Pyrazole derivative, pharmaceutical composition and application

Abstract

The invention relates to a pyrazole derivative, a pharmaceutical composition and application. The pyrazole derivative has a structure as shown in a formula (I). The pyrazole derivative has good activity inhibition selectivity on CDK2 (Cyclin-dependent K2). # imgabs0 #

Description

Pyrazole derivatives, pharmaceutical compositions and applications Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a pyrazole derivative, a pharmaceutical composition and an application thereof. Background Art

[0002] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family. They participate in physiological processes such as cell proliferation and transcription. CDKs can be divided into two major categories based on their functions: 1) CDKs involved in cell cycle regulation, primarily including CDK1, CDK2, CDK4, and CDK6; 2) CDKs involved in transcriptional regulation, primarily including CDK7, CDK8, CDK9, CDK12, and CDK13.

[0003] Dysregulated CDK2 activity frequently occurs in various human cancers, making it of particular interest to researchers. CDK2 plays a key role in promoting the G1 / S transition and S phase progression. CDK2 forms a complex with cyclin E, phosphorylating retinoblastoma family members (such as pRb), leading to the release and activation of E2F transcription factors, driving the transition from G1 to S phase of the cell cycle. This in turn activates CDK2 / cyclin A, promoting DNA synthesis and replication in the cell cycle.

[0004] Increased copy number and overexpression of Cyclin E1 have been identified in ovarian, gastric, endometrial, and breast cancers, among other cancers, and are positively correlated with poor prognosis in these tumors. In ER+ breast cancer cells, elevated expression of Cyclin E2 is often associated with resistance to hormone therapy (Mol. Cancer Ther., 2012, 11, 1488-1499), and amplification or overexpression of Cyclin E is closely associated with poor prognosis in breast cancer (N. Engl. J. Med, 2002, 347, 1566-1575). In HER2+ breast cancer, amplification of Cyclin E has also been reported to contribute to resistance to trastuzumab (Proc. Natl. Acad. Sci., 2011, 108, 3671-3676). There are also reports that overexpression of Cyclin E plays a key role in the progression of triple-negative breast cancer (Breast Care, 2011, 6, 273-278) and inflammatory breast cancer (Oncotarget, 2017, 8, 14897-14911). Therefore, CDK2 may become an important anti-tumor target.

[0005] Currently, there are a few small molecule inhibitors with CDK2 activity in clinical research, such as Pfizer's PF-3600, which has the structural formula: It can inhibit CDK2, CDK4, and CDK6, but it also has strong inhibitory activity against other CDK isoforms, which inevitably leads to some off-target side effects. In addition, to date, no CDK2 inhibitors have been approved, so there is an urgent need to develop novel, safe, and effective CDK2 inhibitors that can treat a variety of cancers, especially small molecule inhibitors that selectively target CDK2, which may have better safety.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a pyrazole derivative with good selectivity for inhibiting the activity of CDK2.

[0008] The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0009] in,

[0010] R1 is selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, nitro, isocyano, -(CH2) n R5;

[0011] R5 is selected from -CN, -OR6, -NR6R7, -C(O)OR6, -C(O)R6, -S(O)2R6, -P(O)(OR6)2, -O-alicyclic, -O-heteroalicyclic, -O-aryl, -O-heteroaryl or -C(O)-heteroaryl, wherein the alicyclic, alicyclic, aryl or heteroaryl is unsubstituted or substituted with one or more R0;

[0012] R0 is selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, cyano, amino, nitro or hydroxy;

[0013] R6 and R7 are each independently selected from H, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, aryl or heteroaryl;

[0014] n is 0, 1, 2, 3 or 4;

[0015] Ring A is selected from

[0016] X is each independently N or CR6;

[0017] R8 is selected from H, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl;

[0018] R2 and R3 are each independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl are unsubstituted or substituted with one or more R9;

[0019] R9 is selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano, amino, nitro or hydroxyl groups;

[0020] R4 is selected from H, halogen, amino, hydroxy or C1-C6 alkyl;

[0021] One or more hydrogen atoms in the structure represented by formula (I) are substituted by deuterium atoms or are not substituted;

[0022] The compound does not have the structure shown below:

[0023] In some embodiments, when the structure shown in formula (I), R1 is selected from -CH2-O-CH3, and ring A is selected from When R2 is selected from H, R3 is selected from -CH(CH3)2, and R4 is selected from H, one or more hydrogen atoms in the structure represented by formula (I) are replaced by deuterium atoms.

[0024] It is understood that when R1, Ring A, R2, R3 and R4 are selected from other groups in the structure represented by formula (I), one or more hydrogen atoms in the structure represented by formula (I) may be substituted by a deuterium atom or may not be substituted.

[0025] In some embodiments, the R1 is selected from -CH2R5, the R5 is selected from -OR 61 , -NR6R7, -CN, -C(O)OR6, -C(O)R6, -S(O)2R6, -P(O)(OR6)2, -O-alicyclic, -O-alicyclic, -O-heterocyclic, -O-aryl, -O-heteroaryl or -C(O)-heteroaryl, wherein the alicyclic, alicyclic, aryl and heteroaryl groups are unsubstituted or substituted with one or more R0;

[0026] The R 61 Selected from H, C in which one or more hydrogen atoms are replaced by deuterium atoms 1-6 Alkyl, halogenated C1-C6 alkyl, C3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, aryl or heteroaryl.

[0027] Further, the R1 is selected from -CH2R5, and the R5 is selected from -OR 61 , -NR6R7 or -CN.

[0028] In some preferred embodiments, the R1 is selected from -CH2R5, the R5 is selected from -OR 61 or-NR6R7;

[0029] The R 61 Selected from H, C in which one or more hydrogen atoms are replaced by deuterium atoms 1-6 Alkyl or halogenated C1-C6 alkyl;

[0030] Said R6 and R7 are each independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0031] More preferably, the R1 is -OH.

[0032] In some preferred embodiments, R2 is H, R3 is selected from C 1-6 Alkyl or halogenated C1-C6 alkyl.

[0033] More preferably, R3 is -C(CH3)3.

[0034] In some preferred embodiments, the R1 is selected from -(CH2) n R5, wherein one or more hydrogen atoms in R5 are replaced by deuterium atoms. Further preferably, R5 is selected from -OR6.

[0035] In some preferred embodiments, the structure represented by formula (I) is selected from the structure represented by any one of formulas (I-1) to (I-3):

[0036] Further preferably, the structure represented by formula (I) is selected from the structure represented by formula (I-4):

[0037] In some preferred embodiments, X is selected from CR6. Further preferably, R6 is selected from H, C 1-6 Alkyl, halogen or halogenated C 1-6 alkyl.

[0038] In some preferred embodiments, R1 is selected from H, halogen, C 3-7 Cycloalkyl, 3- to 7-membered heterocycloalkyl, nitro, isocyano, -(CH2) n R5;

[0039] More preferably, n is 1, and R1 is -CH2R5. In this case, the structure represented by formula (I) is selected from the structure represented by formula (I-5):

[0040] In some preferred embodiments, X is selected from CR6. Further preferably, R6 is selected from H, C 1-6 Alkyl, halogen or halogenated C 1-6 alkyl.

[0041] Further preferably, said R5 is selected from -CN, -OR6 or -NR6R7;

[0042] Said R6 and R7 are each independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0043] In some embodiments, R5 is selected from -CN, -OC 1-3 Alkyl, -N(H)C 1-3 Alkyl, -N(C 1-3 Alkyl)(C 1-3 alkyl).

[0044] In some preferred embodiments, R2 is selected from H, C1-C6 alkyl or halogenated C1-C6 alkyl;

[0045] R3 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl are unsubstituted or substituted with one or more R9.

