Selective CDK inhibitor compound and application thereof

Abstract

Provided is a compound targeting a cyclin-dependent kinase (CDK), and specifically provided is a compound as represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The compound has the substituents and structural features as described in the present application. Also described are a pharmaceutical composition containing the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical application of the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Description

Selective CDK inhibitor compounds and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of the following patent applications for invention, the contents of which are hereby incorporated by reference in their entirety:

[0003] Chinese Patent Application No. 202410730128.7, filed on June 6, 2024, with the State Intellectual Property Office of the People’s Republic of China. TECHNICAL FIELD

[0004] The present disclosure belongs to the field of medicine, and relates to a selective Cyclin-Dependent Kinases (CDK) inhibitor compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and the use thereof as a selective CDK inhibitor in the prevention or treatment of related diseases. BACKGROUND

[0005] The occurrence of tumors is related to the imbalance of a variety of oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes ultimately converge on the cell cycle. Therefore, it can be said that tumors are a class of cell cycle diseases (CCD), and regulating or blocking the cell cycle is one of the ways to treat tumors. At present, many molecules related to cell cycle regulation have been found, among which Cyclin-Dependent Kinases (CDKs) are the core molecules of the cell cycle regulation network.

[0006] CDKs are a class of serine / threonine protein kinases that drive the cell cycle through phosphorylation of serine / threonine proteins and are important factors in cell cycle regulation in conjunction with cyclins. Disregulation of CDK-cyclin complex activity leads to loss of cell cycle and transcriptional control in tumor cells. In the past three decades, some important progress has been made in the research of CDK inhibitors. Selective CDK4 / 6 inhibitors have been approved for use in cancer patients, but more selective inhibitors targeting other subtypes of the CDK family are still in urgent need of development. Another important CDK isoform is CDK2, which can phosphorylate Retinoblastoma (Rb) to release E2F transcription factor (E2F) consistent with the sequence of CDK4 / 6. CDK2, together with its typical binding partner Cyclin E1 (CCNE1), drives the G1 / S progression. The amplification of this protein has been observed in many cancer types and is associated with lower overall survival in breast cancer, ovarian cancer and other cancer patients. In addition, selective CDK2 inhibitors have the potential to benefit cancer patients who are resistant to CDK4 / 6 inhibitor therapy due to CCNE1 amplification. Therefore, the present application is committed to developing new selective CDK2 inhibitors. SUMMARY

[0007] The present disclosure relates to a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0008] wherein:

[0009] Z 1 , Z 2 are each independently selected from -C(R Z1 R Z2 )-, -C(R Z1 R Z2 )C(R Z3 R Z4 )- or -C(R Z1 )=C(R Z2 )-;

[0010] R Z1 , R Z2 , R Z3 , R Z4 are each independently selected from hydrogen, deuterium or halogen;

[0011] X 1 is selected from NH(C(R X3 R X4 )) k or S;

[0012] k is selected from 0, 1 or 2;

[0013] ring A is absent or ring A is selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 4-14 membered heterocyclic ring, a 5-10 membered heteroaromatic ring, or a phenyl ring, said 3-7 membered saturated or partially unsaturated carbocyclic ring, 4-14 membered heterocyclic ring, 5-10 membered heteroaromatic ring, or phenyl ring being optionally substituted with one or more R A substituted;

[0014] L 4 selected from a bond, -C(R L1 R L2 )-, -C(R L1 R L2 )C(R L3 R L4 )-, -C(=O)-, -C(=O)O-, -C(R L1 R L2 )C(=O)O-, -C(R L1 R L2 )OC(=O)-, -C(=O)NR 1a -, -C(R L1 R L2 )C(=O)NR 1a -, -C(R L1 R L2 )NR 1a C(=O)-, -NR 1a C(=O)NR 1b -, -NR 1a C(=O)O-, -S(=O)-, -S(=O)2-, -SO2NR 1a -, -C(R L1 R L2 )SO2NR 1a -, -C(R L1 R L2 )NR 1a SO2-, -NR 1a SO2NR 1b -, -C(R L1 R L2 )NR 1a SO2NR 1b -, -NR 1a S(=O)2O-, -NR 1a S(=O)-, -NR 1a S(=O)O-, -N=S(=O)R 1a -, -P(=O)R 1a - or -S(=O)(=NR 1a )-;

[0015] R 1halogen, CN, OH, NH2, C1-C4alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said OH, NH2, C1-C4alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl optionally substituted with one or more R 2 or -NR 2a R 2b , said C1-C6alkyl, C3-C7cycloalkyl, 4-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl optionally substituted with one or more R B ;

[0016] X 3 is selected from NH or O;

[0017] X 2 is selected from NR X1 , C(R X1 R X2 ), O or S;

[0018] L 1 , L 2 , L 3 are each independently selected from a bond, -C(=O)-, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -O-, -OC(R 1c R 1d )-, -NR 1c -, -NR 1c C(R 1e R 1f )-, -C(R 1c ) = C(R 1e )-, -CºC-, a 3-6 membered saturated or partially unsaturated carbocyclic ring, a 3-6 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaromatic ring, said 3-6 membered saturated or partially unsaturated carbocyclic ring, 3-6 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaromatic ring optionally substituted with one or more R E ;

[0019] R X1 , R X2 , R X3 , R X4 , R 1c , R 1d , R 1e , R 1f are each independently selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said OH, NH2, C1-C4alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl optionally substituted with one or more RC substituted;

[0020] R X1 , R X2 and the atoms to which they are attached together form a 3-6 membered saturated or partially unsaturated carbocyclic ring or a 3-6 membered heterocyclic ring, or R X1 , R 1c and the atoms to which they are attached or R X1 , R 1e and the atoms to which they are attached together form a 3-6 membered saturated or partially unsaturated carbocyclic ring, a 3-6 membered heterocyclic ring, a phenyl ring or a 5-6 membered heteroaromatic ring, which 3-6 membered saturated or partially unsaturated carbocyclic ring, 3-6 membered heterocyclic ring, phenyl ring or 5-6 membered heteroaromatic ring is optionally substituted by one or more R C substituted;

[0021] R A is selected from deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered-heterocyclyl, phenyl or 5-6 membered-heteroaryl, which OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered-heterocyclyl, phenyl or 5-6 membered-heteroaryl is optionally substituted by one or more R D substituted;

[0022] R L1 , R L2 , R L3 , R L4 , R 1a , R 1b , R 2 , R 2a , R 2b are independently from each other selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered-heterocyclyl, phenyl or 5-6 membered-heteroaryl, which OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered-heterocyclyl, phenyl or 5-6 membered-heteroaryl is optionally substituted by one or more R D substituted;

[0023] R B , R C , R D , R E are independently from each other selected from deuterium, =0, OH, CN, halogen, NH2, C1-C4-alkyl, C1-C4-alkoxy or C3-C6-cycloalkyl, which C1-C4-alkyl, C1-C4-alkoxy or C3-C6-cycloalkyl is optionally substituted by one or more R;

[0024] R is selected from deuterium, =0, OH, CN, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy or C3-C6-cycloalkyl.

[0025] In some embodiments, Z 1 is selected from -C(R Z1 R Z2 )-, -C(R Z1 R Z2 )C(R Z3 R Z4 )-, or -C(R Z1 ) = C(R Z2 )-, Z 2 is selected from -C(R Z1 R Z2 )-.

[0026] In some embodiments, Z 1 is selected from -C(R Z1 R Z2 )-, or -C(R Z1 R Z2 )C(R Z3 R Z4 )-, Z 2 is selected from -C(R Z1 R Z2 )-.

[0027] In some embodiments, R Z1 , R Z2 , R Z3 , R Z4 are independently selected from hydrogen or deuterium. In some embodiments, R Z1 , R Z2 , R Z3 , R Z4 are selected from hydrogen.

[0028] In some embodiments, Z 1 is selected from CH2or CH2CH2, Z 2 is selected from CH2.

[0029] In some embodiments, Z 1 is selected from CH2CH2, Z 2 is selected from CH2.

[0030] In some embodiments, X 1 is selected from NH(C(R X3 R X4 )) k , and k is selected from 0, 1, or 2.

[0031] In some embodiments, X 1 is selected from NH(C(R X3 R X4 )) k , and k is selected from 0 or 1.

[0032] In some implementation schemes, R X3 R X4 The components are independently selected from hydrogen, deuterium, halogen, CN, OH, NH2, or C1-C4 alkyl groups, wherein the OH, NH2, or C1-C4 alkyl group is optionally converted by one or more R groups. C replace.

[0033] In some implementation schemes, R X3 R X4 They are independently selected from hydrogen, deuterium, or methyl.

[0034] In some implementation schemes, X 1 Selected from NH.

[0035] In some embodiments, ring A is absent or ring A is selected from 3-6 membered saturated carbocyclic rings, 4-8 membered heterocyclic rings, 5-6 membered heteroaromatic rings, or benzene rings, wherein the 3-6 membered saturated carbocyclic ring, 4-8 membered heterocyclic ring, 5-6 membered heteroaromatic ring, or benzene ring is optionally surrounded by one or more R A What it replaced.

[0036] In some embodiments, ring A is selected from 4-8-membered heterocycles, 5-6-membered heteroaromatic rings, or benzene rings, wherein the 4-8-membered heterocycle, 5-6-membered heteroaromatic ring, or benzene ring is optionally surrounded by one or more R... A What it replaced.

[0037] In some implementations, ring A is selected from... The rings are tetrahydropyrrole ring, tetrahydrofuran ring, piperidine ring, pyrazole ring, or benzene ring. The tetrahydropyrrole ring, tetrahydrofuran ring, piperidine ring, pyrazole ring, or benzene ring may be optionally surrounded by one or more R A What it replaced.

