Macrocyclic compound as well as preparation and use thereof

Abstract

The present invention relates to a macrocyclic compound as well as a preparation method therefor and a use thereof. Specifically, the macrocyclic compound of the present invention has a structure represented by formula (I), wherein the definitions of groups and substituents are as described in the description. Further disclosed in the present invention are a preparation method for the compound, and a use of the compound in regulating CDK2 activity and / or preventing and / or treating CDK2-related diseases.

Description

Macrocyclic compounds and their preparation and application Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a class of macrocyclic compounds used as CDK2 kinase inhibitors. Background Art

[0002] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases, important cellular enzymes that perform essential functions in regulating cell division and proliferation.

[0003] Heterodimerization of CDKs and regulatory subunits (cyclins) fully activates and regulates key cellular processes including cell cycle progression and cell division (Morgan, do, Annu Rev Cell Dev Biol, 1997, 13: 261-91). Uncontrolled proliferation is a characteristic of cancer cells. Abnormal regulation of CDK activity is associated with abnormal regulation of the cell cycle and can be detected in almost all forms of human cancer (Sherr, cj, Science, 1996, 274 (5293): 1672-7).

[0004] CDK2 plays a crucial role in the G1 / S transition and S phase progression. CDK2 and cyclin E (CCNE) complex phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), releasing E2F transcription factors and promoting the transition from G1 phase to S phase (Henley, Sa and FADick, Cell Div, 2012, 7(1):10). This in turn activates CDK2 / cyclin A, phosphorylating endogenous substrates, thereby allowing DNA synthesis, replication and centrosome duplication (Ekholm, SV and SI Reed, Curr Opin Cell Biol, 2000, 12(6):67684). It is reported that the CDK2 pathway mainly affects tumorigenesis through the amplification and / or overexpression of CCNE1 and the mutational inactivation of CDK2 endogenous inhibitors (such as p27).

[0005] CCNE1 copy number increase and overexpression have been confirmed in ovarian, gastric, endometrial, breast and other tumors and are associated with poor prognosis in these tumors (Keyomarsi, K., et al., N Engl J Med., 2002, 347(20):1566-75; Nakayama, N., et al., Cancer, 2010, 116(11):2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017, 23(7):1862-1874; Rosen, DG, et al., Cancer, 2006, 106(9):1925-32). CCNE1 amplification and / or overexpression have also been reported to lead to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor-positive breast cancer. Inhibitors targeting CDK2 have been shown to induce cell apoptosis and inhibit tumor proliferation.

[0006] However, due to the highly similar ATP-binding domains of the CDKs family of kinases, selective inhibitors targeting CDK2 are currently lacking. Most small molecules can simultaneously inhibit multiple CDK kinase isoforms, or even other non-CDK family kinases. While these off-target effects lead to potent cell killing or inhibition, they also carry significant side effects. Therefore, the development of new, selective CDK2 kinase inhibitors holds broad promise.

[0007] Summary of the Invention

[0008] One object of the present invention is to provide a macrocyclic compound as a CDK2 kinase inhibitor and its use.

[0009] In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,

[0010] in:

[0011] X1 is a bond, -O-, or -NR a -、-S-、C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, -(CH2) 1-2 O-, -(CH2) 1-2 NR a -、-(CH2) 1-2 S-, -C(O)-, -NR a C(O)-, or -C(O)NRa -, wherein the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0012] X2 is a bond, -O-, or -NR a -、-S-、C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0013] X3 is a key, C 1-6 Alkylene, -NR-, C 3-6 Cycloalkyl, or 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0014] L1 is a bond, -O-, or -NR a -、-S-、C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, -(CH2) 1-2O-, -(CH2) 1-2 NR a -、-(CH2) 1-2 S-, -C(O)-, -NR a C(O)-, or -C(O)NR a -, wherein the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0015] Ring A is selected from the group consisting of: C 4-6 Cycloalkyl, saturated or partially saturated 5-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or phenyl-5-6 membered heterocycloalkyl, 5-6 membered cycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the group is optionally substituted by 0, 1, 2, 3 or 4 R1;

[0016] Ring B is selected from the group consisting of:

[0017] R is selected from the following group: H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S;

[0018] R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, =O, -(CH2) 0-2 OR b 、-(CH2) 0-2 NR b R c 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b、-C(O)NR b R c 、-NR b SO2R c 、-OC(O)NR b R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =0, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, -NR d R e 、-SO2R d 、-SO2NR d R e 、-C(O)OR d 、-C(O)NR d R e 、-NR d SO2R e 、-OC(O)NR d R e 、-NR d C(O)OR e ,