[0046] Further preferably, said R2 is selected from H;

[0047] The R3 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, and 5-membered heterocycloalkyl which is unsubstituted or substituted with one R9.

[0048] Further preferably, said R9 is selected from halogen, C 1-6 Alkyl or halogenated C 1-6 Alkyl; the heteroatom of the 5-membered heterocycloalkyl is an oxygen atom.

[0049] More preferably, in the formula (I) Select one of the following structures:

[0050] In some preferred embodiments, R4 is selected from H, F or methyl. Further preferably, R4 is selected from H.

[0051] In some preferred embodiments, R0 is selected from C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, cyano, amino, nitro or hydroxy.

[0052] In some preferred embodiments, R8 is selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl.

[0053] In some embodiments, the compound includes but is not limited to the following structure:

[0054] In some embodiments, the pharmaceutically acceptable salt is an alkyl salt. Further, the pharmaceutically acceptable salt is a formate salt.

[0055] The second aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0056] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and the pharmaceutical composition described in the third aspect of the present invention in the preparation of a drug for treating or preventing diseases related to or mediated by CDK2 activity.

[0057] In certain embodiments, the disease associated with or mediated by CDK2 activity is cancer.

[0058] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one.

[0059] After extensive and intensive research, the inventors unexpectedly discovered a compound represented by Formula (I). This compound exhibits unexpected inhibitory activity against CDK2 and is useful for treating various cancers with high Cyclin E expression, particularly in patients with cancers resistant to CDK4 / 6 inhibitors. Based on this discovery, the inventors completed the present invention. DETAILED DESCRIPTION

[0060] Definition of terms

[0061] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0062] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0063] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0064] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0065] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

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

[0067] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0068] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

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

[0070] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0071] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer, or a mixture of the two isomers of the compound. For example, the following formula (A) represents that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as a mixture of the two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists as a single isomer of formula (B-1) or formula (B-2) or as a mixture of the two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as a mixture of the two isomers of formula (C-1) and formula (C-2).

[0072] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert into each other. For example, in the present invention, isomers. If tautomers are possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0073] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0074] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0075] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0076] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0077] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0078] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The type and number of substituents can be any chemically feasible basis. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0079] When any variable (e.g., R1) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 instances of R1, the group may optionally be substituted with up to two instances of R1, with each instance of R1 being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0080] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0081] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0082] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the substituent is listed without specifying which atom it is connected to the substituted group, the substituent can be bonded through any atom of the substituent. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0083] When the listed linking groups do not specify their linking direction, their linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0084] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0085] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "3-7 membered ring" refers to a "ring" having 3-7 atoms arranged around it.

[0086] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-4 Alkyl groups, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl, and sec-butyl).

[0087] Unless otherwise specified, the term “C 1-6 "Alkoxy" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy. C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0088] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino. C 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0089]

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

[0090] Unless otherwise specified, the terms "5-membered heteroaryl ring" and "5-membered heteroaryl" are used interchangeably in the present invention. The term "5-membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or carbon atom. Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2 (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).

[0091] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-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 range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0092] Unless otherwise specified, “C 3-7 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-7 Cycloalkyl groups include C 3-6 、C 4-6 、C 4-5 、C 5-7 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-7 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0093] Unless otherwise specified, the term "3-7 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 7 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). This includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the term "3-7 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The term "3-7 membered heterocycloalkyl" includes 5-7 membered, 3 membered, 4 membered, 5 membered, 6 membered and 7 membered heterocycloalkyls, etc. Examples of 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.

[0094] Unless otherwise specified, the term "3-7 membered nitrogen-containing heterocycloalkyl" refers to a 3-7 membered heterocycloalkyl group containing at least one nitrogen atom.

[0095] Alicyclic refers to a saturated or partially unsaturated all-carbon ring system. Wherein "partially unsaturated" refers to a ring portion that includes at least one double bond or triple bond. "Partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein. Non-limiting examples include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptatrienyl rings, cyclopentanone rings, cyclopentane-1,3-dione rings, and the like.

[0096] Alicyclic groups are saturated or partially unsaturated alicyclic groups in which one, two or three ring carbon atoms are selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2) is substituted by a heteroatom, excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Non-limiting examples include an oxetane ring, an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-one ring, an oxetane-2-one ring, a pyrrolidine-2-one ring, a pyrrolidine-2,5-dione ring, a piperidin-2-one ring, a dihydrofuran-2(3H)-one ring, a dihydrofuran-2,5-dione ring, a tetrahydro-2H-pyran-2-one ring, a piperazin-2-one ring, and a morpholine-3-one ring. Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetidine ring, 1,2-dihydrooxetadiene ring, 2,5-dihydro-1H-pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2,3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring. Cyclic, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine Ring, etc.

[0097] "Aryl" and "aromatic ring" are used interchangeably to refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, which may be fused to a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl ring. 6-10 The term "aryl" refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms. Non-limiting examples of aryl include phenyl, naphthyl, and the like.

[0098] "Heteroaryl" and "heteroaryl ring" are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present invention, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. The heteroaryl ring may be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. "8- to 10-membered heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, The term "heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.

[0099] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[0100] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0101] Unless otherwise defined, the "substituents independently selected from..." described in the present invention means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.

[0102] Generally, the compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer can be formed into a suitable dosage form for administration with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules and syrups. The compound of the present invention contained in these preparations can be a solid powder or granules; a solution or suspension in an aqueous or non-aqueous liquid; an oil-in-water or water-in-oil emulsion, etc. The above dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol and polyethylene glycol, etc. The active compound can form a solution or suspension with the above carriers.

[0103] The compositions of the present invention are formulated, dosed and administered in a manner consistent with standard medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0104] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0105] The therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer contained in the pharmaceutical composition or pharmaceutical use composition of the present invention is preferably 0.1 mg-5 g / kg (body weight).

[0106] "Patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0107] "Treatment" refers to alleviating, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0108] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0109] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0110] The solvent used in the present invention can be obtained commercially. The present invention uses the following abbreviations: Pd / C represents palladium on carbon; H2 represents hydrogen; N2 represents nitrogen; mL represents milliliter; MeNH2 represents dimethylamine; BBr3 represents boron tribromide.

[0111] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0112] The present invention is described in detail below through the examples, but it is not intended to limit the present invention in any way. The present invention has been described in detail herein, and its specific embodiments are disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0113] Compound 1

[0114] Step 1:

[0115] Dissolve compound 1-1 in tetrahydrofuran (2 mL) and replace the air with nitrogen three times. Cool the system to 0-10 ° C and slowly add diisobutylaluminum hydride (1M, 4.43 mL, 5.00 eq) under nitrogen. Monitor after reacting at 20-30 ° C for 3 hours. LCMS shows that compound 1-1 is completely consumed and a target product peak (m / z=183.9) is detected. Water (0.70 mL), 15% sodium hydroxide aqueous solution (0.70 mL) and water (2.00 mL) are added to the reaction solution under ice-water bath conditions. After stirring the reaction for 10 minutes, add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate to obtain the crude product compound 1-2. LCMS: m / z (M+H) + =183.9. 1 H NMR: (400MHz, DMSO-d6) δ 8.78 (d, J = 4.6 Hz, 1H), 7.72 (d, J = 4.8 Hz, 1H), 6.92 (s, 1H), 5.51 (t, J = 5.8 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H).

