Preparation method of cyclopentane compounds and their application as antifungal agents

Abstract

The present invention discloses a preparation method of a paracyclic compound and its application as an antifungal agent. Specifically, the present invention discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and the antifungal application of the compound.

Description

Technical Field

[0001] The present invention relates to a preparation method of a cyclopentadiene compound and its application as an antifungal agent. The present invention also relates to a compound represented by formula (I) and its pharmaceutically acceptable salt, and the antifungal application of the compound. Background Art

[0002] In recent years, with the long-term and widespread use of broad-spectrum antibiotics, the increase in radiotherapy and chemotherapy, the popularization of bone marrow and organ transplantation, the increased use of immunosuppressants, and the development of interventional treatments such as heart valve implantation, the morbidity and mortality of clinical invasive fungal infections caused by Candida, Aspergillus, and Cryptococcus neoformans have shown a significant upward trend. There are tens of millions of fungal infections worldwide each year, and at least 1.5 million people die from deep fungal invasion.

[0003] The antifungal drugs currently used in clinical practice include azoles, polyenes and echinocandins, etc. Azoles are the largest class of antifungal drugs and are also the most common antifungal drugs in clinical practice. They have a broad antibacterial spectrum and low toxicity. Compared with amphotericin B, they are better tolerated, so they are the most widely used.

[0004] Despite their widespread clinical use, these azole antifungal drugs still have some shortcomings and limitations. For example, ketoconazole has great toxic side effects and is currently used only as a topical medication. Fluconazole, as a first-line drug for the treatment of local and deep fungal infections, has limited activity and has developed serious drug resistance due to long-term use. Itraconazole has poor water solubility and low bioavailability. The cyclodextrin contained in its oral solution may also cause osmotic diarrhea, which is harmful to patients with renal insufficiency. Posaconazole is a strong CYP3A4 inhibitor. This strong drug-drug interaction (DDI) limits its clinical application, and its physical and chemical properties and metabolic properties are also unsatisfactory, which greatly reduces the stability of its efficacy. Isavuconazole is a moderate CYP3A4 inhibitor and still has the problem of drug DDI.

[0005] Voriconazole is considered to be the most successful fluconazole derivative. It has strong activity against deep pathogenic fungi including fluconazole-resistant strains such as Candida krusei and Candida parapsilosis. It is currently the best drug for the treatment of fungal infections, especially invasive fungal diseases caused by Aspergillus. Its disadvantage is that it is mainly metabolized by CYP2C19 in the body. There is an excessively high blood drug concentration due to individual differences in CYP2C19 metabolism, which is particularly prone to adverse reactions in Chinese people. Side effects after taking voriconazole, such as abnormal visual reactions and liver dysfunction, have also been reported one after another.

[0006] In view of the defects and limitations of existing fluconazole antifungal drugs, it is necessary to develop new, highly effective, broad-spectrum, low-toxic CYP51 inhibitor antifungal drugs that are superior to existing drugs in terms of activity, metabolism and drug interactions, overcome the limitations and defects of existing clinical drugs, and overcome the resistance to fluconazole and the like. This has great clinical value for the treatment and prevention of various fungal infections, especially deep infections caused by Candida and Aspergillus, and for reducing the mortality rate of clinical invasive fungal infections. Summary of the invention

[0007] Based on the discovery of the above problems, the present invention proposes a series of compounds with novel azole structures. Compared with existing clinical therapeutic drugs, the content of the present invention has better or equivalent anti-Candida infection activity, overcomes the limitations and defects of existing clinical drugs, and can be used clinically to reduce the mortality rate of invasive fungal infections.

[0008] In the first aspect of the present invention, the present invention provides a compound represented by formula (I), its optical isomers, tautomers and pharmaceutically acceptable salts thereof,

[0009] in,

[0010] Ring A is selected from 5-6 membered heteroaryl;

[0011] Ring B is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkyl;

[0012] Ring C is independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2 or 3 Rx;

[0013] Ring D is independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 R Y replace;

[0014] Furthermore, ring C and ring D are not aromatic ring systems at the same time;

[0015] R3 is selected from OH, NH2, -OSi(R9)3, F, Cl, Br, I, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, The C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 NH2;

[0016] R2, R X , R Y are independently selected from H, CN, OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl, SF3, SF6, SCN, SO3H and SO2R7, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally substituted with 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0017] Or, R3 and Rx are connected together to form a 3-9 membered heterocyclic group or C 3-9 cycloalkyl;

[0018] R7 and R9 are independently selected from NH2, C 1-6 alkyl, phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0019] n is independently selected from 0, 1, 2 or 3;

[0020] L1 is selected from a single bond, C 1-6 Alkyl, C 2-6 Alkynyl, phenyl and 5-6 membered heteroaryl, the C 1-6 Alkyl, C 2-6 Alkynyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0021] L2 is selected from a single bond, O, S, NH, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic group, C 3-6 Cycloalkyl and phenyl-OC 1-6 Alkyl-, the C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic group, C 3-6 Cycloalkyl or phenyl-OC 1-6 Alkyl - optionally substituted with 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0022] L3 is selected from a single bond, -C(=O)-, -C(=O)NH-, C 1-6 Alkyl, 3-6 membered heterocyclic group, C 3-6 Cycloalkyl, phenyl and 5-6 membered heteroaryl, the C 1-6 Alkyl, 3-6 membered heterocyclic group, C 3-6Cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0023] L4 is selected from H, F, Cl, Br, I, OH, CN, NH2, COOH, SF3, SF6, SCN, SO2R7, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 1-6 Alkyl-5-6 membered heterocyclic group, 5-6 membered heteroaryl group and benzo 4-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, C 1-6 Alkyl-5-6 membered heterocyclic group, 5-6 membered heteroaryl group or benzo-5-6 membered heterocyclic group is optionally substituted by 1, 2, 3, 4 or 5 R L replace;

[0024] R L Selected from CN, OH, F, Cl, Br, I, NH2, C 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally substituted with 1, 2 or 3 CN, OH, NH2, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0025] The C 1-6 The heteroalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0026] In another aspect of the present invention, the present invention also provides a compound represented by formula (II-1) or (II-2), its optical isomers, tautomers and pharmaceutically acceptable salts thereof,

[0027]

[0028] in,

[0029] X1, X2, X3, and X8 are independently selected from C(R X )2. NR X , S and O;

[0030] X4, X5, X6, and X7 are independently selected from CR Y and N;

[0031] R6 is selected from H, CN, OH, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl, SF3, SF6, SCN, SO3H and SO2R7, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally substituted with 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution;

[0032] Or, R3 and R6 are connected together to form a 3-6 membered heterocyclic group or C 3-6 cycloalkyl;

[0033] Ring A, Ring B, R2, R3, R X , R Y , L1, L2, L3, L4, n are as defined above.

[0034] In some embodiments of the present invention, the ring A is selected from tetrazolyl, triazolyl, oxazolyl, pyrimidinyl, thiazolyl or pyrazolyl, and the remaining variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the ring A is selected from The remaining variables are as defined in the present invention.

[0036] In some embodiments of the present invention, the above ring B is selected from phenyl and pyridyl, and the remaining variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above R3 is selected from OH, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC(=O)C 1-3 Alkyl and -NHC(=O)C 1-3 The remaining variables are as defined herein.

[0039] In some embodiments of the present invention, the above L1 is selected from a single bond, CH2, The remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above L2 is selected from a single bond, O, S, CH2, NH, NCH3, The remaining variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above L3 is selected from a single bond, CH2, CH2CH2, -C(=O)-, -C(=O)NH-, The remaining variables are as defined in the present invention.

[0042] In some embodiments of the present invention, L4 is selected from H, F, Cl, Br, I, OH, CN, NH2, CHF2, CF3, OCH3, OCF3, OCHF2, OCH2CH3, COOH, CONHMe, CONMe2, NMe2,

[0043] The remaining variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above structural unit Selected from H, I, CN, OH, CF3, COOH, CONHMe, CONMe2,

[0045]

[0046]

[0047] The remaining variables are as defined in the present invention.

[0048] In some embodiments of the present invention, the above-mentioned ring C and ring D are independently selected from cyclopentanyl, cyclohexanyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, pyridinyl and pyrimidinyl, and the cyclopentanyl, cyclohexanyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, pyridinyl or pyrimidinyl is optionally substituted with 1, 2 or 3 halogens, methyl, ethyl or cyclopropyl, and ring C and ring D are not aromatic ring systems at the same time, and the other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the above structural unit Selected from

[0050] The remaining variables are as defined in the present invention.

[0051] In another aspect of the present invention, the present invention also proposes the following compounds, their optical isomers, tautomers and pharmaceutically acceptable salts thereof, which are selected from

[0052]

[0053] In another aspect of the present invention, the present invention also proposes the following compounds, their optical isomers, tautomers and pharmaceutically acceptable salts thereof, which are selected from

[0054]

[0055]

[0056] In another aspect of the present invention, the present invention also proposes the use of the aforementioned compound, its optical isomers, tautomers or pharmaceutically acceptable salts thereof in the preparation of antifungal infection drugs.

[0057] Definition and Description

[0058] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0059] As in the present invention, the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.

[0060] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0061] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the 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 a pure 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 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 a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0062] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0063] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from and wait.

[0064] A hyphen ("-") not between two letters or symbols indicates the point of attachment of a substituent. 1-6 Alkylcarbonyl - refers to a C- 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0065] When the group bond is marked with a dotted line When, for example, In the example, the dashed line indicates the point of attachment of the group to the rest of the molecule. When, for example, In the example, the dashed line represents a single bond or its absence, which also means Represents a single bond or double bond

[0066] The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.

[0067] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L1 represents a single bond, it means that the structure is actually

[0068] When the substituent is listed without indicating the atom through which it is connected to the substituted group, such substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0069] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH2O-, in which case -CH2O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0070] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0071] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 , C 1-4 , C1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). 1-6 Examples of alkyl groups include, but are not limited to, CH3,

[0072] wait.

