Pyrazole derivatives, pharmaceutically acceptable salts, stereoisomers, pharmaceutical compositions and uses thereof

Abstract

The present invention discloses a pyrazole derivative represented by structural formula (I), its pharmaceutically acceptable salt, its stereoisomer, pharmaceutical composition, and use thereof. This compound has good inhibitory activity and selectivity against CDK2. [Formula 1] JPEG2026504054000033.jpg34170

Description

[Technical Field]

[0001] This application claims priority to a Chinese patent application filed on January 19, 2023, bearing application number CN2023100596930.

[0002] The present invention relates to the technical field of medicine, in particular to pyrazole derivatives, their pharmaceutically acceptable salts, stereoisomers, pharmaceutical compositions and uses. [Background technology]

[0003] Cell cycle-dependent kinases (CDKs) belong to the serine / threonine kinase family and are involved in physiological processes such as cell proliferation and transcription. Based on the differences in CDK functions, they can be divided into two types: one type of CDK is involved in regulating the cell cycle and mainly includes CDK1, CDK2, CDK4, CDK6, etc., and the other type of CDK is involved in regulating transcription and mainly includes CDK7, CDK8, CDK9, CDK12, CDK13, etc.

[0004] CDK2 has attracted considerable research interest because impaired CDK2 activity is commonly observed in various human cancers. CDK2 plays an important role in promoting the G1 / S transition and S phase processes. CDK2 forms a complex with cyclin E and phosphorylates members of the retinoblastoma family (e.g., pRb), which releases and activates E2F transcription factors, promoting the transition from G1 to S phase of the cell cycle and further activating CDK2 / Cyclin A, which promotes cell cycle processes such as DNA synthesis and replication.

[0005] Increased copy number or overexpression of cyclin E1 has been confirmed in ovarian, gastric, endometrial, breast, and other cancers, and is positively correlated with poor prognosis in these tumors. In ER+ breast cancer cells, high expression of cyclin E2 is often associated with resistance to hormonal therapy, and amplification or overexpression of cyclin E is closely associated with poor prognosis in breast cancer. In HER2+ breast cancer, cyclin E amplification has also been reported to contribute to resistance to trastuzumab. Furthermore, overexpression of cyclin E has been reported to play an important role in the progression of triple-negative and inflammatory breast cancers. Therefore, CDK2 may be an important antitumor target. Summary of the Invention [Problem to be solved by the invention]

[0006] Based on this, the present invention provides pyrazole derivatives, pharmaceutically acceptable salts, or stereoisomers thereof, which have excellent inhibitory activity and selectivity against CDK2. [Means for solving the problem]

[0007] The present invention is realized by the following technical means.

[0008] The pyrazole derivative is represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. [ka] (In the formula, X is independently selected at each occurrence from N or CR4, and R4 is absent or selected from -H, -D, -F, -Cl, -Br, -I, a linear alkyl group having 1 to 6 C atoms, a linear deuterated alkyl group having 1 to 6 C atoms, a branched alkyl group having 3 to 6 C atoms, or an aromatic heterocycle; R1 is selected from -H, -D, -F, -Cl, -Br, -I, a linear alkyl group having 1 to 20 C atoms, a linear deuterated alkyl group having 1 to 20 C atoms, a branched alkyl group having 3 to 20 C atoms, a branched deuterated alkyl group having 3 to 20 C atoms, a cyclic alkyl group having 3 to 20 C atoms, a cyclic deuterated alkyl group having 3 to 20 C atoms, a linear alkoxy group having 1 to 20 C atoms, a linear deuterated alkoxy group having 1 to 20 C atoms, a branched alkoxy group having 3 to 20 C atoms, a branched deuterated alkoxy group having 3 to 20 C atoms, a cyclic alkoxy group having 3 to 20 C atoms, and a cyclic deuterated alkoxy group having 3 to 20 C atoms; R3 is selected from a substituted or unsubstituted alkyl group having 1 to 6 C atoms, a substituted or unsubstituted fluoroalkyl group having 1 to 6 C atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 C atoms, and a substituted or unsubstituted heterocyclic group having 4 to 7 ring atoms; R2 is -F, -Cl, -OH, -CN, -NR5R6, -CH2-ONR7R8, -CH2-ON=R9, -CH2N(R 10 ) OR 11 , a substituted or unsubstituted alkyl group having 1 to 4 C atoms, a substituted or unsubstituted fluoroalkyl group having 1 to 4 C atoms, a substituted or unsubstituted alkoxy group having 1 to 4 C atoms, a substituted or unsubstituted fluoroalkoxy group having 1 to 4 C atoms, and a substituted or unsubstituted cycloalkyl group having 3 to 8 C atoms; R5, R6, R7, R8, R 10 , R 11are each independently selected from -H, -D, a linear alkyl group having 1 to 20 C atoms, a linear deuterated alkyl group having 1 to 20 C atoms, a branched alkyl group having 3 to 20 C atoms, a branched deuterated alkyl group having 3 to 20 C atoms, a cyclic alkyl group having 3 to 20 C atoms, a cyclic deuterated alkyl group having 3 to 20 C atoms, a linear alkoxy group having 1 to 20 C atoms, a linear deuterated alkoxy group having 1 to 20 C atoms, a branched alkoxy group having 3 to 20 C atoms, a branched deuterated alkoxy group having 3 to 20 C atoms, a cyclic alkoxy group having 3 to 20 C atoms, and a cyclic deuterated alkoxy group having 3 to 20 C atoms; R9 is selected from a linear alkylene group having 1 to 20 C atoms, a linear deuterated alkylene group having 1 to 20 C atoms, a branched alkylene group having 3 to 20 C atoms, a branched deuterated alkylene group having 3 to 20 C atoms, a cyclic alkylene group having 3 to 20 C atoms, a cyclic deuterated alkylene group having 3 to 20 C atoms, or a combination thereof.

[0009] In one embodiment, the pyrazole derivative has a structure represented by formula (II). [ka]

[0010] In one embodiment, the pyrazole derivative has a structure represented by formula (III). [ka]

[0011] In one embodiment, R1 is selected from -H, -D, -F, -Cl, -Br, -I, a linear alkyl group having 1 to 10 C atoms, a linear deuterated alkyl group having 1 to 10 C atoms, a branched alkyl group having 3 to 10 C atoms, a branched deuterated alkyl group having 3 to 10 C atoms, a cyclic alkyl group having 3 to 10 C atoms, a cyclic deuterated alkyl group having 3 to 10 C atoms, or a combination thereof.

[0012] In one embodiment, R1 is selected from -H, -D, -F, -Cl, -Br, a linear alkyl group having 1 to 6 C atoms, a linear deuterated alkyl group having 1 to 6 C atoms, a branched alkyl group having 3 to 6 C atoms, and a branched deuterated alkyl group having 3 to 6 C atoms.

[0013] In one embodiment, R1 is selected from -H, -D, -F, -Cl, -Br, a linear alkyl group having 1 to 3 C atoms, a linear deuterated alkyl group having 1 to 3 C atoms, a branched alkyl group having 3 to 6 C atoms, and a branched deuterated alkyl group having 3 to 6 C atoms.

[0014] In one embodiment, R1 is selected from -H, -D, -F, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2.

[0015] In one embodiment, R2 is -F, -Cl, -OH, -CN, -NR5R6, -CH2-ONR7R8, -CH2-ON=R9, -CH2N(R 10 ) OR 11 a substituted or unsubstituted alkyl group having 1 to 4 C atoms, a substituted or unsubstituted fluoroalkyl group having 1 to 4 C atoms, a substituted or unsubstituted alkoxy group having 1 to 4 C atoms, a substituted or unsubstituted fluoroalkoxy group having 1 to 4 C atoms, and a substituted or unsubstituted cycloalkyl group having 3 to 8 C atoms.

[0016] In one embodiment, R3 is selected from a substituted or unsubstituted alkyl group having 1 to 3 C atoms, a substituted or unsubstituted fluoroalkyl group having 1 to 3 C atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 C atoms, and a substituted or unsubstituted heterocyclic group having 4 to 7 ring atoms.

[0017] In one embodiment, R3 is selected from substituted or unsubstituted -CH3, substituted or unsubstituted -CH2CH3, substituted or unsubstituted -CH2CH2CH3, and substituted or unsubstituted -CH(CH3)2.

[0018] In one embodiment, R3 is selected from substituted or unsubstituted -CH(CH3)2. In one embodiment, R2 is selected from -F, -Cl, -OH, -CN, -NR5R6, -CH2-ONR7R8, -CH2-ON=R9, -CH2N(R 10 ) OR 11 , substituted or unsubstituted -CH3, substituted or unsubstituted -CH2CH3, substituted or unsubstituted -CH2CH2CH3, substituted or unsubstituted -CH(CH3)2, substituted or unsubstituted fluoro-CH3, substituted or unsubstituted fluoro-CH2CH3, substituted or unsubstituted fluoro-CH2CH2CH3, and substituted or unsubstituted fluoro-CH(CH3)2.

[0019] In one embodiment, R5, R6, R7, R8, R 10 , R 11are each independently selected from -H, -D, a linear alkyl group having 1 to 10 C atoms, a linear deuterated alkyl group having 1 to 10 C atoms, a branched alkyl group having 3 to 10 C atoms, a branched deuterated alkyl group having 3 to 10 C atoms, a cyclic alkyl group having 3 to 10 C atoms, a cyclic deuterated alkyl group having 3 to 10 C atoms, a linear alkoxy group having 1 to 10 C atoms, a linear deuterated alkoxy group having 1 to 10 C atoms, a branched alkoxy group having 3 to 10 C atoms, a branched deuterated alkoxy group having 3 to 10 C atoms, a cyclic alkoxy group having 3 to 10 C atoms, and a cyclic deuterated alkoxy group having 3 to 10 C atoms.

[0020] In one embodiment, R5, R6, R7, R8, R 10 , R 11 are each independently selected from -H, -D, a linear alkyl group having 1 to 6 C atoms, a linear deuterated alkyl group having 1 to 6 C atoms, a branched alkyl group having 3 to 6 C atoms, a branched deuterated alkyl group having 3 to 6 C atoms, a cyclic alkyl group having 3 to 6 C atoms, a cyclic deuterated alkyl group having 3 to 6 C atoms, a linear alkoxy group having 1 to 6 C atoms, a linear deuterated alkoxy group having 1 to 6 C atoms, a branched alkoxy group having 3 to 6 C atoms, a branched deuterated alkoxy group having 3 to 6 C atoms, a cyclic alkoxy group having 3 to 6 C atoms, and a cyclic deuterated alkoxy group having 3 to 6 C atoms.