[0116] Step 2:

[0117] Compound 1-2 was dissolved in tetrahydrofuran (2.00 mL), the atmosphere was replaced with nitrogen three times, and the temperature was lowered to 0-10°C. Sodium hydride (28.3 mg, 708 μmol, 60% purity, 1.30 eq) was added to the reaction mixture under nitrogen. After 30 minutes of reaction, iodomethane (116 mg, 817 μmol, 50.9 μL, 1.50 eq) was added. The reaction was monitored at 10-20°C for 1 hour. LCMS showed complete consumption of compound 1-2, with a peak of the desired product (m / z = 198.5) detected. The reaction mixture was slowly poured into saturated ammonium chloride solution (3.00 mL) and extracted three times with ethyl acetate (3.00 mL x 3). The organic phases were combined, washed once with saturated brine (3.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified using preparative HPLC (preparative column: 3-Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 22%-52%, 7 mins). The pH of the preparative solution was adjusted to 7-8 using sodium carbonate, and the solution was extracted three times with ethyl acetate (10.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1-3. LCMS: m / z (M+H) + =198.5. 1 H NMR: (400MHz, DMSO-d6) δ 8.81 (dd, J = 4.71, 0.92Hz, 1H), 7.76 (d, J = 4.77Hz, 1H), 6.99 (s, 1H), 4.64 (s, 2H), 3.34 (s, 3H).

[0118] Step 3:

[0119] Under nitrogen, compound 1-4 (300 mg, 839 umol, 1.00 eq) and p-nitrobenzoyl chloride (219 mg, 1.09 mmol, 1.30 eq) were dissolved in dichloromethane (3.00 mL). The reaction system was cooled to 0°C, and pyridine (199 mg, 2.52 mmol, 203 uL, 3.00 eq) and 4-dimethylaminopyridine (10.3 mg, 83.9 umol, 0.10 eq) were added sequentially. After 2 hours of reaction, TLC (petroleum ether:ethyl acetate = 2:1) showed that compound 1-4 (Rf = 0.20) was completely consumed and a main spot (Rf = 0.70) was generated. The reaction solution was concentrated to obtain compound 1-6. LCMS: m / z (M+H) + =523.3.

[0120] Step 4:

[0121] Compound 1-6 (600 mg, 1.15 mmol, 1.00 eq) was dissolved in dichloromethane (6.00 mL), and N,N-diisopropylethylamine (594 mg, 4.59 mmol, 800 uL, 4.00 eq) and isopropylamine (204 mg, 3.44 mmol, 296 uL, 3.00 eq) were added sequentially. After reacting at 25°C for 1 hour, TLC (petroleum ether:ethyl acetate = 2:1) showed complete consumption of compound 1-6 (Rf = 0.70) and the formation of a major new spot (Rf = 0.30). The reaction solution was slowly poured into water (3.00 mL) and extracted twice with dichloromethane (3.00 mL x 2). The organic phases were combined, washed twice with saturated brine (3.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether:ethyl acetate = 100:1 to 2:1, product: Rf = 0.3) to give compound 1-7. LCMS: m / z (M+H) + =443.3.

[0122] Step 5:

[0123] Compound 1-7 (300 mg, 678 μmol, 1.00 eq) was dissolved in anhydrous tetrahydrofuran (3.00 mL), the air was replaced three times with nitrogen, and wet palladium carbon (30.0 mg, 50% purity) was added. The nitrogen was replaced three times with hydrogen (15 psi). The reaction was monitored after 2 hours at 25°C and hydrogen (15 psi). TLC (petroleum ether:ethyl acetate = 1:1) showed that compound 1-7 (Rf = 0.70) was completely consumed and a major new spot (Rf = 0.40) was generated. The reaction solution was filtered and the filtrate was concentrated to obtain compound 1-8. LCMS: m / z (M+H) + =309.3.

[0124] Step 6:

[0125] Compound 1-8 (312 mg, 1.01 mmol, 2.50 eq) and compound 1-3 (0.08 g, 404 umol, 1.00 eq) were dissolved in dioxane (2.00 mL). Tris(dibenzylideneacetone)dipalladium (37.1 mg, 40.5 umol, 0.10 eq), sodium carbonate (85.8 mg, 810 umol, 2.00 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (46.9 mg, 81.0 umol, 0.20 eq) were added sequentially. The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 50-60°C for 12 hours and monitored. LCMS showed complete consumption of compound 1-8, with a peak of the desired product (m / z = 470.3) detected. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether:ethyl acetate = 10:1 to 1:1) to give compound 1-9. LCMS: m / z (M+H) + =470.4.

[0126] Step 7:

[0127] Compound 1-9 (60.0 mg, 128 umol, 1.00 eq) was dissolved in anhydrous formic acid (3.00 mL). The reaction was carried out at 100 ° C for 16 hours and monitored. TLC (petroleum ether: ethyl acetate = 1:2) showed that compound 1-9 (Rf = 0.60) was completely consumed and a new spot (Rf = 0.10) was generated. The reaction solution was concentrated to remove formic acid, diluted with dichloromethane (10.0 mL), washed twice with saturated sodium bicarbonate aqueous solution and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (300-400 mesh silica gel, petroleum ether: ethyl acetate = 5:1 to 0:1, product: petroleum ether: ethyl acetate = 1:2, R f =0.10) to give compound 1. LCMS: m / z (M+H) + =414.3. 1 H NMR: (400MHz, CDCl3)δ7.86(m,1H)7.36-7.51(m,1H)6.71-6.87(m,1H)6.48-6.69(m,1H)5.09-5.29(m,1H)4.71(s,1H)4.65(s ,2H)3.66-3.90(m,1H)3.44(s,3H)3.13-3.28(m,1H)2.43-2.61(m,1H)2.11-2.22(m,1H)1.87-1.98(m,4H)1.09-1.16(m,6H).

[0128] Compound 2

[0129] Step 1:

[0130] At room temperature, compound 1-3 (5.00 g, 25.3 mmol, 100% purity, 1.00 eq) and potassium fluoride (7.35 g, 127 mmol, 2.96 mL, 5.00 eq) were dissolved in N,N-dimethylformamide (50.0 mL). The atmosphere was replaced with N₂ three times. The reaction was carried out at 140°C under N₂ conditions for 16 hours and monitored by LCMS. LCMS showed complete consumption of compound 1-3 and the formation of a product peak (m / z = 182.0 (M+H)⁺). Water (50.0 mL) was added to the reaction solution, and the product was extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, washed three times with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. Purification by column chromatography (SiO₂, petroleum ether:ethyl acetate = 5:1 to 2:1, product: Rf = 0.60) afforded compound 2-1. LCMS: m / z=181.9 (M+H) + .

[0131] Step 2:

[0132] At room temperature, compound 1-4 (8.00 g, 22.4 mmol, 1.00 eq) and imidazole (2.29 g, 33.6 mmol, 1.50 eq) were dissolved in N,N-dimethylformamide (80.0 mL), and dimethyl tert-butylsilyl chloride (5.06 g, 33.6 mmol, 4.11 mL, 1.50 eq) was added. After replacing the nitrogen atmosphere three times, the reaction was carried out at 20°C under nitrogen for 6 hours. LCMS showed complete consumption of compound 1-4 and a peak of the desired product (m / z = 472.1 (M+H)+) was detected. The reaction solution was slowly poured into water (80.0 mL) and extracted three times with ethyl acetate (80.0 mL*3). The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (50.0 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 2:1, product: Rf = 0.50) to give compound 2-2. LCMS: m / z = 472.3 (M+H) + .

[0133] Step 3:

[0134] At room temperature, tetrahydrofuran (100 mL) and ethyl acetate (100 mL) were added to a 500 ml three-necked flask. Under N2 protection, wet palladium carbon (1.89 g, 1.78 mmol, 1.91 mL, 10.0% purity) and compound 2-2 (9.50 g, 20.0 mmol, 99.5% purity, 1.00 eq) were added in sequence. The hydrogen atmosphere was replaced three times. Under hydrogen (15.0 Psi), the reaction was monitored at 20 ° C for 3 hours. LCMS showed that compound 2-2 was completely consumed and a target product peak (m / z = 338.0 (M+H) +) was detected. Filter and concentrate the filtrate to obtain compound 2-3. LCMS: m / z = 338.0 (M+H) + .