[0073] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 , C 1-3 , C 3-4 and C 2-3 Alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). 1-4 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0074] Unless otherwise specified, “C 2-6 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-6 Alkynyl groups include C 2-3 , C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 5-6 , C6, C5, C4, C3 and C2 alkynyl. 2-6 Examples of alkynyl groups include, but are not limited to wait.

[0075] Unless otherwise specified, “C 2-3 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to wait.

[0076] The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-6 In other embodiments, the heteroalkyl group is C 1-3 Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is a customary expression to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3.

[0077] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0078] 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. 1-3 Alkoxy includes C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 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.

[0079] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through an amino group. 1-6 Alkylamino groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0080] Unless otherwise specified, the term “C 1-3 "Alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an amino group. 1-3 Alkylamino groups include C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0081] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc.1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0082] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0083] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic system. 3-6 Cycloalkyl groups include C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0084] Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 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 bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected to the rest of the molecule. The 3-6 membered heterocyclic group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclic 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 or homopiperidinyl, etc.

[0085] Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 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 systems, wherein bicyclic systems include spirocyclic, fused and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected to the rest of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups, etc. Examples of 5-6 membered heterocyclic groups include, but are not limited to, 1,3-dioxolane, 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 or homopiperidinyl, etc.

[0086] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), 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.), furanyl (including 2-furanyl and 3-furanyl, 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.).

[0087] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.

[0088] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0089] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0090] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore may exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0091] 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. All of these isomers and their mixtures are included within the scope of the present invention.

[0092] The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.

[0093] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0094] The term "diastereomer" as used herein refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0095] Stereochemical definitions and conventions may be followed in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

[0096] The racemic mixture can be used in its own form or split into individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by splitting. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0097] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetautomers) include interconversions carried out 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.

[0098] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14C). For another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0099] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0100] 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 embodiments of the present invention.

[0101] The solvent used in the present invention is commercially available.

[0102] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0103] The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration. The chiral centers of some of the compounds disclosed in the present invention are marked with *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single configuration enantiomer monomer, or a single configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: other chiral center configurations have not been resolved). When the absolute configuration (R configuration, or S configuration) of the chiral center of the compounds disclosed in the present invention has not been identified, such compounds can be identified according to their corresponding retention time (R configuration) under corresponding chromatographic column conditions (for example, chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.). T ) for confirmation.

[0104] The present invention is explained in more detail in the following examples. However, it should be understood that these examples are for illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental methods in the following examples, if no specific conditions are specified, are usually based on the conventional conditions of this type of reaction, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. Unless otherwise stated, the ratio of liquid is volume ratio.

[0105] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. DETAILED DESCRIPTION

[0106] The present application is described in detail below by way of examples, but this does not mean that there are any adverse limitations to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0107] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0108] In all embodiments, 1 H-NMR, 13 C-NMR and 19 F-NMR spectra were recorded using a Bruker Ascend 400 MHz NMR instrument and processed using Topspin software, with deuterated solvents used as internal deuterium locks. 13 C-NMR and 19 F-NMR 1 H decoupling. Assignments were made based on well-defined chemical shift / coupling patterns or based on 2D Cosy, HMBC, HSQC or NOESY experiments. Peak multiplicities were defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad, br.s broad singlet; coupling constants (J) were accurate to 0.1 Hz. Mass spectra were recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separations were performed using an Agilent 1290 UV-guided fully automated purification system ( Prep C18OBDTM 21.2×250mm10μm column) or Gilson GX281 UV-guided automatic purification system ( Prep C18OBDTM 19×250mm10μm column) or Waters QDa-guided fully automated purification system ( Unless otherwise specified, separation was performed using SepaFlash prepacked normal phase silica gel columns (Sinopharm Chemical Reagent Co., Ltd.) and TLC analysis plates (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, specification: 2.5×5 cm), and the ratio of eluents was by volume.

[0109] Among them, the Chinese names of the reagents represented by chemical formulas or English abbreviations are as follows:

[0110] CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d or CDCl3 represents deuterated chloroform; AcOH represents acetic acid; AlCl3 represents aluminum chloride; Aq represents aqueous solution; N2 represents nitrogen; Ar represents argon; B2Pin2 represents diboronic acid pinacol ester; BBr3 represents boron tribromide; BH3 represents borane; (Boc)2O represents di-tert-butyl dicarbonate; Et3SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphorus salt; HOBt represents 1-hydroxybenzotriazole; K2CO3 represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; LiHMDS represents lithium bis(trimethylsilyl)amide; LiOH represents lithium hydroxide; m-CPBA represents m-chloroperbenzoic acid; Na2CO3 represents sodium carbonate; NaBH4 represents sodium borohydride; NaCl represents sodium chloride; NaHCO3 represents sodium bicarbonate; NaOH represents sodium hydroxide; Na2SO4 represents sodium sulfate; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; NH4Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr3 represents phosphorus tribromide; Pd(dppf)Cl2 or PdCl2(dppf) represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; Pd(OAc)2 represents palladium acetate; conc. represents concentrated; (COCl)2 represents oxalyl chloride; Cs2CO3 represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; DCM represents dichloromethane; Dioxane or 1,4-dioxane represents 1,4-dioxane; MeCN, ACN or CH3CN represents acetonitrile; MeOH or met hanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; Toluene or tol. represents toluene; SOCl2 represents dichlorothionyl; TFA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilyl cyanide; H2O represents water; HCl represents hydrogen chloride gas; HCl aq.stands for aqueous hydrochloric acid; ℃ stands for ℃; rt or RT stands for room temperature; h stands for hour; min stands for minute; g stands for g; mg stands for mg; mL stands for mL; mmol stands for mmol; M stands for mole; cm stands for centimeter; mm stands for millimeter; μm stands for micrometer; nm stands for nanometer; mL / min stands for mL per minute; Hz stands for hertz; MHz stands for megahertz; bar stands for bar; psi stands for pounds per square inch; N2 stands for nitrogen; HPLC stands for high performance liquid chromatography; ID stands for inner diameter; LCMS or LC-MS stands for liquid chromatography-mass spectrometry; m / z stands for mass-to-charge ratio; ESI stands for electrospray ionization; CO2 stands for carbon dioxide; TLC stands for thin layer chromatography; UV stands for ultraviolet. .

[0111] Example 1: Preparation of Compounds 1-5, 1-6, 1-7, 1-8, 1-9 and 1-10

[0112]

[0113] Preparation of compound 1-2

[0114] Compound 1-1 (2 g, 9.05 mmol) was dissolved in acetonitrile (25 mL), and the reaction solution was stirred at room temperature for 0.5 hours. 1,3-dibromopropane (3.65 g, 18.10 mmol) and potassium carbonate (2.5 g, 18.10 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction system was filtered, and the filtrate was dried to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 1-2 (2.5 g, yield 50%), which was a yellow oil. Compound 1-2: 1 H NMR (400MHz, DMSO-d6) δ7.99-7.98(m,1H),7.43–7.33(m,2H),4.20(t,J=6.8Hz,2H),3.75(t,J=6.8Hz,2H),2.32–2.21(m,2H).

[0115] Preparation of Compound 1-3

[0116] Compound 1-2 (2.5 g, 7.31 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to -70 °C. n-Butyl lithium (1.6 M, 5.5 mL) was added dropwise to the system, and the reaction solution was stirred at -70 °C for 1 hour. The reaction was quenched with saturated aqueous ammonium bicarbonate solution (15 mL), extracted with ethyl acetate (20 mL × 3), and concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 1-3 (900 mg, yield 91%), as a yellow oil. Compound 1-3: 1 H NMR (400MHz, DMSO-d6) δ8.04(m,1H),7.15–7.07(m,2H),4.20–4.11(m,2H),2.85(t,J=6.8Hz,2H),2.05–2.00(m,2H).

[0117] Preparation of compounds 1-5 and 1-6

[0118] Compound 1-3 (1 g, 7.40 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to -70°C. n-Butyl lithium (1.6 M, 6.9 mL) was added dropwise to the system, and the reaction solution was stirred at -70°C for 1 hour. A tetrahydrofuran solution (5 mL) containing compound 1-4 (1.65 g, 7.40 mmol) was added dropwise to the reaction system, and the reaction solution was stirred at -70°C for 1 hour. The reaction was quenched with saturated aqueous ammonium bicarbonate solution (15 mL), extracted with ethyl acetate (20 mL×3), and concentrated to obtain a crude product. The crude product was prepared and separated (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 1-5 (78 mg, yield 3%) and the title compound 1-6 (150 mg, yield 6%).

[0119] Compound 1-5: Chiral analysis method (chromatographic column model: Cellulose-2 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: mobile phase 5% B increased to 40% B within 5 minutes and maintained at 40% B for 2.5 minutes, then 5% B equilibrated for 2.5 minutes; flow rate: 2.5mL / min; column temperature: 35°C; column pressure: 1500psi; detection wavelength: 220nm; RT=6.026min). LC-MS (ESI): m / z 359.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.26(s,1H),8.23-8.21(m,1H),7.64(s,1H),7.38–7.14(m,4H),6.92-6.87(m,1H),6.02(s,1H),5.17(d,J=14 .6Hz,1H),5.03(d,J=14.6Hz,1H),4.37-4.32(m,1H),4.04-4.01(m,1H),3.59(t,J=5.6Hz,1H),1.88-1.80(m,1H),1.68–1.50(m,1H).

