Aminopyrimidine compounds as CDK2 / 4 / 6 triple inhibitors

Abstract

Aminopyrimidine compounds as CDK2 / 4 / 6 inhibitors are disclosed, specifically compounds of formula (I) and pharmaceutically acceptable salts thereof, and the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of solid tumors. JPEG2023501110000077.jpg3069

Description

[Technical field]

[0001] This application claims priority to: CN201910988432.0, the filing date is October 17, 2019; CN202010558823.1, application date is June 18, 2020. The present invention relates to aminopyrimidine compounds as novel CDK2 / 4 / 6 inhibitors, in particular to the compounds of formula (I) and their pharma- ceutically acceptable salts, and the use of the compounds of formula (I) and their pharma- ceutically acceptable salts in the manufacture of a medicament for the treatment of solid tumors. [Background technology]

[0002] Malignant tumors are one of the major diseases that endanger human life today. In the past 100 years, mankind has developed a variety of diagnostic and therapeutic methods to fight malignant tumors, including the most commonly used chemotherapy, surgery, radiation therapy and targeted therapy. These treatments have delayed the development of tumors to a certain extent and extended the lifespan of patients. However, since malignant tumors have the characteristics of unlimited growth, invasion and metastasis, the above treatments still could not achieve the desired inhibitory effect. At the same time, the toxicity and side effects of the above treatments are also important factors that limit their application.

[0003] Regulation of the cell cycle is mainly influenced by a series of serine / threonine kinases called cyclin-dependent kinases (CDKs), which are expected to bind to their corresponding regulatory subunits (cyclins) to promote cell cycle progression, transcription of genetic information, and normal cell division and proliferation. Abnormal activation of CDKs is associated with tumor development, and CDK inhibitors have been shown to be useful in tumor therapy. Currently, CDK4 / 6 inhibitors Palbociclib, Abemaciclib, and Ribociclib have been approved as therapeutic agents for HR-positive / HER-2-negative breast cancer. CDK4 / 6 inhibitors have shown excellent clinical efficacy in HR-positive metastatic breast cancer, but their inhibitory activity against other CDK subtypes is weak, and they are prone to primary and acquired drug resistance.

[0004] Overexpression of CDK2 is associated with abnormal regulation of the cell cycle, and CDK2 / Cyclin E is involved in regulating the cell cycle from G1 to S phase. At the end of G1 phase, the CDK2 / Cyclin E complex can also catalyze the phosphorylation of Rb, thereby promoting the progression of the cell cycle from G1 to S phase; in S phase, the CDK2 / cyclin A complex can also promote the process of DNA replication. (Asghar et al. The history and future of targeting cyclin-dependent kinases in cancer therapy, Nat. Rev. Drug. Discov.2015;14(2):130-146) Cyclin E, the corresponding cyclin of CDK2, is commonly overexpressed in tumors. Amplification and overexpression of Cyclin E1 are associated with poor prognosis in tumors such as ovarian, gastric, and breast cancers.(Nakayama et al., gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, cancer (2010) 116:2621-34; Etemadmoghadam et al., Resistance to CDK2 inhibitors is associated with selection of polyploidy cells in CCNE1-Amplified Ovarian cancer, clin cancer res (2013)19:5960-71;Au-Yeung et al., selective targeting of cyclin E1-Amplified high-grade serous ovarian cancer by cyclin-dependent kinase 2 and AKT inhibition, Clin. Cancer res.(2017) 30:297-303;Ooi et al., gene amplification of CCNE1, CCND1, and CDK6 ingastric cancers detected by multiplexLigation-dependent probe amplification and fluorescence in situ hybridization, Hum Pathol.(2017) 61: 58-67; Noske et al., detection of CCNE1 / UR / (19q12) amplification by in situ hybridization is common in highgrade and type 2 endometrial cancer, oncotarget (2017) 8:14794-14805). Cyclin E2 overexpression is associated with endocrine therapy resistance in breast cancer, and CDK2 inhibition can resensitize tamoxifen-resistant and CCNE2-overexpressing cells to tamoxifen and CDK4 / 6 inhibitors.(Caldon et al., Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells.mol cancer Ther. (2012) 11:1488-99; Herrera-abreu et al., Early adaptation and acquired resistance to CDK4 / 6 inhibition in Estrogen Receptor-positive breast cancer, cancer res.(2016) 76:2301-2313). Cyclin E amplification has also been linked to trastuzumab resistance in HER2-positive breast cancer. (Scaltriti et al., Cyclin E amplification / overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci.(2011) 108:3761-6).

[0005] Dinaciclib, a small molecule CDK inhibitor, simultaneously inhibits CDK1, CDK2, CDK5 and CDK9 and is currently undergoing clinical trials for breast cancer and hematological tumors. Seliciclib simultaneously inhibits CDK2, CDK7 and CDK9 and is currently undergoing clinical trials in combination with chemotherapy for the treatment of solid tumors. The CDK2 / 4 / 6 inhibitor PF-06873600 (WO2018033815A1) developed by Pfizer has already undergone clinical trials and has high CDK2 activity but low selectivity for other CDK subtypes such as CDK9. Currently, no CDK2 inhibitors have yet been approved for sale.

[0006] [ka] Summary of the Invention [Problem to be solved by the invention]

[0007] Small molecule drugs with inhibitory activity against CDK2 and novel kinase inhibition profiles remain an unmet clinical need. [Means for solving the problem]

[0008] On the other hand, the present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

[0009] [ka]

[0010] Where: T is N or CH; R1 is C 4-6 cycloalkyl, wherein said C 4-6 Cycloalkyl can have one, two or three R a Replaced by; Each R a are independently F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; R2 and R3 are each independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; or R2 and R3 are linked together and, together with the linked carbon atom, form C 3-5 Forming a cycloalkyl, 3-5Cycloalkyl can have one, two or three R b is optionally replaced by; Each R b are independently H, F, Cl, Br, I, -CN, -OH, and C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 is haloalkyl; R4 and R5 are each independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; or R3 and R4 are linked together and, together with the linked carbon atom, form C 3-5 Forming a cycloalkyl, 3-5 Cycloalkyl can have one, two or three R c is optionally replaced by; Each R c are independently H, F, Cl, Br, I, -CN, -OH, and C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 is haloalkyl; R6 is H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 is haloalkyl; R7 is -NH2, C 1-3 Alkylamino, C 1-6 Alkyl, C 3-5 cycloalkyl, 4-6 heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein 1-6 Alkyl, C 3-5 Cycloalkyl, 4-6 heterocycloalkyl, 5-6 membered heteroaryl and phenyl are each 1, 2 or 3 R d is optionally replaced by; Each R d are independently H, F, Cl, Br, I, -CN, -OH, C1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; n is 0, 1 or 2; The 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl each contain 1, 2, 3, or 4 heteroatoms independently selected from N, -O-, and -S-.

[0011] The present invention further provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

[0012] [ka]

[0013] Where: T is N or CH; R1 is C 4-6 cycloalkyl, wherein said C 4-6 Cycloalkyl can have one, two or three R a is optionally replaced by; Each R a are independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; R2 and R3 are each independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; or R2 and R3 are linked together and, together with the linked carbon atom, form C 3-5 Forming a cycloalkyl, 3-5 Cycloalkyl can have one, two or three R b is optionally replaced by; Each R b are independently H, F, Cl, Br, I, -CN, -OH, and C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 is haloalkyl; R4 and R5 are each independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, -CN, -OH and -NH2; or R3 and R4 are linked together and, together with the linked carbon atom, form C 3-5 Forming a cycloalkyl, 3-5 Cycloalkyl can have one, two or three R c is optionally replaced by; Each R c are independently H, F, Cl, Br, I, -CN, -OH, and C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 is haloalkyl; R6 is H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy, C 1-3 Alkyl or C 1-3 is haloalkyl; R7 is -NH2, C 1-3 Alkylamino, C 1-6 Alkyl, C 3-5 cycloalkyl, 4-6 heterocycloalkyl, 5-6 membered heteroaryl or phenyl, 1-6 Alkyl, C 3-5 Cycloalkyl, 4-6 heterocycloalkyl, 5-6 membered heteroaryl and phenyl are each 1, 2 or 3 Rd is optionally replaced by; Each R d are independently H, F, Cl, Br, I, -CN, -OH, C 1-3 Alkoxy or C 1-3 alkyl, wherein 1-3 Alkoxy and C 1-3 The alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, -CN, -OH, and -NH2; n is 0, 1 or 2; The 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl each contain 1, 2, 3 or 4 heteroatoms independently selected from N, -O- and -S-.

[0014] In some embodiments of the present invention, each R a are independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3, or -CH2CH3, and all other variables are as defined herein.

[0015] In some embodiments of the present invention, each R a are independently F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3 or -CH2CH3, and all other variables are as defined herein.

[0016] In some embodiments of the present invention, R1 is

[0017] [ka]

[0018] where

[0019] [ka]

[0020] 1, 2 or 3 R a and each Ra and other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, R1 is

[0022] [ka]

[0023] where

[0024] [ka]

[0025] 1, 2 or 3 R a and each R a and other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, R1 is

[0027] [ka]

[0028] And each R a and other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, R1 is

[0030] [ka]

[0031] and other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, R1 is

[0033] [ka]

[0034] and other variables are as defined in the present invention.

[0035] In some embodiments of the invention, the compound has a structure represented by formula (I-1):

[0036] [ka]

[0037] Here, R2, R3, R4, R5, R6, R7, R a and n is as defined herein and p is 0, 1, 2 or 3.

[0038] In some embodiments of the invention, the compound has a structure represented by formula (I-1):

[0039] [ka]

[0040] Here, R2, R3, R4, R5, R6, R7, R a and n is as defined herein and p is 1, 2 or 3.

[0041] In some embodiments of the invention, the compound has a structure represented by formula (I-2):

[0042] [ka]

[0043] Here, R2, R3, R4, R5, R6, R7, R a and n is as defined herein.

[0044] In some embodiments of the present invention, each R bare independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3, or -CH2CH3, and all other variables are as defined herein.

[0045] In some embodiments of the present invention, R and R are linked together to form a cyclopropyl group with the carbon atom to which they are linked, and the cyclopropyl group is selected from the group consisting of one, two, or three R b and each R b and other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, R4 and R5 are independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3 or -CH2CH3, and other variables are as defined herein.

[0047] In some embodiments of the present invention, each R c are independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3, or -CH2CH3, and the other variables are as defined herein.

[0048] In some aspects of the invention, R and R are linked together to form a cyclopropyl group with the carbon atom to which they are linked, and the cyclopropyl group is selected from the group consisting of one, two or three R c and each R c and other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the compound has a structure represented by any one of formulas (I-3) to (I-7):

[0050] [ka]

[0051] Here, R a , R b , R c, T, R6, R7 and p are as defined herein; and q is 0, 1, 2 or 3.

[0052] In some embodiments of the present invention, the compound has a structure represented by any one of formulas (I-8) to (I-12):

[0053] [ka]

[0054] Here, R a , R b , R c , T, R6, R7, p and q are as defined herein.

[0055] In some embodiments of the invention, R2 and R3 are each independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3 or -CH2CH3, and all other variables are as defined herein.

[0056] In some aspects of the invention, R6 is H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3 or -CH2CH3, and all other variables are as defined herein.

[0057] In some embodiments of the present invention, each R d are independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3, or -CH2CH3, and the other variables are as defined herein.

[0058] In some embodiments of the present invention, each R d are independently H, F, Cl, Br, I, -CN, -OH, -OCH3, -CH3, -CF3, -CH2CH3, or -CH(CH3)2, and all other variables are as defined herein.