[0135] Step 4:

[0136] At room temperature, compound 2-3 (6.20 g, 18.4 mmol, 1.00 eq) was dissolved in tetrahydrofuran (100 mL), cooled to -20 ° C, and lithium bis(trimethylsilyl)amide, 1M n-hexane solution (1.00 M, 55.1 mL, 3.00 eq) was added under N2 protection. Stirring was continued at -20 ° C for 1 hour. Compound 2-1 (3.43 g, 17.8 mmol, 94.1% purity, 0.970 eq) was dissolved in tetrahydrofuran (20.0 mL) and added. The air was replaced with N2 three times. Under N2 conditions, the reaction was monitored at -20 ° C for 1 hour. LCMS showed that compound 3 was completely consumed and a target product peak was detected (m / z = 499.2 (M+H) + ). The reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (300 mL) and extracted three times with ethyl acetate (120 mL * 3). The organic phases were combined, washed twice with a saturated aqueous sodium chloride solution (120 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5:1 to 1:1, product: Rf = 0.50) to obtain compound 2-4. LCMS: m / z = 499.2 (M + H) +1H NMR: (400MHz, DMSO-d6) δ9.00(s,1H),8.04(d,J=4.4Hz,1H),7.30(d,J=4.4Hz,1H ),6.85-6.77(m,1H),6.01(s,1H),4.56(s,2H),4.37-4.25(m,1H),3.33-3.31(m,3 H),3.04-2.91(m,1H),2.31-2.21(m,1H),1.96-1.86(m,1H),1.85-1.72(m,2H),1 .65-1.59(m,1H),1.57-1.52(m,1H),1.49(s,9H),0.83(s,9H),0.05-0.02(m,6H).

[0137] Step 5:

[0138] At room temperature, compound 2-4 (9.00 g, 16.4 mmol, 91.0% purity, 1.00 eq) was dissolved in formic acid (200 g, 4.34 mol, 164 mL, 264 eq). The air was replaced with N2 three times, and the mixture was stirred at 20 ° C for 2 hours. The mixture was concentrated to remove most of the formic acid, and methanol (160 mL) and water (40.0 mL) were added to the residue and stirred to dissolve it. Lithium hydroxide monohydrate (6.89 g, 164 mmol, 10.0 eq) was added under N2 protection. The air was replaced with N2 three times, and the reaction was monitored after 1 hour at 20 ° C. LCMS showed that compound 2-4 was completely consumed, and a target product peak was detected (m / z = 385.1 (M+H) + The reaction solution was slowly poured into water (450 mL) and extracted three times with ethyl acetate (160 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Compound 2-5 was obtained by column chromatography purification (SiO2, petroleum ether: ethyl acetate = 50:1 to 0:1, product: Rf = 0.50). LCMS: m / z = 385.1 (M+H) + .

[0139] Step 6:

[0140] At room temperature, compound 2-5 (101 mg, 260 μmol, 98.8% purity, 1.00 eq) was dissolved in 2-methyltetrahydrofuran (1.00 mL), and 1,1-carbonyldiimidazole (127 mg, 780 μmol, 3.00 eq) and 4-dimethylaminopyridine (6.36 mg, 52.0 μmol, 0.200 eq) were added sequentially. The air was replaced with N2 three times, and the mixture was stirred at 20°C for 1 hour. Compound 2-6 (237 mg, 2.34 mmol, 9.00 eq) and triethylamine (263 mg, 2.60 mmol, 362 μL, 10.0 eq) were added sequentially. The air was replaced with N2 three times, and the mixture was stirred at 20°C for 24 hours. LCMS showed that compound 2-5 was completely consumed and a peak of the target product (m / z = 512.1 (M+H)) was detected. + The reaction solution was slowly poured into water (5.00 mL) and extracted three times with ethyl acetate (10.0 mL*3). The organic phases were combined, washed once with saturated sodium chloride aqueous solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 2-7. LCMS: m / z = 512.1 (M+H) + .

[0141] Step 7:

[0142] Compound 2-7 (159 mg, 311 μmol, 1.00 eq) was dissolved in formic acid (3.55 g, 77.1 mmol, 2.91 mL, 248 eq) at room temperature. The atmosphere was replaced with N₂ three times. The reaction was carried out at 80°C under N₂ conditions for 1 hour and monitored by LCMS. LCMS showed complete consumption of compound 2-7, with a peak of the desired product (m / z = 456.1 (M+H)⁺) detected. The mixture was concentrated to remove most of the formic acid. Dichloromethane (10.0 mL) was added to the residue to dissolve it completely. The mixture was then extracted three times with saturated aqueous sodium bicarbonate (20.0 mL x 3) and saturated aqueous sodium chloride (20.0 mL x 3), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 9%-39%, 10 min) and lyophilized to obtain compound 2. LCMS: m / z = 456.1 (M+H) + . 1H NMR: (400MHz, MeOD) δ7.93(d,J=4.4Hz,1H),7.39(s,1H),7.07(s,1H),6.30(s,1H),5.09(s,1H),4.64(s,2H),3.98-3.91(m,1H),3.90-3 .82(m,2H),3.57(d,J=8.8Hz,1H),3.43(s,3H),3.24-3.12(m,1H),2.61-2.50(m,1H),2.27-2.08(m,2H),2.01-1.81(m,5H),1.42(s,3H).

[0143] Compound 3

[0144] Step 1:

[0145] Compound 2-5 (101 mg, 260 μmol, 98.8% purity, 1.00 eq) was dissolved in 2-methyltetrahydrofuran (1.00 mL) at room temperature. 1,1-Carbonyldiimidazole (127 mg, 780 μmol, 3.00 eq) and 4-dimethylaminopyridine (6.36 mg, 52.0 μmol, 0.200 eq) were added sequentially. The air was replaced with N₂ three times and the reaction was carried out at 20°C under N₂ conditions for 1 hour. Triethylamine (79.0 mg, 780 μmol, 109 μL, 3.00 eq), N,N-dimethylformamide (1.00 mL), and compound 3-1 (193 mg, 1.56 mmol, 6.00 eq) were then added sequentially. The air was replaced with N2 three times. The reaction was carried out at 80°C under N2 for 16 hours. TLC (petroleum ether:ethyl acetate = 0:1) showed complete consumption of compound 2-5 (Rf = 0.50) and the formation of a main spot (Rf = 0.70). The reaction solution was poured into water (6.00 mL) and extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-2.

[0146] Step 2:

[0147] At room temperature, compound 3-2 (180 mg, 362 μmol, 1.00 eq) was dissolved in formic acid (4.13 g, 89.7 mmol, 3.38 mL, 248 eq). The air was replaced with N2 three times. The reaction was carried out at 80°C under N2 conditions for 1 hour. LCMS showed that compound 9 was completely consumed and a peak of the target product (m / z = 442.1 (M+H)) was detected. +The mixture was concentrated to remove most of the formic acid, and dichloromethane (10.0 mL) was added to the residue to dissolve it completely. The mixture was then extracted three times with a saturated aqueous sodium bicarbonate solution (20.0 mL*3) and a saturated aqueous sodium chloride solution (20.0 mL*3), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified and lyophilized using HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 6%-36%, 10 min) to obtain compound 3. LCMS: m / z = 442.2 (M+H) + . 1 H NMR: (400MHz, DMSO) δ12.26-12.03(m,1H),10.07-9.89(m,1H),8.01(d,J=4.8Hz ,1H),7.41-7.32(m,2H),7.27(s,1H),6.70-6.46(m,1H),5.12-4.96(m,1H),4.5 6(s,2H),4.10-3.95(m,1H),3.73(dd,J=6.0,8.8Hz,2H),3.64(d,J=7.2Hz,1H), 3.42(dd,J=4.0,8.4Hz,1H),3.32(s,3H),3.19-3.02(m,1H),2.12-1.60(m,8H).