[0019] Alternatively, two R1 attached to the same atom may be linked to each other to form a C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0020] R a are independently selected from the group consisting of hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S;

[0021] R b 、R c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (a 3-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy,

[0022] Or, R b and R c Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and the 3-6 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0023] R d 、R e are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (a 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C1-4 Alkyl, halogenated C 1-4 Alkoxy,

[0024] Or, R d and R e Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and the 3-6 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0025] In another preferred embodiment, the compound has a structure selected from the following group:

[0026] wherein Ring A, X1, X2, L1, and R are as defined herein;

[0027] Ring C is selected from the group consisting of: C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0028] In another preferred embodiment, ring A has a structure selected from the following group:

[0029] in,

[0030] Y1 is selected from the following group: N, CH;

[0031] Y2 is selected from the following group: N, CH;

[0032] Y3 is selected from the following group: NH, NR1, O, CH2;

[0033] R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, =O, -(CH2) 0-2 OR b 、-(CH2) 0-2 NR b R c 、C 1-6 Alkyl, halogenated C1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, phenyl, 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b 、-C(O)NR b R c 、-NR b SO2R c 、-OC(O)NR b R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, -NR d R e 、-SO2R d 、-SO2NR d R e 、-C(O)OR d 、-C(O)NR d R e 、-NR d SO2R e 、-OC(O)NR d R e 、-NR d C(O)OR e ;

[0034] m is selected from the following group: 0, 1, 2, 3, 4, 5, 6;

[0035] It represents the connection position of ring A in the structure of formula I, with one end connected to NH and the other end connected to X1.

[0036] In another preferred embodiment, ring A is

[0037] In another preferred embodiment, ring A is

[0038] In another preferred embodiment, ring A is

[0039] In another preferred embodiment, ring A is

[0040] In another preferred embodiment, ring A is selected from the following group:

[0041] In another preferred embodiment, X1 is a bond or C 1-3 Alkylene; wherein the C 1-3 The alkylene group is optionally substituted with 0, 1 or 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl.

[0042] In another preferred embodiment, L1 is O or S; preferably L1 is O.

[0043] In another preferred embodiment, X2 is a bond, C 1-6 Alkylene, C 3-6 Cycloalkyl; wherein the C 1-6 Alkylene or C 3-6 The cycloalkyl group is optionally substituted with 0, 1 or 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 alkyl.

[0044] In another preferred embodiment, X3 is a bond, -NR-, C 3-6 Cycloalkyl, or a 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, or 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S is optionally substituted with 0, 1 or 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, C 1-3 Alkyl and halogenated C 1-3 Alkyl; R is selected from the following group: H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl or C 3-4 Cycloalkyl.

[0045] In another preferred embodiment, ring A has one oxo (=O) substituent.

[0046] In another preferred embodiment, X2 has a structure selected from the group consisting of:

[0047] In another preferred embodiment, ring C has a structure selected from the following group:

[0048] In another preferred embodiment, R1 is independently selected from the following group: C 1-3 Alkyl, halogenated C 1-3 Alkyl and C 3-6 Cycloalkyl; more preferably methyl, ethyl, isopropyl, CF2CH2-, CF3CH2-, cyclopropyl.

[0049] In a second aspect, the present invention provides a compound represented by Formula Ia, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof,

[0050] in,

[0051] X1 and L1 are each independently a bond, -O-, -S-, or -NR a -, substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-10 Alkenylene, substituted or unsubstituted C 2-10 Alkynylidene, substituted or unsubstituted C 3-6 Cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 O-, -(CH2) 0-4 S-, -(CH2) 0-4 NR a -、-C(O)-、-NR a C(O)-、-C(O)NR a -, wherein the substitution refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0052] X2 is a bond, substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-6 Alkenylene, substituted or unsubstituted C 2-6 Alkynylidene, substituted or unsubstituted C 3-6 Cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 (C 3-6Cycloalkyl), wherein the substitution refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0053] Ring A is selected from the following group: a substituted or unsubstituted saturated or partially saturated 5-6 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O or S, a substituted or unsubstituted oxo 9-10 membered ring, wherein the substitution means that one or more hydrogen atoms (for example, 1, 2, 3, 4, 5 or 6) on the group are replaced by R1,