[0059] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyridinyl, or phenyl, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyridinyl, and phenyl are selected from the group consisting of one, two, or three R d and each R d and other variables are as defined in the present invention.

[0060] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyridinyl, or phenyl, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclopentyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyrazolyl, pyridinyl, and phenyl are each independently selected from the group consisting of one, two, or three R d and each R d and other variables are as defined in the present invention.

[0061] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -C(R d )3, -CH2CH2R d ,

[0062] [ka]

[0063] And each R dand other variables are as defined in the present invention.

[0064] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -C(R d )3, -CH2CH2R d ,

[0065] [ka]

[0066] And each R d and other variables are as defined in the present invention.

[0067] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -C(R d )3, -CH2CH2R d , -CH(CH3)2,

[0068] [ka]

[0069] And each R d and other variables are as defined in the present invention.

[0070] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -N(CH3)2, -CH3, -CF3, -CH2CH3,

[0071] [ka]

[0072] and other variables are as defined in the present invention.

[0073] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -N(CH3)2, -CH3, -CF3, -CH2CH3,

[0074] [ka]

[0075] and other variables are as defined in the present invention.

[0076] In some embodiments of the invention, R7 is -NH2, -NH(CH3), -N(CH3)2, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3,

[0077] [ka]

[0078] and other variables are as defined in the present invention.

[0079] Some further aspects of the present invention are formed by any combination of the above variables.

[0080] In some aspects of the invention, the compound is as shown below:

[0081] [ka]

[0082] In some aspects of the invention, the compound is as shown below:

[0083] [ka]

[0084] [ka]

[0085] In some forms of the invention, the pharma- ceutically acceptable salt is a hydrochloride salt.

[0086] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0087] Meanwhile, the present invention further provides the use of the above compound or a pharma- ceutically acceptable salt thereof and the above pharmaceutical composition in the manufacture of a medicament for CDK2 / 4 / 6 inhibitor.

[0088] The present invention further provides the use of the compound or a pharma- ceutically acceptable salt thereof and the pharmaceutical composition in the manufacture of a medicament for treating a solid tumor, in some embodiments, the solid tumor is colorectal cancer or breast cancer. Effect of the Invention

[0089] The present invention provides a novel structure of CDK2 / 4 / 6 triple inhibitor. This series of compounds shows excellent inhibitory activity against CDK2 / 4 / 6 enzyme levels, and its selectivity against CDK9 is significantly better than PF-06873600, and the safety risk caused by off-target is reduced; it shows significant inhibitory activity against the proliferation of colorectal cancer cells HCT116 and triple-negative breast cancer cells HCC1806 with high Cyclin E expression levels, and has significantly better selectivity against Rb-negative triple-negative breast cancer MDA-MB-468 cells than PF-06873600. The compounds of the present invention also have lower clearance, higher AUC, higher oral bioavailability, and better overall pharmacokinetic properties. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0090] Unless otherwise stated, the following terms and phrases used herein have the following meanings: A particular term or phrase, unless otherwise defined, should be understood to have its ordinary definition, not to be indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0091] As used herein, "pharmaceutically acceptable salts" refer to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0092] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents discovered in this invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a separate solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting these compounds with a sufficient amount of acid in a separate solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any suitable base or acid addition salt.

[0093] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0094] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both within the scope of the present invention.

[0095] Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.

[0096] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0097] Unless otherwise explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.

[0098] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0099] [ka]

[0100] The compounds of the present invention can exist in a specific form. Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can be rapidly converted between each other. Tautomers can reach chemical equilibrium of tautomers if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by rearrangement of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-penten-2-one.

[0101] Unless otherwise explained, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of such isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0102] Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0103] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. A single enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is decomposed to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to provide the isolated enantiomer. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic techniques using chiral stationary phases and in combination with any chemical derivatization technique (e.g., carbamate formation from an amine). The compounds of the invention may contain unnatural atomic isotopes at one or more of the atoms that constitute the compound. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 The compounds can be labeled with radioisotopes such as radioisotopes C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic effect, and extended biological half-life. Conversion of the isotopic composition of the compounds of the present invention, whether radioactive or not, is within the scope of the present invention. "Optional" and "optionally" mean that the following items or circumstances are possible but not necessarily present, and the description includes the cases where the items or circumstances described therein are not present when the items or circumstances described therein occur.

[0104] The term "effective amount" or "therapeutically effective amount" of a pharmaceutical or pharmacologically active agent refers to a non-toxic but sufficient amount of the pharmaceutical or agent to achieve a desired effect. In the case of an oral pharmaceutical of the present invention, the "effective amount" of one active agent in a composition refers to the amount necessary to achieve a desired effect when used in combination with another active agent in the composition. The determination of an effective amount varies from person to person and depends on the age and general condition of the subject, and also on the specific active agent, and the appropriate effective amount in each case can be determined by those skilled in the art based on routine experimentation.

[0105] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, which may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound is stable after substitution. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto group substitution does not occur in aromatic groups. The term "optionally substituted" refers to either substituted or unsubstituted, and unless otherwise defined, the type and number of substituents are any that are chemically stable and feasible.

[0106] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0107] When the number of linking groups is 0, for example, -(CRR)0- means that the linking group is a single bond.

[0108] When one of the variables is a single bond, the two groups that it links are directly linked; for example, when L in ALZ represents a single bond, the structure is actually AZ.

[0109] The absence of a substituent represents that the substituent is not present, for example, the absence of X in AX represents that the structure is actually A. When no atom through which a substituent is substituted for a given substituent is specified, such a substituent may be bonded through any atom thereof, for example, a pyridinyl group as a substituent may be bonded to the substituent through any carbon atom of the pyridine ring.

[0110] If the listed linking group does not specify another linking direction, then the linking direction is arbitrary, for example:

[0111] [ka]

[0112] In the formula, the linking group L is -MW-, and in this case, -MW- constitutes ring A and ring B in the same direction as the reading order from left to right.

[0113] [ka]

[0114] You can also construct rings A and B in the reverse order of reading from left to right.

[0115] [ka]

[0116] Combinations of the above linking groups, substituents and / or variables are permissible only if such combinations result in stable compounds.

[0117] [ka]

[0118] Unless otherwise stated, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "5- to 7-membered ring" refers to a "ring" of 5 to 7 atoms arranged around it.

[0119] Unless otherwise defined, the term "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon consisting of 1 to 6 carbon atoms. 1-6 Alkyl has C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-6 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), and the like.

[0120] Unless otherwise defined, the term "C 1-4 "Alkyl" refers to a straight or branched chain saturated hydrocarbon consisting of 1 to 4 carbon atoms. 1-4 Alkyl has C1-2, C 1-3 and C. 2-3 Alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-4 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, t-butyl), and the like.

[0121] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a straight or branched chain saturated hydrocarbon consisting of 1 to 3 carbon atoms. 1-3 Alkyl has C 1-2 and C. 2-3and alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Examples of C1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).

[0122] Unless otherwise defined, the term "C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule via an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. 1~3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like.

[0123] Unless otherwise defined, the term "C 1-3 "Alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule via an amino group. 1-3 Alkylamino is C 1-2 , C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0124] Unless otherwise defined, the terms "halogen" or "halo," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0125] Unless otherwise defined, the term "C 1-3 "Haloalkyl" refers to monohaloalkyl and polyhaloalkyl containing 1 to 3 carbon atoms. 1-3 Haloalkyl is C 1-2 , C 2-3 , C3, C2 and C1 haloalkyl, etc. 1-3Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl, and the like.

[0126] Unless otherwise defined, "C 4-6 "Cycloalkyl" means a cyclic saturated hydrocarbon consisting of 4 to 6 carbon atoms, which represents a monocyclic or bicyclic ring system, and is defined as above. 4-6 Cycloalkyl includes C4-5 or C5-6 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0127] Unless otherwise defined, "C 3-5 "Cycloalkyl" means a saturated cyclic hydrocarbon composed of 3 to 5 carbon atoms, which represents a monocyclic ring system, and is defined as C 3-5 Cycloalkyl has C 3-4 Or C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. C 3-5 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0128] Unless otherwise defined, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group composed of 4-6 ring atoms, of which 1, 2, 3, and 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)P, where p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Additionally, with respect to "4-6 membered heterocycloalkyl," the heteroatom can occupy the position of the connection between the heterocycloalkyl and the rest of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc. Illustrative examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl.

[0129] Unless otherwise defined, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" of the present invention can be used interchangeably, and the term "5-6 membered heteroaryl" refers to a monocyclic group having a conjugated π electron system composed of 5-6 ring atoms, of which 1, 2, 3, and 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. In this case, 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 is linked to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5- or 6-membered heteroaryl. Illustrative examples of 5-6 membered heteroaryls are 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 (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), aryl ... 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.), pyridinyl (including 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl or 4-pyrimidinyl, etc.).

[0130] Unless otherwise defined, the carbon atom is referred to in the invention as the term "C 6-10 Aromatic ring" and "C 6-10 Aryl" may be used interchangeably, and the term "C 6-10 Aromatic ring" and "C 6-10"Aryl" means a cyclic hydrocarbon group having a conjugated pi-electron system composed of 6 to 10 carbon atoms, which may be a monocyclic, fused bicyclic or fused tricyclic ring system, in which each ring is aromatic. It may be monovalent, divalent or polyvalent, and C 6-10 Aryl is C 6-9 , C9, C 10 and C6 aryl. 6-10 Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.), and the like.

[0131] Unless otherwise defined, C n-n+m Or C n-Cn+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 Including any one of the ranges of n to n+m, for example, C 1-12 is 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 Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0132] The term "leaving group" refers to a functional group or atom that may be replaced by another functional group or atom in a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate, chlorine, bromine, iodine, sulfonate ester groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like, and acyloxy groups such as acetyloxy, trifluoroacetyloxy, and the like.

[0133] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen of an amino group. Representative amino acid protecting groups include, but are not limited to, formyl, acyl such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl), alkoxycarbonyl such as t-butoxycarbonyl (Boc), arylmethoxycarbonyl such as benzoxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc), arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis(4'-methoxyphenyl)methyl, silyl such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of hydroxy. Representative hydroxy protecting groups include, but are not limited to, alkyl, such as methyl, ethyl, and t-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylethyl (Fm), and diphenylmethyl (DPM); silyl, such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS); and the like.

[0134] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, after collecting the relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis.

[0135] The compounds of the present invention can be prepared by various synthetic methods familiar to those skilled in the art, including the specific embodiments given below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0136] All solvents used in this invention can be obtained commercially.

[0137] The present invention uses the following abbreviations: DIBAL-H stands for diisobutylaluminum hydride; DMSO stands for dimethylsulfoxide; DBU stands for 1,8-diazabicycloundec-7-ene; EDTA stands for ethylenediaminetetraacetic acid; HPMC stands for hydroxypropylmethylcellulose; LCMS stands for liquid chromatography; Rh(PPH3)3Cl stands for tris(triphenylphosphine)rhodium chloride; SFC stands for supercritical fluid chromatography; TLC stands for thin layer chromatography; Pd(dppf)Cl2·CH2Cl2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane; Psi stands for pounds per inch; DMSO stands for dimethylsulfoxide; ATP stands for adenosine triphosphate; ADP-Glo ​​stands for kit. EXAMPLES

[0138] The present invention will be specifically described below by way of examples, but is not intended to be an adverse restriction of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0139] Example 1: Compound 1, Compound 1A and Compound 1B

[0140] [ka]

[0141] Synthesis of compound 1-n:

[0142] Compound 1-l (100 g, 438.84 mmol, 56.18 mL) was added to acetonitrile (1 L), triethylamine (66.61 g, 658.26 mmol, 91.62 mL) was added, cooled to 0 ° C, compound 1-m (60.65 g, 526.61 mmol) was slowly added dropwise, the temperature of the reaction system was maintained at 0-5 ° C, and the reaction solution was stirred at 0-5 ° C for 3 hours. Water (500 mL) was added to the reaction system, extracted with ethyl acetate (500 mL × 3), the organic phase was combined, washed with saturated saline (600 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was suspended and stirred in petroleum ether: ethyl acetate = 10: 1 (500 mL) at 20 ° C for 2 hours, and filtered to obtain compound 1-n. 1 H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 5.50 (br d, J = 2.6 Hz, 1H), 4.36 (br s, 1H), 4.23 (ddd, J = 5.7, 8.1, 10.2 Hz, 1H), 2.36 - 2.28 (m, LCMS (ESI): m / z: 308.0 (M+1).