[0038] In some implementations, ring A is selected from... The tetrahydropyrrole ring, piperidine ring, pyrazole ring, or benzene ring are described. The tetrahydropyrrole ring, piperidine ring, pyrazole ring, or benzene ring may optionally be surrounded by one or more R... A What it replaced.

[0039] In some implementations, ring A is selected from one or more Rs. A The following structures are replaced: Where * represents X 1 The connected positions.

[0040] In some implementations, ring A is selected from one or more Rs. A The following structures are replaced: Where * represents X 1 The connected positions.

[0041] In some implementation schemes, R A Selected from deuterium, halogens, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic groups, wherein the OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclic group is optionally surrounded by one or more R... D replace.

[0042] In some implementation schemes, R A The hydroxyl group is selected from deuterium, halogen, CN, OH, NH2, or C1-C4 alkyl, wherein the OH, NH2, or C1-C4 alkyl group is optionally converted by one or more R. D replace.

[0043] In some implementations, ring A is selected from... Where * represents X 1 The connected positions.

[0044] In some implementations, ring A is selected from... Where * represents X 1 The connected positions.

[0045] In some implementations, L 4 Selected from key, -C(R) L1 R L2 )-, -C(=O)O-, -S(=O)2-, -SO2NR 1a -、-C(=O)-、-C(=O)NR 1a -、-P(=O)R 1a -or-C(R) L1 R L2 )NR 1a SO2-.

[0046] In some implementations, L 4 Selected from key, -C(R) L1 R L2 -, -C(=O)O-, -S(=O)2- or -SO2NR 1a -

[0047] In some implementations, L 4 Selected from bond, -S(=O)2- or -SO2NR 1a -

[0048] In some implementation schemes, R L1 R L2 R L3 R L4 R 1a R 1bindependently of each other, are selected from hydrogen, deuterium, halogen, CN, OH, NH2or Ci-C4-alkyl, said OH, NH2or Ci-C4-alkyl being optionally substituted with one or more R D substituted.

[0049] In some embodiments, R L1 , R L2 , R L3 , R L4 , R 1a , R 1b are independently of each other selected from hydrogen, deuterium or Ci-C4-alkyl, said Ci-C4-alkyl being optionally substituted with one or more R D substituted.

[0050] In some embodiments, R L1 , R L2 , R L3 , R L4 , R 1a , R 1b are independently of each other selected from hydrogen or deuterium.

[0051] In some embodiments, L 4 is selected from a bond, CH2, -C(=0)0-, SO2or SO2NH.

[0052] In some embodiments, L 4 is selected from a bond, SO2or SO2NH.

[0053] In some embodiments, R 1 is selected from hydrogen, deuterium, halogen, Ci-C6-alkyl, C3-C6-cycloalkyl, -OR 2 or -NR 2a R 2b , said Ci-C6-alkyl or C3-C6-cycloalkyl being optionally substituted with one or more R B substituted.

[0054] In some embodiments, R 1 is selected from hydrogen, deuterium, halogen, Ci-C6-alkyl or C3-C6-cycloalkyl, said Ci-C6-alkyl or C3-C6-cycloalkyl being optionally substituted with one or more R B substituted.

[0055] In some embodiments, R 1 is selected from hydrogen or Ci-C6-alkyl optionally substituted with one or more R B substituted.

[0056] In some embodiments, R 2 , R 2a , R 2bindependently from each other, are selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4- alkyl or C3-C6-cycloalkyl, said OH, NH2, C1-C4-alkyl or C3-C6-cycloalkyl being optionally substituted with one or more R D substituted.

[0057] In some embodiments, R 2 , R 2a , R 2b are independently from each other selected from hydrogen, deuterium or C1-C4-alkyl, said C1-C4-alkyl being optionally substituted with one or more R D substituted.

[0058] In some embodiments, R 1 is selected from hydrogen, deuterium, methyl, ethyl, tert-butyl or cyclopropyl.

[0059] In some embodiments, R 1 is selected from hydrogen, methyl or ethyl.

[0060] In some embodiments, -L 4 -R 1 is selected from hydrogen,

[0061] In some embodiments, -L 4 -R 1 is selected from hydrogen,

[0062] In some embodiments, X 3 is selected from NH.

[0063] In some embodiments, X 2 is selected from NR X1 , C(R X1 R X2 ) or O.

[0064] In some embodiments, X 2 is selected from NR X1 or O.

[0065] In some embodiments, X 2 is selected from NH or O.

[0066] In some embodiments, L 1 , L 2 , L 3 are independently from each other selected from a bond, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f)-, -O-, -OC(R 1c R 1d )-, -NR 1c -, 1c C(R 1e R 1f )-, -C(R 1c ) = C(R 1e )-, 3-6 membered saturated or partially unsaturated carbocycle or 3-6 membered heterocycle, which 3-6 membered saturated or partially unsaturated carbocycle or 3-6 membered heterocycle is optionally substituted with one or more R E substituents.

[0067] In some embodiments, L 1 , L 2 , L 3 are each independently selected from a bond, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -O-, -OC(R 1c R 1d )-, -NR 1c -, 1c C(R 1e R 1f )-, -C(R 1c ) = C(R 1e )-, 3 or 4 membered saturated carbocycle, pyrrolidine ring, or piperazine ring. E

[0068] In some embodiments, L 1 , L 2 , L 3 are each independently selected from a bond, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -O-, -OC(R 1c R 1d )-, -NR 1c -, 1c C(R 1e R 1f )-, -C(R 1c ) = C(R 1e )-, 3 or 4 membered saturated carbocycle, pyrrolidine ring, or piperazine ring.

[0069] In some embodiments, R​X1 R X2 R 1c R 1d R 1e R 1f are each independently selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with one or more R C ; or, R X1 R 1c and the atom to which they are attached, or R X1 R 1e and the atom to which they are attached, together form a 3-6 membered saturated or partially unsaturated carbocyclic ring, 3-6 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaromatic ring, optionally substituted with one or more R C .

[0070] In some embodiments, R X1 R X2 R 1c R 1d R 1e R 1f are each independently selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, optionally substituted with one or more R C .

[0071] In some embodiments, R X1 R X2 R 1c R 1d R 1e R 1f are each independently selected from hydrogen, deuterium, halogen, CN, OH, NH2, or C1-C4 alkyl, optionally substituted with one or more R C .

[0072] In some embodiments, R X1 R X2 R 1c R 1d R 1e R 1findependently of one another selected from hydrogen, deuterium, halogen or Ci-C4-alkyl, which is optionally substituted by one or more R C substituted.

[0073] In some embodiments, X 2 is selected from NR X1 or O, L 1 is a bond or -C(R 1c R 1d )-, wherein R X1 is hydrogen, R 1c , R 1d are independently of one another selected from hydrogen, deuterium or Ci-C4-alkyl. X1 , R 1c and the atom to which they are attached together form a 4-6 membered saturated heterocyclic ring, which is optionally substituted by one or more R C .

[0074] In some embodiments, X 2 is selected from NR X1 or O, L 1 is a bond or -C(R 1c R 1d )-, wherein R X1 is hydrogen, R 1c , R 1d are independently of one another selected from hydrogen, deuterium or Ci-C4-alkyl.

[0075] In some embodiments, X 2 is NH, L 1 is a bond, CH2or CHCH3.

[0076] In some embodiments, X 2 is selected from NR X1 , L 1 is -C(R 1c R 1d )-, R 1d is selected from hydrogen, deuterium or Ci-C4-alkyl, R X1 , R 1c and the atom to which they are attached together form a 4-6 membered saturated heterocyclic ring, which is optionally substituted by one or more R C and contains 1 nitrogen atom as heteroatom.

[0077] In some embodiments, X 2 is selected from NR X1 , L 1 is -C(R 1c R 1d )-, R 1d is hydrogen, R X1 , R 1cand the atoms bound thereto form a tetrahydropyrrole ring.

[0078] In some embodiments, L 2 is selected from -C(R 1c R 1d )-, -C(R 1c R 1d )-, -C(R 1e R 1f )-, or a 3-6 membered saturated carbocyclic ring, which is optionally substituted with one or more R E , R 1c , R 1d , R 1e , R 1f are each independently selected from hydrogen, deuterium, or C1-C4alkyl.

[0079] In some embodiments, L 2 is selected from CH2or CH2CH2.

[0080] In some embodiments, L 3 is selected from -C(R 1c R 1d )-, -O-, -NR 1c -, E or a 4-6 membered saturated heterocyclic ring, which is optionally substituted with one or more R 1c , R 1d are each independently selected from hydrogen, deuterium, or C1-C4alkyl.

[0081] In some embodiments, L 3 is selected from -C(R 1c R 1d )-, -NR 1c -, wherein * represents the position of attachment to the carbonyl group in formula (I). 1c , R 1d are each independently selected from hydrogen, deuterium, or C1-C4alkyl.

[0082] In some embodiments, L 3 is selected from NH, CH2or wherein * represents the position of attachment to the carbonyl group in formula (I).

[0083] In some embodiments, R B , R C , R D are each independently selected from deuterium, =O, OH, CN, halogen, NH2, C1-C4alkyl, or C1-C4alkoxy, which is optionally substituted with one or more R

[0084] In some embodiments, R is selected from deuterium, =0, OH, CN, halogen, NH2, or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted with one or more R. B , R C , R D are independently from each other selected from deuterium, =0, OH, CN, halogen, NH2, or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted with one or more R.

[0085] In some embodiments, R is selected from deuterium, =0, OH, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.