[0120] Compound 1-6: Chiral analysis method (chromatographic column model: Cellulose-2 150×4.6mm ID, 3μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); elution gradient: mobile phase 5% B increased to 40% B within 5 minutes and maintained at 40% B for 2.5 minutes, then 5% B equilibrated for 2.5 minutes; flow rate: 2.5mL / min; column temperature: 35°C; column pressure: 1500psi; detection wavelength: 220nm; RT=6.026min). LC-MS (ESI): m / z 359.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 8.04 (t, J = 3.0Hz, 1H), 7.63 (s, 1H), 7.55 -7.49(m,1H),7.19(d,J=3.0Hz,2H),7.12(s,1H),7.07–7.01(m,1H),6.97–6.9 2(m,1H),5.23(d,J=14.6Hz,1H),4.71(d,J=14.6Hz,1H),3.98-3.93(m,1H),3 .65-3.59(m,1H),3.46(t,J=6.4Hz,1H),2.42–2.31(m,1H),2.02–1.79(m,1H).

[0121] Preparation of compounds 1-7 and 1-8

[0122] Compound 1-5 (78 mg) was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); chromatographic column model: Cellulose-2, 250×30 mm ID, 10 μm; mobile phase: A for CO2 and B for Ethanol; elution gradient: B 40%; flow rate: 70 mL / min; column pressure: 100 bar; column temperature: 38°C; detection wavelength: 220 nm; cycle: ~8 min) to obtain the title compounds 1-7 (25 mg) and 1-8 (25 mg).

[0123] Compound 1-7: LC-MS (ESI) m / z 359.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.26(s,1H),8.23-8.21(m,1H),7.64(s,1H),7.41–7.16(m,4H),6.92-6.87(m,1H),6.02(d,J=1.2Hz,1H),5.17(d, J=14.8Hz,1H),5.03(d,J=14.8Hz,1H),4.37-4.31(m,1H),4.04-4.00(m,1H),3.59(t,J=5.6Hz,1H),1.88-1.80(m,1H),1.64-1.59(m,1H).

[0124] Compound 1-8: LC-MS (ESI) m / z 359.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.26(s,1H),8.23-8.21(m,1H),7.64(s,1H),7.41–7.16(m,4H),6.92-6.87(m,1H),6.02(d,J=1.2Hz,1H),5.17(d, J=14.8Hz,1H),5.03(d,J=14.8Hz,1H),4.37-4.31(m,1H),4.04-4.00(m,1H),3.59(t,J=5.6Hz,1H),1.88-1.80(m,1H),1.64-1.59(m,1H).

[0125] Preparation of compounds 1-9 and 1-10

[0126] Compound 1-6 (150 mg) was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-1); chromatographic column model: Cellulose-2, 250×30mm ID, 10μm; mobile phase: A for CO2 and B for Ethanol; elution gradient: B40%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38°C; detection wavelength: 220nm; cycle: ~8min) to obtain the title compound 1-9 (60 mg) and the title compound 1-10 (60 mg).

[0127] Compound 1-9: LC-MS (ESI) m / z 359.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.05-8.33(m,1H),7.63(s,1H),7.55-7 .49(m,1H),7.19(d,J=2.8Hz,2H),7.11(s,1H),7.07-7.01(m,1H),6.97-6.92 (m,1H),5.23(d,J=14.8Hz,1H),4.71(d,J=14.8Hz,1H),3.98-3.93(m,1H),3. 65-3.60(m,1H),3.46(t,J=6.4Hz,1H),2.40-2.31(m,1H),1.96-1.89(m,1H).

[0128] Compound 1-10: LC-MS (ESI) m / z 359.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.05-8.33(m,1H),7.63(s,1H),7.55-7 .49(m,1H),7.19(d,J=2.8Hz,2H),7.11(s,1H),7.07-7.01(m,1H),6.97-6.92 (m,1H),5.23(d,J=14.8Hz,1H),4.71(d,J=14.8Hz,1H),3.98-3.93(m,1H),3. 65-3.60(m,1H),3.46(t,J=6.4Hz,1H),2.40-2.31(m,1H),1.96-1.89(m,1H).

[0129] Example 2: Preparation of Compounds 2-8 and 2-9

[0130]

[0131] Preparation of compound 2-2

[0132] Compound 2-1 (22 g, 122.1 mmol) was dissolved in dichloroethane (250 mL), and boron tribromide (52.7 mL, 555.0 mmol) was slowly added. The reaction solution was stirred at 80 ° C for 16 hours. The reaction solution was poured into a saturated sodium bicarbonate solution (150 mL), and then the pH was adjusted to about 4 with acetic acid, and ethyl acetate (50 mL × 3) was added for extraction and concentrated to obtain the target product 2-2 (15 g, yield 59%). LC-MS (ESI): m / z 165.0 [M+H] + .

[0133] Preparation of compound 2-3

[0134] Compound 2-2 (15.0 g, 73.19 mmol) was dissolved in tetrahydrofuran (150 mL), and then 3-butene-1-ol (8.0 mL, 87.2 mmol) and triphenylphosphine (38.1 g, 145.4 mmol) were added. The solution was then cooled to 0°C, and diisopropyl azodicarboxylate (28.8 mL, 145.4 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 12 hours, and the reaction was completed by TLC. The reaction solution was then poured into water (200 mL), and ethyl acetate (100 mL × 3) was added for extraction. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by a normal phase silica gel column (biotage, silica gel column, 330 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 2-3 (7.5 g, yield 47%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ8.18(s,1H),5.98-5.79(m,1H),5.35-5.08(m,2H).4.20(m,2H),2.64(m,2H).

[0135] Preparation of Compound 2-4

[0136] Compound 2-3 (12 g, 55.04 mmol) was dissolved in 1,4-dioxane (200 mL), and potassium acetate (16.08 g, 164.34 mmol), triphenylphosphine (5.7 g, 21.91 mmol), and palladium acetate (1.80 g, 8.20 mmol) were added respectively, and the reaction system was stirred at 100 ° C for 12 h. The reaction solution was filtered and the filtrate was concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 120 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 2-4 (6.5 g, yield 64%), which was a white solid. LC-MS (ESI): m / z 183.0 [M+H] + .

[0137] Preparation of Compound 2-5

[0138] At room temperature, compound 2-4 (7.7 g, 42.17 mmol) was dissolved in dichloromethane (100 mL), the reaction solution was cooled to -60 ° C, and then ozone was introduced into the reaction system for 40 minutes. TLC detected that the raw material reaction was complete, and then dimethyl sulfide (5 mL) was added to quench the reaction. The crude product was concentrated in vacuo to obtain a crude product. The crude product was purified by normal phase silica gel column (biotage, silica gel column, 120 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain compound 2-5 (1.93 g, yield 27%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ8.66 (s, 1H), 4.71 (t, J = 8.0Hz, 2H), 3.04 (t, J = 8.0Hz, 2H).

[0139] Preparation of Compound 2-6

[0140] Compound 2-5 (0.9 g, 2.89 mmol) was dissolved in dichloromethane (10 mL) and ethanol (2 mL), sodium borohydride (92 mg, 2.44 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was poured into water (50 mL), and then dichloromethane (50 mL×3) was added for extraction. The organic phase was dried by rotation to obtain a crude compound 2-6 (305 mg, yield 100%), which was a yellow oil. The crude product was directly used for the next step reaction. LC-MS (ESI): m / z 187.0 [M+H] + .

[0141] Preparation of Compound 2-7

[0142] Compound 2-6 (500 mg, 2.68 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (814 mg, 8.06 mmol) and methanesulfonyl chloride (366 mg, 3.21 mmol) were added. After the reaction solution was stirred at 25 ° C for 1 hour, the reaction solution was poured into water (50 mL), and then dichloromethane (50 mL × 3) was added for extraction. The organic phase was dried by rotation to obtain a crude product 2-7 (580 mg, yield 100%), which was directly used for the next step reaction. LC-MS (ESI): m / z 264.9 [M+H] + .

[0143] Preparation of Compound 2-8

[0144] Compound 1-4 (363 mg, 1.63 mmol) was dissolved in tetrahydrofuran (10 mL), zinc powder (349 mg, 5.45 mmol) and lead powder (225 mg, 1.09 mmol) were added, and the reaction system was replaced with argon three times, and the reaction solution was heated to 70°C, and then a tetrahydrofuran solution (2 mL) of compound 2-7 (290 mg, 1.09 mmol) was slowly added dropwise, and the reaction was allowed to proceed overnight at 70°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was dried to obtain a crude product 2-8 (360 mg), which was prepared and separated (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 2-8 (78 mg, yield 3%). LC-MS(ESI):m / z 394.2[M+H] + .

[0145] Preparation of Compound 2-9

[0146] The crude compound 2-8 (950 mg, 2.41 mmol) was dissolved in methanol (10 mL), and then Pd / C (50 mg, 10% wt) and triethylamine (950 mg, 2.41 mmol) were added. After hydrogen replacement three times, the reaction solution was heated to 60°C and reacted for 2 hours. The reaction solution was filtered and the filtrate was dried to obtain a crude product, which was prepared and separated (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 2-9 (17.0 mg, yield 0.98%). LC-MS (ESI): m / z 360.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.82 (s, 1H), 8.42 (s, 1H), 8.19 (m, 1H), 7.62 (s, 1H), 7.36-7.12 (m, 2H), 6.94-6.89 (m, 1H), 5.81 (s, 1H), 5.24-5.20 (m, 1H), 5.06-5.02 (m, 1H) 4.41-4.35 (m, 1H), 4.15-4.10 (m, 1H), 3.64-3.61 (m, 1H), 1.91-1.711 (m, 1H), 1.62-1.57 (m, 1H). Example 3: Preparation of Compounds 3-4 and 3-5

[0147]

[0148] Preparation of compound 3-3

[0149] Compound 3-1 (4 g, 17.02 mmol) and tetrazole 3-2 (1.19 g, 17.02 mmol) were dissolved in acetonitrile (25 mL), and the reaction solution was stirred at room temperature for 0.5 hours. Potassium carbonate (3.53 g, 25.53 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction system was filtered, and the filtrate was dried to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 3-3 (1.5 g, yield 39%) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ8.81 (s, 1H), 8.09 (td, J = 8.6, 6.4Hz, 1H), 7.13-7.08 (m, 1H), 7.06-7.01 (m, 1H), 5.88 (d, J = 3.6Hz, 2H).