[0143] Synthesis of compound 1-o: Compound 1-n (110 g, 358.79 mmol) and compound 1-k (115.56 g, 538.19 mmol, HCl) were added to dimethyl sulfoxide (1100 mL), followed by potassium carbonate (148.76 g, 1.08 mol), and the mixture was stirred at 120° C. for 16 hours. The mixture was cooled to 20° C., water (1 L) was added, and the mixture was extracted with ethyl acetate (500 mL×3), and the combined organic phase was washed with saturated brine (800 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The obtained crude product was stirred in ethyl acetate:petroleum ether=2:3 (500 mL) at 70° C. for 30 minutes, then cooled to 20° C. and stirred for 3 hours. Compound 1-o was obtained by filtration. LCMS (ESI): m / z: 450.0 (M+1).

[0144] Synthesis of compound 1-q: Compound 1-o (100g, 218.77mmol, 98.09% purity) was added to N,N-dimethylformamide (1000mL), ethyl acrylate (219.02g, 2.19mol, 237.81mL) was added, triethylamine (88.55g, 875.07mmol, 121.80mL) and Pd(dppf)Cl2·CH2Cl2 (17.87g, 21.88mmol) were added, and the mixture was purged with nitrogen gas several times, heated to 100℃, and stirred under nitrogen gas protection for 16 hours. The reaction solution was cooled to 20℃, water (1000mL) was added, and extracted with ethyl acetate (800mL×3). The organic phase was combined, washed with saturated brine (500mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was stirred with methyl tert-butyl ether (500 mL) at 20° C. for 16 hours, and then petroleum ether (200 mL) was added and stirring was continued for 3 hours, followed by filtration to obtain compound 1-q. 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 5.28 (br t, J = 8.5 Hz, 1H), 4.15 (quin, J = 7.6 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.74 (br dd, J = 3.7, 12.4 Hz, 2H), 3.68 (t, J = 8.5 Hz, 2H), 3.46 (t, J = 8.1 Hz, 2H), 3.02 (br t, J = 11.7 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.65 - 2.56 (m, 4H), 2.53 - 2.43 (m, 1H), 2.24 - 2.04 (m, 4H), 1.95 - 1.86 (m, 2H), 1.79 - 1.72 (m, 1H), 1.62 - 1.49 (m, 2H), 1.18 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H);LCMS (ESI): m / z: 468.1 (M+1).

[0145] Synthesis of compound 1-r: Compound 1-q (101 g, 210.30 mmol, 97.36% purity) was added to ethanol (1000 mL), and under the protection of nitrogen gas, wet Pd / C (10%, 10 g) was added, and the reaction system was replaced with hydrogen gas several times. The reaction solution was stirred under hydrogen gas (15 psi) at 80° C. for 32 hours. The mixture was cooled to 20° C., filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was stirred with methyl tert-butyl ether (500 mL) at room temperature for 3 hours, and filtered to obtain compound 1-r. 1H NMR (400 MHz, CD3OD): δ 7.56 (s, 1H), 4.36 (t, J = 8.3 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.79 (tt, J = 4.0, 10.6 Hz, 1H), 3.74 - 3.67 (m, 2H), 2.95 (dt, J = 2.6, 11.9 Hz, 2H), 2.87 (s, 3H), 2.73 - 2.67 (m, 2H), 2.58 - 2.52 (m, 2H), 2.23 - 2.04 (m, 3H), 1.90 - 1.72 (m, 5H), 1.64 - 1.53 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.16 (s, 3H); LCMS (ESI): m / z: 470.3 (M+1).

[0146] Synthesis of compound 1A: Compound 1-r (7.8 g, 16.61 mmol) was added to dimethyl sulfoxide (80 mL), followed by DBU (5.06 g, 33.22 mmol, 5.01 mL). The mixture was heated to 120 °C and stirred for 10 h. The reaction was cooled to 20 °C, water (100 mL) was added, extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative chromatography (column: Waters Xbridge BEH C18 50 x 50 mm x 10 μm; mobile phase: 0.05% aqueous ammonia was mobile phase A, acetonitrile was mobile phase B, B%: 20% to 42%, gradient time: 15 min) to give compound 1A. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 5.24 - 5.11 (m, 1H), 4.22 (s, 1H), 3.90 - 3.73 (m, 1H), 3.61 - 3.46 (m, 2H), 2.92 - 2.78 (m, 5H), 2.66 - 2.58 (m, 2H), 2.56 - 2.51 (m, 2H), 2.35 - 2.22 (m, 1H), 2.09 - 1.85 (m, 5H), 1.81 - 1.70 (m, 2H), 1.65 - 1.43 (m, 3H), 1.11 - 0.99 (m, 3H);LCMS (ESI): m / z: 424.2 (M+1).

[0147] [ka]

[0148] Synthesis of compound 1-B: Compound 1-a (100 g, 429.76 mmol) was added to tetrahydrofuran (1000 mL), cooled to -78 ° C, and under the protection of nitrogen gas, DIBAL-H (1 M, 859.52 mL) was slowly added dropwise. After the completion of the addition, the reaction solution was heated to 25 ° C and stirred under the protection of nitrogen gas for 16 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that a small amount of compound 1-a remained and a new product was produced. The reaction was stopped, quenched with saturated ammonium chloride (800 mL), extracted with ethyl acetate (500 mL × 3), the organic phase was combined and washed with saturated saline (500 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was stirred at 25 ° C with petroleum ether: ethyl acetate = 10: 1 (200 mL) for 16 hours to obtain compound 1-b.

[0149] 1 H NMR (400 MHz, CDCl3): 8.57 (s, 1H), 4.76 (s, 2H), 2.59 (s, 3H).

[0150] Synthesis of compound 1-d: Compound 1-b (20 g, 104.90 mmol) and compound 1-c (12.69 g, 110.15 mmol) were added to acetonitrile (200 mL), followed by triethylamine (15.92 g, 157.36 mmol, 21.90 mL), and the reaction solution was stirred at 80° C. for 12 h. TLC (petroleum ether:ethyl acetate=3:1) showed that compound 1-b had reacted completely and a new product had been formed. The reaction solution was cooled to 25° C. and concentrated under reduced pressure to remove excess acetonitrile. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain compound 1-d. 1 H NMR (400 MHz, CDCl3): 7.71 (s, 1H), 4.25 (m, 1H), 3.49 (s, 3H), 2.50 (s, 3H), 2.21 (dt, J = 3.8, 8.1 Hz, 1H), 1.96 (dt, J = 3.6, 7.7 Hz, 1H), 1.90 - 1.77 (m, 4H), 1.76 - 1.68 (m, 1H), 1.58 - 1.49 (m, 1H), 1.11 (s, 3H).

[0151] Synthesis of compound 1-e: Compound 1-d (20 g, 74.25 mmol) was added to ethyl acetate (150 mL) and methanol (50 mL), followed by the addition of activated manganese dioxide (64.55 g, 742.50 mmol), and the reaction solution was stirred at 50° C. for 4 hours. TLC (petroleum ether:ethyl acetate=1:1) showed that compound 1-d had reacted completely and a new product had been produced. The reaction solution was cooled to 25° C., filtered, the cake was washed with methanol (50 mL×2), and the filtrate was concentrated under reduced pressure to give compound 1-e. 1H NMR (400 MHz, CDCl3): 9.65 (s, 1H), 8.27 (s, 1H), 4.31 (ddd, J = 6.5, 8.2, 9.5 Hz, 1H), 2.49 (s, 3H), 2.26 - 2.15 (m, 1H), 1.92 - 1.85 (m, 1H), 1.81 - 1.73 (m, 2H), 1.67 - 1.50 (m, 2H), 1.09 (s, 3H).

[0152] Synthesis of compound 1-g: Compound 1-e (5 g, 18.70 mmol) was added to dichloromethane (100 mL), followed by addition of 1-f (6.84 g, 19.64 mmol), and the reaction solution was stirred at 25° C. for 2 h. TLC (petroleum ether:ethyl acetate=3:1) showed that compound 1-e had reacted completely and a new product had been produced. The reaction solution was concentrated under reduced pressure to remove excess dichloromethane. The resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound 1-g. 1 H NMR (400 MHz, CDCl3): 8.21 (d, J = 0.6 Hz, 1H), 7.52 (d, J = 15.9 Hz, 1H), 6.32 (d, J = 15.8 Hz, 1H), 5.06 (br d, J = 5.1 Hz, 1H), 4.32 - 4.29 (m, 2H), 2.55 (s, 3H), 2.31 - 2.21 (m, 1H), 2.07 - 1.97 (m, 1H), 1.93 - 1.71 (m, 3H), 1.64 - 1.52 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.14 (s, 3H).

[0153] Synthesis of compound 1-h: Compound 1-g (560 mg, 1.66 mmol) was added to tetrahydrofuran (10 mL), and then (PPh3)3RhCl (307.09 mg, 331.91 μmol) was added under the protection of nitrogen gas. The reaction solution was replaced with hydrogen gas several times, and then the reaction solution was stirred at 50°C under a hydrogen pressure of 50 Psi for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 25°C and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 1-h. 1 H NMR (400 MHz, CDCl3): 7.74 (s, 1H), 5.73 (br d, J = 4.3 Hz, 1H), 5.46 (s, 1H), 4.19 - 4.12 (m, 1H), 2.66 - 2.59 (m, 2H), 2.55 - 2.48 (m, 2H), 2.42 (s, 3H), 2.17 - 2.07 (m, 1H), 1.96 - 1.87 (m, 1H), 1.81 - 1.70 (m, 2H), 1.57 - 1.47 (m, 2H), 1.21 - 1.18 (m, 3H), 1.01 (s, 3H).

[0154] Synthesis of compound 1-i: Compound 1-h (360 mg, 1.06 mmol) was added to N-methylpyrrolidone (5 mL), followed by DBU (322.90 mg, 2.12 mmol, 319.71 μL), and the reaction solution was stirred at 120° C. for 16 h. LCMS showed that the reaction was complete. The reaction solution was cooled to 25° C. and extracted with ethyl acetate (10 mL×3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain compound 1-i. LCMS (ESI): m / z: 294.2 (M+1);

[0155] 1H NMR (400 MHz, CDCl3): 8.23 ​​(s, 1H), 5.00 (t, J = 8.8 Hz, 1H), 2.88 - 2.81 (m, 2H), 2.75 - 2.65 (m, 4H), 2.57 (s, 3H), 2.05 - 1.90 (m, 4H), 1.19 (s, 3H).