[0021] In one embodiment, R5, R6, R7, R8, R 10 , R 11are each independently selected from -H, -D, a linear alkyl group having 1 to 3 C atoms, a linear deuterated alkyl group having 1 to 3 C atoms, a branched alkyl group having 3 to 6 C atoms, a branched deuterated alkyl group having 3 to 6 C atoms, a cyclic alkyl group having 3 to 6 C atoms, a cyclic deuterated alkyl group having 3 to 6 C atoms, a linear alkoxy group having 1 to 3 C atoms, a linear deuterated alkoxy group having 1 to 3 C atoms, a branched alkoxy group having 3 to 6 C atoms, a branched deuterated alkoxy group having 3 to 6 C atoms, a cyclic alkoxy group having 3 to 6 C atoms, and a cyclic deuterated alkoxy group having 3 to 6 C atoms.

[0022] In one embodiment, R5, R6, R7, R8, R 10 , R 11 are each independently selected from -H, -D, -CH3, -CH2CH3, -CH2CH2CH3, and -CH(CH3)2.

[0023] In one embodiment, R9 is selected from a linear alkylene group having 1 to 20 C atoms, a linear deuterated alkylene group having 1 to 20 C atoms, a branched alkylene group having 3 to 20 C atoms, a branched deuterated alkylene group having 3 to 20 C atoms, a cyclic alkylene group having 3 to 20 C atoms, and a cyclic deuterated alkylene group having 3 to 20 C atoms.

[0024] In one embodiment, R9 is selected from a linear alkylene group having 1 to 10 C atoms, a linear deuterated alkylene group having 1 to 10 C atoms, a branched alkylene group having 3 to 10 C atoms, a branched deuterated alkylene group having 3 to 10 C atoms, a cyclic alkylene group having 3 to 10 C atoms, and a cyclic deuterated alkylene group having 3 to 10 C atoms.

[0025] In one embodiment, R9 is selected from a linear alkylene group having 1 to 6 C atoms, a linear deuterated alkylene group having 1 to 6 C atoms, a branched alkylene group having 3 to 6 C atoms, a branched deuterated alkylene group having 3 to 6 C atoms, a cyclic alkylene group having 3 to 6 C atoms, and a cyclic deuterated alkylene group having 3 to 6 C atoms.

[0026] In one embodiment, R9 is selected from a linear alkylene group having 1 to 3 C atoms, a linear deuterated alkylene group having 1 to 3 C atoms, a branched alkylene group having 3 to 6 C atoms, a branched deuterated alkylene group having 3 to 6 C atoms, a cyclic alkylene group having 3 to 6 C atoms, and a cyclic deuterated alkylene group having 3 to 6 C atoms.

[0027] In one embodiment, R9 is selected from =CH2, =CHCH3, =CHCH2CH3, and =C(CH3)2.

[0028] In one embodiment, R2 is any one selected from the following structures: [ka]

[0029] The present application provides the following compound or a pharmaceutically acceptable salt thereof: [ka]

[0030] In one specific embodiment, the pharmaceutically acceptable salt is an alkyl acid salt, and further, the pharmaceutically acceptable salt is a formate salt.

[0031] In one specific embodiment, the pharmaceutically acceptable salt is a formate or hydrochloride salt.

[0032] The present invention further provides use of the above-mentioned pyrazole derivatives, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a drug for treating and / or preventing a disease associated with or mediated by CDK2 activity.

[0033] In one specific embodiment, the disease associated with or mediated by CDK2 activity is cancer.

[0034] In one specific embodiment, the cancer is one or more of ovarian cancer, gastric cancer, endometrial cancer, and breast cancer.

[0035] The present invention further provides a pharmaceutical composition comprising the above-mentioned pyrazole derivative, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0036] 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 specifically described below (for example, in the Examples) can be combined with each other to form new or preferred technical solutions, and due to space limitations, they will not be listed comprehensively here. [Effects of the Invention]

[0037] Compared with the prior art, the pyrazole derivatives, or pharmaceutically acceptable salts thereof, or stereoisomers thereof of the present invention have the following beneficial effects:

[0038] After extensive and in-depth research, the inventors have unexpectedly discovered new pyrazole derivatives. The pyrazole derivatives of the present invention have unexpected inhibitory activity and selectivity against CDK2, and can be used to treat various cancers with high Cyclin E expression, and have particularly excellent therapeutic effects on cancer patients resistant to CDK4 / 6 inhibitors. DETAILED DESCRIPTION OF THE INVENTION

[0039] To facilitate understanding of the present invention, the present invention will now be described more fully with reference to the associated examples. The examples set forth preferred embodiments of the present invention. However, the present invention may be embodied in many different forms and is not limited to the embodiments set forth herein. Rather, the purpose of providing these examples is to provide a more complete and thorough understanding of the present disclosure.

[0040] Definition of Terms Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings: A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear and should be understood in its ordinary sense. Trade names listed herein are intended to refer to the corresponding products or their active ingredients.

[0041] The term "pharmaceutically acceptable" means that the compound, material, composition and / or dosage form is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, and is commensurate with a reasonable benefit / risk ratio.

[0042] The term "pharmaceutically acceptable salt" means that salts of the compounds of the present invention are prepared with compounds having specific substituents discovered in this invention and relatively non-toxic acids or bases. When a compound of the present invention has a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a neat solution or in a suitable inert solvent. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids and organic acids, including salts of amino acids (e.g., arginine) and organic acids such as glucuronic acid. By containing basic and acidic functional groups, certain compounds of the present invention can be converted into any base or acid addition salt.

[0043] The pharmaceutically acceptable salts of the present invention are synthesized by conventional chemical methods using parent compounds that contain an acid or base group. Such salts are usually prepared by reacting these compounds, in their free acid or base form, with the stoichiometrically appropriate base or acid in water or an organic solvent, or a mixture of both.

[0044] The compounds of the present invention may have specific geometric or stereoisomeric forms. For purposes of the present invention, such compounds include all cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures. All of these mixtures are within the scope of the present invention. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0045] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another. Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" refer to isomers caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms.

[0046] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer whose molecules have two or more centers of chirality and the relationship between the molecules is not mirror image. Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0047] JPEG2026504054000007.jpg23170

[0048] JPEG2026504054000008.jpg74170

[0049] Unless otherwise specified, the terms "isomer-enriched," "isomer-enriched," "enantiomer-enriched," or "enantiomer-enriched" refer to less than 100% isomer or enantiomer content and 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more of that isomer or enantiomer.

[0050] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the relative percentage difference between the two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0051] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. Enantiomers of certain compounds of the present invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary. The resulting diastereomeric mixture is separated, and the auxiliary is cleaved to provide the desired pure enantiomer. Alternatively, if the molecule contains basic (e.g., amino) or acidic (e.g., carboxyl) functional groups, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by conventional separation of the diastereomers and recovery of the pure enantiomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatographic methods, which utilize chiral stationary phases and, if necessary, chemical derivatization (e.g., carbamates from amines).

[0052] The compounds of the present invention may contain atomic isotopes at unnatural abundances at one or more atoms that constitute the compounds. For example, radioactive isotopes (tritium ( 3H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with C). Furthermore, deuterium can be substituted for hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have the advantages of effectively reducing toxicity and side effects, improving drug stability and therapeutic efficacy, and extending the biological half-life of drugs. All isotopic versions of the compounds of the present invention are within the scope of the present invention, regardless of their radioactivity.

[0053] "Optional" or "as needed" means something that may, but does not necessarily, occur depending on the events or circumstances described below, and includes cases where the events or circumstances do or do not occur.

[0054] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, and the substituent includes deuterium and hydrogen variants, as long as the valence of the atom is normal and the compound after the substitution is stable. The type and number of substituents are arbitrary as long as it is chemically achievable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0055] When any variable (e.g., R1) occurs more than once in any composition or structure of a compound, that variable is independent in its definition at each occurrence. Thus, if a group is substituted with 0-2 R1, that group may be optionally substituted with at most 2 R1, and at any given occurrence, R1 has independent options. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0056] When the number of linking groups is 0 (for example, -(CRR)0-), this indicates that the linking group is a single bond.

[0057] When a variable is selected from a single bond, it indicates that the two groups connecting it are directly linked, e.g., when L in ALZ is a single bond, the structure is essentially AZ.

[0058] If a substituent is vacant, it means that the substituent is absent. For example, if X in AX is vacant, it means that the structure is essentially A. If no atom in a listed substituent is specified to be bonded to the substituted group, the substituent can be bonded to any atom. For example, a pyridyl group can be bonded to the substituted group as a substituent through any carbon atom on the pyridine ring.

[0059] JPEG2026504054000009.jpg68170

[0060] JPEG2026504054000010.jpg130170

[0061] Unless otherwise specified, the number of atoms in a ring is usually defined as the number of members in the ring, for example, a "3- to 7-membered ring" refers to a "ring" in which 3 to 7 atoms are arranged in a ring.

[0062] Unless otherwise stated, the term "C 1-6 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-4 C is an alkyl group, which may be monovalent (e.g., a methyl group), divalent (e.g., a methylene group) or polyvalent (e.g., a methine group). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and butyl (including n-butyl, isobutyl, tert-butyl, and sec-butyl).

[0063] Unless otherwise stated, the term "C 1-6An "alkoxy group" refers to an alkyl group containing 1 to 6 carbon atoms linked to the rest of the molecule through an oxygen atom. 1-3 It is an alkoxy group. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups (including n-propoxy groups and isopropoxy groups), and the like.

[0064] Unless otherwise stated, the term "C 1-6 An "alkylamino group" refers to an alkyl group containing 1 to 6 carbon atoms that is linked to the rest of the molecule via an amino group. 1-3 It is an alkylamino group. 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.

[0065] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0066] Unless otherwise stated, as used herein, the terms "5-membered heteroaryl ring" and "5-membered heteroaryl group" can be used interchangeably, and the term "5-membered heteroaryl group" refers to a monocyclic group having a conjugated π-electron system, consisting of five ring atoms, of which one, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 5-membered heteroaryl group can be linked to the rest of the molecule via a heteroatom or a carbon atom. Examples of the 5-membered heteroaryl group include a pyrrolyl group (including an N-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, etc.), a pyrazolyl group (including a 2-pyrazolyl group, a 3-pyrazolyl group, etc.), an imidazolyl group (including an N-imidazolyl group, a 2-imidazolyl group, a 4-imidazolyl group, a 5-imidazolyl group, etc.), an oxazolyl group (including a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, etc.), a triazolyl group (including a 1H-1,2,3-triazolyl group, a 2H-1,2, Examples of such groups include, but are not limited to, a 3-triazolyl group, a 1H-1,2,4-triazolyl group, a 4H-1,2,4-triazolyl group, etc.), a tetrazolyl group, an isoxazolyl group (a 3-isoxazolyl group, a 4-isoxazolyl group, a 5-isoxazolyl group, etc.), a thiazolyl group (including a 2-thiazolyl group, a 4-thiazolyl group, a 5-thiazolyl group, etc.), a furanyl group (including a 2-furanyl group, a 3-furanyl group, etc.), and a thienyl group (including a 2-thienyl group, a 3-thienyl group, etc.).