[0086] In some embodiments, R is selected from deuterium, =0, OH, CN, halogen, or C1-C4 alkyl.

[0087] In some embodiments, L 1 , L 2 , L 3 is independently from each other selected from a bond, -0-, -NH-, -CH2-, -CH2O-, -CH2NH-, -CH2N(CH3)-, -CH2CH2-, -CH2CH(CH3)-, -NHCH(CH3)-, -NHCH(Et)-, -OCH(CH3)-, -OCH(Et)-, -CH(CH3)-, -CH(Et)-, -CH(CH3)CH(CH3)-, -CH(CH3)CH(Et)-, a 3- or 4- membered saturated carbocyclic ring, a tetrahydropyrrole ring, or a piperazine ring.

[0088] In some embodiments, -L 1 -L 2 -L 3 - is selected from wherein * represents the position of attachment to X 2 .

[0089] In some embodiments, the compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0090] wherein, Z 1 , Z 2 , X 1 , ring A, L 4 , R 1 , X 3 , X 2 , L 1 , L 2 , L 3 are as defined hereinabove.

[0091] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0092] wherein Z 1 , Z 2 , X 1 , ring A, L 4 , R 1 , X 3 , X 2 , L 1 , L 2 , L 3 are as defined above.

[0093] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (I)-1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0094] wherein X 1 , ring A, L 4 , R 1 , X 2 , L 1 , L 2 , L 3 are as defined above.

[0095] In some embodiments, the compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (I)-2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0096] wherein n is 0 or 1, X 1 , ring A, L 4 , R 1 , X 2 , L 1 , L 2 , L 3 are as defined above.

[0097] In some embodiments, the compound of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0098] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound represented by the general Formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0099] In another aspect, the present disclosure provides a method of treating a CDK2-mediated disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100] In another aspect, the present disclosure provides a method of treating a tumor in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0101] In another aspect, the present disclosure provides the use of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for preventing or treating a CDK2-mediated disease.

[0102] In another aspect, the present disclosure provides the use of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for preventing or treating a tumor.

[0103] In another aspect, the present disclosure provides the use of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a CDK2-mediated disease.

[0104] In another aspect, the present disclosure provides the use of a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a tumor.

[0105] In another aspect, the present disclosure provides a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a CDK2-mediated disease.

[0106] In another aspect, the present disclosure provides a compound of Formula (I) or a specific compound described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a tumor.

[0107] In some embodiments, the CDK2-mediated disease is selected from a tumor.

[0108] In some embodiments, the tumor is selected from a cancer.

[0109] Terminology definitions and explanations

[0110] Unless otherwise indicated, the terms used in the present disclosure have the following meanings, the definitions of the groups and terms recited in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions recited in the tables, definitions of specific compounds in the examples, etc., can be combined and incorporated with each other arbitrarily. A particular term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0111] Herein represents a point of attachment.

[0112] The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge and a dashed wedge represents the absolute configuration of a stereocenter, with a solid and a dashed bond represents the relative configuration of a stereocenter (e.g., the cis-trans configuration of an alicyclic compound).

[0113] The term "tautomer" refers to isomers of a functional group that result from the rapid movement of an atom in a molecule between two positions. The compounds of the present disclosure can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0114] The term "stereoisomer" refers to isomers that have the same molecular formula but different spatial arrangement of atoms. Stereoisomers include enantiomers (mirror images of the other), and diastereomers (non-mirror images of the other).

[0115] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric forms can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that contain an enantiomeric or diastereomeric excess, all of which are within the scope of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms can be present in a substituent group, and all such isomers and mixtures thereof are included within the definition of the compounds of the present disclosure. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically active form or as racemic mixtures, and the optically active forms can be obtained by separation from the racemic mixtures or by using chiral starting materials or chiral reagents in the synthetic sequence.

[0116] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, which can include deuterium and variations of hydrogen, as long as the valency of the particular atom is not exceeded and the resulting compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced, and oxo cannot be on an aromatic group.

[0117] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, an ethyl group "optionally" substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), poly-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). One skilled in the art will appreciate that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not physically or synthetically possible.

[0118] The term "optionally substituted" means that the group can or can not be substituted and that the types and number of substituents, if present, are optional, and can be any chemically feasible.

[0119] The term "substituted" refers to the fact that a specific atom or group can be replaced with a specified other atom or group. For example, the CH2 in -CH2CH2CH2- can be replaced by O, S, or NH to obtain -CH2OCH2-, -OCH2CH2-, -CH2SCH2-, -SCH2CH2-, -CH2NHCH2-, or -NHCH2CH2-, etc.

[0120] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options; for group N(C1-C6 alkyl)2, when C1-C6 alkyl is R b When substituted, the two C1-C6 alkyl groups have independent R groups. b Options.

[0121] When one of the variables is selected as a bond or does not exist, it indicates that the two groups it is connected to are directly linked, such as X. 1 -AL 4 -R 1 When A is absent, it means that the structure is actually X. 1 -L 4 -R 1 .

[0122] Unless otherwise specified, the linking direction of the linking groups mentioned in this article is arbitrary. For example, when AL... 4 -R 1 L in 4 For "-SO2NR" 1a When -", L4 can form "A-SO2NR" by connecting ring A in the direction from left to right. 1a -R 1 Alternatively, loop A can be connected from right to left to form "A-NR". 1a SO2-R 1 ".

[0123] C in this article m -C n It refers to having an integer number of carbon atoms, either mn or in the range m to n. For example, "C1-C 10"" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Similarly, "m-membered" to "n-membered" indicates that the number of ring atoms is m to n. For example, 5-14-membered rings include 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, and 14-membered rings. It also includes any range from n to m. For example, 5-14-membered rings include 6-14-membered, 6-11-membered, 5-10-membered, 6-10-membered, and 6-8-membered rings.

[0124] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The hydrocarbon group is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. The term "C1-C" is used. 10 "Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1, 3-Dimethylbutyl or 1,2-Dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood as referring to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C4 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms. The "C1-C6 alkyl" 10 "alkyl" can include the range of "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and "C1-C6 alkyl" can further include "C1-C4 alkyl" or "C1-C3 alkyl", and "C1-C4 alkyl" can further include "C1-C3 alkyl".

[0125] The term "haloalkyl" refers to groups resulting from further substitution of an alkyl group with halogen, e.g., "C1-C4haloalkyl" refers to a C1-C4alkyl group further substituted with halogen.

[0126] The term "alkoxy" refers to a univalent radical resulting from removal of a hydrogen atom from the hydroxyl group of a straight or branched chain alcohol and is understood as "alkyl- oxy" or "alkyl-O-," wherein alkyl is as defined above. The term "C1-C6alkoxy" is understood as "C1-C6alkyl-oxy" or "C1-C6alkyl-O-"; the term "C1-C3alkoxy" is understood as "C1-C3alkyl-oxy" or "C1-C3alkyl-O-." The "C1-C6alkoxy" can include "C1-C3alkoxy" and the like ranges, which the "C1-C6alkoxy" can further include "C1-C3alkoxy." 10 The term "alkoxy" refers to a univalent radical resulting from removal of a hydrogen atom from the hydroxyl group of a straight or branched chain alcohol and is understood as "alkyl- oxy" or "alkyl-O-," wherein alkyl is as defined above. The term "C1-C6alkoxy" is understood as "C1-C6alkyl-oxy" or "C1-C6alkyl-O-"; the term "C1-C3alkoxy" is understood as "C1-C3alkyl-oxy" or "C1-C3alkyl-O-." The "C1-C6alkoxy" can include "C1-C3alkoxy" and the like ranges, which the "C1-C6alkoxy" can further include "C1-C3alkoxy." 10 The term "alkoxy" refers to a univalent radical resulting from removal of a hydrogen atom from the hydroxyl group of a straight or branched chain alcohol and is understood as "alkyl- oxy" or "alkyl-O-," wherein alkyl is as defined above. The term "C1-C6alkoxy" is understood as "C1-C6alkyl-oxy" or "C1-C6alkyl-O-"; the term "C1-C3alkoxy" is understood as "C1-C3alkyl-oxy" or "C1-C3alkyl-O-." The "C1-C6alkoxy" can include "C1-C3alkoxy" and the like ranges, which the "C1-C6alkoxy" can further include "C1-C3alkoxy." 10 The term "alkoxy" refers to a univalent radical resulting from removal of a hydrogen atom from the hydroxyl group of a straight or branched chain alcohol and is understood as "alkyl- oxy" or "alkyl-O-," wherein alkyl is as defined above. The term "C1-C6alkoxy" is understood as "C1-C6alkyl-oxy" or "C1-C6alkyl-O-"; the term "C1-C3alkoxy" is understood as "C1-C3alkyl-oxy" or "C1-C3alkyl-O-." The "C1-C6alkoxy" can include "C1-C3alkoxy" and the like ranges, which the "C1-C6alkoxy" can further include "C1-C3alkoxy." 10 The term "alkoxy" refers to a univalent radical resulting from removal of a hydrogen atom from the hydroxyl group of a straight or branched chain alcohol and is understood as "alkyl- oxy" or "alkyl-O-," wherein alkyl is as defined above. The term "C1-C6alkoxy" is understood as "C1-C6alkyl-oxy" or "C1-C6alkyl-O-"; the term "C1-C3alkoxy" is understood as "C1-C3alkyl-oxy" or "C1-C3alkyl-O-." The "C1-C6alkoxy" can include "C1-C3alkoxy" and the like ranges, which the "C1-C6alkoxy" can further include "C1-C3alkoxy."