[0156] Synthesis of compound 1-j: Compound 1-i (100 mg, 340.85 μmol) was added to 2-methyltetrahydrofuran (1 mL) and water (0.2 mL), followed by addition of potassium hydrogen persulfate complex salt (523.86 mg, 852.13 μmol) and stirring at 25° C. for 2 hours. LCMS showed the reaction was complete. The reaction solution was quenched with saturated sodium sulfite (15 mL), extracted with ethyl acetate (10 mL×3), the combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-j. LCMS (ESI): m / z: 307.8 (M-18+1);

[0157] 1 H NMR (400 MHz, CDCl3): 8.45 (s, 1H), 5.01 (t, J = 8.7 Hz, 1H), 3.25 (s, 3H), 2.96 - 2.91 (m, 2H), 2.76 - 2.69 (m, 2H), 2.12 - 1.98 (m, 2H), 1.96 - 1.88 (m, 2H), 1.84 - 1.78 (m, 2H), 1.09 (s, 3H).

[0158] Synthesis of compound 1: Compound 1-j (80 mg, 245.86 μmol) was added to dimethylsulfoxide (1 mL), followed by 1-k (79.19 mg, 368.80 μmol, hydrochloride salt) and diisopropylethylamine (158.88 mg, 1.23 mmol, 214.13 μL), and the reaction solution was stirred at 120° C. for 16 h. LCMS showed the reaction was complete. The reaction solution was cooled to 25 ° C., water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated saline (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by preparative chromatography (column: 3_PhenomenexLuna C18 75 × 30 mm × 3 μm; mobile phase: 0.05% hydrochloric acid solution was mobile phase A, acetonitrile was mobile phase B, B%: 11% to 31%, gradient time: 6.5 min). The purified mixed solution was adjusted to pH 7 to 8 with saturated sodium bicarbonate, and then extracted with dichloromethane (10 mL × 3). The combined organic phase was washed with saturated saline (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 1. LCMS (ESI) m / z: 424.1 (M+1).

[0159] Synthesis of compound 1B: Compound 1 was subjected to chiral separation by SFC to give 1A and 1B. Compound 1 was purified by SFC (column: polyoxymethylene-coated chiral stationary phase (250 mm × 30 mm × 10 μm); mobile phase: 45% [0.1% ammonia in ethanol]; to obtain compound 1A (retention time 0.548 min) and compound 1B (retention time 0.895 min).

[0160] Compound 1B: 1H NMR (400MHz, MeOD) δ 7.87 (s, 1H), 5.17 (br t, J = 8.6 Hz, 1H), 3.85-3.76 (m, 1H), 3.64-3.55 (m, 2H), 2.89-2.81 (m, 2H), 2.76 (s, 3H), 2.66-2.59 (m, 2H), 2.54-2.48 (m, 2H), 2.40-2.31 (m, 1H), 2.12-1.92 (m, 4H), 1.82-1.73 (m, 2H), 1.67-1.60 (m, 1H), 1.57-1.46 (m, 2H), 1.06 (s, 3H).

[0161] Example 2: Hydrochloride salt of compound 2

[0162] [ka]

[0163] [ka]

[0164] Synthesis of compound 2-a: Compound 1-b (5 g, 26.23 mmol) was added to ethyl acetate (50 mL), followed by the addition of activated manganese dioxide (22.80 g, 262.26 mmol), and the reaction solution was stirred at 50° C. for 16 h. TLC (petroleum ether:ethyl acetate=3:1) showed that compound 1-b had reacted completely and a new product had been produced. The reaction solution was cooled to 25° C., filtered, the cake was washed with methanol (30 mL×3), the filtrate was evaporated to dryness, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound 2-a. 1 H NMR (400 MHz, CDCl3): δ 10.33 (s, 1H), 8.89 (s, 1H), 2.66 (s, 3H).

[0165] Synthesis of compound 2-b: Compound 2-a (3 g, 15.90 mmol) was added to dichloromethane (20 mL), followed by compound 1-f (5.82 g, 16.70 mmol), and the reaction solution was stirred at 30° C. for 2 h. TLC (petroleum ether:ethyl acetate=10:1) showed that compound 2-a had reacted completely and a new product had been produced. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound 2-b.

[0166] 1 H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 7.81 (d, J = 16.1 Hz, 1H), 6.51 (d, J = 16.3 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 2.61 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0167] Synthesis of compound 2-c: Compound 2-b (4.2 g, 16.23 mmol) was added to 2-methyltetrahydrofuran (20 mL), followed by the addition of Rh(PPh3)3Cl (3.00 g, 3.25 mmol). The reaction solution was purged with hydrogen gas several times, and then the reaction solution was stirred with hydrogen gas (15 Psi) at 80° C. for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 20° C. and concentrated under reduced pressure to remove excess 2-methyltetrahydrofuran, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain compound 2-c. LCMS (ESI): m / z: 260.9 (M+1).

[0168] Synthesis of compound 2-d: Compound 2-c (1.9 g, 7.29 mmol) was added to tetrahydrofuran (20 mL), cooled to -78 ° C, and under the protection of nitrogen gas, lithium diisopropylamide (1 M, 18.22 mL) was slowly added, and the reaction solution was stirred at -78 ° C for 30 minutes, after which iodomethane (1.55 g, 10.93 mmol, 680.46 μL) was added, and the reaction solution was heated to 25 ° C and stirred for 1.5 hours. TLC (petroleum ether: ethyl acetate = 10: 1) showed that compound 2-c had reacted completely and a new product had been produced. The reaction solution was quenched with saturated ammonium chloride (25 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 2-d.

[0169] Synthesis of compound 2-e: Compound 2-d (1.2 g, 4.37 mmol) and compound 1-c (1.01 g, 8.73 mmol) were added to dimethyl sulfoxide (20 mL), followed by the addition of diisopropylethylamine (1.69 g, 13.10 mmol, 2.28 mL), and the reaction solution was stirred at 110° C. for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 25° C., water (5 mL) was added, and extracted with ethyl acetate (10 mL×3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound 2-e. LCMS (ESI): m / z: 354.2 (M+1); 1H NMR (400 MHz, CDCl3): 7.84 - 7.81 (m, 1H), 4.17 - 4.11 (m, 2H), 2.80 (td, J = 8.0, 15.0 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.51 (d, J = 0.6 Hz, 3H), 2.49 - 2.41 (m, 1H), 2.28 - 2.17 (m, 1H), 2.00 (dt, J = 3.5, 7.5 Hz, 1H), 1.90 - 1.81 (m, 2H), 1.79 - 1.68 (m, 1H), 1.61 (s, 5H), 1.27 - 1.25 (m, 3H), 1.11 (d, J = 8.2 Hz, 3H).

[0170] Synthesis of compound 2-f: Compound 2-e (1.1 g, 3.11 mmol) was added to N-methylpyrrolidone (15 mL), followed by DBU (947.50 mg, 6.22 mmol, 938.12 μL), and the reaction solution was stirred at 120° C. for 12 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 25° C., water (20 mL) was added, extracted with ethyl acetate (20 mL×3), the combined organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain compound 2-f. LCMS (ESI): m / z: 208.2 (M+1).

[0171] Synthesis of compound 2-g: Compound 2-f (1 g, 3.25 mmol) was added to 2-methyltetrahydrofuran (10 mL) and water (2 mL), followed by potassium hydrogen persulfate complex (5.00 g, 8.13 mmol), and the reaction solution was stirred at 25° C. for 2 hours. LCMS showed the reaction was complete. The reaction solution was quenched with saturated sodium sulfite (50 mL), extracted with ethyl acetate (20 mL×3), the combined organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 2-g. LCMS (ESI): m / z: 322.1 (M-18+1); 1 H NMR (400 MHz, CDCl3): 8.46 - 8.42 (m, 1H), 3.31 (t, J = 7.1 Hz, 2H), 3.25 (s, 3H), 3.00 (dt, J = 4.5, 14.1 Hz, 1H), 2.77 (s, 3H), 2.28 - 2.28 (m, 1H), 2.30 (t, J = 8.1 Hz, 1H), 1.81 - 1.77 (m, 1H), 1.27 - 1.19 (m, 4H), 1.10 - 1.06 (m, 3H).

[0172] Synthesis of compound 2: Compound 2-g (500 mg, 1.47 mmol) and compound 1-k (474.46 mg, 2.21 mmol, hydrochloride salt) were added to dimethylsulfoxide (8 mL), followed by diisopropylethylamine (951.95 mg, 7.37 mmol, 1.28 mL), and the reaction solution was stirred at 140° C. for 16 h. LCMS showed the reaction was complete. The reaction solution was cooled to 25°C, water (20mL) was added, and extracted with ethyl acetate (10mL x 3). The combined organic phase was washed with saturated saline (15mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The obtained crude product was purified by preparative chromatography (column: 3_PhenomenexLuna C18 75 x 30mm x 3μm; mobile phase: 0.05% hydrochloric acid solution was mobile phase A, acetonitrile was mobile phase B, B%: 13%~33%, gradient time: 6.5min) to obtain the hydrochloride salt of compound 2. LCMS (ESI): m / z: 438.1 (M+1);

[0173] 1 H NMR (400 MHz, MeOD) δ 8.01 (d, J = 2.4 Hz, 1H), 3.83-3.75 (m, 1H), 3.09-2.93 (m, 4H), 2.90 (s, 3H), 2.78-2.57 (m, 2H), 2.53-2.25 (m, 2H), 2.25-2.10 (m, 4H), 1.97-1.89 (m, 2H), 1.82-1.67 (m, 4H), 1.28 (dd, J = 6.7, 11.4 Hz, 3H), 1.17 (d, J = 2.4 Hz, 3H).

[0174] Example 3: Compound 3

[0175] [ka]

[0176] [ka]

[0177] Synthesis of compound 3-b: Compound 3-a (5 g, 24.97 mmol) and triethylamine (5.05 g, 49.93 mmol) were dissolved in dichloromethane (50 mL), and the resulting mixture was stirred at 15° C. under nitrogen gas protection for 0.5 hours, after which benzyl chloroformate (6.39 g, 37.45 mmol) was slowly added, and the resulting mixture was stirred at the same temperature for 1.5 hours. The reaction solution was diluted with water (80 mL) and extracted with dichloromethane (30 mL×4). The resulting organic phase was washed with saturated saline (60 mL×1), dried over anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was purified by stirring with petroleum ether (50 mL) at 25° C. for 3 hours to obtain compound 3-b. 1H NMR (400 MHz, CD3OD) δ ppm 1.24 - 1.37 (m, 2 H) 1.43 (s, 9 H) 1.83 (br d, J=10.51 Hz, 2 H) 2.95 (br s, 2 H) 3.44 - 3.57 (m, 1 H) 4.05 (br d, J=13.51 Hz, 2 H) 5.10 (s, 2 H) 7.23 - 7.40 (m, 5 H); LCMS (ESI): m / z: 335.2 (M+1).

[0178] Synthesis of compound 3-c: Compound 3-b (7 g, 20.93 mmol) was dissolved in ethyl acetate (100 mL), and then an HCl-ethyl acetate solution (4 M, 52.33 mL) was added. The resulting mixture was stirred at 15° C. for 2 hours. The reaction solution was concentrated to give compound 3-c. 1 H NMR (400 MHz, CD3OD) δ ppm 1.49 (qd, J=12.29, 4.46 Hz, 2 H) 2.00 (br d, J=12.35 Hz, 2 H) 2.94 (br s, 2 H) 3.34 (s, 2 H) 4.22 (dt, J=13.97, 2.25 Hz, 2 H) 5.12 (s, 2 H) 7.27 - 7.38 (m, 5 H); LCMS (ESI): m / z: 235.2 (M+1).