[0067] Unless otherwise stated, C n-n+m or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and any one of the ranges n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12and the like. Similarly, n- to n+m-membered rings indicate that the number of atoms in the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one range of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0068] Unless otherwise stated, "C 3-7 The term "cycloalkyl group" refers to a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, and includes monocyclic and bicyclic rings, and bicyclic rings include spiro rings, fused rings, and bridged rings. 3-7 The cycloalkyl group is C 3-6 , C 4-6 , C 4-5 , C 5-7 or C 5-6 C may be monovalent, divalent or polyvalent, including cycloalkyl groups. 3-7 Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0069] Unless otherwise stated, the term "3- to 7-membered heterocycloalkyl group" by itself or in combination with other terms refers to a saturated cyclic group of 3 to 7 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and where the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). It includes monocyclic and bicyclic rings, and bicyclic rings include spiro rings, fused rings, and bridged rings. Furthermore, with regard to the "3- to 7-membered heterocycloalkyl group," a heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule. Examples of 3- to 7-membered heterocycloalkyl groups include 5- to 7-membered, 3-membered, 4-membered, 5-membered, 6-membered, and 7-membered heterocycloalkyl groups. Examples of 3- to 7-membered heterocycloalkyl groups include azetidinyl, oxetanyl, thioxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothienyl-2-yl and tetrahydrothienyl-3-yl), tetrahydrofuran (including tetrahydrofuran-2-yl), tetrahydropyranyl, piperidinyl (1-piperidinyl, 2-pyridinyl, etc.), and the like. Examples of the alkyl group include, but are not limited to, a 1-piperazinyl group (including a 1-piperazinyl group and a 2-piperazinyl group), a 3-piperazinyl group, a piperazinyl group (including a 1-piperazinyl group and a 2-piperazinyl group), a morpholinyl group (including a 3-morpholinyl group and a 4-morpholinyl group), a dioxane group, a dithianyl group, an isoxazolidinyl group, an isothiazolyl group, a 1,2-oxazinyl group, a 1,2-thiazinyl group, or a hexahydropyridazinyl group.

[0070] Unless otherwise stated, the term "3- to 7-membered nitrogen-containing heterocycloalkyl group" refers to a 3- to 7-membered heterocycloalkyl group containing at least one N atom.

[0071] Alicyclic refers to a saturated or partially unsaturated all-carbon ring system. "Partially unsaturated" refers to a ring moiety containing at least one double or triple bond, and "partially unsaturated" includes rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclopentanone, cyclopentane-1,3-dione, and the like.

[0072] An aliphatic heterocyclic group is a saturated or partially unsaturated alicyclic group in which one, two, or three ring carbon atoms are nitrogen, oxygen, or S(O). t (wherein t is an integer of 0 to 2), but does not contain -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Non-limiting examples include a propylene oxide 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, a dioxane, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidin-2-one ring, an oxetan-2-one ring, a pyrrolidin-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 morpholin-3-one ring. Non-limiting examples of partially unsaturated monocyclic heterocycles include a 1,2-dihydroazate ring, a 1,2-dihydrooxacyclobutadiene ring, a 2,5-dihydro-1H-pyrrole ring, a 2,5-dihydrofuran ring, a 2,3-dihydrofuran ring, a 2,3-dihydro-1H-pyrrole ring, a 3,4-dihydro-2H-pyran ring, a 1,2,3,4-tetrahydropyridine ring, a 3,6-dihydro-2H-pyran ring, a 1, Examples include a 2,3,6-tetrahydropyridine ring, a 4,5-dihydro-1H-imidazole ring, a 1,4,5,6-tetrahydropyrimidine ring, a 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazole oxacin ring, a 1,6-dihydropyrimidine ring, a 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, and a 2,5,6,7-tetrahydro-1,3,5-oxadiazepine ring.

[0073] The terms "aryl group" and "aryl ring" can be used interchangeably and refer to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated π-electron system, which may be fused with a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring, or heteroaryl group. 6-10 "Aryl group" refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, non-limiting examples of aryl groups include phenyl, naphthyl, and the like.

[0074] The terms "heteroaryl group" and "heteroaryl ring" are used interchangeably and refer to 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, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In the present invention, heteroaryl groups further include ring systems in which the heteroaryl ring is fused with one or more cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, or aryl rings. Heteroaryl rings may be optionally substituted. A "5- to 10-membered heteroaryl group" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, in which 1, 2, 3, or 4 ring atoms are heteroatoms. The term "5- or 6-membered heteroaryl group" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. Non-limiting examples 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.The term "8- to 10-membered heteroaryl group" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, in which 1, 2, 3, or 4 ring atoms are heteroatoms. Non-limiting examples include an indolyl group, an isoindolyl group, an indazolyl group, a benzotriazole group, a benzothienyl group, an isobenzothienyl group, a benzofuryl group, a benzisofuranyl group, a benzimidazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzoxadiazolyl group, a benzothiazolyl group, a benzisobenzoyl group, a benzo ... Examples include thiazolyl, benzothiadiazolyl, indolizinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolyl, quinoxalyl, phthalazinyl, and quinazolyl. A heteroatom refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Bicyclic heteroaryl ring systems may contain one or more heteroatoms in one or both rings.

[0075] The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom via 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, and the like, acyloxy such as acetoxy, trifluoroacetoxy, and the like.

[0076] 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 nitrogen site of an amino group. Representative amino-protecting groups include, but are not limited to, a formyl group, an acyl group such as an alkanoyl group (e.g., an acetyl group, a trichloroacetyl group, or a trifluoroacetyl group), an alkoxycarbonyl group such as a tert-butoxycarbonyl group (Boc), an arylmethoxycarbonyl group such as a benzyloxycarbonyl group (Cbz) and a 9-fluorenylmethoxycarbonyl group (Fmoc), an arylmethyl group such as a benzyl group (Bn), a trityl group (Tr), a 1,1-bis(4'-methoxyphenyl)methyl group, a silyl group such as a trimethylsilyl group (TMS) and a tert-butyldimethylsilyl group (TBS), and the like. The term "hydroxy-protecting group" refers to a protecting group suitable for preventing side reactions of a hydroxyl group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl, and tert-butyl groups, acyl groups such as alkanoyl groups (e.g., acetyl), arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (DPM), silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0077] Unless otherwise specified, the phrase "substituents independently selected from" used in the present invention means that when one or more hydrogen atoms in a group are substituted with substituents, the types of the substituents may be the same or different, and the selected substituents are each independently selected.

[0078] In general, the compounds of the present invention, or their pharmaceutically acceptable salts, or their stereoisomers, can be administered in appropriate dosage forms with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, buccal, and other non-alimentary tract administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present invention contained in these dosage forms may be solid powders or particles, solutions or suspensions in aqueous or non-aqueous liquids, water-in-oil or oil-in-water emulsions, etc. The dosage forms may be prepared from the active compound and one or more carriers or excipients by conventional pharmaceutical methods. The carrier must be compatible with the active compound or other excipients. For solid formulations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid formulations include water, saline, aqueous glucose solution, ethylene glycol, polyethylene glycol, etc. The active compound may form a solution or suspension with the carrier.

[0079] The compositions of the present invention are prepared, measured, and administered in a manner consistent with good medical practice. The "therapeutically effective amount" of the compound administered will depend on factors such as the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0080] A "therapeutically effective amount" refers to an amount of a compound of the invention that elicits a biological or medical response in a subject, such as, for example, reducing or inhibiting the activity of an enzyme or protein, ameliorating a symptom, alleviating a disease condition, slowing or delaying the progression of a disease, or preventing a disease.

[0081] The therapeutically effective amount of the pharmaceutical composition according to the present invention or the compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof contained in the pharmaceutical composition is preferably 0.1 mg to 5 g / kg (body weight).

[0082] "Patient" means an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.

[0083] "Treatment" means alleviating, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the progression of, or alleviating to some extent, one or more symptoms of the disease or condition.

[0084] The compounds of the present invention can be prepared by multiple synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed from combinations with other chemical synthetic methods, and equivalent alternatives known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0085] The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of a compound, its absolute configuration can be confirmed by conventional techniques in the art. For example, in single crystal X-ray diffraction (SXRD), the grown single crystal is collected by a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning method is φ scanning. After collecting the data, the crystal structure is further analyzed by a direct method (Shelxs97), thereby confirming the absolute configuration.

[0086] The solvent used in the present invention may be commercially available. The following abbreviations are used in the present invention: N2 represents nitrogen gas, DMSO represents dimethyl sulfoxide, Pd(dppf)Cl2 represents 1,1'-bisdiphenylphosphinoferrocene palladium dichloride, DIEA represents N,N-diisopropylethylamine, THF represents tetrahydrofuran, EtOAc represents ethyl acetate, FA represents formic acid, TFA represents trifluoroacetic acid, Select-F represents selective fluorine reagent, tBuOK represents potassium tert-butoxide, HCl represents hydrochloric acid, and MeOH represents methanol.

[0087] Compounds are named according to conventional naming principles in the art or using ChemDraw® software; commercially available compounds adopt the names from the supplier catalog.

[0088] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art of the present invention. The terms used herein are only for describing particular embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more associated items. [Brief explanation of the drawings]

[0089] [Figure 1] FIG. 10 is a graph showing the results of Experimental Example 7. [Example]

[0090] The pyrazole derivatives and the method for producing the same of the present invention will be described in more detail below with reference to specific examples. Unless otherwise specified, all raw materials used in the following examples are commercially available products.

[0091] Example 1 This example provides Compound 1, whose structural formula is as follows: [ka]

[0092] The reaction pathway is shown below. [ka]

[0093] Step 1: Compound 1-2 (186 g, 1.77 mol, 192 mL) was dissolved in tetrahydrofuran (700 mL) at room temperature and cooled to 0 °C. Under N protection, a 2 M solution of trimethylaluminum in toluene (2.00 M, 883 mL) was added and stirred at 25 °C for 1 hour. The reaction mixture was then cooled to 0 °C, and compound 1-1 (250 g, 1.18 mol) was dissolved in tetrahydrofuran (500 mL) and added to the reaction mixture. The atmosphere was purged with N three times, and the reaction mixture was allowed to react at 25 °C for 4 hours under N conditions. The temperature was controlled at 0 °C, and methanol (1.00 L) was slowly added dropwise to the reaction mixture. After 2 hours of reaction at 20 °C, complete quenching of trimethylaluminum was ensured. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 100:1-1:100) to give compound 1-3. MS (ESI) m / z = 239.9 [M+H] + .

[0094] Step 2: Compound 1-3 (260 g, 958 mmol) was dissolved in water (500 mL) at room temperature, cooled to 0°C, and hydrochloric acid (12 M, 479 mL) was added. The mixture was reacted at 25°C for 4 hours. The mixture was filtered, and the filter cake was centrifuged and dried to obtain compound 1-4. MS (ESI) m / z = 226.1 [M+H] + .