[0150] Preparation of compounds 3-4 and 3-5

[0151] Compound 1-3 (600 mg, 4.44 mmol) was dissolved in tetrahydrofuran (28 mL), cooled to -70 ° C, and n-butyl lithium (1.6 M, 2.77 mL) was added dropwise. The reaction solution was stirred at -70 ° C for 1 hour. A tetrahydrofuran solution (5 mL) containing compound 3-3 (0.995 g, 4.44 mmol) was added dropwise to the reaction system. The reaction solution was stirred at -70 ° C for 1 hour. The reaction system was quenched by adding saturated aqueous ammonium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL × 3), and concentrated to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; gradient: 55%-75% acetonitrile in 12min; flow rate: 30mL / min) to obtain the title compound 3-4 (70mg) and the title compound 3-5 (50mg).

[0152] Compound 3-4: LC-MS (ESI): m / z 360.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),8.25-8.24(m,1H),7.41–7.16(m,4H),6.91(td,J=8.4,2.4Hz,1H),6.16(s,1H),5.49(d,J=14 .6Hz,1H),5.33(d,J=14.6Hz,1H),4.36-4.30(m,1H),4.06-4.01(m,1H),3.68-3.65(m,1H),1.86-1.78(m,1H),1.66-1.59(m,1H).

[0153] Compound 3-5: LC-MS (ESI): m / z 360.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.12-8.10(m,1H),7.53-7.47(m,1H),7.31(s,1H),7.27–7.17(m,2H),7.12-7.10(m,1H),6.99-6.94 (m,1H),5.59(d,J=14.6Hz,1H),4.92(dd,J=14.6,1.2Hz,1H),3.97-3.93(m,1H),3.55–3.49(m,2H),2.38–2.31(m,1H),1.97-1.90(m,1H).

[0154] Example 4: Preparation of Compounds 4-4 and 4-5

[0155]

[0156] Preparation of compounds 4-2 and 4-3

[0157] Dissolve compound 4-1 (500 mg, 4.20 mmol) in tetrahydrofuran (5 mL) and cool to -65 °C. Add n-butyl lithium (1.6 M, 3.93 mL) at -65 °C and stir at -65 °C for 20 minutes. Add a tetrahydrofuran solution (2 mL) containing compound 1-4 (468 mg, 2.1 mmol) dropwise to the reaction system and continue stirring for 10 minutes. Add saturated aqueous ammonium chloride solution (15 mL) to quench the reaction system. Extract with ethyl acetate (50 mL × 3), combine the organic phases and spin dry to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12min; flow rate: 30mL / min) to obtain the title compound 4-2 (30mg, yield 2%) and compound 4-3 (50mg, yield 3%).

[0158] Compound 4-2: LC-MS (ESI): m / z 343.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.44–8.01(m,2H),7.63(s,1H),7.39(dd,J=21.0,8.1Hz,2H),7.03(t,J=6.2Hz,1H),6.80(q,J=8.9,8.3Hz,2H),5 .94(s,1H),5.13(d,J=14.5Hz,1H),4.71(d,J=14.4Hz,1H),3.59(d,J=8.4Hz,1H),2.57–2.48(m,1H),2.07(ddd,J=47.8,21.5,8.9Hz,3H).

[0159] Compound 4-3: LC-MS (ESI): m / z 343.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.39(dd,J=5.0,1.5Hz,1H),8.21(s,1H),7.63–7.50(m,2H),7.24–7.01(m,3H),6.82(td,J=8.5,2.6Hz,1H),5.65–5.25(m ,2H),4.94(d,J=14.6Hz,1H),3.84(dd,J=9.0,6.6Hz,1H),2.84(td,J=9. 6,9.1,4.5Hz,1H),2.66(ddd,J=15.9,8.9,6.3Hz,1H),1.79–1.52(m,2H).

[0160] Preparation of compounds 4-4 and 4-5

[0161] Compound 4-3 (34 mg) was subjected to SFC chiral preparative separation (preparative separation method, instrument model: MGⅡpreparative SFC (SFC-14); chromatographic column model: ChiralPak AD, 250×30mm ID, 10μm; mobile phase: A for CO2 and B for Ethanol (0.1% NH3H2O); elution gradient: B 35%; flow rate: 70mL / min; column pressure: 100bar; column temperature: 38°C; detection wavelength: 220nm; cycle: ~7min) to obtain the title compound 4-4 (17mg) and the title compound 4-5 (15mg).

[0162] Compound 4-4: LC-MS (ESI): 343.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.39(dd,J=5.0,1.5Hz,1H),8.21(s,1H),7.63–7.50(m,2H),7.24–7.01(m,3H),6.82(td,J=8.5,2.6Hz,1H),5.65–5.25(m ,2H),4.94(d,J=14.6Hz,1H),3.84(dd,J=9.0,6.6Hz,1H),2.84(td,J=9. 6,9.1,4.5Hz,1H),2.66(ddd,J=15.9,8.9,6.3Hz,1H),1.79–1.52(m,2H).

[0163] Compound 4-5: LC-MS (ESI): 343.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.39(dd,J=5.0,1.5Hz,1H),8.21(s,1H),7.63–7.50(m,2H),7.24–7.01(m,3H),6.82(td,J=8.5,2.6Hz,1H),5.65–5.25(m ,2H),4.94(d,J=14.6Hz,1H),3.84(dd,J=9.0,6.6Hz,1H),2.84(td,J=9. 6,9.1,4.5Hz,1H),2.66(ddd,J=15.9,8.9,6.3Hz,1H),1.79–1.52(m,2H).

[0164] Example 5: Preparation of Compounds 5A, 5B1, 5B2 and 5C

[0165]

[0166] Preparation of compound 5-2

[0167] To a solution of 5-fluoropyridin-3-ol (3.80 g, 33.60 mmol) in water (92 mL) was added sodium carbonate (7.138 g, 67.22 mmol) and potassium iodide (11.158 g, 67.19 mmol) at room temperature. A solution of iodine (1.94 g, 47.05 mmol) in water (13 mL) was added dropwise over 1.5 hours with stirring. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the pH value of the reaction mixture was adjusted to 5-6 with hydrochloric acid solution (4 M) until a precipitate was obtained, which was collected by filtration and dried in a vacuum oven to obtain the title compound 5-2 (2.97 g, 37%). 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),7.96(d,J=2.8Hz,1H),7.03(dd,J=10.2,2.8Hz,1H).

[0168] Preparation of compound 5-3

[0169] Compound 5-2 (1 g, 4.18 mmol) and potassium carbonate (1.16 g, 8.37 mmol) were dissolved in acetonitrile (25 mL), and the reaction solution was stirred at room temperature for 0.5 hours, and then 1,3-dibromopropane (1.01 g, 5.03 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction system was filtered, and the filtrate was dried to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 10 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 5-3 (1.3 g, yield 86%). 1H NMR (400MHz, DMSO-d6) δ7.99(d,J=2.4Hz,1H),6.83(dd,J=9.7,2.4Hz,1H),4.19(t,J=5.6Hz,2H),3.71(t,J=6.0Hz,2H),2.41(p,J=6.0Hz,2H).

[0170] Preparation of compounds 5-4 and 5-4a

[0171] Compound 5-3 (1.3 g, 3.61 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to -70°C. n-Butyl lithium (1.6 M, 3.4 mL) was added dropwise and the reaction solution was stirred at -70°C for 1 hour. The reaction system was quenched with saturated aqueous ammonium bicarbonate solution (60 mL), extracted with ethyl acetate (20 mL × 3), and concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 5-4 (100 mg) and the title compound 5-4a (400 mg).

[0172] Compound 5-4: 1 H NMR (400MHz, DMSO-d6) δ8.19(dd,J=2.4,0.8Hz,1H),7.20(dd,J=9.0,2.4Hz,1H),4.35–4.27(m,2H),3.12(td,J=6.8,1.2Hz,2H),2.23–2.10(m,2H).

[0173] Compound 5-4a: 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.99(s,1H),4.24–4.19(m,2H),2.73(t,J=6.4Hz,2H),1.98–1.92(m,2H).

[0174] Preparation of compound 5A

[0175] Compound 5-4 (100 mg, 0.652 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to -70 °C. n-Butyl lithium (1.6 M, 0.4 mL) was added dropwise, and the reaction solution was stirred at -70 °C for 1 hour. A tetrahydrofuran solution (2 mL) containing compound 1-4 (145 mg, 0.652 mmol) was added dropwise to the reaction system, and the reaction solution was stirred at -70 °C for 1 hour. The reaction system was quenched with aqueous ammonium bicarbonate (60 mL), extracted with ethyl acetate (20 mL × 3), and concentrated to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 × 21.2 mm; column temperature: 25 °C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 5A (2.5 mg).

[0176] Compound 5A: LC-MS (ESI): m / z 377.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.22(s,1H),8.00(d,J=2.8Hz,1H),7.62(s,1H),7.27-7.22(m,1H),7.09-7.05(m,1H),6.89-6.8 5(m,1H),6.66(s,1H),5.21–5.06(m,2H),4.13-4.09(m,1H),4.02-3.98(m,1H),2.84(t,J=6.4Hz,2H),1.97-1.92(m,2H).

[0177] Preparation of compounds 5B1, 5B2 and 5C

[0178] Compound 5-4a (400 mg, 2.61 mmol) was dissolved in tetrahydrofuran (3 mL) and cooled to -70°C. n-Butyl lithium (1.6 N / L, 2.61 mL) was added dropwise, and the reaction solution was stirred at -70°C for 1 hour. A tetrahydrofuran solution containing compound 1-4 (583 mg, 0.652 mmol) was added dropwise to the reaction system, and stirred at -70°C for 1 hour. The reaction system was quenched with aqueous ammonium bicarbonate (60 mL), extracted with ethyl acetate (20 mL×3), and concentrated to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the target products 5C (26 mg), 5B1 (17 mg), and 5B2 (40 mg).

