j (20 mg, 45.79 μmol, 1 eq) was added to sulfolane (2 mL), followed by sodium hydroxide (45.78 mg, 1.14 mmol, 25 eq). The reaction was stirred at 80°C for 20 hours. Water (20 mL) was added to the reaction mixture, and the pH was adjusted to 4-5 with citric acid. The mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL x 2), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative reversed-phase liquid chromatography (separation conditions: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [H2O(FA)-ACN]; ACN%: 20%-60%; 9 min) to obtain compound 18 (three parallel reactions were performed to obtain 4 mg, yield 6.46%). MS (ESI, m / z): 418.9 [M+1].

[0471] 1 H NMR (400MHz, DMSO-d6) δ = 11.59 (s, 1H), 9.86-9.15 (m, 1H), 7.43 (br d, J = 7.5Hz, 1H), 7.25 (br t,J=10.0Hz,1H),7.18-7.05(m,1H),5.37-5.28(m,1H),4.64(br s,2H),4.43-4.36(m,1H),4.31(br dd,J=4.6,11.4Hz,2H),3.68-3.59(m,1H),3.50-3.41(m,1H),1.34(br d,J=6.0Hz,3H).

[0472] Biological testing

[0473] Experimental Example 1: Evaluation of the in vitro antiviral activity of test compounds using the HIV pseudovirus (PsV) system

[0474] The half effective concentration (EC50) of the compound was determined 50 ) value to evaluate the antiviral activity of compounds against HIV pseudovirus. HIV pseudovirus reporter gene assays are widely used in early screening to replace HIV virus assays to evaluate the anti-HIV activity of compounds.

[0475] HIV pseudovirus reporter gene assay:

[0476] On the first day, 293T cells were seeded into 96-well test plates at a density of 55,000 cells per well in 100 μL per well and cultured overnight in a 5% CO 2 , 37°C incubator.

[0477] On the second day, add serially diluted compounds (8 concentration points, duplicate wells), 50 μL per well. Subsequently, add 50 μL of diluted virus to the cells at 100 TCID50 per well. Set up cell controls (cells without compound treatment or virus infection), virus controls (cells infected with virus, without compound treatment), and culture medium controls (culture medium only). The final culture medium volume for this experiment was 200 μL, and the final DMSO concentration in the culture medium was 0.5%. Cells were cultured in a 5% CO2, 37°C incubator for 3 days.

[0478] Luciferase activity in each well of the test plate was measured using the Britelite plus kit (PerkinElmer), and the data were used for antiviral activity analysis. Cell viability was measured in each well using the CellTiter Glo assay and a BioTek microplate reader, and the data were used for cytotoxicity analysis.

[0479] The dose-effect curve was drawn using GraphPad Prism software. The antiviral activity of the antibody (﹪Inhibition) was calculated as follows: Antiviral activity (%) = (EC 50 Test well reading - virus control average) / (cell control average - virus control average) × 100

[0480] EC 50 GraphPad Prism (version 5) software was used to perform nonlinear fitting analysis on the inhibitory activity of the antibody and the cell viability, using the "log (inhibitor) vs. response--Variable slope" fitting method.

[0481] The inhibitory activities of the compounds of the present invention against HIV pseudovirus are shown in Table 1.

[0482] Table 1 Inhibitory activity of the compounds of the present invention against HIV pseudovirus (PsV)

[0483] Conclusion: The compounds of the present invention showed positive effects in the experiment of inhibiting HIV pseudovirus gene replication at the cellular level.

[0484] Experimental Example 2: Evaluation of the pharmacokinetic properties of the test compound using SD rats

[0485] In this study, SD male rats were selected as test animals. The LC / MS / MS method was used to quantitatively determine the drug concentration in the plasma of rats at different time points after oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in rats.

[0486] The clear solution of the test compound was injected into the tail vein of SD rats (7-10 weeks old, fasted overnight). The test compound was also administered orally to SD rats (7-10 weeks old, fasted overnight). Approximately 200 μL of blood was collected from the jugular vein or tail vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an anticoagulant tube supplemented with EDTA-K2 and centrifuged at 3200 g for 10 minutes at 4°C to obtain plasma. Plasma concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated using the non-compartmental model open linear logarithmic trapezoidal method using Phoenix WinNonlin 6.3 pharmacokinetic software. The experimental results are shown in Table 2.

[0487] Table 2 Pharmacokinetic parameters of the compounds of the present invention in rats

[0488] Conclusion: Pharmacokinetic testing of the compounds in rats demonstrated that compounds in Examples 2 and 5 performed well in terms of clearance, half-life, maximum plasma concentration, and AUC, comparable to cabotegravir. Furthermore, compounds in Examples 2 and 5 exhibited oral bioavailability of 66% and 20%, respectively, surpassing cabotegravir by 9.9%.