[0095] Step 3: Compound 1-4 (50.0 g, 222 mmol) was dissolved in methanesulfonic acid (400 g, 4.16 mol, 296 mL) at room temperature and reacted at 25 °C for 10 hours. The reaction mixture was slowly poured into saturated sodium bicarbonate solution (500 mL) and extracted six times with ethyl acetate (200 mL × 6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-5. MS (ESI) m / z = 207.7 [M+H] + .

[0096] Step 4: Compound 1-5 (11.0 g, 53.1 mmol) and N,N-diisopropylethylamine (6.86 g, 53.1 mmol, 9.25 mL) were dissolved in toluene (100 mL) at room temperature. The solution was cooled to 0 °C, and phosphorus oxychloride (16.3 g, 106 mmol, 9.87 mL) was added under N2 protection and stirred at 120 °C for 10 h. The mixture was concentrated to remove excess toluene and extracted three times with ethyl acetate (100 mL × 3). The combined organic phases were washed twice with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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) to obtain compound 1-6. MS (ESI) m / z = 225.7 [M+H] + . 1 H NMR: DMSO-d6, 400 MHz, δ ppm 8.94 (dd, J = 4.8, 0.80 Hz, 1H), 7.92 (d, J = 4.75 Hz, 1H), 7.46 (d, J = 0.80 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.13 Hz, 3H).

[0097] Step 5: Compound 1-6 was dissolved in tetrahydrofuran (100 mL) and the atmosphere was purged with nitrogen gas three times. The reaction mixture was cooled to -68°C, and diisobutylaluminum hydride (1 M, 75.3 mL) was slowly added under a nitrogen atmosphere. The reaction mixture was allowed to react at 25°C for 1 hour. Methanol (40.0 mL) was added to the reaction mixture at 0°C, and the mixture was allowed to react at 25°C. After stirring for 2 hours, anhydrous sodium sulfate was added to dry the mixture, filtered, and the filtrate was concentrated to give compound 1-7. MS (ESI) m / z = 183.7 [M+H] + . 1 H NMR: DMSO-d6,400 MHz δ ppm 8.77(d,J=4.8 Hz,1H),7.72 (d,J=4.4 Hz,1H),6.92(s,1H),4.70 (d,J=6.0Hz,2H).

[0098] Step 6: Compound 1-7 was dissolved in N,N-dimethylformamide (50.0 mL), and the mixture was purged with nitrogen gas three times and cooled to -5°C. Under a nitrogen atmosphere, iodomethane (24.5 g, 173 mmol, 10.7 mL) and sodium hydride (1.27 g, 31.7 mmol, 60% purity) were added sequentially to the reaction mixture, and the mixture was allowed to react at -5°C for 1 hour. The reaction mixture was slowly poured into saturated ammonium chloride solution (30.0 mL) and extracted three times with ethyl acetate (20.0 mL x 3). The organic phases were combined, washed once with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-8. MS (ESI) m / z = 197.7 [M+H] + . 1 H NMR: DMSO-d6,400 MHz δ ppm 8.81(d,J=4.8 Hz,1H),7.75(d,J =4.4 Hz,1H),6.99 (s,1H),4.64 (s,2H), 3.34(s,3H).

[0099] Step 7: Tetrabutylammonium fluoride (21.7 g, 83.3 mmol) was dissolved in N-methylpyrrolidone (25 mL) at room temperature, heated to 130 °C, and reacted for 1 h. Compound 1-8 (5.49 g, 27.7 mmol) was added under N2 protection and stirred at 130 °C for 3 h. The reaction mixture was poured into ice water (200 mL) and extracted three times with ethyl acetate (50 mL × 3). The combined organic phase was washed twice with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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) to obtain compound 1-9.

[0100] MS(ESI) m / z=181.7[M+H] + . 1 H NMR: CDCl3, 400 MHz δ ppm 8.24 (d, J=4.8 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 6.88 (s, 1H), 4.72 (s, 2H), 3.48 (s, 3H).

[0101] Step 8: Compound 1-9 (1.00 g, 5.52 mmol) and N-iodosuccinimide (2.48 g, 11.0 mmol) were dissolved in acetonitrile (10.0 mL) at room temperature and stirred at 25 °C for 20 hours. The mixture was poured into water (10.0 mL) and extracted three times with ethyl acetate (10.0 mL × 3). The organic phases were combined, washed twice with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-10. MS (ESI) m / z = 307.8 [M+H] + .

[0102] Step 9: Compound 1-10 (3.20 g, 10.4 mmol) was dissolved in dioxane (20.0 mL), trimethylboroxine (50% tetrahydrofuran) (3.5 M, 29.7 mL), and potassium carbonate (4.32 g, 31.2 mmol) were added sequentially to the reaction mixture. The air was purged with nitrogen gas three times. Pd(dppf)Cl2 (762 mg, 1.04 mmol) was added under a nitrogen atmosphere, and the mixture was reacted at 90 °C for 10 h. The mixture was poured into water (20.0 mL) and extracted three times with ethyl acetate (10.0 mL × 3). The combined organic phase was washed twice with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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) to obtain compound 1-12. MS(ESI) m / z=196.1[M+H] + .

[0103] Step 10: Compound 1-13 (250 g, 1.76 mol) was dissolved in anhydrous methanol (1.00 L), and trimethyl orthoformate (1.31 kg, 12.3 mol, 1.35 L) and p-toluenesulfonic acid (6.06 g, 35.2 mmol) were added sequentially. The reaction mixture was allowed to react at 25 °C for 30 hours. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate (300 mL). The mixture was concentrated to remove excess methanol and extracted twice with ethyl acetate (200 mL × 2). The organic phases were combined, washed twice with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-15.

[0104] Step 11: Acetonitrile (139 g, 3.40 mol, 179 mL) was dissolved in tetrahydrofuran (700 mL) at room temperature and cooled to -68 °C. Under N protection, 2.5 M n-butyllithium solution in n-hexane (2.50 M, 1.36 L) was added and stirred at -68 °C for 1 hour. Compound 1-15 (320 g, 1.70 mol) was dissolved in tetrahydrofuran (300 mL) and added to the reaction system. The atmosphere was purged with N three times, and the reaction was continued at -68 °C for 1 hour under N conditions. The reaction solution was slowly poured into ice water (2.00 L), the pH was adjusted to 7 with 1 M aqueous hydrochloric acid, and extracted three times with ethyl acetate (1.50 L × 3). The organic phases were combined, washed twice with saturated aqueous sodium chloride (700 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-16. 1 H NMR: CDCl3, 400 MHz δ ppm 3.52 (s, 2H), 3.20 (d, J = 2.40 Hz, 6H), 2.08 (d, J = 8.40 Hz, 3H), 1.97 - 2.04 (m, 1H), 1.83 - 1.92 (m, 3H).

[0105] Step 12: Sodium hydroxide (73.0 g, 1.83 mol) was dissolved in ethanol (500 mL) at room temperature, and tert-butylhydrazine salt (227 g, 1.83 mol) was added under the protection of N2 and stirred at 25 °C for 1 hour. Compound 1-16 (320 g, 1.70 mol) was dissolved in ethanol (250 mL) and then added to the reaction system. The air was replaced with N2 three times, and the reaction was carried out at 75 °C under N2 conditions for 15 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 1-18.

[0106] Step 13: Compound 1-18 (425 g, 1.59 mol) was dissolved in acetonitrile (1.00 L) at room temperature. Benzyl chloroformate (542 g, 3.18 mol, 452 mL) was added under N2 protection. The mixture was stirred at 25°C for 2 hours, and sodium bicarbonate (401 g, 4.77 mol, 185 mL) was added to the reaction mixture. The atmosphere was replaced with N2 three times, and the reaction was continued at 25°C for 11 hours under N2 conditions. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 1-19. MS (ESI) m / z = 356.1 [M+H] + .

[0107] Step 14: Compound 1-19 (758 g, 1.89 mol) and p-toluenesulfonic acid (39.0 g, 226 mmol) were dissolved in water (1.00 L) and acetone (1.00 L) at room temperature. The mixture was purged with N2 three times and stirred at 60 °C for 10 h. The mixture was concentrated to remove excess acetone and extracted three times with dichloromethane (300 mL x 3). The combined organic phases were washed twice with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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) to obtain compound 1-20. MS (ESI) m / z = 356.0 [M+H] + .

[0108] Step 15: Compound 1-20 (177 g, 497 mmol) was dissolved in tetrahydrofuran (900 mL) at room temperature and cooled to -68 °C. Under N2 protection, 1 M lithium triethylborohydride solution in tetrahydrofuran (1 M, 996 mL) was added and stirred at -68 °C for 1.5 hours. The temperature was controlled at -30 °C, and saturated aqueous sodium bicarbonate (900 mL) was slowly added dropwise to the reaction mixture. The temperature was controlled at 10 °C, and hydrogen peroxide (362 g, 3.20 mol, 307 mL, 30% purity) was slowly added dropwise to the reaction mixture. After reacting at 10 °C for 1 hour, complete quenching of the 1 M lithium triethylborohydride solution in tetrahydrofuran was ensured. After completion of the reaction, the mixture was extracted with ethyl acetate (1000 mL x 3). The combined organic phase was then slowly poured into a stirred saturated sodium sulfite solution, taking care to avoid bumping due to exothermic reaction. The oxidizing property was confirmed with moistened potassium iodide starch paper to ensure that the test paper did not turn blue. The organic phase was then washed twice with aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The mixture was extracted three times with ethyl acetate (1.00 L × 3). The combined organic phase was washed twice with saturated aqueous sodium chloride solution (700 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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) to obtain the desired product. The product was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 micrometers), mobile phase: [CO₂-MeOH], B%: 35%, isocratic elution) to obtain compound 1-21.

[0109] Compounds 1-21: SFC (Column: Chiralpak AD-3 50 × 4.6 mm ID, 3 micrometers, Mobile phase: Phase A: CO2, Phase B: MeOH (0.05% DEA), Elution gradient: 5% to 40% B in A, Flow rate: 3 mL / min, Detector: PDA, Column temperature: 35 °C, Back pressure: 100 Bar), RT = 1.158 min; MS (ESI) m / z = 358.7 [M+H]+ . 1 H NMR: DMSO-d6, 400 MHz δ ppm 9.06 (s, 1H), 7.27 - 7.46 (m, 5H), 5.92 (s, 1H), 5.12 (s, 2H), 4.56 (d, J = 4.4 Hz, 1H), 4.10 - 4.19 (m, 1H), 2.89 (t, J = 8.0 Hz, 1H), 2.14 - 2.23 (m, 1H), 1.80 - 1.91 (m, 1H), 1.65 - 1.78 (m, 2H), 1.52 - 1.62 (m, 2H), 1.48 (s, 9H), 1.04 (d, J = 6.2 Hz, 1H).