[0148] Compound 4

[0149] Step 1:

[0150] At room temperature, compound 2-5 (170 mg, 437 μmol, 98.8% purity, 1.00 eq) was dissolved in dichloromethane (2.00 mL) and cooled to 0°C. Pyridine (104 mg, 1.31 mmol, 106 μL, 3.00 eq), 4-dimethylaminopyridine (5.34 mg, 43.7 μmol, 0.100 eq), and 4-nitrophenol chloroformate (114 mg, 568 μmol, 1.30 eq) were added sequentially. The air was replaced with N2 three times, and the reaction was carried out at 20°C under N2 conditions for 0.5 hours. Compound 4-1 (639 mg, 8.74 mmol, 918 μL, 20.0 eq) was then added, and the air was replaced with N2 three times. The reaction was carried out at 20°C under N2 conditions for 2 hours. LCMS showed that compound 5 still remained (m / z = 385.0 (M+H) + ), and there is a product peak (m / z=484.2(M+H) +) was generated. The reaction solution was poured into water (5.00 mL) and extracted three times with ethyl acetate (10.0 mL*3). The organic phases were combined, washed once with saturated sodium chloride aqueous solution (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purification by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 1:1, product: Rf = 0.50) gave compound 4-2. LCMS: m / z = 484.2 (M+H) + .

[0151] Step 2:

[0152] At room temperature, compound 4-2 (180 mg, 372 μmol, 100% purity, 1.00 eq) was dissolved in formic acid (4.20 g, 91.2 mmol, 3.44 mL, 245 eq). The air was replaced with N2 three times. The reaction was carried out at 80°C under N2 conditions for 1 hour. LCMS showed that compound 4-2 was completely consumed and a peak of the target product (m / z = 428.0 (M+H)) was detected. + The mixture was concentrated to remove most of the formic acid, and dichloromethane (10.0 mL) was added to the residue to dissolve it completely. The mixture was then extracted three times with a saturated aqueous sodium bicarbonate solution (20.0 mL*3) and a saturated aqueous sodium chloride solution (20.0 mL*3), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, compound 4-3. LCMS: m / z = 428.0 (M+H) + .

[0153] Step 3:

[0154] At room temperature, compound 4-3 (100 mg, 234 μmol, 1.00 eq) was dissolved in dichloromethane (1 mL), cooled to -78°C, and BBr3 (117 mg, 468 μmol, 45.1 μL, 2.00 eq) was added dropwise. The air was replaced with N2 three times, and the reaction was carried out at 0°C for 1 hour under N2 conditions. LCMS showed that compound 4-3 still remained (m / z = 428.1 (M+H) + ), there is a target product peak (m / z=414.1(M+H) +). The reaction solution was poured into 0-5°C ice water (15.0 mL), adjusted to pH 6-8 with saturated sodium bicarbonate aqueous solution, and extracted three times with dichloromethane (20.0 mL*3). The organic phases were combined, washed twice with saturated sodium chloride aqueous solution (30.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified and lyophilized using HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 10%-40%, 10 min) to obtain compound 4. LCMS: m / z=414.1 (M+H) + . 1 H NMR: (400MHz, MeOD) δ7.95(d,J=4.8Hz,1H),7.39(d,J=4.8Hz,1H),7.13(s,1H),6.29(s,1H),5.07(d,J=3.2H z,1H),4.80(s,2H),3.26-3.12(m,1H),2.64-2.50(m,1H),2.22-2.08(m,1H),2.06-1.76(m,5H),1.29(s,9H).

[0155] Compound 5

[0156] Step 1:

[0157] At room temperature, compound 1 (700 mg, 1.69 mmol, 1.00 eq) was dissolved in dichloromethane (7 mL), cooled to -70°C, and boron tribromide (5.20 g, 20.8 mmol, 2.00 mL, 12.3 eq) was added dropwise. The air was replaced with N2 three times, and the reaction was carried out at -70 to -50°C under N2 conditions for 1 hour. LCMS showed that compound 1 was completely consumed, and the target product peak (m / z = 463.9 (M+H) + The reaction solution was poured into 0-5°C ice water (50.0 mL), the pH was adjusted to 6-8 with saturated sodium bicarbonate aqueous solution, and extracted three times with dichloromethane (50.0 mL*3). The organic phases were combined, washed twice with saturated sodium chloride aqueous solution (50.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5-1. LCMS: m / z=463.9 (M+H) + .

[0158] Step 2:

[0159] Compound 5-1 (100 mg, 216 mmol, 1.00 eq) was dissolved in tetrahydrofuran (7 mL) at room temperature. The air was replaced three times with N₂. Under N₂ conditions, a solution of MeNH₂ (2 M, 541 μL, 5.00 eq) was slowly added dropwise. The reaction was monitored at 20°C for 1 hour. LCMS showed complete consumption of compound 5-1 and the target product peak (m / z = 413.2 (M+H)⁺) was detected. The reaction solution was slowly poured into a 1 M aqueous hydrochloric acid solution (maintaining the solution pH = 7-8) and extracted three times with dichloromethane (15.0 mL x 3). The organic phases were combined, washed twice with a saturated aqueous sodium chloride solution (15.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 1%-31%, 10 min) and lyophilized to obtain the formate salt of compound 5. LCMS: m / z = 413.2 (M+H) + . 1 H NMR: (400MHz, MeOD) δ8.50(s,1H),7.97(d,J=4.8Hz,1H),7.44(d,J=4.4Hz,1H),7.11(s,1H),6.41-6.38(m,1H),5.13-5.08(m, 1H),4.38(s,2H),3.73-3.67(m,1H),3.19-3.13(m,1H),2.77(s,3H),2.60-2.54(m,1H),2.15-1.83(m,5H),1.13-1.10(m,6H).

[0160] Compound 6

[0161] At room temperature, compound 1 (700 mg, 1.69 mmol, 1.00 eq) was dissolved in dichloromethane (7 mL), cooled to -70°C, and boron tribromide (5.20 g, 20.8 mmol, 2.00 mL, 12.3 eq) was added dropwise. The air was replaced with N2 three times. The reaction was carried out at -70 to -50°C under N2 conditions and monitored after 1 hour. LCMS showed complete consumption of compound 1 and the target product peak (m / z = 400.1 (M+H)+) was detected. The reaction solution was poured into 0-5°C ice water (50.0 mL), the pH was adjusted to 6-8 with saturated sodium bicarbonate aqueous solution, and extracted three times with dichloromethane (50.0 mL*3). The organic phases were combined, washed twice with saturated sodium chloride aqueous solution (50.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by HPLC (preparative column: YMC Triart C18 250*50mm*7um; mobile phase: [water(FA)-ACN]; B%: 30%-60%, 20 min) and lyophilized to obtain compound 6. LCMS: m / z = 400.1 (M+H) + . 1 H NMR: (400MHz, MeOD) δ7.91 (s, 1H), 7.37 (d, J = 4.8Hz, 1H), 7.05 (s, 1H), 6.38-6.25 (m, 1H), 5.16-5.09 (m, 1H), 4.7 9(s,2H),3.72-3.63(m,1H),3.13(d,J=0.8Hz,1H),2.59-2.52(m,1H),2.14-1.82(m,5H),1.11(d,J=6.4Hz,6H).