[0179] Compound 5C: LC-MS (ESI): m / z 377.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.01(s,1H),7.64(s,1H),7.38-7.32(m,1H),7.08-7.02(m,1H),6.92 -6.87(m,1H),6.62(s,1H),5.20–5.08(m,2H),4.20(t,J=5.2Hz,2H),2.64–2.61(m,2H),1.93-1.88(m,2H).

[0180] Compound 5B1: LC-MS (ESI): m / z 377.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.98(s,1H),7.76(s,1H),7.68(s,1 H),7.15-7.09(m,1H),7.03-6.97(m,1H),6.81-6.76(m,1H),5.73(s,1H) ,5.05(d,J=14.2,1H),4.84(d,J=14.2Hz,1H),4.60-4.53(m,1H),4.35-4 .31(m,1H),3.73(d,J=4.8Hz,1H),2.59-2.54(m,1H),2.00-1.90(m,1H).

[0181] Compound 5B2: LC-MS (ESI): m / z 377.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),8.19(s,1H),8.14(s,1H),7.60(s,1H),7.33–7.20(m,2H),6.94-6.89(m,1H),5.86(s,1H),4.97(dd,J=14. 2,2.4Hz,1H),4.57-4.40(m,1H),4.42(dd,J=14.2,3.6Hz,1H),4.23–4. 10(m,1H),3.76(d,J=4.8Hz,1H),1.80-1.70(m,1H),1.44-1.39(m,1H).

[0182] Example 6: Preparation of Compounds 6-8 and 6-9

[0183]

[0184] Preparation of compound 6-3

[0185] Compound 5-2 (crude, 33.60 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to 0°C. 3-Butene-1-ol (2.54 g, 35.28 mmol), DEAD (6.14 g, 35.28 mmol), and triphenylphosphine (9.69 g, 36.96 mmol) were added, and the reaction solution was stirred at 0°C for 1 hour. The mixture was extracted with ethyl acetate (20 mL × 3) and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the target product 6-3 (12 g, crude).

[0186] Preparation of compound 6-4

[0187] Compound 6-3 (crude, 34.12mmol), triphenylphosphine (2.68g, 10.24mmol), palladium acetate (0.766g, 3.41mmol) and potassium acetate (16.74g, 170.10mmol) were added to a round-bottom flask. After adding anhydrous DMF (200mL) to dissolve under nitrogen protection, stir in an oil bath at 105℃. After 10 hours, the plate was spotted and TLC detected that the raw material reaction was complete. After the reaction solution was cooled to room temperature, water (100mL) was added to quench the reaction, ethyl acetate (20mL×3) was extracted, washed with saturated brine (20mL×3), and dried over anhydrous sodium sulfate. Filter, add silica gel to the filtrate and spin dry, and purify with a normal phase silica gel column (biotage, silica gel column, 20g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 6-4 (1.2g) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=2.4Hz,1H),6.90(dd,J=9.2,2.4Hz,1H),6.1 1(d,J=1.6Hz,1H),5.05(dd,J=1.6,0.8Hz,1H),4.38–4.20(m,2H),2.91–2.72(m,2H).

[0188] Preparation of compound 6-5

[0189] Compound 6-4 (1 g, 6.05 mmol) and dichloromethane (60 mL) were added to a round-bottom flask, cooled to -78 ° C in a dry ice-acetone bath, and ozone gas was introduced. After the reaction solution turned dark blue, the aeration was stopped. Dimethyl sulfide (5 mL) was added to the reaction solution and the temperature was naturally raised to room temperature. After stirring for 2 hours, water (50 mL) was added to the reaction system, extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 6-5 (636 mg, yield 63%) as a white solid. 1 HNMR (400MHz, CDCl3) δ8.33(d,J=2.3Hz,1H),7.10(dd,J=8.8,2.4Hz,1H),4.64(t,J=6.5Hz,2H),3.05–2.83(m,2H).

[0190] Preparation of compound 6-6

[0191] Compound 6-5 (636 mg, 3.81 mmol) was dissolved in THF (28 mL) and cooled to 0°C. DIBAL-H (1 M, 5.70 mL) was added and the reaction solution was stirred at 0°C for 1 hour. The crude product was obtained by spin drying and purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 6-6 (500 mg, yield 78%). LC-MS (ESI): m / z 170.0 [M+H] + .

[0192] Preparation of Compound 6-7

[0193] Compound 6-6 (300 mg, 1.17 mmol) was dissolved in dichloromethane (28 mL) and cooled to 0°C. Methanesulfonyl chloride (304 mg, 2.66 mmol) was added and the reaction solution was stirred at 0°C for 1 hour. Water (50 mL) was added to the reaction system, extracted with dichloromethane (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 6-7 (438 mg, yield 100%).

[0194] Preparation of compounds 6-8 and 6-9

[0195] Compound 1-4 (271 mg, 1.21 mmol) was dissolved in tetrahydrofuran (10 mL), zinc powder (396 mg, 6.07 mmol) and lead powder (25 mg, 0.121 mmol) were added, and then argon was replaced three times, and DIBAL-H (1 M, 0.5 mL) was added for activation for 40 min, the reaction solution was heated to 70°C, and then a tetrahydrofuran solution of 7-7 (300 mg, 1.21 mmol) was slowly added dropwise, and the reaction was carried out at 60°C overnight. After the reaction was completed, the solution was filtered and the filtrate was dried to obtain a crude product, which was prepared and separated (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 6-8 (20 mg) and the title compound 6-9 (20 mg).

[0196] Compound 6-8: LC-MS (ESI): m / z 377.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.26(d,J=2.4Hz,1H),8.20(s,1H),7.62(s,1H),7.36–7.19(m,3H),6.93-6.90(m,1H),5.70(s,1H),5 .18–4.90(m,2H),4.43–4.29(m,1H),4.07(dd,J=9.6,4.8Hz,1H),3.62(d,J=4.8Hz,1H),1.88–1.72(m,1H),1.65–1.48(m,1H).

[0197] Compound 6-9: LC-MS (ESI): m / z 377.0 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.30(s,1H),8.04(d,J=2.4Hz,1H),7.65(s,1H),7.40-7.34(m,1H),7.22-7.18(m,1H),7.04-7.00(m,1H),6.92-6.88(m ,1H),6.39(s,1H),5.22(d,J=14.6Hz,1H),4.79(d,J=14.6Hz,1H),4.06 -3.99(mz,1H),3.54-3.52(m,2H),2.43-2.39(m,1H),2.05–1.85(m,1H).

[0198] Example 7: Preparation of Compounds 7-11 and 7-11a

[0199]

[0200] Preparation of compound 7-2

[0201] Compound 7-1 (12 g, 54.30 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to 0°C. 3-Butene-1-ol (4.11 g, 57.01 mmol), DEAD (15.67 g, 59.73 mmol), and triphenylphosphine (9.93 g, 57.01 mmol) were added, and the reaction solution was stirred at 0°C for 1 hour. Ethyl acetate (50 mL × 3) was extracted, and the ethyl acetate was concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-2 (14.5 g, yield 97%). 1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J=4.4,1.6Hz,1H),7.18(dd,J=8.0,4.4Hz,1H),6.98(dd,J =8.0,1.6Hz,1H),5.99-5.94(m,1H),5.28–5.10(m,2H),4.07(t,J=6.4Hz,2H),2.70–2.55(m,2H).

[0202] Preparation of compound 7-3

[0203] Compound 7-2 (14.50 g, 52.71 mmol), triphenylphosphine (4.15 g, 15.81 mmol), palladium acetate (1.18 g, 5.27 mmol) and potassium acetate (25.87 g, 263.55 mmol) were added to a round-bottom flask. After adding anhydrous DMF (200 mL) to dissolve under nitrogen protection, stir in an oil bath at 105 °C. After 10 hours, the plate was spotted and TLC detected that the raw material reaction was complete. After the reaction solution was cooled to room temperature, water (100 mL) was added to quench the reaction, ethyl acetate (50 mL × 3) was extracted, saturated brine (50 mL × 3) was washed, and dried over anhydrous sodium sulfate. Filter, add silica gel to the filtrate, spin dry and make sand, and use a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-3 (5.5 g, yield 71%) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ8.17 (dd, J=4.2, 1.6Hz, 1H), 7.32–7.16 (m, 2H), 6.09 (d, J= 2.0Hz,1H),5.07(d,J=2.0Hz,1H),4.20(dd,J=6.0,5.2Hz,2H),2.80-2.75(m,2H).

[0204] Preparation of compound 7-4

[0205] Compound 7-3 (6 g, 40.77 mmol) and dichloromethane (150 mL) were added to a round-bottom flask, cooled to -78 °C in a dry ice-acetone bath, and ozone gas was introduced. After the reaction solution turned dark blue, the aeration was stopped. Dimethyl sulfide (30 mL) was added to the reaction solution and the temperature was naturally raised to room temperature. After stirring for 2 hours, water (100 mL) was added to the reaction system, extracted with dichloromethane (100 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-4 (5.9 g, yield 97%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.48 (ddd, J=18.0, 3.9, 1.6Hz, 1H), 7.43–7.36 (m, 2H), 4.66–4.56 (m, 2H), 2.98 (dd, J=8.4, 4.6Hz, 2H).

[0206] Preparation of compound 7-5

[0207] Compound 7-4 (200 mg, 1.34 mmol) was dissolved in dichloromethane (28 mL) and cooled to 0°C. Copper trifluoromethanesulfonate (485 mg, 1.34 mmol) was added and the reaction solution was stirred at 0°C for 1 hour. The reaction system was washed with water (20 mL × 3), dried, and spin-dried to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-5 (100 mg, yield 30%). LC-MS (ESI): m / z 249.2 [M+H] + .