[0110] Step 16: Compound 1-21 (43.0 g, 120 mmol) was dissolved in tetrahydrofuran (100 mL), and triethylamine (36.5 g, 360 mmol, 50.2 mL) and isopropyl isocyanate (40.9 g, 481 mmol, 47.2 mL) were added sequentially. The mixture was allowed to react at 80 °C for 10 hours. The reaction mixture was slowly poured into water (100 mL) and extracted twice with dichloromethane (100 mL x 2). The combined organic phases were washed twice with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether:ethyl acetate = 100:1-2:1) to obtain compound 1-23. MS (ESI) m / z = 443.8 [M+H] + .

[0111] 1H NMR: DMSO-d6, 400 MHzδ ppm 9.07 (s, 1H), 7.23 - 7.46 (m, 5H), 6.92 (d, J =8.0 Hz, 1H), 5.93 (s, 1H), 5.11 (s, 2H), 3.55 - 3.62 (m, 1H), 2.90 - 2.99 (m, 1H), 2.36 (t, J= 16, 8.0 Hz, 1H), 1.89 - 1.97 (m, 1H), 1.84 (td, J= 8.0, 4.4 Hz, 1H), 1.56 - 1.75 (m, 4H), 1.47 (s, 9H), 1.02 (d, J= 6.6 Hz, 6H).

[0112] Step 17: Compound 1-23 (32.0 g, 72.3 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and the mixture was purged with nitrogen gas three times. Wet palladium on carbon (4.00 g, 50% purity) was added. The nitrogen gas was purged with hydrogen gas (15 psi) three times. The reaction was carried out at 25°C under hydrogen gas (15 psi) for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give compound 1-24. MS (ESI) m / z = 309.3 [M+H] + .

[0113] 1 H NMR: CDCl 3, 400 MHz δ ppm 6.90 (d, J = 8.0 Hz, 1H), 5.22 (s, 1H), 4.70 (s, 2H), 3.52 - 3.60 (m, 1H), 2.78 (s, 1H), 2.25 - 2.33 (m, 1H), 1.51 - 1.89 (m, 6H), 1.47 (s, 9H), 1.03 (d, J = 6.4 Hz, 6H).

[0114] Step 18: Compound 1-24 (1.10 g, 3.57 mmol) was dissolved in tetrahydrofuran (10.0 mL) at room temperature, and the temperature was controlled at -20 °C. Under the protection of N2, 1.0 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 M, 10.7 mL, 3.00 eq) was added and stirred at -20 °C for 1 hour. Compound 1-12 (730 mg, 3.74 mmol) was dissolved in tetrahydrofuran (5.00 mL) and then added to the reaction system. The air was replaced with N2 three times, and the reaction was carried out at -20 °C for 1 hour under N2 conditions. The reaction solution was poured into saturated aqueous ammonium chloride solution (10.0 mL) and extracted three times with ethyl acetate (10.0 mL × 3). The organic phases were combined, washed twice with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-25. MS(ESI) m / z=484.2[M+H] + .

[0115] Step 19: Compound 1-25 (1.00 g, 2.07 mmol) was dissolved in formic anhydride (5.00 mL) and reacted at 100° C. for 0.5 hours. The reaction mixture was concentrated to remove formic acid, yielding compound 1-26. MS (ESI) m / z = 428.2 [M+H] + .

[0116] Step 20: Compound 1-26 (160 mg, 374 μmol) was dissolved in dichloromethane (2.00 mL) at room temperature. The temperature was controlled at -70°C. Boron tribromide (187 mg, 748 μmol, 72.1 μL) was added under N2 protection and stirred at 20°C for 10 hours. The reaction mixture was poured into an ice-water solution (5.00 mL) and extracted three times with dichloromethane (3.00 mL × 3). The organic phases were combined, washed twice with saturated brine (3.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-27. MS (ESI) m / z = 478.0 [M+H] + .

[0117] Step 21: DIEA (157 mg, 1.22 mmol, 212 μL) was added to a solution of compound 1-27 (44.7 mg, 93.9 μmol) and compound 1-28 (44.1 mg, 939 μmol) in THF (1.00 mL) at room temperature and stirred at 50 °C for 5 h. The reaction mixture was diluted with 5.0 mL of HO, extracted three times with 15.0 mL of EtOAc (5.0 mL * 3), washed three times with 15.0 mL of saturated sodium chloride solution (5.0 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification by high-performance liquid chromatography (FA conditions: column: Phenomenexluna C18 150*25.0 mm*10.0 μm, mobile phase: [water (FA) ACN], gradient: 46.0%-76.0% B over 10.0 min) gave the formate salt of compound 1. MS (ESI) m / z = 443.1 [M+H] + . 1 H NMR: DMSO-d6, 400MHz δ = 12.28 - 12.13 (m, 1H), 11.72 - 11.52 (m, 1H), 8.27 (br s, 1H), 8.07 - 7.98 (m, 1H), 7.34 (dd, J = 5.6, 11.8 Hz, 1H), 7.31 - 7.30 (m, 1H), 7.05 - 7.00 (m, 1H), 6.83 - 6.75 (m, 1H), 5.97 - 5.88 (m, 1H), 5.12 - 4.99 (m, 2H), 4.14 - 4.12 (m, 1H), 4.04 (d, J = 6.4 Hz, 1H), 3.71 - 3.57 (m, 2H), 3.41 (s, 4H), 3.21 - 3.09 (m, 2H), 2.60 (s, 3H), 2.13 - 2.08 (m, 1H), 2.00 - 1.95 (m, 1H), 1.71 (br s, 4H), 1.12 - 1.07 (m, 10H).

[0118] Example 2 This example provides compound 2, whose structural formula is as follows: [ka]

[0119] The reaction pathway is shown below. [ka]

[0120] Step 1: Compound 2-1 (245 mg, 2.52 mmol) and N,N-diisopropylethylamine (406 mg, 3.15 mmol, 548 μL) were dissolved in tetrahydrofuran (2.00 mL). The mixture was purged with nitrogen gas three times. Compound 1-27 (150 mg, 314 μmol) was dissolved in tetrahydrofuran (1.00 mL) and added to the reaction mixture. The mixture was reacted at 25 °C for 10 hours and extracted three times with ethyl acetate (10.0 mL × 2). The organic phases were combined, washed twice with saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (0.1% formic acid) to obtain the formate salt of compound 2. MS (ESI) m / z = 457.1 [M+H] + . 1 H NMR: DMSO-d6, 400 MHz δ ppm12.18 (br s, 1H), 11.59 (s, 1H), 7.99 (d, J = 4.8 Hz, 1H), 7.29 (dd, J = 5.2, 16.8 Hz, 1H), 7.01 - 6.91 (m, 1H), 5.88 (s, 1H), 5.01 (br s, 1H), 3.93 (s, 1H), 3.84 (s, 1H), 3.58 (br d, J = 6.8 Hz, 1H), 3.31 (s, 3H), 3.09 (brdd, J = 1.6, 6.4 Hz, 1H), 2.56 (s, 3H), 2.53 (br s, 3H), 2.08 - 2.02 (m, 1H), 1.95 - 1.86 (m, 1H), 1.75 - 1.64 (m, 4H), 1.05 - 1.02 (m, 6H).

[0121] Example 3 This example provides compound 3, whose structural formula is as follows: [ka]

[0122] The reaction pathway is shown below. [ka]

[0123] Step 1: Compound 1-27 (350 mg, 657 μmol) was dissolved in formic acid (3.00 mL) at room temperature and reacted at 90° C. for 30 minutes. The reaction mixture was concentrated to give a crude product. The crude product was purified by HPLC (preparative column: Welch Xtimate C18 150*25 mm*5 μm, mobile phase: [water (TFA)-ACN], gradient: 24%-54% B over 10 min) to give compound 3-1. MS (ESI) m / z = 478.0 (M+H). + .

[0124] Step 2: Compound 3-2 (154 mg, 1.50 mmol) was dissolved in tetrahydrofuran (1.00 mL) at room temperature, cooled to 0 °C, and sodium hydride (10.5 mg, 262 μmol, purity 60%) was added and stirred at 0 °C for 30 minutes. Compound 3-1 (50.0 mg, 52 μmol, TFA) was then dissolved in tetrahydrofuran (0.50 mL) and slowly added dropwise to the reaction mixture at 0 °C. After the addition was complete, the mixture was heated to 25 °C and reacted for 30 minutes. The reaction mixture was poured into ice water (1.00 mL) and extracted three times with ethyl acetate (1.00 mL * 3). The organic phases were combined, washed with saturated aqueous sodium chloride (1.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by HPLC (preparative column: Welch Xtimate C18 150*25mm*5μm, mobile phase: [water(TFA)-ACN], gradient: 27%-57% B over 10 min) to give compound 3-3. MS(ESI) m / z=543.7(M+H)+ .

[0125] Step 3: Compound 3-3 (28.0 mg, 42.6 μmol, TFA) was dissolved in HCl / dioxane (1.00 mL) at room temperature and reacted at 25° C. for 30 minutes. The reaction solution was concentrated, dissolved in methanol, and dried to obtain the hydrochloride salt of compound 3. m / z=443.1 (M+H). + . 1 H NMR: (400 MHz METHANOL-d4) δ= 8.23 ​​(d, J = 5.6 Hz, 1H), 7.49 (d, J = 5.6 Hz, 1H), 6.40 (s, 1H), 5.45 (s, 2H), 5.12 (br s, 1H), 3.76 - 3.65 (m, 1H), 3.29 - 3.22 (m, 1H), 3.06 (s, 3H), 2.78 (s, 3H), 2.69 - 2.57 (m, 1H), 2.29 - 2.14 (m, 1H), 2.06 - 1.77 (m, 4H), 1.17 - 1.08 (m, 6H).

[0126] Example 4 This example provides compound 4, whose structural formula is: [ka]

[0127] The reaction pathway is shown below. [ka]

[0128] Step 1: Compound 1-9 (500 mg, 2.76 mmol) and Select-F (2.93 g, 8.28 mmol) were dissolved in acetonitrile (10.0 mL) at room temperature and stirred at 25 °C for 20 hours. The mixture was poured into water (10.0 mL) and extracted three times with ethyl acetate (10.0 mL × 3). The organic phases were combined, washed twice with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 4-1. MS (ESI) m / z = 199.9 [M+H] + .

[0129] Step 2: Compound 1-24 (800 mg, 2.59 mmol) was dissolved in tetrahydrofuran (8.00 mL) at room temperature, and the temperature was controlled at -20 °C. Under the protection of N2, a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 7.78 mL) was added and stirred at -20 °C for 1 hour. Compound 4-1 (516 mg, 2.59 mmol) was dissolved in tetrahydrofuran (5.00 mL) and then added to the reaction system. The atmosphere was replaced with N2 three times, and the reaction was carried out at -20 °C for 1 hour under N2 conditions. The reaction solution was poured into saturated aqueous ammonium chloride solution (10.0 mL) and extracted three times with ethyl acetate (10.0 mL × 3). The organic phases were combined, washed twice with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-2. MS(ESI) m / z=488.1[M+H] + .