[0127] The term "cycloalkyl" refers to a fully saturated carbon ring that exists as a monocyclic, fused, bridged, or spirocyclic ring, unless otherwise indicated. The carbon ring is typically a 3- to 10-membered ring, unless otherwise indicated. The term "C3-C7cycloalkyl" is understood to mean a saturated, monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, or 8 carbon atoms. The term "C3-C7cycloalkyl" can include "C3-C6cycloalkyl" or "C5-C7cycloalkyl." 10 The term "cycloalkyl" refers to a fully saturated carbon ring that exists as a monocyclic, fused, bridged, or spirocyclic ring, unless otherwise indicated. The carbon ring is typically a 3- to 10-membered ring, unless otherwise indicated. The term "C3-C7cycloalkyl" is understood to mean a saturated, monovalent monocyclic, fused, spirocyclic, or bridged ring having 3, 4, 5, 6, 7, or 8 carbon atoms. The term "C3-C7cycloalkyl" can include "C3-C6cycloalkyl" or "C5-C7cycloalkyl."

[0128] The term "heterocyclyl" or "heterocycle" refers to a fully saturated or partially saturated (not aromatic overall as a heteroaromatic) monovalent monocyclic, annelated, spirocyclic, or bridged cyclic group containing 1, 2, 3, 4, or 5 heteroatoms or groups of heteroatoms (i.e., groups of atoms containing heteroatoms) in its ring atoms, including but not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S), phosphorus atoms (P), boron atoms (B), -S(=0)2-, -S(=0)-, and optionally substituted -NH-, -S(=0)(=NH)-, -C(=0)NH-, -C(=NH)-, -S(=0)2NH-, S(=0)NH-, or -NHC(=0)NH-, etc., which typically contain 3 to 20 ring atoms. The term "3-6 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, or 6 ring atoms, and containing 1-2 heteroatoms or groups of heteroatoms independently selected from the above-mentioned heteroatoms or groups of heteroatoms. The term "4-14 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, and containing 1-5 heteroatoms or groups of heteroatoms independently selected from the above-mentioned heteroatoms or groups of heteroatoms. The "4-14 membered heterocyclyl" can include "4-10 membered heterocyclyl", "4-7 membered heterocyclyl", "4-6 membered heterocyclyl", or "5-6 membered heterocyclyl". The term "3-6 membered heterocyclyl" can include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "3-5 membered heterocyclyl", or "4-5 membered heterocyclyl". Specific examples of 4-membered heterocyclyl groups include but are not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyl groups include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl groups include but are not limited to diazepanyl. The heterocyclyl group can also be a bicyclic group, where specific examples of 5,5 membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic groups include but are not limited to hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl group can be a benzo-fused ring of the above-mentioned 4-7 membered heterocyclyl groups, specific examples include but are not limited to dihydroisoquinolinyl, etc. Although some bicyclic heterocyclyl moieties contain a benzene ring or a heteroaromatic ring partially in the present disclosure, the heterocyclyl group is still non-aromatic overall.

[0129] The term "aryl" refers to all-carbon aromatic groups having the conjugated n-electron system. Aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. The term "C6-Ci0aryl" is understood to mean a monovalent aromatic ring radical of 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9aryl"), such as an indanyl or indenyl group; or a ring having 10 carbon atoms ("Cioaryl"), such as a tetrahydronaphthyl, dihydronaphthyl, or naphthyl group. 10 The term "aryl" refers to all-carbon aromatic groups having the conjugated n-electron system. Aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. The term "C6-Ci0aryl" is understood to mean a monovalent aromatic ring radical of 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9aryl"), such as an indanyl or indenyl group; or a ring having 10 carbon atoms ("Cioaryl"), such as a tetrahydronaphthyl, dihydronaphthyl, or naphthyl group. 10 The term "aryl" refers to all-carbon aromatic groups having the conjugated n-electron system. Aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. The term "C6-Ci0aryl" is understood to mean a monovalent aromatic ring radical of 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9aryl"), such as an indanyl or indenyl group; or a ring having 10 carbon atoms ("Cioaryl"), such as a tetrahydronaphthyl, dihydronaphthyl, or naphthyl group.

[0130] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or fused polycyclic ring system having aromaticity, which contains at least one, preferably 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being carbon. The heteroaryl group is preferably a 5- to 10-membered, more preferably a 5- or 6-membered heteroaryl group. The term "5- to 10-membered heteroaryl" is understood to include a monovalent monocyclic or bicyclic aromatic ring system having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3, heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and the like and their benzo derivatives, such as, for example, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and the like and their benzo derivatives, such as, for example, quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl or phenoxazinyl and the like. The term "5- to 6-membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S. The term "6-membered heteroaryl" refers to an aromatic ring system having 6 ring atoms, and which contains 1, 2 or 3, preferably 1 or 2, heteroatoms independently selected from N, O and S. The term "5- to 10-membered heteroaryl" can include "5- to 6-membered heteroaryl" or "6-membered heteroaryl", and the term "5- to 6-membered heteroaryl" can include "6-membered heteroaryl".

[0131] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0132] The term "hydroxy" refers to an -OH group.

[0133] The term "cyano" refers to a -CN group.

[0134] The term "amino" refers to a -NH2 group.

[0135] The term "nitro" refers to a -NO2 group.

[0136] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner by a consideration of the factors known in the art.

[0137] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt" refers to a salt of an acid or a base which is pharmaceutically acceptable, including salts of compounds with inorganic acids or organic acids, and salts of compounds with inorganic or organic bases.

[0139] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure, or stereoisomers or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0140] The term "pharmaceutically acceptable carrier" refers to those carriers that do not cause an appreciable level of stimulation or harm to an organism, and do not abrogate the biological activity and properties of the active compounds. Suitable carriers are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0141] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in this document, are to be interpreted as open-ended, non- exhaustive, that is, "including but not limited to".

[0142] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like.

[0143] Certain isotopically-labeled compounds of the present disclosure (for example, those 3 H, and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by

[0144] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with a suitable pharmaceutically acceptable excipient, such as can be formulated into solid, semi-solid, liquid, or gaseous dosage forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols, and the like.

[0145] Typical routes of administering a compound of the present disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0146] The pharmaceutical compositions of the present disclosure can be manufactured in a manner appropriate to the type of composition by known methods, such as the conventional methods used for mixing, dissolving, granulating, levigating, emulsifying, freeze-drying or lyophilizing, etc.

[0147] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, dragees, sugar-coated tablets, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to a patient.

[0148] Solid oral compositions can be prepared by conventional mixing or compaction techniques. For example, the active compound can be mixed with a solid excipient, optionally ground, and if necessary, charged with an additional excipient, and then processed into granules by a method such as drying, gluing, or granulating, to obtain the core of tablets or sugar-coated tablets. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents, etc.

[0149] The pharmaceutical composition can also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0150] The dosage of the compound or composition used in the therapeutic methods of the present disclosure will generally vary with the severity of the disease, the body weight of the patient, and the relative efficacy of the compound, but as a general guide, a suitable daily dose of a compound of Formula (I) as described herein is 0.01 mg / kg to 1000 mg / kg.

[0151] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by the combination of the other chemical synthetic methods well known to those skilled in the art, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0152] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In order to obtain the compounds of the present disclosure, it can be necessary to modify the synthetic procedures described in the embodiments or to choose alternative routes of synthesis as appreciated by those skilled in the art.

[0153] In some embodiments, the compounds of Formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis by the following routes:

[0154] Compound M1 was subjected to Mitsunobu reaction with compound M2 to give compound M3, which was then reacted with sodium thiomethoxide to give compound M4, followed by deprotection to give intermediate Int-I; compound M5 or M6 was reacted with intermediate Int-I under basic condition to give compound M7, which was then deprotected to give compound M8, followed by ring closure under basic condition to give compound M9, which was then oxidized in the presence of m-CPBA to give intermediate Int-II-a; intermediate Int-I was reacted with compound M10 or M11 under basic condition to give compound M12, which was then deprotected to give compound M13, followed by ring closure under basic condition to give compound M14, which was then oxidized in the presence of m-CPBA to give intermediate Int-II-b; intermediate Int-II-a or Int-II-b was reacted with compound M15 under basic condition to give compound M16, which was then deprotected to give compound M17, which was finally reacted with compound M18 to give the partial general formula I compound. Alternatively, intermediate Int-II-a or Int-II-b was also reacted with compound M19 under basic condition to give the partial general formula I compound. DETAILED DESCRIPTION

[0155] The present disclosure is described in detail below by specific embodiments, but is not meant to be limited by any unfavorable restrictions. Various specific embodiments of the present disclosure have been described in detail herein, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0156] All reagents used in the present disclosure are commercially available and can be used without further purification.

[0157] Unless otherwise specified, the ratio indicated by the mixed solvent is the volume mixing ratio. Unless otherwise specified, % refers to wt%.

[0158] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half maximal inhibitory concentration, which refers to the concentration at which the maximum inhibitory effect is halved.

[0159] The eluent hereinafter can be formed by two or more solvents to form a mixed eluent, and the ratio is the volume ratio of each solvent.