[0054] wherein R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, oxo (=O), -(CH2) 0-4 OR b 、-(CH2) 0-4 NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b 、-NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-OC(O)NR b R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, oxo (=O), hydroxy, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, phenyl, benzyl, -NR b R c 、-SO2R b 、-C(O)OR b 、-OC(O)NR b R c 、-SO2NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-NR b C(O)OR c ;

[0055] Alternatively, two R1 on the same atom and the atom to which they are attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or a substituted or unsubstituted 3-6 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O or S, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group being replaced by a substituent selected from the group consisting of deuterium, hydroxyl, halogen, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0056] R a are independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms each independently selected from N, O or S;

[0057] R b 、R c are independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 (C3-6 Cycloalkyl), -(CH2) 0-4 (a 3-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy,

[0058] Or, R b and R c Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl-containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl- is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, oxo (=O), C 1-4 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0059] In another preferred embodiment, X1 and L1 are each independently a bond, -O-, -S-, or -NR a -, substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-6 Alkenylene, substituted or unsubstituted C 2-6 Alkynylidene, substituted or unsubstituted C 3-6 Cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2) 0-2 O-, -(CH2) 0-2 S-, -(CH2) 0-2 NR a -、-C(O)-、-NR a C(O)-、-C(O)NR a -, wherein the substitution refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0060] X2 is a bond, substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-6 Alkenylene, substituted or unsubstituted C 2-6 Alkynylidene, substituted or unsubstituted C 3-6 Cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 (C 3-6 Cycloalkyl), wherein the substitution refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0061] Ring A is selected from the following group: a substituted or unsubstituted saturated or partially saturated 5-6 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O or S, a substituted or unsubstituted oxo 9-10 membered ring, wherein the substitution means that one or more hydrogen atoms (for example, 1, 2, 3, 4, 5 or 6) on the group are replaced by R1,

[0062] wherein R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, oxo (=O), -(CH2) 0-2 OR b 、-(CH2) 0-2 NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b 、-NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-OC(O)NR b Rc 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, oxo (=O), hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, phenyl, benzyl, -NR b R c 、-SO2R b 、-C(O)OR b 、-OC(O)NR b R c 、-SO2NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-NR b C(O)OR c ;

[0063] Alternatively, two R1 on the same atom and the atom to which they are attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or a substituted or unsubstituted 3-6 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O or S, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group being replaced by a substituent selected from the group consisting of deuterium, hydroxyl, halogen, cyano, oxo (=O), C 1-6 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 alkoxy;

[0064] R a are independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms each independently selected from N, O or S;

[0065] R b 、R c are independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (a 3-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, oxo (=O), C 1-6 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy,

[0066] Or, R b and R c Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl-containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl- is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, oxo (=O), C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0067] In another preferred embodiment, the compound has a structure shown in Formula II-a or Formula III-a:

[0068] Wherein, ring A, X1, X2, and L1 are as defined in the first aspect of the present invention.

[0069] In another preferred embodiment, ring A is selected from the following group: substituted or unsubstituted oxo 5-membered heterocyclic 6-membered heteroaryl, substituted or unsubstituted oxo 5-6-membered heteroaryl.

[0070] In another preferred embodiment, Ring A is selected from the following group: substituted or unsubstituted oxo 9-10 membered rings.

[0071] In another preferred embodiment, ring A is a structure selected from the following group:

[0072] in,

[0073] Y1 is selected from the group consisting of N, CH;

[0074] Y2 is selected from the group consisting of N, CH;

[0075] Y3 is selected from the group consisting of NH, NR1, O, S, CH2;

[0076] R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, oxo (=O), -(CH2) 0-4 OR b 、-(CH2) 0-4 NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S, 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O or S, phenyl, benzyl, -SO2R b 、-C(O)OR b 、-SO2NR b R c 、-OC(O)NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O or S, -SO2R b 、-C(O)OR b 、-SO2NR b R c 、-OC(O)NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-NR b C(O)OR c ;

[0077] m is selected from the following group: 0, 1, 2, 3, 4, 5, 6;

[0078] It represents the connection position of ring A in the structure of formula I, with one end connected to NH and the other end connected to X1.

[0079] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, and R1 are as shown in the second aspect of the present invention.

[0080] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, and R1 are as shown in the second aspect of the present invention.

[0081] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, and R1 are as shown in the second aspect of the present invention.

[0082] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, m, and R1 are as shown in the second aspect of the present invention.