[0130] Step 3: Compound 4-2 (1.12 g, 2.30 mmol) was dissolved in formic anhydride (5.00 mL). The reaction was allowed to proceed at 100°C for 0.5 hours. The reaction mixture was concentrated to remove the formic acid, yielding a crude product. The crude product was purified by reversed-phase high-performance liquid chromatography (0.1%, formic acid condition) to yield compound 4-3. MS (ESI) m / z = 432.0 [M+H] + .

[0131] Step 4: Compound 4-3 (315 mg, 730 μmol) was dissolved in dichloromethane (3.00 mL) at room temperature. The temperature was controlled at -70 °C. Boron tribromide (365 mg, 1.46 mmol, 140 μL) was added under N2 protection and stirred at 20 °C for 10 hours. The reaction mixture was poured into an ice-water solution (5.00 mL) and extracted three times with dichloromethane (3.00 mL × 3). The organic phases were combined, washed twice with saturated brine (3.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 4-4. MS (ESI) m / z = 481.9 [M+H] + .

[0132] Step 5: To a solution of compound 4-4 (150 mg, 312 μmol) and compound 4-5 (415 mg, 3.12 mmol) in THF (1.00 mL), tBuOK (105 mg, 936 μmol) was added and stirred at 0 °C for 10 min. The reaction mixture was diluted with 10.0 mL of HO, extracted three times with 15.0 mL (5.0 mL x 3) of EtOAc, washed three times with 15.0 mL (5.00 mL x 3) of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 4-6. MS (ESI) m / z = 533.2 [M+H] + .

[0133] Step 6: Compound 4-6 (160 mg, 300 μmol) was stirred in HCl / ethyl acetate (1.00 mL) for 1 hour. The reaction mixture was diluted with 10.0 mL of HO and extracted three times with 15.0 mL (5.0 mL * 3) of EtOAc. The mixture was then washed three times with 15.0 mL (5.00 mL * 3) of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 4-7. MS (ESI) m / z = 433.0 [M+H] + .

[0134] Step 7: Paraformaldehyde (90.2 mg, 3.01 mmol, 82.8 μL) was added to a solution of compound 4-7 (130 mg, 300 μmol) in MeOH (0.80 mL) and HO (0.20 mL), and the resulting mixture was stirred for 25 minutes. oThe mixture was stirred at RT for 1 h. The reaction mixture was diluted with 10.0 mL of HO and extracted three times with 15.0 mL of EtOAc (5.00 mL each). The mixture was then washed three times with 15.0 mL of saturated sodium chloride solution (5.00 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification by high-performance liquid chromatography (FA conditions: column: Phenomenexluna C18 150 x 25 mm x 10 μm, mobile phase: [water (FA)-ACN], gradient: 21.0% - 51.0% B over 10 min) gave compound 4. MS(ESI) m / z = 445.0 [M+H] + . 1 H NMR: DMSO-d6, 400MHz δ = 12.21 - 12.09 (m, 1H), 8.02 - 7.95 (m, 1H), 7.42 - 7.34 (m, 1H), 7.15 - 7.07 (m, 1H), 7.02 - 6.90 (m, 1H), 6.65 (br d, J = 7.2 Hz, 1H), 5.28 - 5.18 (m, 2H), 5.17 - 4.95 (m, 2H), 4.92 - 4.92 (m, 1H), 3.63 - 3.52 (m, 1H), 3.30 (br s, 1H), 3.13 - 3.04 (m, 2H), 2.08 - 2.01 (m, 1H), 1.94 - 1.87 (m, 1H), 1.79 - 1.60 (m, 4H), 1.03 (br d, J = 5.2 Hz, 6H).

[0135] Example 5 This example provides compound 5, whose structural formula is as follows: [ka]

[0136] The reaction pathway is shown below. [ka]

[0137] Step 1: Compound 5-1 (139 mg, 1.67 mmol, 126 μL) and N,N-diisopropylethylamine (565 mg, 4.37 mmol, 761 μL) were dissolved in tetrahydrofuran (2.00 mL). The mixture was purged with nitrogen gas three times. Compound 4-4 (100 mg, 208 μmol) was dissolved in tetrahydrofuran (1.00 mL) and reacted at 25 °C for 10 h. The reaction mixture was quenched by pouring into ice water (5.00 mL) and extracted three times with ethyl acetate (5.00 mL × 2). The combined organic phases were washed twice with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (0.1% formic acid) to obtain compound 5. MS (ESI) m / z = 447.2 [M+H] + . 1 H NMR: DMSO-d6, 400 MHz δ ppm12.24 - 12.12 (m, 1H), 8.61 - 8.43 (m, 1H), 7.96 (br d, J = 7.0 Hz, 1H), 7.39 - 7.28 (m, 1H), 7.00 - 6.93 (m, 1H), 6.91 - 6.88 (m, 1H), 6.53 - 6.42 (m, 1H), 5.01 (br s, 1H), 4.09 (d, J = 6.0 Hz, 2H), 3.61 - 3.54 (m, 1H), 3.36 (s, 3H), 3.11 - 3.04 (m, 1H), 2.07 - 2.00 (m, 1H), 1.95 - 1.86 (m, 1H), 1.80 - 1.68 (m, 4H), 1.05 - 1.01 (m, 6H).

[0138] Example 6 This example provides compound 6, whose structural formula is: [ka]

[0139] The reaction pathway is shown below. [ka]

[0140] Step 1: Compound 2-1 (162 mg, 1.67 mmol) and N,N-diisopropylethylamine (269 mg, 2.08 mmol, 362 μL) were dissolved in tetrahydrofuran (2.00 mL). The mixture was purged with nitrogen gas three times. Compound 4-4 (100 mg, 208 μmol) was dissolved in tetrahydrofuran (1.00 mL) and reacted at 25 °C for 10 hours. The reaction mixture was quenched by pouring into ice water (5.00 mL) and extracted three times with ethyl acetate (5.00 mL × 2). The combined organic phases were washed twice with saturated brine (5.00 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by reverse-phase high-performance liquid chromatography (0.1% formic acid) to obtain compound 6. MS (ESI) m / z = 461.1 [M+H] + . 1 H NMR: DMSO-d6, 400 MHz δ ppm 12.24 - 12.09 (m, 1H), 8.59 - 8.45 (m, 1H), 8.02 - 7.92 (m, 1H), 7.34 (br d, J = 4.8 Hz, 1H), 6.96 (br d, J = 8.4 Hz, 1H), 6.49 (br s, 1H), 5.07 - 4.92 (m, 1H), 3.98 (s, 2H), 3.58 (br dd, J = 6.8, 12.0 Hz, 1H), 3.33 - 3.33 (m, 3H), 3.10 (br s, 1H), 2.60 - 2.55 (m, 3H), 2.11 - 1.99 (m, 1H), 1.96 - 1.85 (m, 1H), 1.80 - 1.60 (m, 4H), 1.03 (dd, J = 2.4, 6.4 Hz, 6H).

[0141] Example 7 This example provides compound 7, whose structural formula is: [ka]

[0142] The reaction pathway is shown below. [ka]

[0143] Step 1: Compound 3-2 (367 mg, 2.50 mmol) was dissolved in tetrahydrofuran (1.00 mL) at room temperature. The mixture was purged with nitrogen gas three times and cooled to 0 °C. Sodium hydride (14.9 mg, 374 μmol, purity 60%) was added and stirred for 30 minutes. Compound 4-4 (60.0 mg, 124 μmol) was then dissolved in tetrahydrofuran (1.00 mL) and slowly added dropwise to the reaction mixture. The mixture was heated to 20 °C and allowed to react for 30 minutes. The reaction mixture was poured into ice water (1.00 mL) and extracted three times with ethyl acetate (1.00 mL * 3). The organic phases were combined, washed with saturated aqueous sodium chloride (1.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by HPLC (preparative column: Welch Xtimate C18 150*25mm*5.0μm, mobile phase: [water(FA)-ACN], gradient: 32.0%-62.0% B over 10min) to give compound 7-1. m / z=547.5 (M+H). + .

[0144] Step 2: Compound 7-1 (35.0 mg, 59.0 μmol) was dissolved in HCl / EtOAc (0.50 mL) at room temperature. The reaction was allowed to proceed at 25°C for 30 minutes. The reaction mixture was concentrated, dissolved in methanol, diluted with deionized water, and then lyophilized to obtain the hydrochloride salt of compound 7. m / z = 447.0 (M+H). + . 1H NMR: (400 MHz METHANOL-d4) δ8.17 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 6.34 (s, 1H), 5.40 (s, 2H), 5.12 (br s, 1H), 3.75 - 3.65 (m, 1H), 3.03 (s, 3H), 2.68 - 2.57 (m, 1H), 2.25 - 2.16 (m, 1H), 2.11 - 1.88 (m, 4H), 1.82 (br d, J = 8.4 Hz, 1H), 1.14 - 1.10 (m, 6H).

[0145] In vitro activity test Experimental Example 1: In vitro CDK2 / CyclinE enzyme activity test Test materials: CDK2 / CyclinE1 was purchased from SignalChem. Ulight-4E-BP1 polypeptide, 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 (PerkinElmer).

[0146] Experimental Method: Preparation of kinase buffer: The kinase buffer contains 50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, and 0.01% Brij-35, and has a pH of 7.4. To 200 ml of the buffer, 2.38 g of HEPES, 58 mg of EDTA, 406 mg of MgCl2, and 20 mg of Brij-35 were added, and the pH was adjusted to 7.4.

[0147] Preparation of stop solution: A stop solution was prepared by adding 0.625 μL of 1× detection buffer to 100 μL of 1 M EDTA stock solution and mixing with 1725 μL of distilled water.

[0148] The enzyme, Ulight-4E-BP1 polypeptide, ATP, and inhibitor were diluted in kinase buffer. Eu-anti-phosphotyrosine antibody was diluted in detection buffer to a concentration of 8 nM / L. The test compounds were diluted 5-fold using a multichannel pipette to eight concentrations, from 4 μM to 0.0512 nM. The final DMSO concentration was 4%. A double-well experiment was set up. 2.5 μL of each inhibitor concentration gradient, 5 μL of CDK2 / CyclinE1 enzyme (10 ng), and 2.5 μL of a mixture of substrate and ATP (4 mM ATP, 100 nM Ulight4E-BP1 polypeptide) were added to a microplate. The final compound concentration gradient was from 1 μM to 0.0128 nM, and the final ATP and substrate concentrations were 1 mM and 25 nM. The reaction mixture was incubated at 25°C for 120 minutes. After the reaction was completed, 5 μL of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well, and the reaction was continued at 25°C for 60 minutes. Data were then collected in TR-FRET mode using a PerkinElmer Nivo multilabel analyzer (excitation wavelength: 320 nm, emission wavelengths: 615 nm and 665 nm).