[0160] Abbreviations:

[0161] DIAD: diethyl azodicarboxylate; PPh3: triphenylphosphine; THF: tetrahydrofuran; MeSNa: sodium methanethiolate; DCM: dichloromethane; DIEA: N,N- diisopropylethylamine; dioxane: 1,4-dioxane; mCPBA: meta-chloroperoxybenzoic acid; MeCN: acetonitrile; Boc: tert-butyloxycarbonyl; NMP: N-methylpyrrolidone; Ms20: methanesulfonic anhydride; BTC: triphosgene; HEPES: 4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid; DTT: dithiothreitol; ATP: adenosine triphosphate; EDTA: ethylenediaminetetraacetic acid; HATU: 2-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0162] Example 1: Synthesis of (2R,5S)-14-[[(3S)-pyrrolidin-3-yl]amino]-1,6,8,11,13,16,19- heptazatetracyclo[10.5.2.12,5.015,18]icosacosa-12,14,16,18-tetraene-7-one (Compound 1)

[0163] Step 1: Synthesis of tert-butyl N-[(1S,3R)-3-(2,6-dichloropurin-9-yl)cyclopentyl]carbamate (1c)

[0164] To 2,6-dichloro-9H-purine 1a (0.57 g, 3.0 mmol), tert-butyl N-[(1S,3S)-3- hydroxycyclopentyl]carbamate (0.72 g, 3.6 mmol) and triphenylphosphine (1.0 g, 4.0 mmol) in dry tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (0.70 g, 4.0 mmol) dropwise at room temperature with stirring. The reaction was continued for 3 hours. The reaction was concentrated under reduced pressure and the concentrate was purified by reverse phase C18 column (mobile phase: acetonitrile-water (0.025% ammonia in water), acetonitrile ratio 10-90%, gradient elution for 12 column volumes) and the eluted fractions were lyophilized to give the title compound 1c (0.24 g, 0.65 mmol, 21.6% yield). m / z (ESI): 372.2 [M+H] + .

[0165] Step 2: Synthesis of tert-butyl N-[(1S,3R)-3-(2-chloro-6-methylsulfanyl-purin-9-yl)cyclopentyl]carbamate (1d)

[0166] Compound 1c (0.14 g, 0.38 mmol) was dissolved in dry tetrahydrofuran (4 mL) and 20% sodium thiomethoxide aqueous solution (0.16 g, 0.45 mmol) was added. The resulting mixture was stirred at 60 °C overnight. The reaction was concentrated under reduced pressure to give the title compound 1d (crude 0.17 g) which was used directly in the next step. m / z (ESI): 384.2 [M+H] + .

[0167] Step 3: Synthesis of (1S,3R)-3-(2-chloro-6-methylsulfanyl-purin-9-yl)cyclopentylamine hydrochloride (1e)

[0168] The crude compound 1d (0.17 g) was dissolved in dry dichloromethane (5 mL) and 4 M hydrochloric acid in dioxane (3 mL) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and dioxane (10 mL) was added. The mixture was again concentrated under reduced pressure and dried to give the title compound 1e (crude 0.16 g) which was used directly in the next step. m / z (ESI): 284.2 [M+H] + .

[0169] Step 4: Synthesis of 1-(2-aminoethyl)-3-[(1S,3R)-3-(2-chloro-6-methylsulfanyl-purin-9-yl)cyclopentyl]urea (1f)

[0170] The title compound 1e (crude 0.16 g) was dissolved in dichloromethane (2 mL) and N,N-diisopropylethylamine (0.29 g, 2.3 mmol) was added. The resulting solution was added dropwise to a solution of triphosgene (60 mg, 0.20 mmol) in dichloromethane (4 mL) at 0 °C and the stirring was continued for 5 min at 0 °C. Ethylenediamine (0.20 g, 3.3 mmol) was added to the resulting solution and the stirring was continued for half an hour at 0 °C. The reaction was concentrated under reduced pressure and the concentrate was purified by reverse phase C18 column (mobile phase: acetonitrile-water (0.025% ammonia in water), acetonitrile gradient 5-50% over 12 column volumes) and the eluted fractions were lyophilized to give the title compound 1f (68 mg, 0.18 mmol, 48.5% over three steps). m / z (ESI): 370.2 [M+H] + .

[0171] Step 5: Synthesis of intermediate 1g

[0172] Compound 1f (68 mg, 0.18 mmol), potassium carbonate (50 mg, 0.36 mmol) were added into 1,4-dioxane (20 mL), the resulting reaction was heated at 100 °C for 16 h. The reaction was concentrated under reduced pressure, the concentrate was purified by reverse phase C18 column (mobile phase: acetonitrile-water (0.025% ammonia in water), acetonitrile ratio 5-50% gradient elution for 12 column volumes), the eluted fractions were lyophilized to give the title compound 1g (32 mg, 0.096 mmol, 53.2% yield). m / z (ESI): 334.2 [M+H] + .

[0173] Step 6: Synthesis of intermediate 1h

[0174] Compound 1g (32 mg, 96.1 μmol) was dissolved in anhydrous acetonitrile (3 mL), m-chloroperoxybenzoic acid (17.3 mg, 0.10 mmol) was added, the reaction was stirred at 25 °C for 16 h. The reaction was quenched by adding 0.2 mol / L aqueous sodium sulfite solution (5 mL), followed by 1 mL saturated sodium bicarbonate solution, and extracted with ethyl acetate (5 mL*3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfite, filtered and the filtrate was concentrated under reduced pressure to give the title compound 1h (35 mg, crude). MS m / z (ESI): 350.2 [M+H] + .

[0175] Step 7: Synthesis of intermediate 1j

[0176] Compound 1h (crude 35 mg) was dissolved in N-methylpyrrolidone (2 mL), (3S)-3- aminopyrrolidine-1-carboxylic acid tert-butyl ester 1i (37 mg, 0.20 mmol) and N- diisopropylethylamine (26 mg, 0.20 mmol) were added. The reaction was stirred at 120 °C under nitrogen atmosphere for 2 h. The reaction was directly purified by reverse phase C18 column (mobile phase: acetonitrile-water (0.025% ammonia in water), acetonitrile ratio 5-70% gradient elution for 12 column volumes), lyophilized to give the title compound 1j (25 mg, 52.9 μmol, 55.3% yield for two steps). m / z (ESI): 472.3 [M+H] + .

[0177] Step 8: Synthesis of (2R,5S)-14-[[(3S)-pyrrolidin-3-yl]amino]-1,6,8,11,13,16,19- heptazatetracyclo[10.5.2.1 2,5 .0 15,18 ]icos-12,14,16,18-tetraene-7-ketone (Compound 1)

[0178] Compound 1j (25 mg, 52.9 μmol) was added to dry dichloromethane (5 mL), followed by 4 M hydrochloric acid in dioxane (3 mL), and the mixture was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and the crude product was purified directly by reverse phase C18 column (mobile phase: acetonitrile-water (0.025% ammonia in water), acetonitrile gradient from 5 to 40% over 12 column volumes), and the eluted fractions were lyophilized to give the title compound 1 (12 mg, 32.3 μmol, 61% yield). m / z (ESI): 372.3 [M+H] + .

[0179] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (br s, 1H), 7.72 (s, 1H), 6.09-5.99 (m, 1H), 4.96-4.84 (m, 1H), 4.51 (s, 1H), 4.14 (s, 1H), 3.84 (s, 1H), 3.60-3.56 (m, 1H), 3.25-3.03 (m, 4H), 2.99-2.83 (m, 3H), 2.78-2.64 (m, 2H), 2.19-1.87 (m, 4H), 1.78-1.50 (m, 4H).

[0180] Example 2: (2R,5S)-14-[[(3S)-1-methanesulfonylpyrrolidin-3-yl]amino]-1,6,8,11,13,16,19- heptazatetracyclo[10.5.2.1 2,5 .0 15,18 Synthesis of (2R,5S)-14-[[(3S)-1-methanesulfonylpyrrolidin-3-yl]amino]-1,6,8,11,13,16,19- heptazatetracyclo[10.5.2.1

[0181] Compound 1 (4.0 mg, 10.8 μmol) was added to dry dichloromethane (1 mL), followed by N,N- diisopropylethylamine (6 mg, 46.5 μmol). The mixture was cooled to 0 °C, followed by the addition of methanesulfonic anhydride (2.7 mg, 16.0 μmol). The mixture was stirred at 0 °C for 0.5 h, followed by the addition of 1 mL of saturated aqueous sodium bicarbonate solution, and stirring for 10 min. The reaction was concentrated under reduced pressure and the crude product was purified directly by preparative purification (mobile phase: acetonitrile-water (2.0 mmol / L ammonium bicarbonate in water), acetonitrile gradient from 5 to 60% over 12 column volumes), and lyophilized to give the title compound 2 (0.9 mg, 2.0 μmol, 18.5% yield). m / z (ESI): 450.2 [M+H] + .

[0182] Example 3: Synthesis of (3S)-N-ethyl-3-[[(2R,5S)-7-carbonyl-1,6,8,11,13,16,19- heptazatetracyclo[10.5.2.1 2,5 .0 15,18 Synthesis of (3S)-N-ethyl-3-[[(2R,5S)-7-carbonyl-1,6,8,11,13,16,19- heptazatetracyclo[10.5.2.1

[0183] Compound 1 (4.0 mg, 10.8 μmol) was added to dry dichloromethane (1 mL) and N,N- diisopropylethylamine (6 mg, 46.5 μmol). The resulting mixture was cooled to 0 °C and ethyl sulfamoyl chloride 3a (2.3 mg, 16.0 μmol) was added. The resulting mixture was stirred at 0 °C for 0.5 h, then 1 mL of saturated aqueous sodium bicarbonate solution was added and stirring was continued for 10 min. The reaction was concentrated under reduced pressure and the crude product was directly purified by preparative HPLC (mobile phase: acetonitrile-water (2.0 mmol / L ammonium bicarbonate in water), acetonitrile gradient 5-60% in 12 column volumes) and lyophilized to give the title compound 3 (0.5 mg, 1.0 μmol, 9.3% yield). m / z (ESI): 479.2 [M+H] + .