Claims

1. A compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, Is a single bond or a double bond; Each R1 is independently selected from H, halogen, CN, OH, NH2, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Each alkoxy group is independently optionally substituted with 1, 2 or 3 R a replace; Each R a independently selected from H, halogen, CN, OH, NH2 and -COOH; Each R2 is independently selected from H, halogen, CN, OH, NH2, -C(=O)N(R 1a )2、-S(=O)2N(R 1a )2、-N(R 1a )C(=O)N(R 1a )2、C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Each alkoxy group is independently optionally substituted with 1, 2 or 3 R b replace; Each R 1a Independently selected from H, C 1-3 Alkyl and C 1-3 Alkoxy, wherein the C 1-3 Alkyl and C 1-3 Alkoxy is optionally substituted with 1, 2 or 3 H, halogen, CN, OH or NH2; Each R b independently selected from H, halogen, CN, OH and NH2; Each R3 is independently selected from H, halogen, CN, OH, NH2, 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 replace; Each R c independently selected from H, halogen, CN, OH and NH2; L1 is selected from -(C(R 1b )2) p - and C 3-5 Cycloalkyl, the C 3-5 The cycloalkyl group is optionally substituted with 1, 2, 3 or 4 R d replace; Each R 1b Selected from H, F, CI, Br, I, OH, NH2, 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 substituents selected from H, F, CI, Br, I, OH and NH2; Each R d independently selected from H, halogen, CN, OH and NH2; T1 is selected from CH, N, O and S; T2 is selected from CH and N; m, n and q are independently selected from 0, 1, 2, 3 and 4; p is selected from 1 and 2; Ring A is selected from 3-10 membered heterocycloalkyl; Ring B is selected from 5-6 membered heteroaryl; The 3-10 membered heterocycloalkyl and 5-6 membered heteroaryl each independently contain 1, 2 or 3 heteroatoms or heteroatom groups each independently selected from N, O, S and NH.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Each R1 is independently selected from H, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 Each alkoxy group is independently optionally substituted with 1, 2 or 3 R a replace.

3. The compound according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R1 is independently selected from H and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R a replace.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R1 is independently selected from H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)2CH3, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)2CH3 are optionally replaced by 1, 2 or 3 R a replace.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Each R2 is independently selected from H, F, Cl, Br, I, CN, -C(=O)NH2, -S(=O)2NH2, -NHC(=O)NH2 and C 1-3 Alkoxy, the C 1-3 Alkoxy is optionally substituted independently by 1, 2 or 3 R b replace.

6. The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Each R2 is independently selected from H, F, Cl, CN, -C(=O)NH2, -S(=O)2NH2, -NHC(=O)NH2, -OCH3, -OCH2CH3 and -OCH2CH2CH3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L1 is selected from -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(OCH3)-, -C(OCH3)2- and 8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3-8 membered heterocycloalkyl groups.

9. The compound according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from 10. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Structural unit Selected from wherein T1, R1, R3, m, q and ring B are as defined in claim 1.

11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in formula (IA): wherein T1 is selected from CH and N; R1, R2, R3, L1, T2, m, n, q, Ring A and Ring B are as defined in claim 1.

12. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound has a structure represented by formula (I-1), (I-2), (I-3) or (I-4): wherein R1, R2, R3, L1, q and n are as defined in claim 1; T1 is selected from CH and N; T3 is selected from CH and N; T4 is selected from N and CH; T5 is selected from CH2, NH, O and S.

13. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound has the structure shown in formula (IB): wherein T1 is selected from O and S; R1, R2, R3, L1, T2, m, n, q, Ring A and Ring B are as defined in claim 1.

14. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compound has the structure shown in formula (I-5): wherein R1, R2, R3, L1, q and n are as defined in claim 1; T1 is selected from O and S; T6 is selected from CH and N.

15. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein The compounds have the structures represented by formula (I-1A), (I-1B), (I-1C), (I-1D), (I-2A), (I-3A), (I-4A) and (I-5A): wherein R1, R2, R3, L1, q and n are as defined in claim 1.

16. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

17. The compound according to claim 16, its stereoisomer or pharmaceutically acceptable salt thereof, which is selected from:

18. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 17, its stereoisomers or pharmaceutically acceptable salts thereof; optionally further comprising a pharmaceutically acceptable excipient, adjuvant or carrier.

19. Use of the compound according to any one of claims 1 to 17, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and / or treating HIV infection.

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