[0179] Synthesis of compound 3-e: Compound 3-d (1.2 g, 3.69 mmol), compound 3-c (2.59 g, 11.06 mmol) and diisopropylethylamine (3.81 g, 29.50 mmol) were dissolved in dimethyl sulfoxide (20 mL), and the resulting mixture was stirred at 110° C. for 12 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (60 mL×3). The resulting organic phase was washed with saturated saline (100 mL×1), dried over anhydrous Na2SO4, filtered and concentrated. The resulting crude product compound was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 3-e. LCMS (ESI): m / z: 480.3 (M+1).

[0180] Synthesis of compound 3-f: Compound 3-e (830 mg, 1.73 mmol) and wet palladium carbon (300 mg, 10%) were dissolved in methanol (15 mL), and the resulting mixture was stirred at 15° C. under 15 psi hydrogen gas for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give compound 3-f.

[0181] Synthesis of compound 3: Compound 3-f (100 mg, 289.49 μmol), 3-g (61.05 mg, 434.23 μmol) and triethylamine (43.94 mg, 434.23 μmol) were dissolved in dichloromethane (2 mL), and the resulting mixed solution was stirred at 15 ° C. for 1 hour. After concentrating the reaction solution, it was purified by preparative chromatography (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: 10 mM ammonium bicarbonate solution was mobile phase A, acetonitrile was mobile phase B, B%: 20% to 50%, gradient time: 9 min) to obtain compound 3. 1 H NMR (400 MHz, CD3OD) δ ppm 1.01 - 1.07 (m, 4 H) 1.16 (s, 3 H) 1.53 - 1.66 (m, 2 H) 1.68 - 1.77 (m, 1 H) 1.83 - 1.92 (m, 2 H) 2.00 - 2.20 (m, 4 H) 2.42 - 2.53 (m, 2 H) 2.56 - 2.64 (m, 2 H) 2.68 - 2.78 (m, 2 H) 3.07 (td, J=12.10, 2.08 Hz, 2 H) 3.74 (br dd, J=12.23, 3.55 Hz, 2 H) 3.86 - 3.98 (m, 1 H) 5.27 (br t, J=8.44 Hz, 1 H) 7.97 (s, 1 H).LCMS (ESI): m / z: 450.3 (M+1).

[0182] Example 4: Compound 4

[0183] [ka]

[0184] [ka]

[0185] Synthesis of compound 4: Compound 3-f (100 mg, 289.49 μmol), 4-a (55.83 mg, 434.23 μmol) and triethylamine (43.94 mg, 434.23 μmol) were dissolved in dichloromethane (2 mL), and the resulting mixed solution was stirred at 15 ° C. for 1 hour. After concentrating the reaction solution, it was purified by preparative chromatography (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: 10 mM ammonium bicarbonate solution was mobile phase A, acetonitrile was mobile phase B, B%: 15% to 48%, gradient time: 10 min) to obtain compound 4. 1 H NMR (400 MHz, CD3OD -d4) δ ppm 1.17 (s, 3 H) 1.34 (t, J=7.40 Hz, 3 H) 1.52 - 1.65 (m, 2 H) 1.69 - 1.77 (m, 1 H) 1.83 - 1.94 (m, 2 H) 2.00 - 2.22 (m, 4 H) 2.42 - 2.52 (m, 1 H) 2.56 - 2.67 (m, 2 H) 2.68 - 2.77 (m, 2 H) 3.00 - 3.09 (m, 4 H) 3.70 - 3.78 (m, 2 H) 3.86 - 3.97 (m, 1 H) 5.27 (br t, J=8.62 Hz, 1 H) 7.98 (s, 1 H); LCMS (ESI): m / z: 438.3 (M+1).

[0186] Example 5: Compound 5

[0187] [ka]

[0188] [ka]

[0189] Synthesis of compound 5: Compound 3-f (100 mg, 289.49 μmol), 5-a (61.92 mg, 434.23 μmol) and triethylamine (43.94 mg, 434.23 μmol) were dissolved in dichloromethane (2 mL), and the resulting mixed solution was stirred at 15 ° C. for 1 hour. After concentrating the reaction solution, it was purified by preparative chromatography (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: 10 mM ammonium bicarbonate solution was mobile phase A, acetonitrile was mobile phase B, B%: 21% to 51%, gradient time: 9 min) to obtain compound 5. 1 H NMR (400 MHz, METHANOL-d4) δ ppm 1.16 (s, 3 H) 1.32 (d, J=6.72 Hz, 6 H) 1.49 - 1.60 (m, 2 H) 1.69 - 1.76 (m, 1 H) 1.83 - 1.93 (m, 2 H) 1.98 - 2.11 (m, 3 H) 2.17 (td, J=11.80, 8.07 Hz, 1 H) 2.41 - 2.52 (m, 1 H) 2.57 - 2.64 (m, 2 H) 2.67 - 2.76 (m, 2 H) 3.10 (br t, J=11.37 Hz, 2 H) 3.73 - 3.82 (m, 2 H) 3.86 - 3.98 (m, 1 H) 5.26 (br t, J=8.56 Hz, 1 H) 7.96 (s, 1 H); LCMS (ESI): m / z: 452.3 (M+1).

[0190] Example 6: Compound 6

[0191] [ka]

[0192] [ka]

[0193] Synthesis of compound 6: At 0°C, 6-a (2.30 mg, 14.47 μmol) was added dropwise to a solution of compound 3-f (5 mg, 14.47 μmol) and triethylamine (2.93 mg, 28.95 μmol, 4.03 μmL) in dichloromethane (1 mL), and the reaction solution was stirred at 15°C for 2 hours. LC-MS showed that the raw materials were completely reacted and the formation of the target product was detected. The reaction solution was concentrated under reduced pressure and purified by preparative chromatography (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: 0.05% aqueous ammonia was mobile phase A, acetonitrile was mobile phase B, B%: 18% to 48%, gradient time: 9 min) to obtain compound 6. 1 H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H),5.17 (br s, 1H),3.84-3.73 (m, 1H),3.68-3.56 (m, 4H),3.28 (s, 3H),3.20-3.15 (m, 2H),2.92 (br t, J = 11.3 Hz, 2H),2.67-2.57 (m, 2H),2.55-2.47 (m, 2H),2.43-2.31 (m, 1H),2.13-1.89 (m, 4H),1.84-1.74 (m, 2H),1.66-1.59 (m, 1H),1.55-1.40 (m, 2H),1.24-1.17 (m, 1H),1.10-1.02 (m, 3H). LCMS (ESI) m / z: 468.4 (M+1).

[0194] Example 7: Compound 7

[0195] [ka]

[0196] [ka]

[0197] Synthesis of compound 7-b: Compound 7-a (7.5 g, 36.19 mmol) and triethylamine (5.49 g, 54.29 mmol, 7.56 mL) were added to dichloromethane (100 mL) and cooled to 0°C. Then, methanesulfonyl chloride (4.98 g, 43.43 mmol, 3.36 mL) was added dropwise to the reaction solution, and the reaction temperature was raised to 15°C and stirred for 3 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that the reaction was complete and a new compound was formed. The reaction solution was quenched with 1M hydrochloric acid solution (50 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound 7-b. 1 H NMR (400 MHz, CDCl3): δ 7.32 - 7.23 (m, 5H), 5.16 (tt, J = 4.2, 6.7 Hz, 1H), 5.03 (s, 2H), 4.32 - 4.26 (m, 2H), 4.13 - 4.08 (m, 2H), 2.99 (s, 3H).

[0198] Synthesis of compound 7-d: Compound 7-b (5 g, 17.52 mmol) was added to N,N-dimethylformamide (50 mL), potassium carbonate (3.63 g, 26.29 mmol) was added, and the reaction solution was cooled to 0 ° C., and then 7-c (2.00 g, 26.29 mmol) was added dropwise. The reaction solution was heated to 80 ° C. and stirred for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 20 ° C., water (100 mL) was added, and extracted with ethyl acetate (50 mL × 3), and the organic phase was combined and washed with saturated brine (100), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 7-d. 1H NMR (400 MHz, CDCl3): δ 7.41 - 7.30 (m, 5H), 5.12 (s, 2H), 4.48 (t, J = 8.8 Hz, 2H), 4.23 (tt, J = 5.6, 8.2 Hz, 1H), 3.92 (dd, J = 5.6, 9.5 Hz, 2H), 2.35 (s, 3H); LCMS (ESI): m / z: 266.0 (M+1).

[0199] Synthesis of compound 7-e: Compound 7-d (2.5 g, 9.42 mmol) was added to water (10 mL) and dichloromethane (20 mL), cooled to 0°C, and then chlorine gas was passed through the reaction system, and the reaction solution was reacted with chlorine gas at 0-10°C for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1) showed that the reaction was completed and a new compound was produced. The reaction solution was separated, and the organic phase was washed with water (50 mL), saturated sodium carbonate (50 mL x 1) and saturated saline (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 7-e. 1 H NMR (400 MHz, CDCl3): δ 7.31 - 7.26 (m, 5H), 5.06 (s, 2H), 4.55 - 4.34 (m, 5H).

[0200] Synthesis of compound 7-f: Compound 3-f (1 g, 2.89 mmol) and triethylamine (585.86 mg, 5.79 mmol, 805.86 μL) were added to dichloromethane (10 mL), followed by compound 7-e (838.75 mg, 2.89 mmol), and the reaction solution was stirred at 15° C. for 16 hours. LCMS showed that the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=0 / 1) to obtain compound 7-f. 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 7.38 - 7.29 (m, 5H), 5.28 (br t, J = 8.5 Hz, 1H), 5.14 - 5.13 (m, 2H), 4.34 - 4.22 (m, 5H), 3.95 - 3.89 (m, 1H), 3.81 - 3.75 (m, 2H), 3.10 - 3.02 (m, 2H), 2.99 - 2.88 (m, 1H), 2.77 - 2.71 (m, 2H), 2.65 - 2.59 (m, 2H), 2.51 - 2.43 (m, 1H), 2.24 - 2.16 (m, LCMS (ESI): m / z: 599.4 (M+1).

[0201] Synthesis of compound 7: Compound 7-f (1.1 g, 1.84 mmol) was added to methanol (20 mL), and under the protection of nitrogen gas, wet palladium / carbon (10%, 200 mg) was added, and the reaction solution was purged with hydrogen gas several times. The reaction solution was stirred at 15° C. under the protection of hydrogen gas (15 psi) for 10 hours. LCMS showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, the filtrate was evaporated to dryness, and the obtained crude product was purified by preparative chromatography (column: Waters Xbridge C18 250×50 mm×10 μm; mobile phase: 0.05% aqueous ammonia was mobile phase A, acetonitrile was mobile phase B, B%: 15% to 30%, gradient time: 20 min) to obtain compound 7. 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 5.28 (br t, J = 8.4 Hz, 1H), 4.39 (quin, J = 7.6 Hz, 1H), 4.02 - 3.70 (m, 7H), 3.02 (br t, J = 11.6 Hz, 2H), 2.77 - 2.70 (m, 2H), 2.66 - 2.59 (m, 2H), 2.51 - 2.41 (m, 1H), 2.23 - 2.03 (m, 4H), 1.94 - 1.86 (m, 2H), 1.78 - 1.73 (m, 1H), 1.55 (dq, J = 8.1, 11.6 Hz, 2H), 1.18 (s, 3H); LCMS (ESI): m / z: 465.3 (M+1).