[0184] Example 4: Synthesis of Compound 4

[0185] Using the synthetic procedures of Example 1, Steps 1-8, trans-N-[3- hydroxycyclopentyl]carbamic acid tert-butyl ester was used in place of N-[(1S,3S)-3- hydroxycyclopentyl]carbamic acid tert-butyl ester in Step 1 and 1,3-propanediamine was used in place of ethylenediamine in Step 4 to synthesize compound 4e. Compound 4 was further synthesized using the synthetic procedure of Example 3, using 4e in place of compound 1. m / z (ESI): 493.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.43 (s, 1H), 7.08 (t, J = 5.8 Hz, 2H), 6.52 (s, 1H), 5.97 (s, 1H), 5.03 - 4.46 (m, 3H), 4.06 - 3.95 (m, 2H), 3.54 - 3.51 (m, 2H), 3.25 - 3.04 (m, 2H), 3.06 - 2.85 (m, 4H), 2.46 - 2.29 (m, 2H), 2.27 - 2.12 (m, 2H), 2.13 - 1.81 (m, 3H), 1.76 - 1.41 (m, 3H), 1.06 (t, J = 7.2 Hz, 3H).

[0186] Example 5: Synthesis of compound 5

[0187] Using the synthetic method of Example 1, Steps 4 to 8, tert-butyl trans-N-[3- hydroxycyclopentyl]carbamate was used to replace tert-butyl N-[(1S,3S)-3- hydroxycyclopentyl]carbamate in Step 1, and 1,2-diaminopropane was used to replace ethylenediamine in Step 4, to synthesize compound 5c. Further using the synthetic method of Example 3, compound 5 was prepared by replacing compound 1 with 5c. m / z (ESI): 493.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 0.5H), 8.85 (s, 0.5H), 7.74 (d, J = 5.9 Hz, 1H), 7.63 (s, 1H), 7.15 - 7.05 (m, 1H), 6.75 - 6.5 (m, 0.5H), 6.30 - 6.20 (m, 0.5H), 4.95 - 4.81 (m, 1H), 4.78 - 4.52 (m, 1H), 4.30 - 3.40 (m, 7H), 3.25 - 3.02 (m, 4H), 2.95 - 2.82 (m, 2H), 2.25 - 1.97 (m, 4H), 1.62 - 1.43 (m, 2H), 1.18 (d, J = 6.5 Hz, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.96 (d, J = 6.5 Hz, 1H).

[0188] Example 6: Synthesis of compound 6

[0189] Using the synthetic method of Example 1, Steps 4 to 8, tert-butyl trans-N-[3- hydroxycyclopentyl]carbamate was used to replace tert-butyl N-[(1S,3S)-3- hydroxycyclopentyl]carbamate in Step 1, and (S)-2-(aminomethyl)pyrrolidine was used to replace ethylenediamine in Step 4, to synthesize intermediate 6d. Further using the synthetic method of Example 3, compound 6 was prepared by replacing compound 1 with 6d. m / z (ESI): 519.6 [M+H] + .

[0190] 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 0.5H), 8.82 (s, 0.5H), 7.90 - 7.59 (m, 2H), 7.07 (t, J = 5.7 Hz, 1H), 6.31 - 6.17 (m, 1H), 5.02 - 4.82 (m, 1H), 4.77 - 4.50 (m, 1H), 4.25 - 4.05 (m, 1H), 3.93 - 3.77 (m, 1H), 3.65 - 3.54 (m, 2H), 3.42 - 3.35 (m, 1H), 3.28 - 3.19 (m, 2H), 3.14 - 3.06 (m, 1H), 3.01 - 2.89 (m, 2H), 2.72 - 2.54 (m, 2H), 2.27 - 1.49 (m, 12H), 1.05 (td, J = 7.2, 0.8 Hz, 3H).

[0191] Example 7: Synthesis of compound 7

[0192] Using the procedure of Example 1, Step 4, and substituting compound 7a for ethylenediamine in Step 4, compound 7b was prepared from intermediate 4b. Then, using the procedure of Example 1, Step 8, the Boc protecting group was removed to give compound 7c. Following the procedures of Example 1, Steps 5 to 8, compound 7d was synthesized, and further using the synthetic method of Example 3, compound 7 was prepared from 7d by the same procedure as compound 1. m / z (ESI): 519.6 [M+H] + .

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 0.5H), 8.82 (s, 0.5H), 7.90 - 7.59 (m, 2H), 7.07 (t, J = 5.7 Hz, 1H), 6.31 - 6.17 (m, 1H), 5.02 - 4.82 (m, 1H), 4.77 - 4.50 (m, 1H), 4.25 - 4.05 (m, 1H), 3.93 - 3.77 (m, 1H), 3.65 - 3.54 (m, 2H), 3.42 - 3.35 (m, 1H), 3.28 - 3.19 (m, 2H), 3.14 - 3.06 (m, 1H), 3.01 - 2.89 (m, 2H), 2.72 - 2.54 (m, 2H), 2.27 - 1.49 (m, 12H), 1.05 (td, J = 7.2, 0.8 Hz, 3H).

[0194] Example 8: Synthesis of compound 8

[0195] Step 1: Synthesis of intermediate 8b

[0196] Intermediate 4b (0.32 g, 1.0 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol), compound 8a (0.28 g, 1.3 mmol) were mixed in dichloromethane (5 mL), the reaction was stirred in ice water for 5 minutes, then N,N-diisopropylethylamine (0.29 g, 2.3 mmol) was added. The resulting reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, the concentrate was purified by reverse phase C18 column (mobile phase: acetonitrile-water (0.025% ammonia in water), acetonitrile ratio 10-90%, gradient elution for 12 column volumes), the eluted fractions were lyophilized to obtain the title compound 8b (0.32 g, 0.66 mmol, yield 66%). m / z (ESI): 483.4 [M+H] + .

[0197] Step 2: synthesis of intermediate 8c

[0198] Intermediate 8b (0.32 g, 0.66 mmol) was dissolved in 5 mL of dichloromethane, 3 mL of 4M hydrochloric acid dioxane solution was slowly added, the resulting reaction was stirred at room temperature for half an hour. The reaction was concentrated and dried, 10 mL of saturated aqueous sodium chloride solution and 2 mL of saturated aqueous sodium carbonate solution were added, and extracted with ethyl acetate (5 mL*3 times), the organic phase was separated, dried with anhydrous sodium sulfate and dried to obtain intermediate 8c (0.21 g, yield 83%). m / z (ESI): 383.4 [M+H] + .

[0199] Compound 8d was synthesized from intermediate 8c using the same method as steps 5 to 8 of Example 1, and compound 8 was further synthesized using the synthesis method of Example 3, replacing compound 1 with 8d. m / z (ESI): 491.5 [M+H] + .

[0200] 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 0.5H), 9.81 (s, 0.5H), 7.73 (d, J = 6.3 Hz, 1H), 7.66 - 7.43 (m, 1H), 7.08 (s, 1H), 6.83 - 6.52 (m, 1H), 5.02 - 4.84 (m, 1H), 4.80 - 4.52 (m, 1H), 4.38 - 4.21 (m, 1H), 3.63 - 3.49 (m, 2H), 3.42 - 3.35 (m, 1H), 3.23 - 3.15 (m, 1H), 3.08 (dd, J = 9.7, 6.5 Hz, 1H), 2.99 - 2.91 (m, 2H), 2.46 - 1.50 (m, 12H), 1.19 (dd, J = 6.5, 2.6 Hz, 3H), 1.10 - 1.02 (m, 3H).

[0201] Example 9: Synthesis of compound 9

[0202] Using the synthetic methods of Example 1, Step 1 to Step 8, using N-Boc-trans-3- aminocyclobutanol instead of N-[(1S,3S)-3-hydroxycyclopentyl]carbamic acid tert-butyl ester in Step 1, and using (S)-2-(aminomethyl)pyrrolidine instead of ethylenediamine in Step 4, compound 9d was synthesized, which was further used to prepare compound 9 using the synthetic method of Example 3 with 9d instead of compound 1. m / z (ESI): 505.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 0.5H), 9.81 (s, 0.5H), 7.73 (d, J = 6.3 Hz, 1H), 7.66 - 7.43 (m, 1H), 7.08 (s, 1H), 6.83 - 6.52 (m, 1H), 5.02 - 4.84 (m, 1H), 4.80 - 4.52 (m, 1H), 4.38 - 4.21 (m, 1H), 3.63 - 3.49 (m, 2H), 3.42 - 3.35 (m, 1H), 3.23 - 3.15 (m, 1H), 3.08 (dd, J = 9.7, 6.5 Hz, 1H), 2.99 - 2.91 (m, 2H), 2.46 - 1.50 (m, 12H), 1.19 (dd, J = 6.5, 2.6 Hz, 3H), 1.10 - 1.02 (m, 3H).

[0203] Example 10: Synthesis of compound 10

[0204] (S)-3-aminotetrahydrofuran (87 mg, 1.0 mmol), intermediate 6c (39 mg, 0.1 mmol), N,N-diisopropylethylamine (0.13 g, 1.0 mmol) were mixed in 1 mL of dioxane. The resulting reaction was stirred at 100 °C for 4 hours. The resulting reaction was directly purified by prep (mobile phase: acetonitrile-water (2.0 mmol / L ammonium bicarbonate in water), acetonitrile ratio 10-80% gradient elution) and lyophilized to give the title compound 10 (12 mg, yield 29%). m / z (ESI): 413.6 [M+H] + .

[0205] 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 0.5H), 8.84 (s, 0.5H), 7.78 - 7.71 (m, 1H), 7.65 (s, 1H), 6.29 - 6.18 (m, 1H), 4.98 - 4.82 (m, 1H), 4.59 (s, 1H), 4.28 - 4.16 (m, 1H), 4.14 - 4.02 (m, 1H), 4.00 - 3.91 (m, 1H), 3.91 - 3.77 (m, 2H), 3.77 - 3.67 (m, 1H), 3.65 - 3.52 (m, 2H), 3.08 (dd, J = 14.8, 6.4 Hz, 1H), 2.75 - 2.56 (m, 1H), 2.25 - 1.48 (m, 12H).