[0162] Compound 7

[0163] At room temperature, compound 5-1 (0.24 g, 519 μmol, 1.00 eq) was dissolved in tetrahydrofuran (3 mL). Potassium cyanide (70.0 mg, 1.08 mmol, 46.1 μL, 2.07 eq) and dimethyl sulfoxide (0.5 mL) were added. After reacting at room temperature for 2 hours, water (0.5 mL) and octadecacrown-6 (206 mg, 779 μmol, 1.50 eq) were added. After reacting at 70°C for 16 hours, LCMS showed complete consumption of compound 5-1 and the presence of the desired product (m / z = 409.2 (M+H)+). The reaction mixture was slowly poured into water (10 mL), extracted three times with ethyl acetate (10 mL x 3), and washed three times with saturated sodium chloride (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(HCl)-ACN]; B%: 11%-41%, 10 min) and lyophilized to obtain compound 7. LCMS: m / z = 409.2 (M+H) + .1H NMR: (400MHz, MeOD) δ8.23(d,J=6.0Hz,1H),7.53-7.50(m,2H),6.20(s,1H),5.11(d,J=2.8Hz,1H),4.25(s,2H),3. 73-3.68(m,1H),3.26-3.24(m,1H),2.66-2.61(m,1H),2.19-2.03(m,1H),2.02-1.79(m,4H),1.12(d,J=6.4Hz,6H).

[0164] Compound 8

[0165] At room temperature, compound 5-1 (100 mg, 216 μmol, 1.00 eq) was dissolved in tetrahydrofuran (1 mL), and dimethylamine tetrahydrofuran solution (1 M, 1.08 mL, 5.00 eq) was slowly added dropwise. The air was replaced with N2 three times. After reaction at room temperature for 1 hour under N2 conditions, LCMS showed that compound 5-1 was completely consumed and the target product peak was detected (RT = 0.385 min, m / z = 427.1 (M+H) +The reaction mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(HCl)-ACN]; B%: 0%-30%, 10 min) and lyophilized to obtain compound 8. LCMS: m / z = 427.1 (M+H) + . 1 H NMR: (400MHz, MeOD) δ8.32(d,J=5.6Hz,1H),7.91(s,1H),7.60(d,J=5.6Hz,1H),6.32(s,1H),5.13(s,1H),4.69(s,2H),3.6 3-3.58(m,1H),3.29-3.22(m,1H),2.99(s,6H),2.70-2.55(m,1H),2.20-2.18(m,4H),2.04-1.90(m,4H),1.20-1.12(m,6H).

[0166] Compound 9

[0167] Step 1:

[0168] Compound 1-2 (1.00 g, 5.45 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.0 mL), the atmosphere was replaced with nitrogen three times, and the temperature was lowered to -5°C. Under nitrogen, deuterated iodomethane (4.64 g, 32.7 mmol, 1.99 mL, 6.00 eq) and sodium hydride (261 mg, 6.54 mmol, 109 uL, 60.0% purity, 1.20 eq) were added sequentially to the reaction mixture. The reaction was allowed to react at -5°C for 1 hour and monitored. LCMS showed complete consumption of compound 1-2. The reaction mixture was slowly poured into saturated ammonium chloride solution (10.0 mL) and extracted three times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed once with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to yield compound 9-1. LCMS: MS (ESI) m / z = 201.0 [M+H]+. 1 H NMR: EC6456-215-P1N1, DMSO-d6, 400MHz δ = 8.28 (d, J = 4.8 Hz, 1H), 7.64 (d, J = 4.4 Hz, 1H), 6.89 (s, 1H), 4.71 (s, 2H).

[0169] Step 2:

[0170] Tetrabutylammonium fluoride (2.66 g, 10.1 mmol, 4.00 eq) was dissolved in N-methylpyrrolidone (5.00 mL) at room temperature and heated to 130°C for 1 hour. Compound 9-1 (0.51 g, 2.54 mmol, 1.00 eq) was added under N2 protection and stirred at 130°C for 3 hours before monitoring. LCMS showed complete consumption of compound 9-1. The reaction mixture was poured into ice water (20.0 mL) and extracted three times with ethyl acetate (30.0 mL x 3). The organic phases were combined, washed twice with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 100:1 to 1:100, product: Rf = 0.33) to obtain the desired product 9-2. LCMS: MS (ESI) m / z=184.9[M+H]+. 1 H NMR: EC6456-218-P1N1, CDCl3, 400MHz δppm 8.24 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 4.4 Hz, 1H), 6.87 (s, 1H), 4.72 (s, 2H).

[0171] Step 3:

[0172] At room temperature, compound 1-8 (100 mg, 324 μmol, 1.00 eq) was dissolved in tetrahydrofuran (2.00 mL). The temperature was controlled at -20°C. Under nitrogen, a 1.00 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.00 M, 972 μL, 3.00 eq) was added. The mixture was stirred at -20°C for 1 hour. Compound 9-2 (59.7 mg, 324 μmol, 1.00 eq) was dissolved in tetrahydrofuran (1.00 mL) and added. The atmosphere was replaced with nitrogen three times. After reacting at -20°C for 1 hour under nitrogen, monitoring by LCMS indicated complete consumption of compound 1-8. The reaction solution was poured into saturated aqueous ammonium chloride (5.00 mL) and extracted three times with ethyl acetate (5.00 mL x 3). The organic phases were combined, washed twice with saturated brine (5.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to yield crude product 9-3. LCMS: MS (ESI) m / z=473.4[M+H]+. 1H NMR: EC6456-219-P1N2, DMSO-d6, 400MHz δ = 9.00 (s, 1H), 8.03 (d, J = 4.8Hz, 1H), 7.29 (d, J = 4.8Hz, 1H), 6.91 (d, J = 7.6Hz, 1H), 6.84 (s, 1H), 6.0 2(s,1H),5.05-4.92(m,1H),4.59-4.51(m,2H),3.64-3.50(m,2H),3.0 5-2.95(m,1H),1.92-1.63(m,6H),1.49(s,9H),1.00(d,J=6.4Hz,6H).

[0173] Step 4:

[0174] Compound 9-3 (100 mg, 211 μmol, 1.00 eq) was dissolved in anhydrous formic acid (1.00 mL). The reaction was incubated at 100°C for 10 minutes and monitored. LCMS indicated complete consumption of compound 9-3. The reaction solution was concentrated to remove formic acid to obtain a crude product. The crude product was purified by reverse-phase HPLC (formic acid conditions) to obtain the formate salt of compound 9. LCMS: MS (ESI) m / z = 417.1 [M+H]+. 1 H NMR: EC6456-222-P1N1, DMSO-d6, 400MHzδ=9.97(s,1H),8.01(d,J=4.80Hz,1H),7.37(d,J=4.80Hz,1H),7.27(s,1H),6.96(d,J=7.60Hz,1H) ,6.58(s,1H),5.01(d,J=4.00Hz,1H),4.55(s,2H),3.57(tt,J=12.0,6.80Hz,2H),3.03-3.14(m,1H),1.58-2.11(m,6H),1.00-1.06(m,6H).

[0175] Compound 10

[0176] Step 1:

[0177] Compound 9-2 (200 mg, 1.09 mmol, 1.00 eq) and N-iodosuccinimide (256 mg, 1.14 mmol, 1.05 eq) were dissolved in acetonitrile (2.00 mL) at room temperature and stirred at 25°C for 20 hours. The mixture was poured into water (5.00 mL) and extracted three times with ethyl acetate (3.00 mL x 3). The organic phases were combined, washed twice with saturated brine (2.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was separated using conventional reverse phase separation (neutral method) to obtain the desired product 10-1. LCMS: MS (ESI) m / z = 310.8 [M+H]+. 1 H NMR:EC6456-221-P1N2, CDCl3, 400MHz

[0178] δ=8.30 (dd, J=4.80, 2.00Hz, 1H), 7.44 (dd, J=4.80, 1.20Hz, 1H), 4.68 (s, 2H).