[0202] Example 8: Compound 8

[0203] [ka]

[0204] [ka]

[0205] Synthesis of compound 8: Compound 7 (70 mg, 145.05 μmol) and acetaldehyde (31.95 mg, 725.27 μmol, 40.70 μL) were added to methanol (2 mL) and stirred at 15° C. for 30 min, then sodium cyanoborohydride (18.23 mg, 290.11 μmol) was added and stirred at 15° C. for 1 h. LCMS showed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and the resulting crude product was purified by preparative chromatography (column: Waters Xbridge C18 150×25 mm×5 μm; mobile phase: 10 mM ammonium bicarbonate solution was mobile phase A, acetonitrile was mobile phase B, B%: 18%-48%, gradient time: 9 min) to give compound 8. 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 5.28 (br t, J = 8.5 Hz, 1H), 4.15 (quin, J = 7.6 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.74 (br dd, J = 3.7, 12.4 Hz, 2H), 3.68 (t, J = 8.5 Hz, 2H), 3.46 (t, J = 8.1 Hz, 2H), 3.02 (br t, J = 11.7 Hz, 2H), 2.77 - 2.71 (m, 2H), 2.65 - 2.56 (m, 4H), 2.53 - 2.43 (m, 1H), 2.24 - 2.04 (m, 4H), 1.95 - 1.86 (m, 2H), 1.79 - 1.72 (m, 1H), 1.62 - 1.49 (m, 2H), 1.18 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H); LCMS (ESI): m / z: 493.4 (M+1).

[0206] Example 9: Compound 9

[0207]

change

[0208]

change

[0209] Compound 7 (70 mg, 145.05 μmol) and acetone (42.12 mg, 725.25 μmol, 53.32 μL) were added to methanol (2 mL) and stirred at 15° C. for 30 min, then sodium cyanoborohydride (18.23 mg, 290.11 μmol) was added and stirred at 15° C. for 1 h. LCMS showed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and the resulting crude product was purified by preparative chromatography (column: Waters Xbridge C18 150×25 mm×5 μm; mobile phase: 10 mM ammonium bicarbonate solution was mobile phase A, acetonitrile was mobile phase B, B%: 22%-52%, gradient time: 9 min) to obtain compound 9. 1 H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 5.28 (br t, J = 8.6 Hz, 1H), 4.08 (quin, J = 7.7 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.74 (br dd, J = 3.8, 12.3 Hz, 2H), 3.67 (t, J = 8.4 Hz, 2H), 3.46 (t, J = 8.2 Hz, 2H), 3.03 (br t, J = 11.7 Hz, 2H), 2.79 - 2.70 (m, 2H), 2.67 - 2.58 (m, 2H), 2.55 - 2.43 (m, 2H), 2.24 - 2.03 (m, 4H), 1.94 - 1.84 (m, 2H), 1.79 - 1.72 (m, 1H), 1.62 - 1.49 (m, 2H), 1.18 (s, 3H), 0.97 (d, J = 6.2 Hz, 6H);LCMS (ESI): m / z: 507.4 (M+1).

[0210] Example 10: Compound 10

[0211] [ka]

[0212] [ka]

[0213] Synthesis of compound 10: Compound 7 (90 mg, 145.05 μmol) and formaldehyde (75.67 mg, 932.49 μmol, 69.42 μL, 37% purity) were added to methanol (2 mL) and stirred at 15 °C for 30 min, then sodium cyanoborohydride (23.44 mg, 372.99 μmol) was added and stirred at 15 °C for 1 h. LCMS showed the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and the resulting crude product was purified by preparative chromatography (column: Waters Xbridge C18 150 × 30 mm × 5 μm; mobile phase: 10 mM ammonium bicarbonate solution was mobile phase A, acetonitrile was mobile phase B, B%: 16% to 46%, gradient time: 11.5 min) to give compound 10. 1 H NMR (400 MHz, CD3OD): δ 7.99 (s, 1H), 5.28 (br t, J = 8.4 Hz, 1H), 4.36 - 4.28 (m, 1H), 4.20 (t, J = 9.4 Hz, 2H), 4.03 (dd, J = 6.5, 10.5 Hz, 2H), 3.97 - 3.90 (m, 1H), 3.80 - 3.74 (m, 2H), 3.11 - 3.03 (m, 2H), 2.78 - 2.70 (m, 5H), 2.66 - 2.60 (m, 2H), 2.53 - 2.42 (m, 1H), 2.24 - 2.04 (m, 4H), 1.95 - 1.85 (m, 2H), 1.79 - 1.72 (m, 1H), 1.63 - 1.52 (m, 2H), 1.18 (s, 3H); LCMS (ESI): m / z: 479.3 (M+1).

[0214] Example 11: Compound 11, Compound 11A and Compound 11B

[0215] [ka]

[0216] [ka]

[0217] Synthesis of compound 11-b: Compound 11-a (4.2 g, 43.67 mmol) was added to dichloromethane (150 mL) and cooled to 0° C., and then m-chloroperoxybenzoic acid (13.30 g, 65.51 mmol, 85% purity) was added slowly in batches, and the reaction solution was reacted at 15° C. for 16 hours. The mixture was filtered, and the filtrate was quenched with saturated sodium sulfite solution (50 mL). The layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL×2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure at 15° C. or less to obtain compound 11-b. 1 H NMR (400 MHz, CDCl3): δ 2.07 - 1.32 (m, 9H), 0.98 (t, J = 7.5 Hz, 3H).

[0218] Synthesis of compound 11-c: Compound 11-b (5.1 g, 45.47 mmol) was added to water (50 mL), and benzylamine (4.38 g, 40.92 mmol, 4.46 mL) was added, and the reaction solution was stirred at 100 °C for 16 h. LCMS showed that the reaction was complete. The reaction solution was cooled with ice water, adjusted to pH = 1 with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL x 2). The aqueous phase was adjusted to pH = 10 with 5 M sodium hydroxide. Extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 11-c. 1H NMR (400 MHz, CDCl3): δ 7.19 - 7.15 (m, 1H), 7.30 - 7.11 (m, 4H), 3.83 - 3.62 (m, 2H), 2.81 (t, J = 6.6 Hz, 1H), 1.79 - 1.43 (m, 8H), 0.93 - 0.86 (m, 3H); LCMS (ESI): m / z: 220.2 (M+1).

[0219] Synthesis of compound 11-d: Compound 11-c (2.6 g, 11.85 mmol) was added to isopropanol (30 mL), and wet palladium hydroxide / carbon (0.5 g, 50%) was added under the protection of nitrogen gas. The reaction system was then purged with hydrogen gas several times, and the reaction solution was stirred at 25° C. under hydrogen gas (50 psi) for 16 hours. TLC (dichloromethane:methanol=10:1) showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain compound 11-d. 1 H NMR (400 MHz, CDCl3): δ 3.10 (dd, J = 5.2, 6.3 Hz, 1H), 2.17 (ddd, J = 2.6, 6.6, 13.1 Hz, 1H), 1.79 - 1.72 (m, 3H), 1.61 - 1.50 (m, 3H), 1.41 - 1.30 (m, 1H), 1.03 - 0.99 (m, 3H).

[0220] Synthesis of compound 11-f: Compound 11-e (2.3 g, 12.06 mmol) and compound 12-d (1.56 g, 12.06 mmol) were added to acetonitrile (30 mL), followed by triethylamine (1.83 g, 18.10 mmol, 2.52 mL), and the reaction solution was stirred at 80° C. for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to 25° C. and concentrated under reduced pressure to remove acetonitrile, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain compound 11-f. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 4.53 (t, J = 6.7 Hz, 1H), 4.49 (s, 2H), 2.53 (s, 3H), 2.37 - 2.27 (m, 1H), 1.87 - 1.49 (m, 8H), 0.96 (t, J = 7.4 Hz, 3H); LCMS (ESI): m / z: 284.2 (M+1).

[0221] Synthesis of compound 11-g: Compound 11-f (2.38 g, 8.40 mmol) was added to ethyl acetate (40 mL), followed by manganese dioxide (7.30 g, 83.98 mmol), and the mixture was reacted at 60° C. for 2 h. TLC (petroleum ether / ethyl acetate=1 / 1) showed that the reaction was complete. The reaction solution was cooled to 25° C., filtered, the cake was washed with methanol (20 mL×3), and the filtrate was evaporated to dryness to obtain compound 11-g. 1 H NMR (400 MHz, CDCl3): δ 9.73 (s, 1H), 8.66 (br d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 4.47 (td, J = 7.6, 8.7 Hz, 1H), 2.58 (s, 3H), 2.34 - 2.26 (m, 1H), 1.95 - 1.70 (m, 5H), 1.66 - 1.60 (m, 1H), 1.41 (q, J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H).

[0222] Synthesis of compound 11-i: Compound 11-g (2.3 g, 8.17 mmol) was added to dichloromethane (50 mL), followed by compound 11-h (2.99 g, 8.58 mmol), and the reaction solution was stirred at 20° C. for 2 h. TLC (petroleum ether / ethyl acetate=5 / 1) showed that the reaction was complete and a new compound was formed. The reaction solution was evaporated to dryness under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain compound 11-i. 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.42 (d, J = 15.8 Hz, 1H), 6.22 (d, J = 15.8 Hz, 1H), 4.95 (br d, J = 5.5 Hz, 1H), 4.29 (ddd, J = 6.0, 7.8, 10.5 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 2.22 - 2.10 (m, 1H), 1.84 - 1.71 (m, 3H), 1.70 - 1.59 (m, 1H), 1.53 - 1.42 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0223] Synthesis of compound 11-j: Compound 11-i (2.7 g, 7.68 mmol) was added to 2-methyltetrahydrofuran (50 mL), followed by the addition of Rh(PPh3)3Cl (710.77 mg, 768.22 μmol). The reaction solution was purged with hydrogen gas several times, and then stirred at 80° C. for 20 hours under hydrogen gas (15 Psi) protection. TLC (petroleum ether / ethyl acetate=3 / 1) showed that the reaction was complete and a new compound was produced. The reaction solution was evaporated to dryness under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound 11-j. 1 H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 5.66 (br d, J = 5.3 Hz, 1H), 4.21 (ddd, J = 5.8, 7.9, 10.4 Hz, 1H), 4.10 - 4.04 (m, 3H), 2.64 - 2.60 (m, 2H), 2.53 - 2.48 (m, 2H), 2.42 (s, 3H), 2.14 - 2.07 (m, 1H), 1.84 - 1.71 (m, 3H), 1.62 - 1.48 (m, 3H), 1.20 - 1.18 (m, 3H), 0.88 - 0.85 (m, 3H).

[0224] Synthesis of compound 11-k: Compound 11-j (600 mg, 1.70 mmol) was added to N-methylpyrrolidone (10 mL), followed by DBU (516.82 mg, 3.39 mmol, 511.70 μL), and the reaction solution was stirred at 80 °C for 16 h. LCMS showed that the reaction was complete. The reaction solution was cooled to 25 °C, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), the combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 11-k. 1 H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 4.96 (br t, J = 8.9 Hz, 1H), 2.77 - 2.71 (m, 2H), 2.64 - 2.60 (m, 2H), 2.48 (s, 3H), 1.96 - 1.73 (m, 6H), 1.48 - 1.41 (m, 1H), 1.22 - 1.18 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H); LCMS (ESI): m / z: 308.1 (M+1).