[0149] Data Analysis: The raw data was converted to percent inhibition using the equation (Sample-Min) / (Max-Min)*100% to obtain IC 50 The values ​​of were obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode). Table 1 shows the enzymatic inhibitory activity of the compounds of the present invention against CDK2 / CyclinE1.

[0150] Experimental Example 2: In vitro CDK1 / CyclinB1 enzyme activity test Test materials: CDK1 / CyclinB1 was purchased from CARNA. Ulight-4E-BP1 polypeptide, 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 (PerkinElmer).

[0151] Experimental Method: Kinase buffer preparation: The kinase buffer contains 50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, and 0.01% Brij-35, and has a pH of 7.4. To 200 ml of the buffer, 2.38 g of HEPES, 58 mg of EDTA, 406 mg of MgCl2, and 20 mg of Brij-35 were added, and the pH was adjusted to 7.4.

[0152] Preparation of stop solution: A stop solution was prepared by adding 0.625 μL of 1× detection buffer to 100 μL of 1 M EDTA stock solution and mixing with 1725 μL of distilled water.

[0153] The enzyme, Ulight-4E-BP1 polypeptide, ATP and inhibitor were diluted in kinase buffer.

[0154] The Eu-anti-phospho-tyrosine antibody was diluted with the detection buffer to a concentration of 8 nM / L.

[0155] The test compounds were diluted 5-fold using a multichannel pipette to the eighth concentration, from 4 μM to 0.0512 nM. The final DMSO concentration was 4%. A double-well experiment was set up. 2.5 μL of each inhibitor concentration gradient, 5 μL of CDK1 / Cyclin B1 enzyme (0.5 ng), and 2.5 μL of a substrate and ATP mixture (4 mM ATP, 200 nM Ulight-4E-BP1 polypeptide) were added to a microplate. The final compound concentration gradient was from 1 μM to 0.0128 nM, and the final ATP and substrate concentrations were 1 mM and 50 nM. The reaction mixture was incubated at 25°C for 60 minutes. After the reaction was completed, 5 μL of stop solution was added to each well, and the reaction was continued at 25°C for 5 minutes. After the reaction was completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well, and the reaction was continued at 25°C for 60 minutes. Data were then collected in TR-FRET mode using a PerkinElmer Nivo multilabel analyzer (excitation wavelength: 320 nm, emission wavelengths: 615 nm and 665 nm).

[0156] Data Analysis: The raw data was converted to percent inhibition using the equation (Sample-Min) / (Max-Min)*100% to obtain IC 50 The values ​​of were obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode). Table 1 provides the enzymatic inhibitory activity of the compounds of the present invention against CDK1 / CyclinB1.

[0157] Experimental Example 3: In vitro OVCAR3 cell activity test Test materials: 1640 medium, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from WISENT. CellTiter-Glo (a chemiluminescent cell viability detection reagent) reagent was purchased from Promega. OVCAR3 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision multilabel analyzer (PerkinElmer).

[0158] Experimental Method: OVCAR3 cells were seeded into a white 384-well plate, and 40 μL of cell suspension containing 300 OVCAR3 cells was added per well. The cell plate was incubated overnight in a carbon dioxide incubator.

[0159] The test compounds were diluted 5-fold using a multichannel pipette to the eighth concentration, i.e., from 2000 μM to 0.00512 μM, and a double-well experiment was set up. 78 μL of medium was added to the middle plate, and 2 μL of the diluted compounds per well was transferred to the corresponding position in the middle plate. After uniform mixing, 10 μL per well was transferred to the cell plate. The compound concentrations transferred to the cell plate ranged from 10 μM to 0.026 nM. The cell plate was cultured in a carbon dioxide incubator for 7 days. A second cell plate was prepared, and the signal value on the day of drug administration was read. This was used as the maximum value (Max value in the equation below) for data analysis. 10 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Data were read using a multilabel analyzer.

[0160] 10 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Data were read using a multilabel analyzer.

[0161] Data Analysis: The raw data was converted to percent inhibition using the equation (Sample-Min) / (Max-Min)*100% to obtain IC 50 The values ​​of were obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode). Table 1 provides the inhibitory activity of compounds of the present invention against OVCAR3 cell proliferation.

[0162] Experimental Example 4: In vitro T47D cell activity test Test materials: 1640 medium, fetal bovine serum, and penicillin / streptomycin antibiotics were purchased from WISENT. CellTiter-Glo (a chemiluminescent cell viability detection reagent) reagent was purchased from Promega. T-47 D cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision multilabel analyzer (PerkinElmer).

[0163] Experimental Method: T-47D cells were seeded into a white 384-well plate, and 40 μL of cell suspension was added per well, containing 300 T-47D cells. The cell plate was incubated overnight in a carbon dioxide incubator.

[0164] The test compounds were diluted 5-fold using a multichannel pipette to the eighth concentration, i.e., from 2000 μM to 0.00512 μM, and a double-well experiment was set up. 78 μL of medium was added to the middle plate, and 2 μL of the diluted compounds per well was transferred to the corresponding position in the middle plate. After uniform mixing, 10 μL per well was transferred to the cell plate. The compound concentrations transferred to the cell plate ranged from 10 μM to 0.026 nM. The cell plate was cultured in a carbon dioxide incubator for 7 days. A second cell plate was prepared, and the signal value on the day of drug administration was read. This was used as the maximum value (Max value in the equation below) for data analysis. 10 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Data were read using a multilabel analyzer.

[0165] 10 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Data were read using a multilabel analyzer.

[0166] Data Analysis: The raw data was converted to percent inhibition using the equation (Sample-Min) / (Max-Min)*100% to obtain IC 50 The values ​​of were obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode). Table 1 provides the inhibitory activity of compounds of the present invention against T-47D cell proliferation. [Table 1]

[0167] Results and Conclusions: The compounds of the present invention have high in vitro activity and high selectivity for CDK2 over CDK1. Specifically, the IC of compound 1 formate for CDK1 was 50 (nM) was 1908, and the IC of Compound 2 formate CDK1 50 (nM) was 4084, and the IC 50 (nM) was 1354, and the IC 50 (nM) was 1501, and the IC 50 (nM) was 3493, and the IC value of the hydrochloride CDK1 of compound 7 50 (nM)>10000, which is superior to PF-07104091.

[0168] In vivo pharmacokinetic studies Experimental Example 5: Pharmacokinetic study of test compounds by oral and intravenous injection in mice Objective of the experiment: ICR male mice were selected as the test animals for this study, and the plasma drug concentrations of the test compound and reference compound administered intravenously or orally to the mice at different time points were quantitatively measured using LC / MS / MS to evaluate the pharmacokinetic characteristics of the test drug in the mouse body.

[0169] Test materials: ICR mice (male, 20–30 g, 6–8 weeks old, Beijing Weitonglihua).

[0170] Experimental Procedure: A clear solution of the test compound was injected into ICR mice via tail vein injection (overnight fasting or fed) or intragastric administration (overnight fasting or fed). For intravenous administration, 50 μL of blood was collected by cheek puncture at time 0 (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an anticoagulant tube containing sodium heparin, thoroughly vortex-mixed at 4°C, and centrifuged at 6000 rpm for 3 minutes. For oral intragastric administration, blood was collected by cheek puncture at time 0 (before administration) and 0.083, 0.25, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an anticoagulant tube containing sodium heparin, thoroughly vortex-mixed, and centrifuged at 6000 rpm for 3 minutes. Blood concentrations were measured using LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the non-compartmental linear-logarithmic trapezoidal method using Phoenix WinNonlin 8.2.0 pharmacokinetic software. The experimental results are shown in Table 2. [Table 2]

[0171] Results and conclusions: The compounds of the present invention exhibit excellent bioavailability, and the time to peak and AUC at the same dose are significantly better than those of PF-07104091.

[0172] In vivo efficacy studies Experimental Example 6: In vivo pharmacodynamic study of human ovarian cancer OVCAR-3 cell subcutaneous xenograft tumor CB17-SCID mouse model Experimental Procedure: Cell culture: OVCAR-3 cells (human ovarian cancer cell line, purchased from the New Cell Bank) were cultured in vitro (37°C, 5% CO2) in RPMI-1640 (ATCC modified, Gibco) medium supplemented with 20% FBS (Gibco) and 1% PS, and passaged twice a week. OVCAR-3 cells in the logarithmic phase were harvested and resuspended in a mixture of PBS and Matrigel (Corning) (1:1 volume ratio of PBS to Matrigel) to a cell concentration of 5 × 10 7 A cell suspension of 100 cells / mL was prepared and inoculated into mice.

[0173] Animals: CB17-SCID mice, female, 6-8 weeks old, weighing 18-21 grams. A total of 40 mice were inoculated. They were provided by Shanghai Lingcheng Biotechnology Co., Ltd.

[0174] Tumor inoculation: Each mouse received 0.2 mL of OVCAR3 tumor cells (10 × 10) in the right dorsal region. 6 ) were inoculated subcutaneously.

[0175] Experimental parameters: Experimental parameters were used to assess whether tumor growth was inhibited, delayed, or cured. Tumor diameters were measured twice a week using calipers. The formula for tumor volume was V = 0.5a × b2, where a and b represent the long and short diameters of the tumor, respectively.

[0176] Antitumor index TGI (%): Reflects the tumor growth inhibition rate. TGI (%) was calculated as follows: TGI (%) = [(1 - (mean tumor volume at the end of treatment of a certain treatment group - mean tumor volume at the start of treatment of that treatment group)) / (mean tumor volume at the end of treatment of the vehicle control group - mean tumor volume at the start of treatment of the vehicle control group)] × 100%.

[0177] Experimental Results: The experimental results are shown in Table 3. [Table 3]

[0178] The compounds of the present application show unexpected tumor regression effects in the OVCAR3 in vivo efficacy model and are well tolerated in animals.

[0179] In vivo PD studies Experimental Example 7: In vivo PD study of the OVCAR-3 mouse model of human ovarian cancer Experimental Procedure: Cell culture: Human ovarian cancer OVCAR-3 cells (ATCC, Manassas, cat#HTB-161). The cells were cultured in vitro in monolayers in RPMI 1640 medium supplemented with 20% fetal bovine serum, 0.01 mg / ml bovine insulin, and 1% diabody (antianti). The cells were cultured in a 37°C, 5% CO2 incubator. They were passaged twice a week by routine trypsin-EDTA digestion. When the cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and inoculated.

[0180] Animals: BALB / c nude mice, female, 7-9 weeks old, weighing 18-23 grams. A total of 100 mice were inoculated. They were provided by the Laboratory Animal Management Department of the Shanghai Institute of Family Planning (formerly Shanghai Xipuer-Bikai).