[0208] Preparation of compound 7-6

[0209] Compound 7-5 (1.10 g, 4.43 mmol) was dissolved in dichloromethane (10 mL), BAST (1.47 g, 6.64 mmol) was added, and then the argon gas was replaced three times, and the reaction solution was heated to 70 ° C and reacted overnight. After the reaction was completed, the filtrate was filtered and the filtrate was dried to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-6 (750 mg, yield 95%). 1 H NMR(400MHz,Chloroform-d)δ8.40(dd,J=4.2,1.2Hz,1H),7.39-7.35(m,1H),7.31-7.28(m,1H),4.50-4.40(m,1H),4.30-4.23(m,1H),2.85–2.56(m,2H).

[0210] Preparation of compound 7-7

[0211] Compound 7-6 (700 mg, 3.93 mmol) was dissolved in concentrated hydrochloric acid (10 mL), and the reaction solution was heated to 70°C for overnight reaction. After the reaction was completed, the filtrate was dried to obtain the crude title compound 7-7 (750 mg, crude).

[0212] Preparation of Compound 7-8

[0213] Compound 7-7 (1g crude, 5.07mmol) was dissolved in dichloromethane (28mL) and cooled to 0℃. DIEA (1.31g, 10.04mmol), HATU (2.31g, 6.09mmol), morpholine (0.530g, 6.09mmol) were added, and the reaction solution was stirred at 0℃ for 1 hour. The reaction system was washed with water (20mL×3), dried, and spin-dried to obtain a crude product. The crude product was purified by normal phase silica gel column (biotage, silica gel column, 20g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-8 (500mg, yield 37%). LC-MS (ESI): m / z 267.2[M+H] + .

[0214] Preparation of Compound 7-9

[0215] 2,4-Difluorobromobenzene (284 mg, 1.46 mmol) was dissolved in ether (4 mL) and cooled to -70 °C. Butyl lithium (2.5 M, 0.58 mL) was added dropwise, and the reaction solution was stirred at -70 °C for 1 hour. A solution of compound 7-8 (300 mg, 1.13 mmol) in ether (5 mL) was added dropwise to the reaction system, and the reaction solution was stirred at -70 °C for 1 hour. Silica gel powder was added and dried, and the title compound 7-9 (100 mg, crude product) was obtained on a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) as a white solid. LC-MS (ESI): m / z 294.1 [M+H] + .

[0216] Preparation of Compound 7-10

[0217] Compound 7-9 (50 mg, 0.170 mmol), trimethyl sulfoxide iodide (56 mg, 0.255 mmol), NaOH (14 mg, 0.314 mmol), dissolved in dichloromethane (5 mL) and water (1 mL), the reaction solution was stirred at 60 ° C for 12 hours. The dichloromethane phase was separated and concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 7-10 (50 mg, impure). LC-MS (ESI): m / z 308.2 [M+H] + .

[0218] Preparation of compounds 7-11 and 7-11a

[0219] Compound 7-10 (50 mg, 0.162 mmol), triazole (23 mg, 0.325 mmol), NaH (10 mg, 0.244 mm, dissolved in DMF (1 mL), the reaction solution was stirred at 60 ° C for 12 hours. Saturated aqueous ammonium bicarbonate solution (10 mL) was added to the reaction system, extracted with ethyl acetate (30 mL × 3), and concentrated to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18250 × 21.2 mm; column temperature: 25 ° C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 7-11 (3 mg, yield 1.9%).

[0220] Compound 7-11: LC-MS (ESI): m / z 377.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.35(dd,J=4.2,1.6Hz,1H),8.32(s,1H),7.67(s,1H),7.48–7.34(m,3H),7.18-7.11(m,1H),6 .92–6.86(m,2H),5.50(q,J=14.7Hz,2H),4.40-4.35(m,1H),4.06-3.99(m,1H),2.26-2.12(m,1H),1.98-1.87(m,1H).

[0221] Example 8: Preparation of Compounds 8-4 and 8-5

[0222]

[0223] Preparation of compound 8-2

[0224] Compound 8-1 (1 g, 8.84 mmol) and potassium carbonate (3.67 g, 26.53 mmol) were dissolved in acetonitrile (25 mL), and the reaction solution was stirred at room temperature for 0.5 hours. 1,3-dibromopropane (2.68 g, 13.26 mmol) was added, and the mixture was stirred at room temperature overnight. Filter, and the filtrate was dried to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 8-2 (1.3 g, yield 63%). LC-MS (ESI): m / z 233.8 [M+H] + .

[0225] Preparation of compound 8-3

[0226] Compound 8-2 (1.3 g, 5.55 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to -70 °C. n-Butyl lithium (2.5 M, 4.89 mL) was added dropwise and the reaction solution was stirred at -70 °C for 1 hour. The reaction was quenched with aqueous ammonium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL × 3), and concentrated to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 8-3 (600 mg, yield 70%). 1 H NMR (400MHz, Chloroform-d) δ8.01(s,1H),7.98(s,1H),4.27–4.19(m,2H),2.77(t,J=6.4Hz,2H),2.07–2.00(m,2H).

[0227] Preparation of compounds 8-4 and 8-5

[0228] Compound 8-3 (300 mg, 1.96 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to -70°C. n-Butyl lithium (1.6 M, 1.2 mL) was added dropwise, and the reaction solution was stirred at -70°C for 1 hour. A solution of compound 3-3 (263 mg, 1.18 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, and the reaction solution was stirred at -70°C for 1 hour. The reaction was quenched with aqueous ammonium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL×3), and concentrated to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 8-4 (4 mg) and the title compound 8-5 (13 mg).

[0229] Compound 8-4: LC-MS (ESI): m / z 378.4 [M+H] + .1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.00(s,1H),7.79(s,1H),7.21-7.17(m,1H),7.00-6.94(m,1H),6.83-6.78(m,1H),6.01(s,1H),5.34( d,J=14.2Hz,1H),5.08(d,J=14.2Hz,1H),4.53-4.47(m,1H),4.36-4.32(m,1H),3.80(d,J=4.8Hz,1H),2.64–2.54(m,1H),2.06–1.88(m,1H).

[0230] Compound 8-5: LC-MS (ESI): m / z 378.4 [M+H] + .1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.21(s,1H),8.16(s,1H),7.39-7.33(m,1H),7.25-7.19(m,1H),6.95-6.90(m,1H),6.05(s,1H),5 .31-5.27(m,1H),4.66-4.62(m,1H),4.56-4.46(m,1H),4.20-4.16(m,1H),3.82(d,J=4.8Hz,1H),1.83-1.73(m,1H),1.44-1.40(m,1H).

[0231] Example 9: Preparation of Compounds 9-6 and 9-7

[0232]

[0233] Preparation of compound 9-2

[0234] Dissolve compound 9-1 (10 g, 38.15 mmol) in an aqueous solution (200 mL) of sodium carbonate (8.3 g, 78.3 mmol), add iodine particles (9.94 g, 38.15 mmol) in batches at room temperature, and stir at room temperature for 6 hours. LC-MS detected that the reaction was complete. Adjust the pH of the reaction system to 6-7 with aqueous hydrochloric acid solution (2 M). Extract with ethyl acetate (20 mL × 3) and concentrate to obtain a crude product. Spin dry to obtain the title compound 9-2 (13 g, yield 66%). LC-MS (ESI): m / z 255.9 [M+H] + .

[0235] Preparation of compound 9-3

[0236] Compound 9-2 (5 g, 19.57 mmol), 3-bromopropanol (3.26 g, 23.49 mmol), triphenylphosphine (6.16 g, 23.49 mmol) were dissolved in tetrahydrofuran (50 mL), and DEAD (4.09 g, 23.49 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was complete when detected by LCMS. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 9-3 (6.0 g, yield 81%). LC-MS (ESI): m / z 375.9 [M+H] + .

[0237] Preparation of compound 9-4

[0238] Compound 9-3 (5 g, 13.28 mmol) was dissolved in tetrahydrofuran (30 mL). At -65 °C, n-butyl lithium (1.6 M, 9.3 mL) was added dropwise. After reacting for 1 hour, a sample was taken and sent to LC-MS to monitor the completion of the reaction. The reaction system was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried to obtain a crude product. The crude product was subjected to a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 9-4 (1.5 g, yield 66%). LC-MS (ESI): m / z 170.0 [M+H] + .

[0239] Preparation of compound 9-5

[0240] Compound 9-4 (1.4 g, 8.25 mmol), tricyclohexylphosphine (231 mg, 0.83 mmol), palladium acetate (185 mg, 0.83 mmol), potassium phosphate (5.26 g, 24.76 mmol), cyclopropylboronic acid (0.78 g, 9.08 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and reacted at 110 ° C for 16 h. Water (50 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried to obtain a crude product. The crude product was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 9-5 (300 mg, yield 20%). LC-MS (ESI): m / z 176.0 [M+H] + . 1 HNMR(400MHz,Chloroform-d)δ7.96(d,J=2.0Hz,1H),6.71(d,J=1.9Hz,1H),4.23–4.08(m,2H),2.93( t,J=6.6Hz,2H),2.17–2.02(m,2H),1.89–1.79(m,1H),1.04–0.91(m,2H),0.67(dt,J=6.6,4.8Hz,2H).

[0241] Preparation of compounds 9-6 and 9-7

[0242] Compound 9-5 (300 mg, 3.23 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to -65 °C. At -65 °C, n-butyl lithium (1.6 M, 3.03 mL) was added and stirred at -65 °C for 20 minutes. A solution of compound 1-4 (382 mg, 1.71 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system and continued to stir for 10 minutes. The reaction system was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12min; flow rate: 30mL / min) to obtain the title compound 9-6 (40mg, yield 6%) and the title compound 9-7 (50mg, yield 7%).

[0243] Compound 9-6: LC-MS (ESI): m / z 399.1 [M+H] +.1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.01(d,J=1.9Hz,1H),7.56(s,1H),7.30–7.07(m,2H ),6.90–6.72(m,2H),5.90(s,1H),5.08(d,J=14.7Hz,1H),4.93(d,J=14.7Hz,1H),4.31–4. 18(m,1H),3.91(dd,J=10.2,4.9Hz,1H),3.47(t,J=5.4Hz,1H),1.96–1.82(m,1H),1.80–1. 67(m,1H),1.52(d,J=4.0Hz,1H),0.92(dd,J=8.3,3.0Hz,2H),0.67(dd,J=7.3,5.1Hz,2H).