[0083] In another preferred embodiment, X2 is selected from the following groups: a bond, a substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-6 Alkenylene, substituted or unsubstituted C 2-6 Alkynylidene, substituted or unsubstituted C 3-6 Cycloalkylene, -(CH2) 0-4 (C 3-6 cycloalkyl);

[0084] Wherein, the substitution refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0085] In another preferred embodiment, X2 is selected from the following group:

[0086] In another preferred embodiment, ring A is selected from the following group:

[0087] X1 is selected from the group consisting of a bond, -O-, a substituted or unsubstituted C 1-6 alkylene;

[0088] L1 is selected from the group consisting of a bond, -O-, -S-, a substituted or unsubstituted C 1-6 alkylene;

[0089] X2 is selected from the following group:

[0090] In another preferred embodiment,

[0091] In the third aspect of the present invention, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, and a pharmaceutically acceptable carrier.

[0092] In another preferred embodiment, in the composition, the compound accounts for 0.001-99.999 wt% of the total weight of the composition; preferably 0.01-99.99 wt%; more preferably 0.1-90 wt%.

[0093] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0094] In the third aspect of the present invention, there is provided a use of the compound described in the first or second aspect of the present invention or the pharmaceutical composition described in the second aspect of the present invention for preparing a drug or preparation, wherein the drug or preparation is used for (a) regulating CDK kinase activity, and / or (b) preventing and / or treating CDK-related diseases.

[0095] In another preferred embodiment, the CDK kinase is CDK2 kinase.

[0096] In another preferred embodiment, the CDK-related disease is cancer.

[0097] In another preferred embodiment, the cell cycle protein-related disease is cancer.

[0098] In another preferred embodiment, the cancer is selected from the following group: breast cancer, ovarian cancer, bladder cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), renal cancer (including RCC), skin cancer, glioblastoma, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), neuroblastoma, sarcoma, liposarcoma, chondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma, pediatric tumor.

[0099] In the fourth aspect of the present invention, there is provided a use of the compound described in the first or second aspect of the present invention or the pharmaceutical composition described in the third aspect of the present invention for preparing a drug or preparation, wherein the drug or preparation is used to prevent and / or treat cyclin-related diseases.

[0100] In another preferred embodiment, the cell cycle protein is cyclin E.

[0101] In another preferred embodiment, the cyclin E is selected from the following group: cyclin E1 and cyclin E2.

[0102] In another preferred embodiment, the cell cycle protein-related disease is cancer.

[0103] In another preferred embodiment, the cancer is selected from the following group: breast cancer, ovarian cancer, bladder cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), renal cancer (including RCC), skin cancer, glioblastoma, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), neuroblastoma, sarcoma, liposarcoma, chondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma, pediatric tumor.

[0104] In a fifth aspect, the present invention provides use of the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof, in the preparation of a CDK kinase inhibitor.

[0105] In a sixth aspect, the present invention provides a method for preventing and / or treating CDK-related diseases, comprising the steps of administering the compound as described in the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, to a subject in need, thereby preventing and / or treating the disease.

[0106] In another preferred embodiment, the subject is a human or non-human mammal, such as a monkey, rat, or mouse.

[0107] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0108] After extensive and in-depth research, the inventors have provided, for the first time, a class of macrocyclic compounds with excellent CDK kinase inhibitory activity. Specifically, through structural optimization, the inventors have obtained a class of compounds with excellent selective CDK2 inhibitory activity. Based on this, the inventors have completed the present invention.

[0109] the term

[0110] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0111] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- includes -OCH2-.

[0112] In the present invention, the term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0113] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0114] In the present invention, "C 1-6 "Alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like. The term "C 1-3 Alkyl" or "C 1-4 "Alkyl" has a similar meaning.

[0115] In the present invention, the term "C 2-6 The term "alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including, but not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl.

[0116] In the present invention, the term "C 2-6 The term "alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl.

[0117] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy. The term "C 1-4 "Alkoxy" has a similar meaning.

[0118] In the present invention, the term "C 2-10 "Alkenylene" refers to a straight or branched chain alkenylene group having 2 to 10 carbon atoms and containing one double bond, including but not limited to: wait.

[0119] In the present invention, the term "C 2-10 "Alkyne" refers to a straight or branched chain alkynyl group having 2 to 10 carbon atoms and containing one triple bond, including but not limited to wait.

[0120] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably it is a C1-C4 alkoxy group.

[0121] In the present invention, the term "C 1-6 “Alkylene” refers to a straight or branched chain alkylene structure comprising 1 to 6 carbon atoms, including, but not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH(CH3)-, etc.