[0225] Synthesis of compound 11-l: Compound 11-k (200 mg, 650.60 μmol) was added to 2-methyltetrahydrofuran (5 mL) and water (1 mL), followed by potassium hydrogen persulfate (999.91 mg, 1.63 mmol), and the reaction solution was stirred at 25° C. for 2 hours. LCMS showed the reaction was complete. The reaction solution was quenched with saturated sodium sulfite solution (20 mL), extracted with ethyl acetate (20 mL×3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give compound 11-l. 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 5.11 (br t, J = 7.4 Hz, 1H), 3.33 (s, 3H), 3.06 - 2.99 (m, 2H), 2.87 - 2.78 (m, 2H), 2.05 - 1.81 (m, 6H), 1.30 - 1.23 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); LCMS (ESI): m / z: 322.1 (M+1-18).

[0226] Synthesis of compound 11: Compound 11-l (390 mg, 1.15 mmol) and compound 1-k (1.23 g, 5.75 mmol, hydrochloride salt) were added to N-methylpyrrolidone (10 mL), followed by diisopropylethylamine (1.04 g, 8.04 mmol, 1.40 mL), and the reaction solution was stirred at 140° C. for 16 h. LCMS showed the reaction was complete. The reaction solution was cooled to 20°C, water (10mL) was added, and extracted with ethyl acetate (15mL x 3). The combined organic phase was washed with saturated saline (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The obtained crude product was purified by preparative chromatography (column: Waters Xbridge C18 150 x 50mm x 10μm; mobile phase: 0.05% aqueous ammonia was mobile phase A, acetonitrile was mobile phase B, B%: 18%~48%, gradient time: 11.5min) to obtain compound 11. 1H NMR (400 MHz, CD3OD): δ 7.99 (s, 1H), 5.31 (br t, J = 8.4 Hz, 1H), 3.96 - 3.86 (m, 1H), 3.72 (br dd, J = 3.4, 11.9 Hz, 2H), 2.97 (dt, J = 2.3, 11.6 Hz, 2H), 2.88 (s, 3H), 2.77 - 2.70 (m, 2H), 2.65 - 2.59 (m, 2H), 2.49 - 2.38 (m, 1H), 2.15 - 2.05 (m, 5H), 1.96 - 1.85 (m, 2H), 1.77 (dd, J = 6.1, LCMS (ESI): m / z: 438.3 (M+1).

[0227] compound 11 Compound 11 was subjected to chiral separation by SFC to give 11A and 11B. Compound 11 was purified by SFC (column: polyoxymethylene-coated chiral stationary phase (250 mm × 30 mm × 10 μm); mobile phase: 65% [0.1% ammonia in ethanol]; to give compound 11A (retention time 0.479 min) and compound 11B (retention time 1.516 min).

[0228] Compound 11A: 1H NMR (400 MHz, CD3OD): δ 7.87 (s, 1H), 5.19 (br t, J = 8.4 Hz, 1H), 3.84 - 3.76 (m, 1H), 3.60 (br dd, J = 3.5, 11.9 Hz, 2H), 2.85 (dt, J = 2.4, 11.6 Hz, 2H), 2.76 (s, 3H), 2.64 - 2.57 (m, 2H), 2.52 - 2.46 (m, 2H), 2.37 - 2.26 (m, 1H), 2.05 - 1.95 (m, 4H), 1.86 - 1.73 (m, 2H), 1.65 (dd, J = 6.0, 12.1 Hz, 1H), 1.55 - 1.45 (m, 2H), 1.40 - 1.30 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H); LCMS (ESI): m / z: 438.3 (M+1).

[0229] Compound 11B: 1 H NMR (400 MHz, CD3OD): δ 7.87 (s, 1H), 5.19 (br t, J = 8.4 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.64 - 3.56 (m, 2H), 2.85 (dt, J = 2.5, 11.6 Hz, 2H), 2.76 (s, 3H), 2.66 - 2.56 (m, 2H), 2.53 - 2.46 (m, 2H), 2.38 - 2.26 (m, 1H), 2.06 - 1.93 (m, 4H), 1.86 - 1.72 (m, 2H), 1.65 (dd, J = 6.2, 11.9 Hz, 1H), 1.57 - 1.44 (m, 2H), 1.39 - 1.28 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H); LCMS (ESI): m / z: 438.3 (M+1).

[0230] Activity test Example 1: Enzyme activity test ■ CDK2 / CyclinA2 activity assay

[0231] Experimental materials: CDK2 / CyclinA2 kinase detection kit was purchased from Promega. Nivo multilabel analyzer (PerkinElmer).

[0232] Experimental method: Enzyme, substrate, adenosine triphosphate and inhibitor were diluted with the kinase buffer of the kit. Test compounds were diluted 5-fold with 8 concentrations by pipette, i.e., diluted from 50μM to 0.65nM, and the concentration of DMSO was 5%, and two wells were set up under the same conditions. 1μL of each concentration gradient of inhibitor, 2μL of CDK2 / CyclinA2 enzyme (1.6ng), 2μL of mixture of substrate and ATP (50μM adenosine triphosphate, 0.1μg / μL substrate) were added to the microplate, and the final concentration gradient of the compound was diluted from 10μM to 0.13nM. The reaction system was placed at 25℃ and reacted for 60 minutes. After the reaction was completed, 5 μL of ADP-Glo ​​reagent was added to each well and the reaction was continued at 25 °C for 40 min. After the reaction was completed, 10 μL of kinase detection reagent was added to each well and the reaction was continued at 25 °C for 30 min. The chemiluminescence was then read using a multi-label analyzer, and the integration time was 0.5 s.

[0233] ■ CDK2 / CyclinE1 kinase activity test Experimental materials: CDK2 / CyclinE1 kinase detection kit was purchased from Promega. Nivo multilabel analyzer (PerkinElmer).

[0234] Experimental method: Enzyme, substrate, adenosine triphosphate and inhibitor were diluted with the kinase buffer of the kit. Test compounds were diluted 5-fold with 8 concentrations by pipette, i.e., diluted from 50μM to 0.65nM, and DMSO concentration was 5%, and two wells were set up under the same conditions. 1μL of each concentration gradient of inhibitor, 2μL of CDK2 / CyclinE1 enzyme (2ng), 2μL of mixture of substrate and ATP (150μM adenosine triphosphate, 0.1μg / μL substrate) were added to the microplate, and the final concentration gradient of the compound was diluted from 10μM to 0.13nM. The reaction system was placed at 25℃ and reacted for 60 minutes. After the reaction was completed, 5 μL of ADP-Glo ​​reagent was added to each well and the reaction was continued at 25 °C for 40 min. After the reaction was completed, 10 μL of kinase detection reagent was added to each well and the reaction was continued at 25 °C for 30 min. The chemiluminescence was then read using a multi-label analyzer, and the integration time was 0.5 s.

[0235] ■ CDK4 / CyclinD1 kinase activity test Experimental materials: CDK4 / CyclinD1 kinase was purchased from Invitrogen, and the reaction substrate LANCE Ultra ULight TM -4E-BP-1 (Thr37146) Peptide and EU-ANTI-P-4EBP1 (THR37 / 46) were purchased from PerkinElmer. Nivo Multilabel Analyzer (PerkinElmer).

[0236] Experimental method: Preparation of kinase buffer: The buffer components are: 50 mM hydroxyethylpiperazineethanethiosulfonic acid solution at pH 7.5, 1 mM ethylenediaminetetraacetic acid, 10 mM magnesium chloride, 0.01% lauryl ethoxylate (Brij-35), 2 mM enzyme dithiothreitol, kinase buffer dilution enzyme, substrate LANCE Ultra ULight TM-4E-BP-1 (Thr37146) Peptide, adenosine triphosphate and inhibitors. The test compounds were diluted 5-fold with a pipette at 8 concentrations, i.e., 40μM to 0.512nM, and the DMSO concentration was 4%, and two wells were set up under the same conditions. 2.5μL of each concentration gradient of inhibitors and 5μL of CDK4 / CyclinD1 enzyme (0.5ng) were added to the microplate, placed at 25℃, and reacted for 60 minutes, and then 2.5μL of a mixture of substrate and ATP (350μM adenosine triphosphate, 12.5nM substrate) was added, and the final concentration gradient of the compounds was diluted from 10μM to 0.128nM. The reaction system was placed at 25℃ and reacted for 120 minutes. After the reaction was completed, 5μL of EDTA and 2XLANCE were added to each well. TM A detection buffer (1:1) mixture was added and reacted at 25°C for 5 minutes. After the reaction was completed, 5 μL of LANCE Ultra Eu-anti-P-4E-BP1 (Thr37MS) (4 nM) was added to each well and reacted at 25°C for 60 minutes. The reaction signal was then detected using a Nivo device according to the principle of time-resolved fluorescence resonance energy transfer.

[0237] ■ CDK6 / CyclinD1 kinase activity test Experimental materials: CDK6 / CyclinD1 kinase was purchased from Carna. Reaction substrate LANCE Ultra ULight TM -4E-BP-1 (Thr37146) Peptide and EU-ANTI-P-4EBP1 (THR37 / 46) were purchased from PerkinElmer. Nivo Multilabel Analyzer (PerkinElmer).

[0238] Experimental method: Preparation of kinase buffer: The buffer components are: 50 mM hydroxyethylpiperazineethanethiosulfonic acid solution at pH 7.5, 1 mM ethylenediaminetetraacetic acid, 10 mM magnesium chloride, 0.01% lauryl ethoxylate (Brij-35), 2 mM enzyme dithiothreitol, kinase buffer dilution enzyme, substrate LANCE Ultra ULight TM-4E-BP-1 (Thr37146) Peptide, adenosine triphosphate and inhibitors. The test compounds were diluted 5-fold with a pipette at 8 concentrations, i.e., 40μM to 0.512nM, and the DMSO concentration was 4%, and two wells were set up under the same conditions. 2.5μL of each concentration gradient of inhibitors and 5μL of CDK6 / CyclinD1 enzyme (0.5ng) were added to the microplate, placed at 25℃, and reacted for 60 minutes, and then 2.5μL of a mixture of substrate and ATP (250μM adenosine triphosphate, 12.5nM substrate) was added, and the final concentration gradient of the compounds was diluted from 10μM to 0.128nM. The reaction system was placed at 25℃ and reacted for 120 minutes. After the reaction was completed, 5μL of EDTA and 2XLANCE were added to each well. TM A detection buffer (1:1) mixture was added and reacted at 25°C for 5 minutes. After the reaction was completed, 5 μL of LANCE Ultra Eu-anti-P-4E-BP1 (Thr37MS) (4 nM) was added to each well and reacted at 25°C for 60 minutes. The reaction signal was then detected using a Nivo device according to the principle of time-resolved fluorescence resonance energy transfer.

[0239] ■ CDK9 / CyclinT1 kinase activity test Materials: CDK9 / CyclinT1 kinase was purchased from Carna, ADP-Glo ​​detection kit was purchased from Promega, PKDTide substrate and kinase buffer were purchased from Signalchem. Nivo multilabel analyzer (PerkinElmer).

[0240] Experimental method: Enzyme, substrate, adenosine triphosphate and inhibitor were diluted with the kinase buffer of the kit. Test compounds were diluted 5-fold with 8 concentrations by pipette, i.e., diluted from 50μM to 0.65nM, and DMSO concentration was 5%, and two wells were set up under the same conditions. 1μL of each concentration gradient of inhibitor, 2μL of CDK9 / CyclinT1 enzyme (4ng), 2μL of mixture of substrate and ATP (100μM adenosine triphosphate, 0.2μg / μL substrate) were added to the microplate, and the final concentration gradient of compound was diluted from 10μM to 0.13nM. The reaction system was placed at 25℃ and reacted for 120 minutes. After the reaction was completed, 5 μL of ADP-Glo ​​reagent was added to each well and the reaction was continued at 25 °C for 40 min. After the reaction was completed, 10 μL of kinase detection reagent was added to each well and the reaction was continued at 25 °C for 30 min. The chemiluminescence was then read using a multi-label analyzer, and the integration time was 0.5 s.