[0244] Compound 9-7: LC-MS (ESI): m / z 399.1 [M+H] + .1H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.83(d,J=2.0Hz,1H),7.56(s,1H),7.46(td,J=8.9,6.8Hz,1H ),7.12(s,1H),6.98(ddd,J=12.1,9.2,2.7Hz,1H),6.88(td,J=8.5,2.7Hz,1H),6.74(d,J=2.0Hz,1H ),5.14(d,J=14.5Hz,1H),4.59(d,J=14.5Hz,1H),3.83(td,J=7.3,3.6Hz,1H),3.55(ddd,J=11.2,8. 0,3.2Hz,1H),2.28–2.14(m,1H),1.82(td,J=8.5,4.2Hz,2H),0.97–0.83(m,2H),0.70–0.58(m,2H).

[0245] Example 10: Preparation of Compounds 10-10, 10-11, 10-2 and 10-13

[0246]

[0247] Preparation of compound 10-2

[0248] Add water (50 mL) to compound 10-1 (10 g, 57.47 mmol) and sodium carbonate (12.18 g, 114.94 mmol). Add iodine granules (16.05 g, 63.22 mmol) in batches at room temperature and stir at room temperature for 6 h. LCMS detected that the reaction was complete. Adjust the pH to 6-7 with aqueous hydrochloric acid solution (2 M). A yellow solid precipitated and stirred for 1 hour. Filter, wash the filter cake with water (50 mL × 3), and dry the filter cake to obtain the title compound 10-2 (14.2 g, yield 82%). LC-MS (ESI): m / z 299.8 [M+H] + .

[0249] Preparation of compound 10-3

[0250] Compound 10-2 (5 g, 16.67 mmol), 3-bromopropanol (2.78 g, 20.01 mmol), triphenylphosphine (5.52 g, 20.01 mmol) were dissolved in tetrahydrofuran (50 mL), and DEAD (3.48 g, 20.01 mmol) was added dropwise at 0°C. The mixture was reacted for 2 hours at room temperature. The reaction was complete when detected by LCMS. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried to obtain a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 10-3 (6.2 g, yield 88%). LC-MS (ESI): m / z 421.8 [M+H] + .

[0251] Preparation of compound 10-4

[0252] Compound 10-3 (3 g, 7.13 mmol) was dissolved in tetrahydrofuran (30 mL). At -65 °C, n-butyl lithium (1.6 M, 4.9 mL) was added dropwise. After 1 hour of reaction, the reaction system was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried to obtain a crude product. The crude product was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 10-4 (600 mg, yield 39%). LC-MS (ESI): m / z 214.0 [M+H] + .

[0253] Preparation of compound 10-6

[0254] Compound 10-4 (1.24 g, 5.79 mmol), compound 10-5 (1.53 g, 6.95 mmol), Pd(dppf)Cl2 (423 mg, 0.58 mmol), potassium carbonate (1.6 g, 11.59 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL) and reacted at 110°C for 16 h. Water (50 mL) was added and extracted with ethyl acetate (50 mL × 3), the organic phases were combined and dried to obtain a crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 10-6 (700 mg, yield 39%). LC-MS (ESI): m / z 310.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.31(d,J=2.0Hz,1H),7.55–7.49(m,2H),7.25(d,J=2.0Hz,1H),7.0 6–6.99(m,2H),4.40(q,J=8.1Hz,2H),4.27–4.18(m,2H),3.01(t,J=6.5Hz,2H),2.21–2.12(m,2H).

[0255] Preparation of compounds 10-8 and 10-9

[0256] Dissolve compound 10-6 (1.0 g, 3.23 mmol) in tetrahydrofuran (10 mL) and cool to -65°C. Add n-butyl lithium (1.6 M, 3.03 mL, 4.85 mmol) at -65°C, stir at -65°C for 20 minutes, then add compound 10-5 (0.616 g, 3.23 mmol) and stir at room temperature for 10 minutes. Add saturated aqueous ammonium chloride solution (50 mL) to quench, extract with ethyl acetate (50 mL × 3), combine the organic phases and spin dry to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12min; flow rate: 30mL / min) to obtain the title compound 10-8 (100mg, yield 6%) and the title compound 10-9 (100mg, yield 6%).

[0257] Compound 10-8: LC-MS (ESI): m / z 464.4 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.42(d,J=2.0Hz,1H),7.58–7.50(m,2H),7.46(d,J=6.3Hz,1H),7.33(d,J=2.0Hz,1H),7.07–7.01(m,2H),6.93–6.81(m, 2H),4.48(d,J=3.7Hz,1H),4.41(q,J=8.1Hz,2H),4.30(s,1H),3.90–3.77( m,1H),3.01(d,J=5.0Hz,1H),2.61(d,J=5.0Hz,1H),2.07(d,J=3.9Hz,2H).

[0258] Compound 10-9: LC-MS (ESI): m / z 464.4 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J=2.0Hz,1H),7.59–7.52(m,2H),7.52–7 .45(m,1H),7.33(d,J=2.0Hz,1H),7.08–7.00(m,2H),6.89–6.69(m,2H),4.41(q ,J=8.1Hz,2H),4.21(dtd,J=17.6,11.2,6.5Hz,2H),3.46(t,J=5.5Hz,1H),3.1 5(d,J=4.8Hz,1H),3.03(d,J=4.7Hz,1H),2.38–2.24(m,1H),2.21–2.09(m,1H).

[0259] Preparation of compounds 10-10 and 10-11

[0260] Compound 10-8 (100 mg, 0.22 mmol) was dissolved in DMF (2 mL), 1H-tetrazole (30.23 mg, 0.43 mmol) and potassium carbonate (59.65 mg, 0.43 mmol) were added, the reaction was heated to 80 ° C and stirred for 4 days, water (10 mL) was added, and ethyl acetate was extracted (10 mL × 3), and the organic phases were combined and dried to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 10-10 (30 mg, yield 26%), and the title compound 10-11 (33 mg, 29%).

[0261] Compound 10-10: LC-MS (ESI): m / z 534.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.16(s,1H),8.44(s,1H),7.74(d,J=8.3Hz,2H),7.50(d,J=8.1Hz,2H),7.18(d,J=8.3Hz,2H),7.12(m,1H),7.02–6.94 (m,1H),5.62(d,J=14.5Hz,1H),4.98(d,J=14.5Hz,1H),4.84(q,J=8.8H z,3H),4.04–3.97(m,1H),3.56(m,2H),2.37(m,1H),2.07–1.92(m,1H).

[0262] Compound 10-11: LC-MS (ESI): m / z 534.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.69(s,1H),8.44(d,J=2.0Hz,1H),7.80–7.71(m,2H),7.51(dd,J=6.2,2.2Hz,2H),7.20–7.14(m,2H),7.15–7.07(m,1H),7 .01–6.92(m,1H),5.84(d,J=14.3Hz,1H),5.21(d,J=14.3Hz,1H),4.84(q ,J=8.8Hz,2H),4.05–3.96(m,1H),3.60(m,2H),2.39(m,1H),1.99(m,1H).

[0263] Preparation of compounds 10-12 and 10-13

[0264] Compound 10-9 (100 mg, 0.22 mmol) was dissolved in DMF (2 mL), 1H-tetrazole (30.23 mg, 0.43 mmol) and potassium carbonate (59.65 mg, 0.43 mmol) were added, the reaction was heated to 80 ° C and stirred for 4 days, water (10 mL) was added, and ethyl acetate was extracted (10 mL × 3), and the organic phases were combined and dried to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 10-12 (50 mg, 43%), and the title compound 10-13 (10 mg, 9%).

[0265] Compound 10-12: LC-MS (ESI): m / z 534.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.57(d,J=2.1Hz,1H),7.87–7.72(m,2H),7.56(d,J =2.1Hz,1H),7.37–7.13(m,4H),6.92(td,J=8.5,2.6Hz,1H),6.10(s,1H),5.52(d,J=14. 7Hz,1H),5.37(d,J=14.7Hz,1H),4.84(q,J=8.8Hz,2H),4.38(td,J=10.4,3.0Hz,1H),4. 08(dt,J=10.0,4.5Hz,1H),3.71(t,J=5.5Hz,1H),1.94–1.78(m,1H),1.72–1.60(m,1H).

[0266] Compound 10-13: LC-MS (ESI): m / z 534.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.68(s,1H),8.56(d,J=2.1Hz,1H),7.83–7.76(m,2H),7.51( d,J=2.1Hz,1H),7.36–7.24(m,2H),7.21–7.15(m,2H),6.94(d,J=2.3Hz,1H),6.09(s, 1H),5.85(d,J=14.3Hz,1H),5.58(d,J=14.4Hz,1H),4.84(q,J=8.9Hz,2H),4.36(d,J= 3.1Hz,1H),4.15–3.97(m,1H),3.73(t,J=5.5Hz,1H),1.80(m,1H),1.68–1.58(m,1H).

[0267] Example 11: Preparation of Compound 11

[0268]

[0269] Compound 10-6 (500 mg, 1.62 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -65 °C. At -65 °C, n-butyl lithium (1.6 M, 1.52 mL) was added, and after stirring at -65 °C for 20 minutes, a solution of compound 1-4 (180 mg, 0.8 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, and the mixture was slowly stirred at room temperature for 10 minutes. The reaction system was quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 11 (70 mg, 8%).

[0270] Compound 11: LC-MS (ESI): m / z 533.2 [M+H] + .