[0179] Step 2:

[0180] Compound 10-1 (66.0 mg, 212 μmol, 1.00 eq) was dissolved in dioxane (2.00 mL). Trimethylboroxine (50% tetrahydrofuran) (608 μL, 10.0 eq) and potassium carbonate (88.2 mg, 638 μmol, 3.00 eq) were added to the system in sequence. The air was replaced with nitrogen three times, and potassium carbonate (7.85 mg, 21.2 μmol, 0.10 eq) was added under nitrogen. The reaction was monitored after 10 hours at 90°C. The mixture was poured into water (5.00 mL) and extracted three times with ethyl acetate (3.00 mL x 3). The organic phases were combined, washed twice with saturated brine (2.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated using conventional reverse phase separation (neutral method) to obtain compound 10-2. LCMS: MS (ESI) m / z=199.0 [M+H]+. 1 H NMR: EC6456-243-P1N1, CDCl3, 400MHz δ = 8.14 (d, J = 4.80Hz, 2.40Hz, 1H), 7.30 (d, J = 4.80Hz, 2.00Hz, 1H), 4.68 (s, 2H), 2.48 (s, 3H).

[0181] Step 3:

[0182] At room temperature, compound 1-8 (38.0 mg, 123 μmol, 1.00 eq) was dissolved in tetrahydrofuran (2.00 mL), the temperature was controlled at -20°C, and lithium bis(trimethylsilyl)amide (1.00 M, 369 μL, 3.00 eq) was added under N₂ protection and stirred at -20°C for 1 hour. Compound 10-2 (24.4 mg, 123 μmol, 1.00 eq) was dissolved in tetrahydrofuran (1.00 mL) and added. The atmosphere was replaced with N₂ three times. After reacting at -20°C for 1 hour under N₂ conditions, monitoring by LCMS indicated complete consumption of compound 10-2. The reaction solution was poured into saturated aqueous ammonium chloride (5.00 mL) and extracted three times with ethyl acetate (5.00 mL x 3). The organic phases were combined, washed twice with saturated brine (5.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. The crude product was separated by conventional reverse phase separation (formic acid method) to give the target product 10-3. LCMS: MS (ESI) m / z = 487.4 [M+H] +.

[0183] Step 4:

[0184] Compound 10-3 (20.0 mg, 41.1 μmol, 1.00 eq) was dissolved in anhydrous formic acid (1.00 mL). The reaction was allowed to proceed at 100°C for 10 minutes and monitored. LCMS indicated complete consumption of compound 3. The reaction solution was concentrated to remove formic acid to obtain a crude product. The crude product was purified by reverse-phase HPLC (formic acid conditions) to obtain the formate salt of compound 10. LCMS: MS (ESI) m / z = 431.3 [M+H]+. 1 H NMR:EC6456-253-P1N2,DMSO-d6,400MHzδppm 12.18(s,1H),7.98(d,J=3.20Hz,1H),7.18-7.37(m,1H),6.95(s,1H)6.43(d,J=2.80Hz,1H),5.88(s,1H),5.00(s,2H),4.44-4.5 3(m,3H),3.55-3.60(m,1H),3.02-3.15(m,1H),2.03-2.07(m,1H),1.85–1.95(m,2H),1.64–1.79(m,4H),1.03(d,J=5.20Hz,6H).

[0185] In vitro activity test

[0186] Experimental Example 1: In vitro CDK2 / CyclinE enzyme activity test

[0187] Experimental Materials:

[0188] CDK2 / Cyclin E1 was purchased from Syngenecon. Ulight-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo Multilabel Analyzer was used (PerkinElmer).

[0189] Experimental methods:

[0190] Preparation of kinase buffer: Kinase buffer contains 50mM HEPES, 1mM EDTA, 10mM MgCl2, 0.01% Brij-35, pH 7.4. Add 2.38g HEPES, 58mg EDTA, 406mg MgCl2, 20mg Brij-35 to 200ml buffer and adjust the pH to 7.4.

[0191] Preparation of stop solution:

[0192] Use 100 μL of 1M EDTA stock solution, 0.625 μL of 1X detection buffer, and 1725 μL of distilled water to prepare the stop solution.

[0193] Use kinase buffer to dilute the enzyme, Ulight-4E-BP1 peptide, ATP, and inhibitor. Use detection buffer to dilute the Eu-anti-phospho-tyrosine antibody to a concentration of 8nM / L. Use a pipette to dilute the test compound 5-fold to the eighth concentration, that is, from 4μM to 0.0512nM, with a final DMSO concentration of 4%, and set up a duplicate well experiment. Add 2.5μL of each inhibitor concentration gradient, 5μL of LCDK2 / CyclinE 1 enzyme (10ng), and 2.5μL of a mixture of substrate and ATP (4mM ATP, 100nM Ulight-4E-BP1 peptide) to the microplate. At this time, the final compound concentration gradient is diluted from 1μM to 0.0128Nm, and the final concentrations of ATP and substrate are 1mM and 25nM. The reaction system is placed at 25 degrees for 120 minutes. After the reaction, 5 μL of stop solution was added to each well, and the reaction was continued at 25 degrees for 5 minutes. After the reaction was completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well. After the reaction was completed at 25 degrees for 60 minutes, data were collected using the PerkinElmer Nivo multi-label analyzer in TR-FRET mode (excitation wavelength was 320 nm, emission wavelengths were 615 nm and 665 nm).

[0194] Data Analysis:

[0195] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (derived by using the log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the inhibitory activities of the compounds of the present invention on CDK2 / CyclinE 1 enzyme.

[0196] Experimental Example 2: In vitro CDK1 / CyclinB1 enzyme activity test

[0197] Experimental Materials:

[0198] CDK1 / Cyclin B1 was purchased from CARNA. Ulight-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo Multilabel Analyzer was used (PerkinElmer).

[0199] Experimental methods:

[0200] Preparation of kinase buffer: Kinase buffer contains 50mM HEPES, 1mM EDTA, 10mM MgCl2, 0.01% Brij-35, pH 7.4. Add 2.38g HEPES, 58mg EDTA, 406mg MgCl2, 20mg Brij-35 to 200ml buffer and adjust the pH to 7.4.

[0201] Preparation of stop solution:

[0202] Use 100 μL of 1M EDTA stock solution, add 0.625 μL of 1X detection buffer and mix with 1725 μL of distilled water to prepare the stop solution.

[0203] Dilute the enzyme, Ulight-4E-BP1 peptide, ATP, and inhibitors in kinase buffer.

[0204] Dilute Eu-anti-phospho-tyrosine antibody to 8 nM / L in assay buffer.

[0205] The test compound was diluted five-fold using a pipette to the eighth concentration, from 4 μM to 0.0512 nM, with a final DMSO concentration of 4%. A duplicate assay was performed. To the microplate, 2.5 μL of each inhibitor concentration gradient, 5 μL of 0.5 ng of LCDK1 / CyclinB1 enzyme, and 2.5 μL of a substrate and ATP mixture (4 mM ATP, 200 nM Ulight-4E-BP1 peptide) were added. The final compound concentration gradient was 1 μM to 0.0128 nM, with final ATP and substrate concentrations of 1 mM and 50 nM, respectively. The reaction system was incubated at 25°C for 60 minutes. After the reaction, 5 μL of stop solution was added to each well, and the reaction was continued at 25 degrees for 5 minutes. After the reaction was completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well. After the reaction was completed at 25 degrees for 60 minutes, data were collected using the PerkinElmer Nivo multi-label analyzer in TR-FRET mode (excitation wavelength was 320 nm, emission wavelengths were 615 nm and 665 nm).

[0206] Data Analysis:

[0207] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (derived by using the log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the inhibitory activities of the compounds of the present invention on CDK1 / CyclinB 1 enzymes.

[0208] Experimental Example 3: In vitro GSK3β enzyme activity test

[0209] Experimental Materials:

[0210] GSK3βActive was purchased from SignalChem; GSK3 Substrate was purchased from SignalChem; ADP-Glo ​​Kinase Assay was purchased from Promega; Kinase assay buffer III was purchased from SignalChem; Nivo multilabel analyzer (PerkinElmer).