[0241] Data Analysis: Converting the original data to percent inhibition using the formula (Sample-Min) / (Max-Min) × 100% gives the IC 50 The value can be determined by curve fitting using four parameters (log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the enzyme inhibitory activity of the compounds of the present invention against CDK2 / CyclinA2, CDK2 / CyclinE1, CDK4 / CyclinD1, CDK6 / CyclinD1, and CDK9 / CyclinT1.

[0242] [Table 1]

[0243] Experimental Conclusion: The compounds of the present invention have significant inhibitory activity against CDK2, CDK4 and CDK6 kinases, and have high selectivity against CDK9.

[0244] Experimental example 2: Cell experiment ■ HCT116 cell activity test Experimental materials: McCoy's 5a medium, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (chemiluminescent detection reagent for cell viability) reagent was purchased from Promega. HCT116 cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. Nivo multilabel analyzer (PerkinElmer).

[0245] Experimental method: HCT116 cells were seeded in a white 96-well plate, and each well contained 80 μL of cell suspension, where 1000 HCT116 cells were included. The cell plate was placed in a carbon dioxide incubator and cultured overnight. The test compounds were diluted 5-fold with nine concentrations by pipette, i.e., diluted from 2 μM to 5.12 nM, and two wells were set up under the same conditions. 78 μL of medium was added to the middle plate, and then 2 μL of gradient diluted compounds were transferred to the middle plate according to the corresponding position, and 20 μL of each well was transferred to the cell plate after uniform mixing. The range of compound concentrations transferred to the cell plate was 10 μM to 0.0256 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 4 days. Another cell plate was prepared, and the signal value was read as the maximum value on the day of drug addition (Max value in the formula below) and was included in the data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal, which was then read by a multi-label analyzer.

[0246] ■ HCC1806 cell activity test Experimental materials: RPMI-1640 medium, fetal bovine serum, penicillin / streptomycin antibiotics were purchased from Vicente. CyQUANT Cell Proliferation Assays reagents were purchased from ThermoFisher. HCC1806 cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. Nivo multi-label analyzer (PerkinElmer).

[0247] Experimental method: HCC1806 cells were seeded in a white 96-well plate, with 80 μL of cell suspension in each well, where 3000 HCC1806 cells were included. The cell plate was placed in a carbon dioxide incubator and cultured overnight. The test compounds were diluted 5-fold with a pipette in 9 concentrations, i.e., diluted from 10 μM to 25.6 nM, and 10 wells were set up under the same conditions. 78 μL of medium was added to the middle plate, and 2 μL of gradient diluted compounds were transferred to the middle plate according to the corresponding positions, and 20 μL of each well was transferred to the cell plate after uniform mixing. The range of compound concentrations transferred to the cell plate was 50 μM to 0.128 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 7 days. After the incubation time was reached, the cell supernatant was removed, and the cell plate was placed in a -80°C refrigerator for 1 hour, after which 100 μL of Cyquant reagent was added to each well and read by a multi-label analyzer. Another cell plate was prepared, and the signal value was read as the maximum value on the day of drug addition (Max value in the formula below), and was included in the data analysis.

[0248] ■ MDA-MB-468 cell activity test Experimental materials: L15 medium, fetal bovine serum, penicillin / streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (chemiluminescent detection reagent for cell viability) reagent was purchased from Promega. MDA-MB-468 cell line was purchased from Nanjing Cobioer Biosciences Co., Ltd. Nivo multi-label analyzer (PerkinElmer).

[0249] Experimental method: MDA-MB-468 cells were seeded in a white 96-well plate, and each well contained 80 μL of cell suspension, where 1000 MDA-MB-468 cells were included. The cell plate was placed in a carbon dioxide incubator and cultured overnight. The test compounds were diluted 5-fold with nine concentrations by pipette, i.e., diluted from 10 μM to 25.6 nM, and two wells were set up under the same conditions. 78 μL of medium was added to the middle plate, and 2 μL of gradient diluted compounds were transferred to the middle plate according to the corresponding position, and 20 μL of each well was transferred to the cell plate after uniform mixing. The range of compound concentrations transferred to the cell plate was 50 μM to 0.128 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 7 days. Another cell plate was prepared, and the signal value was read as the maximum value on the day of drug addition (Max value in the formula below) and was included in the data analysis. 25 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal, which was then read by a multi-label analyzer.

[0250] Data analysis: The raw data was converted to percent inhibition using the formula (Sample-Min) / (Max-Min) × 100%, yielding IC 50 The values ​​can be determined by curve fitting using four parameters (GraphPad Prism log(inhibitor) vs. response--Variable slope mode). Table 2 provides the inhibitory activity of the compounds of the present invention against cell proliferation.

[0251] [Table 2]

[0252] Experimental conclusion: The compounds of the present invention had significant inhibitory activity against the proliferation of HCT116 and HCC1806 cells, and had low activity against Rb-negative MDA-MB-468, with significantly better selectivity than PF-06873600.

[0253] Experimental Example 3: Pharmacokinetic evaluation of the compounds of the present invention Test animals Healthy adult female Balb / c mice used in this study were purchased from Shanghai Lingchang Biotechnology Co., Ltd.

[0254] Drug preparation Preparation of dosing solutions for intravenous injection group Accurately weigh 1.11 mg of the test compound, add 109.8 μL of DMSO and vortex for 1 minute, add 109.8 μL of solutol and vortex for 1 minute to obtain a clear solution, then add 878 μL of water and vortex for 1 minute to obtain a clear solution with a final concentration of 1 mg / mL, and the administration solvent was 10% DMSO + 10% solutol + 80% water. The solution for the intravenous administration group was filtered through a 2 μm filter before administration.

[0255] Preparation of dosing solution for oral administration group 1.61 mg of test compound was accurately weighed, added to 796 μL of 1% HPMC, sonicated at 45° C. for 20 min, and stirred for an additional 15 min to obtain a homogenous suspension with a final concentration of 2 mg / mL, and the dosing solvent was 1% HPMC.

[0256] Administration Four female Balb / c mice were divided into two groups, two per group: the first group received 2 mg / kg of the test compound by intravenous injection, and the second group received 10 mg / kg of the test compound by intragastric administration.

[0257] Sample collection Blood was collected from two animals at each time point using a continuous blood sampling method. Thirty microliters of whole blood was collected before administration and at 0.0833, 0.25, 0.5, 1, 2 (intragastric administration group only), 4, 6, 8 (intravenous administration group only), and 24 hours after administration. The whole blood was placed in anticoagulant tubes and centrifuged at 3200 g for 10 minutes at 4°C to prepare plasma, which was then stored at -80°C. The drug concentration in plasma was measured by LC / MS-MS.

[0258] [Table 3]

[0259] Experimental Conclusion: The compounds of the present invention have low clearance rates, high exposure, good oral bioavailability in mice, and have excellent overall pharmacokinetic properties.

Claims

1. A compound represented by formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (where: T is CH; R １ teeth, 【Chemistry 2】 where 【Chemistry 3】 is one, two or three R ａ is replaced by; Each R ａ are independently -OH or C １－３ is alkyl; R ２ and R ３ are each independently H or C １－３ is alkyl; R ４ and R ５ are each independently H; R ６ is H; R ７ is C １－３ Alkylamino, C １－６ Alkyl, C ３－５ cycloalkyl or 4- to 6-membered heterocycloalkyl, １－６ Alkyl, C ３－５ Cycloalkyl or 4- to 6-membered heterocycloalkyl may have one, two or three R ｄ optionally replaced by; Each R ｄ are independently H, C １－３ Alkoxy or C １－３ alkyl, wherein said C １－３ Alkoxy and C １－３ Alkyl is independently F, Cl, Br, -CN, -OH, and -NH ２ optionally substituted with 1, 2 or 3 substituents selected from n is 1; The 4-6 membered heterocycloalkyl contains 1 or 2 heteroatoms which are N.

2. Each R ａ are independently —OH, —CH ３ or -CH ２ CH ３ 2. The compound of claim 1, wherein:

3. R １ teeth, 【Chemistry 4】 where 【Chemistry 5】 is one or two R ａ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, substituted by:

4. R １ teeth, 【Chemistry 6】 or 【Chemistry 7】 4. The compound of claim 3, wherein:

5. R １ teeth, 【Chemistry 8】 or 【Chemistry 9】 5. The compound of claim 4, which is: or a pharma- ceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound has a structure represented by formula (I-1): or a pharma- ceutically acceptable salt thereof. 【Chemistry 10】 (Here, R ２ , R ３ , R ４ , R ５ , T., R. ６ , R ７ , R ａ and n is as defined in claim 1, and p is 2.

7. The compound of claim 6, wherein the compound has a structure represented by formula (I-2): or a pharma- ceutically acceptable salt thereof. 【Chemistry 11】 (Here, R ２ , R ３ , R ４ , R ５ , T., R. ６ , R ７ , R ａ and n is as defined in claim 6.

8. The compound according to claim 6, wherein the compound has a structure represented by the structural formula (I-3) or a pharma- ceutically acceptable salt thereof. 【Chemistry 12】 (Here, R ２ , R ３ , R ａ , T., R. ６ , R ７ and p are as defined in claim 6.

9. The compound according to claim 8, wherein the compound has a structure represented by the structural formula (I-8): or a pharma- ceutically acceptable salt thereof. 【Chemistry 13】 (Here, R ２ , R ３ , R ａ , T., R. ６ , and R ７ is as defined in claim 8.

10. R ２ and R ３ are each independently H, -CH ３ or -CH ２ CH ３ 10. The compound of claim 1, 6, 7, 8 or 9, which is: or a pharma- ceutically acceptable salt thereof.

11. Each R ｄ are independently H, -OCH ３ , -CH ３ , -CH ２ CH ３ or -CH(CH ３ ) ２ 2. The compound of claim 1, wherein:

12. The above R ７ is -NH(CH ３ ), -NH(CH ２ CH ３ ), -N(CH ３ ) ２ , -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , cyclopropyl, cyclopentyl, azetidinyl, pyrrolidinyl, or piperidinyl, wherein said -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , cyclopropyl, cyclopentyl, azetidinyl, pyrrolidinyl, or piperidinyl is one, two, or three R ｄ 12. The compound of claim 1, 6, 7, 8, 9 or 11, or a pharma- ceutically acceptable salt thereof, optionally substituted by:

13. R ７ は、-NH(CH ３ )、-NH(CH ２ CH ３ )、-N(CH ３ ) ２ 、-C(R ｄ ) ３ 、-CH ２ CH ２ Yes, 【Chemistry 14】 13. The compound of claim 12, wherein:

14. R ７ は、-NH(CH ３ ),-N(CH ３ ) ２ 、-CH ３ 、-CF ３ 、-CH ２ CH ３ ,-EH(EH ３ ) ２ 、-CH ２ CH ２ OCH ３ 、 【Chemistry 15】 14. The compound of claim 13, wherein:

15. The compound or a pharma- ceutically acceptable salt thereof: 【Chemistry 16】

16. The compound or a pharma- ceutically acceptable salt thereof: 【Chemistry 17】

17. 17. The compound or a pharma- ceutically acceptable salt thereof according to any one of claims 1, 15 and 16, wherein the pharma- ceutically acceptable salt is a hydrochloride salt.

18. 20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

19. Use of a compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for inhibiting CDK2 / 4 / 6.

20. Use of a compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for treating a solid tumor.

21. 21. The use according to claim 20, wherein the solid tumor is colorectal cancer or breast cancer.

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