[0181] Tumor inoculation: 0.2 mL (10 × 10 6 OVCAR-3 cells (1:1 volume ratio with Matrigel) were subcutaneously inoculated into the right dorsal region of each mouse, resulting in tumors with an average volume of 171 mm 3 When this was reached, the animals were divided into groups and medication was started, with 6 animals in each group, for a total of 10 groups.

[0182] Tumor Sampling: Tumor samples were collected after 21 consecutive days of dosing.

[0183] Protein extraction and quantification: 1) The flash-frozen tissue samples were removed from a -80°C refrigerator or liquid nitrogen tank. 2) After handling on ice, remove a portion of the tissue (approximately 30-100 mg) and place it in a 2 mL centrifuge tube containing a steel ball. Add 400 μL of RIPA cell lysis solution (freshly supplemented with 1% protease inhibitors and phosphatase inhibitors). 3) The tissue was crushed using a cryo-pulverizer at a frequency of 50 Hz for 5 minutes. 4) The tissue lysis solution was placed on ice for 30 minutes. 5) The mixture was centrifuged at 15,000 rpm at 4°C for 10 minutes, and the supernatant was removed and placed in a new centrifuge tube (1.5 mL). 6) Protein quantification was performed using a BCA quantification kit. 7) Based on the quantitative results, protein samples for loading were prepared, the protein concentration of the samples was standardized to 4 μg / μL, LDS loading buffer (4X) and sample reducing agent (10X) were added, and the samples were heated at a constant temperature of 100°C for 10 minutes. 8) Western blot or denatured samples were stored in a refrigerator at -80°C.

[0184] Immunoblotting: 1) Loading: The samples were thawed and loaded into each well using a Bis-Tris gel at 10 μL. 2) Electrophoresis: in 1X MES electrophoresis buffer at 80 volts for 30 minutes, then at 120 volts for 90 minutes. 3) Blotting: Performed using iBlot2 blotting set and blotting device, program is to run at 20 volts for 7 minutes. 4) After blotting was completed, cut the film according to the molecular weight of the desired detection protein, and washed the film three times with 10 mL of 1xTBS, for 5 minutes each time, and shaken at room temperature. 5) Blocking: The film was blocked by placing it in 10 mL of blocking solution (Intercept (registered trademark) (TBS) blocking solution) and shaking slowly at room temperature for 1 hour. 6) Primary antibody incubation: Add 10 mL of appropriate dilution of primary antibody (diluted in Intercept® (TBS) blocking solution containing 0.1% Tween-20) and incubate at 4°C with gentle shaking. pRb (T821) antibody was diluted 1:1000 and incubated for 3 days, and GAPDH antibody was diluted 1:2000 and incubated overnight. 7) Wash the film three times with 10 mL of 1xTBST, for 10 minutes each time, and shake at room temperature. 8) Secondary antibody incubation: Add 10 mL of appropriate dilution of secondary antibody (diluted in Intercept® (TBS) blocking solution containing 0.1% Tween-20, at a dilution ratio of 1:10000) and shake gently at room temperature for 1 hour. 9) Wash the film three times with 10 mL of 1xTBST, for 10 minutes each time, and shake at room temperature. 10) The film was washed twice with 10 mL of 1xTBS to remove any Tween-20 remaining on the film, for 5 minutes each time, and shaken at room temperature. 11) Fluorescence signal values ​​were detected using Odyssey Clx and its software Image Studio Ver. 5.2.

[0185] Expression quantification: Relative quantification of the fluorescent spectral bands of immunoblots was performed using Image Studio Lite Ver5.2 software.

[0186] Data Analysis: The spectral band density intensity obtained by software quantification was analyzed to calculate the expression ratio of the target protein relative to the internal standard (GAPDH), and the normalized fold expression of the target protein in each treatment group was calculated relative to the blank control group. The normalized fold expression of the protein in each group was displayed in a GraphPad Prism 6.02 pattern.

[0187] Experimental Results: The experimental results are shown in Figure 1.

[0188] Experimental conclusion: Immunoblot experiments showed that the compounds of this application effectively inhibit CDK2 enzyme activity and reduce pRb protein levels, thereby blocking the transition from G1 to S phase of the cell cycle and inhibiting tumor cell proliferation. At the same dose, the inhibitory activity of the compounds of this application on T821 phosphorylation of pRb downstream of CDK2 was superior to that of PF-07104091.

[0189] The technical features of the above-described embodiments can be combined in any manner, and for the sake of brevity, not all possible combinations of the technical features in the above-described embodiments are described, but as long as there is no contradiction in the combination of these technical features, they should be considered within the scope described in this specification.

[0190] The above examples only describe some embodiments of the present invention, and are intended to facilitate a specific and detailed understanding of the technical solutions of the present invention, but should not be construed as limiting the scope of the claims of the present invention. Those skilled in the art may make minor modifications and improvements without departing from the spirit of the present invention, and all of these modifications and improvements fall within the scope of protection of the present invention. It should be understood that any technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited experiments based on the technical solutions provided by the present invention are within the scope of the claims attached to the present invention. Therefore, the patent protection scope of the present invention depends on the content of the claims attached to the present invention, and the specification serves to explain the content of the claims.

Claims

1. A pyrazole derivative represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: 【Chemistry 1】 (In the formula, X, at each occurrence, is independently N or CR ４ and R ４ is absent or selected from -H, -D, -F, -Cl, -Br, -I, a linear alkyl group having 1 to 6 C atoms, a linear deuterated alkyl group having 1 to 6 C atoms, a branched alkyl group having 3 to 6 C atoms or an aromatic heterocycle, R １ is selected from -H, -D, -F, -Cl, -Br, -I, a linear alkyl group having 1 to 20 C atoms, a linear deuterated alkyl group having 1 to 20 C atoms, a branched alkyl group having 3 to 20 C atoms, a branched deuterated alkyl group having 3 to 20 C atoms, a cyclic alkyl group having 3 to 20 C atoms, a cyclic deuterated alkyl group having 3 to 20 C atoms, a linear alkoxy group having 1 to 20 C atoms, a linear deuterated alkoxy group having 1 to 20 C atoms, a branched alkoxy group having 3 to 20 C atoms, a branched deuterated alkoxy group having 3 to 20 C atoms, a cyclic alkoxy group having 3 to 20 C atoms, a cyclic deuterated alkoxy group having 3 to 20 C atoms, R ３ is selected from a substituted or unsubstituted alkyl group having 1 to 6 C atoms, a substituted or unsubstituted fluoroalkyl group having 1 to 6 C atoms, a substituted or unsubstituted cycloalkyl group having 3 to 7 C atoms, and a substituted or unsubstituted heterocyclic group having 4 to 7 ring atoms, R ２ is -F, -Cl, -OH, -CN, -NR ５ R ６ , -CH ２ -ONR ７ R ８ , -CH ２ -ON=R ９ , -CH ２ N (R １０ ) OR １１ , a substituted or unsubstituted alkyl group having 1 to 4 C atoms, a substituted or unsubstituted fluoroalkyl group having 1 to 4 C atoms, a substituted or unsubstituted alkoxy group having 1 to 4 C atoms, a substituted or unsubstituted fluoroalkoxy group having 1 to 4 C atoms, or a substituted or unsubstituted cycloalkyl group having 3 to 8 C atoms; R ５ , R ６ , R ７ , R ８ , R １０ , R １１ are each independently selected from -H, -D, a linear alkyl group having 1 to 20 C atoms, a linear deuterated alkyl group having 1 to 20 C atoms, a branched alkyl group having 3 to 20 C atoms, a branched deuterated alkyl group having 3 to 20 C atoms, a cyclic alkyl group having 3 to 20 C atoms, a cyclic deuterated alkyl group having 3 to 20 C atoms, a linear alkoxy group having 1 to 20 C atoms, a linear deuterated alkoxy group having 1 to 20 C atoms, a branched alkoxy group having 3 to 20 C atoms, a branched deuterated alkoxy group having 3 to 20 C atoms, a cyclic alkoxy group having 3 to 20 C atoms, and a cyclic deuterated alkoxy group having 3 to 20 C atoms; R ９ is selected from a linear alkylene group having 1 to 20 C atoms, a linear deuterated alkylene group having 1 to 20 C atoms, a branched alkylene group having 3 to 20 C atoms, a branched deuterated alkylene group having 3 to 20 C atoms, a cyclic alkylene group having 3 to 20 C atoms, and a cyclic deuterated alkylene group having 3 to 20 C atoms.

2. The pyrazole derivative according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the pyrazole derivative has a structure represented by formula (II): 【Chemistry 2】

3. The pyrazole derivative according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the pyrazole derivative has a structure represented by formula (III). 【Transformation 3】

4. R １ is selected from -H, -D, -F, -Cl, -Br, -I, a linear alkyl group having 1 to 10 C atoms, a linear deuterated alkyl group having 1 to 10 C atoms, a branched alkyl group having 3 to 10 C atoms, a branched deuterated alkyl group having 3 to 10 C atoms, a cyclic alkyl group having 3 to 10 C atoms, and a cyclic deuterated alkyl group having 3 to 10 C atoms.

5. R ５ , R ６ , R ７ , R ８ , R １０ , R １１ are each independently selected from -H, -D, a linear alkyl group having 1 to 10 C atoms, a linear deuterated alkyl group having 1 to 10 C atoms, a branched alkyl group having 3 to 10 C atoms, a branched deuterated alkyl group having 3 to 10 C atoms, a cyclic alkyl group having 3 to 10 C atoms, a cyclic deuterated alkyl group having 3 to 10 C atoms, a linear alkoxy group having 1 to 10 C atoms, a linear deuterated alkoxy group having 1 to 10 C atoms, a branched alkoxy group having 3 to 10 C atoms, a branched deuterated alkoxy group having 3 to 10 C atoms, a cyclic alkoxy group having 3 to 10 C atoms, and a cyclic deuterated alkoxy group having 3 to 10 C atoms; R ９ is selected from a linear alkylene group having 1 to 20 C atoms, a linear deuterated alkylene group having 1 to 20 C atoms, a branched alkylene group having 3 to 20 C atoms, a branched deuterated alkylene group having 3 to 20 C atoms, a cyclic alkylene group having 3 to 20 C atoms, a cyclic deuterated alkylene group having 3 to 20 C atoms, or a combination thereof.

6. R ２ The pyrazole derivative, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein: is any one selected from the following structures: 【Chemistry 4】

7. The pyrazole derivative according to any one of claims 1 to 6, which is any one of the following compounds, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: 【Transformation 5】

8. Use of the pyrazole derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for treating and / or preventing a disease associated with or mediated by CDK2 activity.

9. 9. The use according to claim 8, wherein the disease associated with or mediated by CDK2 activity is cancer.

10. A pharmaceutical composition comprising the pyrazole derivative according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

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