[0211] Experimental methods:

[0212] The test compound was diluted to 100 μM in 100% DMSO as the first concentration, and then diluted five-fold using a pipette to the eighth concentration, from 100 μM to 0.0013 μM. Each compound concentration point was diluted 20-fold in 1X kinase buffer to prepare a compound working solution containing 5% DMSO. 1 μL of each compound concentration gradient working solution was added to a microplate, and duplicate wells were set up. 2 μL of GSK3β enzyme (1 ng) and 2 μL of a mixture of substrate and ATP (62.5 μM ATP, 0.5 μg / μL GSK3 substrate) were added to the microplate. The final compound concentration gradient was 1 μM to 0.013 nM, with final ATP and substrate concentrations of 25 μM and 0.2 μg / μL, respectively. The reaction system was incubated at 25°C for 60 minutes. After the reaction, 5 μl of ADP-Glo ​​reagent was added to each well and the reaction was continued at 25 degrees for 40 minutes. After the reaction was completed, 10 μL of kinase detection reagent was added to each well. After the reaction was completed at 25 degrees for 30 minutes, chemiluminescence was read using a PerkinElmer Nivo multi-label analyzer with an integration time of 0.5 seconds.

[0213] Data Analysis:

[0214] The raw data were converted to inhibition using the equation (Sample-Min) / (Max-Min)*100%. The IC50 value was then obtained by four-parameter curve fitting (using the log(inhibitor) vs. response - Variable slope mode in GraphPad Prism). Table 1 provides the GSK3β enzymatic inhibitory activity of the compounds of the present invention.

[0215] Max well: positive control well reading value, blank well without enzyme

[0216] Min well: Negative control well reading is the well containing 1% DMSO solvent

[0217] Experimental Example 4: In vitro OVCAR3 cell activity test

[0218] Experimental Materials:

[0219] 1640 culture medium, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (a chemiluminescent cell viability assay) was purchased from Promega. The OVCAR3 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. The Envision multi-label analyzer was purchased from PerkinElmer.

[0220] Experimental methods:

[0221] OVCAR3 cells were seeded in a white 384-well plate, with 40 μL of cell suspension per well, containing 300 OVCAR3 cells. The plate was incubated overnight in a CO2 incubator.

[0222] The compound to be tested was diluted 5-fold to the 8th concentration, that is, from 2000 μM to 0.00512 μM, using a dispenser, and a double-well experiment was set up. 78 μL of culture medium was added to the middle plate, and then 2 μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 10 μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.026 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 7 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 10 μL of cell viability chemiluminescence detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.

[0223] Add 10 μL of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0224] Data Analysis:

[0225] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value of can be obtained by four-parameter curve fitting (obtained in the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the present invention on OVCAR3 cell proliferation.

[0226] Experimental Example 5: In vitro T47D cell activity test

[0227] Experimental Materials:

[0228] 1640 culture medium, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (a chemiluminescent cell viability assay) was purchased from Promega. T-47D cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision multi-label analyzer was purchased from PerkinElmer.

[0229] Experimental methods:

[0230] T-47D cells were seeded in a white 384-well plate, with 40 μL of cell suspension per well, containing 300 T-47D cells. The plate was incubated overnight in a CO2 incubator.

[0231] The compound to be tested was diluted 5-fold to the 8th concentration, that is, from 2000 μM to 0.00512 μM, using a dispenser, and a double-well experiment was set up. 78 μL of culture medium was added to the middle plate, and then 2 μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 10 μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.026 nM. The cell plate was placed in a carbon dioxide incubator and cultured for 7 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis. Add 10 μL of cell viability chemiluminescence detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.

[0232] Add 10 μL of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0233] Data Analysis:

[0234] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value of can be obtained by four-parameter curve fitting (obtained in the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the present invention on T-47D cell proliferation.

[0235] Table 1

[0236] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0237] The above-described embodiments merely represent several implementation methods of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make various modifications and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, R1 is selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocycloalkyl, nitro, isocyano or -(CH2) n R5; R5 is selected from -CN, -OR6, -NR6R7, -C(O)OR6, -C(O)R6, -S(O)2R6, -P(O)(OR6)2, -O-alicyclic, -O-heteroalicyclic, -O-aryl, -O-heteroaryl or -C(O)-heteroaryl, wherein the alicyclic, alicyclic, aryl or heteroaryl is unsubstituted or substituted with one or more R0; R0 is selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, cyano, amino, nitro or hydroxy; R6 and R7 are each independently selected from H, C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, aryl or heteroaryl; n is 0, 1, 2, 3 or 4; Ring A is selected from X is each independently N or CR6; R8 is selected from H, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl; R2 and R3 are each independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl are unsubstituted or substituted with one or more R9; R9 is selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano, amino, nitro or hydroxyl groups; R4 is selected from H, halogen, amino, hydroxy or C1-C6 alkyl; One or more hydrogen atoms in the structure represented by formula (I) are substituted by deuterium atoms or are not substituted; The compound does not have the structure shown below:

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: When the structure shown in formula (I), the R1 is selected from -CH2-O-CH3, and the ring A is selected from When R2 is selected from H, R3 is selected from -CH(CH3)2, and R4 is selected from H, one or more hydrogen atoms in the structure represented by formula (I) are replaced by deuterium atoms.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The R1 is selected from -CH2R5, and the R5 is selected from -OR 61 , -NR6R7, -CN, -C(O)OR6, -C(O)R6, -S(O)2R6, -P(O)(OR6)2, -O-alicyclic, -O-alicyclic, -O-heterocyclic, -O-aryl, -O-heteroaryl or -C(O)-heteroaryl, wherein the alicyclic, alicyclic, aryl and heteroaryl groups are unsubstituted or substituted with one or more R0; The R 61 Selected from H, C in which one or more hydrogen atoms are replaced by deuterium atoms 1-6 Alkyl, halogenated C1-C6 alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocycloalkyl, aryl or heteroaryl.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The R1 is selected from -CH2R5, and the R5 is selected from -OR 61 or-NR6R7; The R 61 Selected from H, C in which one or more hydrogen atoms are replaced by deuterium atoms 1-6 Alkyl or halogenated C1-C6 alkyl; Said R6 and R7 are each independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The R1 is -OH.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R2 is H, R3 is selected from C 1-6 Alkyl or halogenated C1-C6 alkyl.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The R3 is -C(CH3)3.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The R1 is selected from -(CH2) n R5, wherein one or more hydrogen atoms in R5 are replaced by deuterium atoms.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The structure represented by formula (I) is selected from the structure represented by any one of formulas (I-1) to (I-3):

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The structure represented by formula (I) is selected from the structure represented by formula (I-4):

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: X is selected from CR6.

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R6 is selected from H, C 1-6 Alkyl, halogen or halogenated C 1-6 alkyl.

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The R1 is -CH2R5.

14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Said R5 is selected from -CN, -OR6 or -NR6R7; Said R6 and R7 are each independently selected from H, C 1-6 Alkyl or halogenated C 1-6 alkyl.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Said R2 is selected from H, C1-C6 alkyl or halogenated C1-C6 alkyl; R3 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl are unsubstituted or substituted with one or more R9.

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Said R2 is selected from H; The R3 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl, and 5-membered heterocycloalkyl which is unsubstituted or substituted with one R9.

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Said R9 is selected from halogen, C 1-6 Alkyl or halogenated C 1-6 Alkyl; the heteroatom of the 5-membered heterocycloalkyl is an oxygen atom.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: In the formula (I) Select one of the following structures:

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound has one of the following structures:

20. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier.

21. Use of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 20 in the preparation of a medicament for treating or preventing a disease associated with or mediated by CDK2 activity.

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