[0206] Test Example 1: Detection of the inhibitory effect of the compound of the present disclosure on CDK2 kinase

[0207] The in vitro activity of CDK2 was determined by detecting the phosphorylation level of the substrate in the kinase reaction using the Lance Ultra TR-FRET kinase assay reagent of Perkin Elmer. The reaction buffer contains the following components: 50 mM HEPES (pH 7.5), 10 mM MgCl2, 2 mM DTT, 0.01% Tween20; human recombinant CDK2 / CyclinE1 protein (Carna Biosciences, 04-165) was diluted with the reaction buffer to a kinase solution of 6 nM; the substrate reaction solution includes ULight-4E-BP1 kinase substrate (PerkinElmer, TRF0128) diluted with the reaction buffer to 100 nM and 400 mM ATP; the detection buffer includes Europium-anti-phospho-4E-BP1 antibody (PerkinElmer, TRF0216) diluted with 1x detection buffer (PerkinElmer, CR97-100) to 2 nM and 20 mM EDTA.

[0208] The Echo 650 automated workstation (Beckman Coulter Life Sciences) was used to add 100 nL of different concentrations of compounds or DMSO to a 384-well assay plate (Perkin Elmer, 6007299), followed by 5 μL of CDK2 kinase solution. After mixing and incubation on ice for 30 min, 5 μL of substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 min. In the reaction system, the final concentration of the compound was 3000 nM starting, 4-fold gradient dilution, and the concentration range was 3000 nM to 0.01 nM. The final concentration of DMSO in the system was 1%. Then 10 μL of detection buffer was added to each well, mixed well and incubated at room temperature for 60 min, and then the signal value was detected by Envision microplate reader (Perkin Elmer) at 615 nm and 665 nm wavelengths. The signal value (absorbance 665 nm / absorbance 615 nm) was positively correlated with the degree of phosphorylation of the substrate, thereby reflecting the kinase activity of CDK2 and the inhibitory effect of the compound.

[0209] The percentage of inhibition of CDK2 activity of the compound can be calculated by the following formula:

[0210] Inhibition percentage (%) = 100-100*(signal value 化合物 -signal value 阴性对照 ) / (signal value 阳性对照 -signal value 阴性对照 ).

[0211] Wherein: signal value 化合物 refers to the signal value of the well containing the compound, enzyme, substrate and ATP; signal value 阴性对照 refers to the signal value of the well containing only 1% DMSO, substrate and ATP; signal value 阳性对照 refers to the signal value of the well containing 1% DMSO, enzyme, substrate and ATP.

[0212] The XLfit (ID Business Solutions Ltd., UK) software was used to fit the inhibition curve by a four-parameter model and calculate the half maximal inhibitory concentration (IC 50 ).

[0213] Experimental results:

[0214] Note: Compound Dinaciclib (Cat: HY-10492) was purchased from MCE.

[0215] While particular embodiments of the present disclosure have been illustrated and described, it would be the prophetic skilled in the art to realize that the technical features described in one embodiment can be applied to, or combined with, the technical features described in another embodiment, and thus the person skilled in the art can make various changes and modifications to the embodiments of the present disclosure without departing from the essence and scope of the present disclosure.

Claims

1. A compound represented by Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: Z 1 Z 2 Selected independently from -C(R) Z1 R Z2 )-、-C(R Z1 R Z2 )C(R Z3 R Z4 - or -C(R) Z1 )=C(R Z2 )-; R Z1 , R Z2 , R Z3 , R Z4 are independently of one another selected from hydrogen, deuterium or halogen; X 1 selected from NH(C(R X3 R X4 )) k or S; k is selected from 0, 1 or 2; R is absent or is selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 4-14 membered heterocyclic ring, a 5-10 membered heteroaromatic ring, or a phenyl ring, said 3-7 membered saturated or partially unsaturated carbocyclic ring, 4-14 membered heterocyclic ring, 5-10 membered heteroaromatic ring, or phenyl ring being optionally substituted with one or more R A substituted; L 4 selected from a bond, -C(R L1 R L2 )-, -C(R L1 R L2 )C(R L3 R L4 )-, -C(=O)-, -C(=O)O-, -C(R L1 R L2 )C(=O)O-, -C(R L1 R L2 )OC(=O)-, -C(=O)NR 1a -, -C(R L1 R L2 )C(=O)NR 1a -, -C(R L1 R L2 )NR 1a C(=O)-, -NR 1a C(=O)NR 1b -, -NR 1a C(=O)O-, -S(=O)-, -S(=O)2-, -SO2NR 1a -, -C(R L1 R L2 )SO2NR 1a -, -C(R L1 R L2 )NR 1a SO2-, -NR 1a SO2NR 1b -, -C(R L1 R L2 )NR 1a SO2NR 1b -, -NR 1a S(=O)2O-, -NR 1a S(=O)-, -NR 1a S(=O)O-, -N=S(=O)R 1a -, -P(=O)R 1a - or -S(=O)(=NR 1a )-; R 1 selected from hydrogen, deuterium, halogen, Ci-C6alkyl, C3-C7cycloalkyl, 4-14 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -OR 2 or -NR 2a R 2b , said Ci-C6alkyl, C3-C7cycloalkyl, 4-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R B ; X 3 is selected from NH or O; X 2 selected from NR X1 , C(R X1 R X2 ), O or S; L 1 、L 2 、L 3 are independently of each other selected from a bond, -C(=0)-, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -0-, -OC(R 1c R 1d )-, -NR 1c -, -NR 1c C(R 1e R 1f )-, -C(R 1c )=C(R 1e )-, -C≡C-, a 3-6 membered saturated or partially unsaturated carbocyclic ring, a 3-6 membered heterocyclic ring, a phenyl ring or a 5-6 membered heteroaromatic ring, which 3-6 membered saturated or partially unsaturated carbocyclic ring, 3-6 membered heterocyclic ring, phenyl ring or 5-6 membered heteroaromatic ring is optionally substituted with one or more R E ; R X1 , R X2 , R X3 , R X4 , R 1c , R 1d , R 1e , R 1f independently of each other are selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl being optionally substituted with one or more R C ; or R X1 , R X2 and the atoms to which they are attached together form a 3-6 membered saturated or partially unsaturated carbocyclic ring or a 3-6 membered heterocyclic ring, or R X1 , R 1c and the atoms to which they are attached, or R X1 , R 1e and the atoms to which they are attached together form a 3-6 membered saturated or partially unsaturated carbocyclic ring, a 3-6 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaromatic ring, which 3-6 membered saturated or partially unsaturated carbocyclic ring, 3-6 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaromatic ring is optionally substituted with one or more R C ; R A selected from deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, said OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl being optionally substituted with one or more R D substituents; R L1 , R L2 , R L3 , R L4 , R 1a , R 1b , R 2 , R 2a , R 2b independently of one another, are selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl being optionally substituted by one or more R D ; R B , R C , R D , R E independently of one another selected from the group consisting of deuterium, =0, OH, CN, halogen, NH2, Ci-C4-alkyl, Ci-C4-alkoxy or C3-C6-cycloalkyl, said Ci-C4-alkyl, Ci-C4-alkoxy or C3-C6-cycloalkyl optionally being substituted by one or more R; R is selected from deuterium, =0, OH, CN, halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy or C3-C6cycloalkyl.

2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Z 1 Selected from -C(R) Z1 R Z2 )-、-C(R Z1 R Z2 )C(R Z3 R Z4 - or -C(R) Z1 )=C(R Z2 )-,Z 2 Selected from -C(R) Z1 R Z2 )-; or, Z 1 Selected from -C(R) Z1 R Z2 - or -C(R) Z1 R Z2 )C(R Z3 R Z4 )-,Z 2 Selected from -C(R) Z1 R Z2 )-.

3. The compound of formula (I) according to any one of claims 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1 selected from NH(C(R X3 R X4 )) k , k is selected from 0, 1 or 2; or, X 1 selected from NH(C(R X3 R X4 )) k , k is selected from 0 or 1.

4. The compound of formula (I) according to any one of claims 1 to 3, wherein R X3 , R X4 are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, NH2or C1-C4-alkyl, said OH, NH2or C1-C4-alkyl being optionally substituted with one or more R C ; or, R X3 , R X4 are independently of each other selected from hydrogen, deuterium or methyl.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein Rings A is absent or is selected from a 3-6 membered saturated carbocyclic ring, a 4-8 membered heterocyclic ring, a 5-6 membered heteroaromatic ring, or a phenyl ring, which is optionally substituted with one or more R A substituents; or, Ring A is selected from a 4-8 membered heterocyclic ring, a 5-6 membered heteroaromatic ring, or a phenyl ring, which is optionally substituted with one or more R A substituents; or, Ring A is selected from a tetrahydropyrrole ring, a tetrahydrofuran ring, a piperidine ring, a pyrazole ring, or a phenyl ring, which is optionally substituted with one or more R tetrahydropyrrole ring, a tetrahydrofuran ring, a piperidine ring, a pyrazole ring, or a phenyl ring, which is optionally substituted with one or more R A substituents; or, Ring A is selected from a tetrahydropyrrole ring, a piperidine ring, a pyrazole ring, or a phenyl ring, which is optionally substituted with one or more R tetrahydropyrrole ring, a piperidine ring, a pyrazole ring, or a phenyl ring, which is optionally substituted with one or more R A substituents; or, Ring A is selected from a A substituents; or, Ring A is selected from a wherein * represents the position of attachment to X 1 .