[0271] Example 12: Preparation of Compound 12-3

[0272]

[0273] Preparation of compound 12-2

[0274] Compound 12-1 (0.90 g, 5.83 mmol) and THF (5 mL) were added to a three-necked flask, replaced with N2, and cooled to -78 ° C. LDA (2M, 2.9 mL, 5.83 mmol) was added dropwise to the three-necked flask and stirred for 30 minutes. A solution of tetrahydrofuran (2 mL) containing compound 1-4 (1.0 g, 4.48 mmol) was added dropwise to the reaction system and reacted at room temperature for 16 hours. The reaction system was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and dried to obtain the crude title compound 12-2 (1.1 g, yield 65%) as a light yellow solid. LC-MS (ESI): m / z 378.2 [M+H] + .

[0275] Preparation of compound 12-3

[0276] Compound 12-2 (200 mg, 0.53 mmol), TEA (1 mL) and methanol (2 mL) were added to a three-necked flask, replaced with H2, and palladium carbon (117 mg, 0.11 mmol) was added to the flask, and reacted at 60°C for 16 hours. After the reaction system was cooled, the reaction solution was filtered, and the crude filtrate was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12 min; flow rate: 30 mL / min) to obtain the title compound 12-3. LC-MS (ESI): m / z 344.0 [M+H] + .1H NMR(400MHz,Chloroform-d)δ8.91(s,1H),8.48(s,1H),8.18(s,1H),7.71(d,J=20.0Hz,2H),6.83(s,1H),6.57(s,1H), 5.86(s,1H),5.17(d,J=14.3Hz,1H),4.92(d,J=14.2Hz,1H),3.71–3.35(m,1H),2.69(s,1H),2.41(s,2H),2.26(s,1H).

[0277] Example 13: Preparation of Compounds 13-3 and 13-4

[0278]

[0279] Preparation of compound 13-2

[0280] At room temperature, add compound 13-1 (1.0 g, 6.70 mmol) and chloroform (15 mL) to a single-mouth bottle (50 mL). Cool to 0°C. Then slowly add phosphorus tribromide (3.58 g, 13.40 mmol). After the addition is complete, warm to room temperature and continue stirring for 1 hour to complete the reaction. At 0°C, slowly add saturated sodium bicarbonate solution (50 mL) to quench the reaction. Extract with ethyl acetate (50 mL × 3), wash with saturated brine (20 mL × 3), dry the organic phase, filter, and concentrate ethyl acetate to obtain a crude product. The crude product is purified by a normal phase silica gel column (biotage, silica gel column, 20 g, UV254, ethyl acetate / petroleum ether = 0-100%) to obtain the title compound 13-2 (1.1 g, yield 77%). LC-MS (ESI): m / z 212.0 [M+H] + .

[0281] Preparation of compounds 13-3 and 13-4

[0282] At room temperature, zinc powder (1.7 g, 25.93 mmol), THF (20 mL), lead powder (107.43 mg, 0.152 mmol) were added to a three-necked flask. After stirring at room temperature for 10 minutes, the mixture was cooled to 0 °C and iodine (1.32 g, 5.19 mmol) was added. After the yellow color disappeared, compound 13-2 (1.1 g, 5.19 mmol) was added dropwise to the reaction system with a solution of compound 1-4 (1.39 g, 6.22 mmol) in tetrahydrofuran (2 mL). The mixture was stirred at room temperature overnight. Water (50 mL × 3) was added to the reaction system to quench the reaction system, and ethyl acetate (50 mL × 3) was added for extraction. The organic phase was dried and concentrated to obtain a crude product. The crude product was prepared (preparation method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Agilent 10Prep-C18 250×21.2mm; column temperature: 25°C; gradient: 55%-75% acetonitrile in 12min; flow rate: 30mL / min) to obtain the title compound 13-3 (75.85mg, yield 4.1%) and the title compound 13-4 (15.44mg, yield 0.84%).

[0283] Compound 13-3: LC-MS (ESI): m / z 357.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=4.4Hz,1H),8.28(s,1H),7.68(s,1H),7.54(d,J=7.7Hz,1H),7.30–7.08(m,3H),6.85(t,J=7.9Hz,1H),6.74(s ,1H),5.17(d,J=14.6Hz,1H),4.92(d,J=14.6Hz,1H),3.50(t,J=6.9Hz, 1H), 2.64 (t, J = 6.0Hz, 2H), 1.99–1.73 (m, 2H), 1.53 (s, 1H), 1.40 (s, 1H).

[0284] Compound 13-4: LC-MS (ESI): m / z 357.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.27(d,J=6.9Hz,3H),7.68(dd,J=15.8,8.9Hz,1H),7.61–7.47(m,2H),7.21(dd,J=7.5,4.7Hz,1H),7.03(dt,J=16.8,9.2Hz ,2H),5.06(d,J=14.6Hz,1H),4.54(d,J=14.7Hz,1H),3.35(m,1H),2.64(s ,2H),2.00(d,J=9.4Hz,1H),1.72(d,J=10.0Hz,2H),1.43(d,J=8.9Hz,1H).

[0285] Test Example 1: Minimal Inhibitory Concentration (MIC) test of compounds on fungal growth

[0286] (1) Main reagents:

[0287] RPMI1640 culture medium: Brand: Gibco, Product No.: 31800-014

[0288] Sabouraud dextrose agar (SDA): Brand: Haibo, Item No.: HB0253-81

[0289] Amphotericin B: Brand: Abcam, Catalog Number: ab141199

[0290] (2) Fungal strains are shown in Table 1 below:

[0291] Table 1

[0292] Strain type Strain code Strain destination Aspergillus fumigatus ATCC MYA-4609 CBS 101355[AF 293] Candida albicans ATCC MYA-2876 SC5314

[0293] (3) Test method:

[0294] MIC testing was performed according to the guidelines and requirements of CLSI M27 (for yeast) and M38 (for Aspergillus).

[0295] Preparation of strains: 1 day in advance, streak the strains on the SDA plate using the glycerol stock stored at -80℃. Incubate for 18-24 hours at 35℃ and 40-60% humidity. Aspergillus fumigatus needs to be streaked 3 and 2 days in advance.

[0296] Preparation of culture medium and compounds: Liquid culture medium RPMI is prepared with pure water, and 0.165 mol / L MOPS is added and the pH is adjusted to 7.0. After sterilization by filtering with a 0.22 μm filter membrane, it is stored at 4°C (no more than 3 months). 0.85% saline is sterilized at 121°C for 30 minutes and then stored at room temperature (no more than 1 week). The compound is dissolved in DMSO to 12.8 mg / mL and stored at -20°C.

[0297] For yeast, pick 3-5 colonies from the SDA plate on the day of the test and fully suspend them in 5mL of sterilized 0.85% saline. Measure the turbidity of the bacterial solution with a turbidity meter and adjust the turbidity to about 0.2. Dilute the bacterial solution 50 times and 20 times (a total of 1000 times) with RPMI1640 medium as the inoculum. The final inoculum concentration is 500-2500 CFU / mL.

[0298] For Aspergillus, take 5 mL of saline to cover the hyphae, gently scrape off the spores with a spreader, and then transfer the spore suspension to a sterile test tube. Take an appropriate amount of spore suspension and count it under a microscope using a hemocytometer. Use RPMI1640 medium to adjust the spore concentration to about 0.4-5x10 4 spores / mL.

[0299] The compound was diluted with DMSO to a maximum of 800 μg / mL (or 400 μg / mL) and 10 two-fold serial dilutions were performed, for a total of 11 concentrations. 2 μL of serially diluted compounds were transferred to the corresponding wells of a 96-well plate, and 198 μL of inoculum was transferred to the test plate and incubated at 35°C for 24 hours (48 and 72 hours for Aspergillus fumigatus and Cryptococcus neoformans, respectively).

[0300] (4) MIC assessment:

[0301] After the incubation, the fungal growth was visually observed. The lowest compound concentration point at which yeast growth was inhibited by ≥50% (Aspergillus inhibition was 100%) was defined as the minimum inhibitory concentration MIC (μg / mL). A magnifying glass or reading OD530nm can be used to assist in MIC determination. The test plate was photographed and recorded for archiving. The results are shown in Table 2 below.

[0302] Table 2: In vitro antifungal activity results of some preferred compounds MIC (μg / mL)

[0303]

[0304]

Claims

1. A compound represented by formula (I), its optical isomers, tautomers and pharmaceutically acceptable salts thereof, in, Ring A is selected from Structural unit Selected from Among them, the structural unit Selected from R3 is selected from OH, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC(=O)C 1-3 Alkyl and -NHC(=O)C 1-3 alkyl; Or, R3 and ring C are connected together to form a 3-9 membered heterocyclic group or C 3-9 Cycloalkyl.

2. A compound represented by formula (II-1) or (II-2), its optical isomers, tautomers and pharmaceutically acceptable salts thereof, in, X1, X2, X3, and X8 are independently selected from C(R X )2. NR X , S and O; X4, X5, X6, and X7 are independently selected from CR Y and N; R X , R Y are independently selected from H, CN, OH, F, Cl, Br, I, C 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally substituted with 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution; R3 is selected from OH, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC(=O)C 1-3 Alkyl and -NHC(=O)C 1-3 alkyl; R6 is selected from H, CN, OH, F, Cl, Br, I, C 1-6 Alkyl and C 1-6 Heteroalkyl, the C 1-6 Alkyl or C 1-6 The heteroalkyl group is optionally substituted with 1, 2 or 3 CN, OH, F, Cl, Br, I or C 1-6 Alkyl substitution; Or, R3 and R6 are connected together to form a 3-6 membered heterocyclic group or C 3-6 cycloalkyl; Ring A is selected from Structural unit Selected from Structural unit Selected from H, I, CN, OH, CF3, COOH, CONHMe, CONMe2, p is 0 or 1.

3. The compound of the following formula, its optical isomers, tautomers and pharmaceutically acceptable salts thereof, which is selected from 4. The compound of the following formula, its optical isomers, tautomers and pharmaceutically acceptable salts thereof, which is selected from 5. Use of the compound according to any one of claims 1 to 4, its optical isomers, tautomers or pharmaceutically acceptable salts thereof in the preparation of antifungal infection drugs.

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