6. The compound of formula (I) according to any one of claims 1 to 5, wherein R A selected from deuterium, halogen, CN, OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl, said OH, NH2, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-7 membered heterocyclyl optionally substituted with one or more R D substituents; or, R A is selected from deuterium, halogen, CN, OH, NH2, or C1-C4 alkyl, said OH, NH2, or C1-C4 alkyl optionally substituted with one or more R D substituents.

7. The compound of formula (I) according to any one of claims 1 to 6, wherein L 4 is selected from a bond, -C(R L1 R L2 )-, -C(=O)O-, -S(=O)2-, -SO2NR 1a -, 1a -C(=O)-, -C(=O)NR 1a -, L1 -P(=O)R L2 - or -C(R 1a SO2-; or, L 4 is selected from a bond, -C(R L1 R L2 )-, -C(=O)O-, -S(=O)2- or -SO2NR 1a -; or, L 4 is selected from a bond, -S(=O)2- or -SO2NR 1a -; or, L 4 is selected from a bond, SO2 or SO2NH.

8. The compound of formula (I) according to any one of claims 1 to 7, wherein R L1 , R L2 , R L3 , R L4 , R 1a , R 1b are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, NH2or C1-C4alkyl, said OH, NH2or C1-C4alkyl is optionally substituted with one or more R D ; or, R L1 , R L2 , R L3 , R L4 , R 1a , R 1b are independently of each other selected from hydrogen, deuterium or C1-C4alkyl, said C1-C4alkyl is optionally substituted with one or more R D ; or, R L1 , R L2 , R L3 , R L4 , R 1a , R 1b are independently of each other selected from hydrogen or deuterium.

9. The compound of formula (I) according to any one of claims 1 to 8, wherein R 1 selected from hydrogen, deuterium, halogen, Ci-C6alkyl, C3-C6cycloalkyl, -OR 2 or -NR 2a R 2b , said Ci-C6alkyl or C3-C6cycloalkyl is optionally substituted with one or more R B ; alternatively, R 1 is selected from hydrogen, deuterium, halogen, Ci-C6alkyl or C3-C6cycloalkyl, said Ci-C6alkyl or C3-C6cycloalkyl is optionally substituted with one or more R B ; alternatively, R 1 is selected from hydrogen or Ci-C6alkyl optionally substituted with one or more R B .

10. The compound of formula (I) according to any one of claims 1 to 9, wherein R 2 , R 2a , R 2b are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4alkyl or C3-C6cycloalkyl, said OH, NH2, C1-C4alkyl or C3-C6cycloalkyl optionally being substituted with one or more R D ; or, R 2 , R 2a , R 2b are independently of each other selected from hydrogen, deuterium or C1-C4alkyl, said C1-C4alkyl optionally being substituted with one or more R D .

11. The compound of formula (I) according to any one of claims 1 to 10, wherein X 3 selected from NH.

12. The compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 2 NR X1 C(R X1 R X2 ) or O; or, X 2 NR X1 or O; or, X 2 NR X1 or O, L 1 is a bond or -C(R 1c R 1d )-, wherein R X1 is hydrogen, R 1c , R 1d are each independently selected from the group consisting of hydrogen, deuterium, or C1-C4alkyl; or R X1 , R 1c and the atom to which they are attached together form a 4-6 membered heterocyclic ring, said 4-6 membered heterocyclic ring being optionally substituted with one or more R C ; or, X 2 NR X1 , L 1 is a bond or -C(R 1c R 1d )-, wherein R X1 is hydrogen, R 1c , R 1d are each independently selected from the group consisting of hydrogen, deuterium, or C1-C4alkyl; or X 2 NR X1 , L 1 is -C(R 1c R 1d )-, R 1d is selected from the group consisting of hydrogen, deuterium, or C1-C4alkyl, R X1 , R 1c and the atom to which they are attached together form a 4-6 membered saturated heterocyclic ring, said 4-6 membered saturated heterocyclic ring being optionally substituted with one or more R C and containing 1 nitrogen atom as a heteroatom; or, X 2 NR X1 , L 1 is -C(R 1c R 1d )-, R 1d is hydrogen, R X1 , R 1c and the atom to which they are attached together form a tetrahydropyrrole ring.

13. The compound of formula (I) according to any one of claims 1 to 12, wherein L 1 、L 2 、L 3 are independently of each other selected from a bond, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -O-, -OC(R 1c R 1d )-, -NR 1c -, -NR 1c C(R 1e R 1f )-, -C(R 1c ) = C(R 1e )-, a 3-6 membered saturated or partially unsaturated carbocyclic ring or a 3-6 membered heterocyclic ring, which 3-6 membered saturated or partially unsaturated carbocyclic ring or 3-6 membered heterocyclic ring is optionally substituted with one or more R E ; or, L 1 , L 2 , L 3 are independently of each other selected from a bond, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -O-, -OC(R 1c R 1d )-, -NR 1c -, -NR 1c C(R 1e R 1f )-, -C(R 1c ) = C(R 1e )-, a 3- or 4-membered saturated carbocyclic ring, a tetrahydropyrrole ring or a piperazine ring, which 3- or 4-membered saturated carbocyclic ring, tetrahydropyrrole ring or piperazine ring is optionally substituted with one or more R E ; or, L 1 , L 2 , L 3 are independently of each other selected from a bond, -C(R 1c R 1d )-, -C(R 1c R 1d )C(R 1e R 1f )-, -O-, -OC(R 1c R 1d )-, -NR 1c -, -NR 1c C(R 1e R 1f )-, -C(R 1c )-, 3- or 4-membered saturated carbocyclic, tetrahydropyrrole or piperazine ring; or, L 1e )-, -C(R 2 )-, -C(R 1c R 1d )-, -C(R 1c R 1d )-, -C(R 1e R 1f )- or 3-6 membered saturated carbocyclic ring, said 3-6 membered saturated carbocyclic ring being optionally substituted with one or more R E , R 1c , R 1d , R 1e , R 1f are independently of each other selected from hydrogen, deuterium or C1-C4alkyl; or, L 2 is selected from CH2or CH2CH2; or, L 3 is selected from -C(R 1c R 1d )-, -O-, -NR 1c - or 4-6 membered saturated heterocyclic ring, said 4-6 membered saturated heterocyclic ring being optionally substituted with one or more R E and containing 1 or 2 nitrogen atoms as heteroatoms, R 1c , R 1d are independently of each other selected from hydrogen, deuterium or C1-C4alkyl; or, L 3 is selected from -C(R 1c R 1d )-, -NR 1c -, wherein * represents the position of attachment to the carbonyl group in formula (I). R 1c , R 1d are independently of each other selected from hydrogen, deuterium or C1-C4alkyl; or, L 3 is selected from NH, CH2or wherein * represents the position of attachment to the carbonyl group in formula (I).

14. The compound of formula (I) according to any one of claims 1 to 13, wherein R X1 , R X2 , R 1c , R 1d , R 1e , R 1f are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl being optionally substituted with one or more R C ; or, R X1 , R 1c and the atom to which they are attached, or R X1 , R 1e and the atom to which they are attached, form together a 3-6 membered saturated or partially unsaturated carbocyclic ring, a 3-6 membered heterocyclic ring, a phenyl ring or a 5-6 membered heteroaromatic ring, said 3-6 membered saturated or partially unsaturated carbocyclic ring, 3-6 membered heterocyclic ring, phenyl ring or 5-6 membered heteroaromatic ring being optionally substituted with one or more R C ; or, R X1 , R X2 , R 1c , R 1d , R 1e , R 1f are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, said OH, NH2, C1-C4-alkyl, C3-C6-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl being optionally substituted with one or more R C ; or, R X1 , R X2 , R 1c , R 1d , R 1e , R 1f are independently of each other selected from hydrogen, deuterium, halogen, CN, OH, NH2or C1-C4-alkyl, said OH, NH2or C1-C4-alkyl being optionally substituted with one or more R C .

15. The compound of formula (I) according to any one of claims 1 to 14, wherein R B , R C , R D are independently from each other selected from deuterium, =0, OH, CN, halogen, NH2, C1-C4 alkyl or C1-C4 alkoxy, said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted with one or more R; or, R B , R C , R D are independently from each other selected from deuterium, =0, OH, CN, halogen, NH2or C1-C4 alkyl, said C1-C4 alkyl is optionally substituted with one or more R.

16. The compound of formula (I) according to any one of claims 1 to 15, wherein R is selected from deuterium, =0, OH, CN, halogen, C1-C4alkyl, C1-C4haloalkyl or C1-C4alkoxy; or, R is selected from deuterium, =0, OH, CN, halogen or C1-C4alkyl.

17. The compound of formula (I) according to any one of claims 1-16, wherein the compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein said Z 1 , Z 2 , X 1 , ring A, L 4 , R 1 , X 3 , X 2 , L 1 , L 2 , L 3 as defined in any one of claims 1 to 16.

18. The compound of formula (I) according to any one of claims 1-16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from a compound of Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein said Z 1 , Z 2 , X 1 , ring A, L 4 , R 1 , X 3 , X 2 , L 1 , L 2 , L 3 as defined in any one of claims 1-16.

19. The compound of formula (I) according to any one of claims 1-16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, the compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (I)-2 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1 , ring A, L 4 , R 1 , X 2 , L 1 , L 2 , L 3 as defined in any one of claims 1 to 16.

20. The compound of formula (I) according to any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, the compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

21. A pharmaceutical composition comprising a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. A method of treating a disease mediated by CDK2 in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.

23. A method of treating a tumor in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.

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