[0122] In the present invention, the term "cycloalkyl" refers to a cyclic alkyl group containing 3 to 12 carbon atoms, including monocyclic alkyl and condensed cyclic alkyl groups. Condensed cyclic alkyl groups include cycloalkyl, bridged cycloalkyl and spirocycloalkyl groups. 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, wherein the ring contains C 3-6 Monocyclic alkyl, C 5-6 Bicycloalkyl, C 5-6 Bridged ring group, C 5-6 Spirocyclyl, including but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0123] The cycloalkyl group may be a saturated or partially saturated cycloalkyl group, which may or may not contain a double bond in the ring. The ring includes: C 5-7 Monocyclic alkyl, C 6-12 Bicycloalkyl, C 5-12 Bridged ring group, C 5-12 Spirocyclyl, including but not limited to: cyclopentyl, cyclohexyl, cycloheptyl,

[0124] In the present invention, the term "heterocycloalkyl" refers to a cycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, including monoheterocycloalkyl and fused-ring heterocycloalkyl groups. Fused-ring heterocycloalkyl groups include fused-ring heterocycloalkyl groups, bridged-ring heterocycloalkyl groups and spirocyclic heterocycloalkyl groups.

[0125] The "3-6 membered heterocycloalkyl" refers to C 3-6 The optional CH2 or CH groups in the cycloalkyl group are replaced by N or NH or O or S atoms, including but not limited to:

[0126] The "saturated or partially saturated 5-6 membered heterocycloalkyl" refers to a C 5-10 The optional CH2 or CH group in the cycloalkyl group is replaced by N or NH or O or S atom, and the ring connected to the parent is a non-aromatic ring structure, including but not limited to:

[0127] The “saturated or partially saturated heterocycloalkyl” refers to a cycloalkyl group containing or not containing a double bond in the ring, wherein the optional CH2 or CH group is replaced by an N or NH or O or S atom, and the ring connected to the parent is a non-aromatic ring structure, including but not limited to:

[0128] In the present invention, the term "a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl and a 5-6 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S" refers to a ring structure containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, and the ring structure has a 5-6 membered cycloalkyl and a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl and a heteroaryl structure, and the ring connected to the parent is a non-aromatic ring structure, including but not limited to:

[0129] In the present invention, the term "oxo 9-10 membered cyclic ring" refers to a cyclic ring structure containing 9 or 10 atoms substituted by a functional group "=O", and the cyclic ring structure can be a saturated ring, an aromatic ring, or a partially saturated ring. The term "5-6 membered heteroaryl or phenyl 5-6 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O, or S" refers to a cyclic ring structure containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and the cyclic ring structure has a 5-6 membered heteroaryl 5-6 membered heterocycloalkyl or phenyl 5-6 membered heterocycloalkyl structure, including but not limited to:

[0130] In the present invention, the terms "aromatic heterocycle" and "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. For example, a "5-6 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 1 to 5 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted.

[0131] In the present invention, the term "deuterated" means substituted with deuterium.

[0132] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is a combination that is stable or chemically feasible. The substituents include, but are not limited to, deuterium, halogen, hydroxyl, cyano, amino, alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, haloalkylamino, 3-7 membered heterocyclic group, aryl, heteroaryl, C 2-6 Acyl, C 2-6 Ester group, C 2-6 Alkynyl, C 2-6 Alkenyl, etc.

[0133] In the present invention, the term 1 to 4 refers to 1, 2, 3 or 4. Other similar terms have similar meanings.

[0134] In the present invention, "-SO2-" means

[0135] In the present invention, "-C(O)-" means

[0136] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the group:" has the same meaning as the term "independently selected from the group:".

[0137] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0138] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0139] Compound

[0140] The present invention provides a macrocyclic compound with CDK kinase inhibitory activity, which is used for inducing cell apoptosis and inhibiting tumor proliferation.

[0141] Specifically, the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,

[0142] wherein, Ring A, Ring B, X1, X2, X3, and L1 are as defined above.

[0143] Alternatively, the compound is a compound of formula Ia, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof,

[0144] Ia wherein Ring A, X1, X2, and L1 are as defined above.

[0145] In another preferred embodiment, in the compound, any one of ring A, ring B, X1, X2, X3, and L1 is independently a corresponding specific group in the specific compound.

[0146] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0147] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0148] The term "stereoisomer" refers to isomers of the compounds of the present invention resulting from different spatial arrangements of atoms in the molecules, including cis-trans isomers and enantiomers and diastereomers resulting from chiral atoms.

[0149] The term "deuterated compound" refers to a compound in which any hydrogen atom attached to carbon in the compound of the present invention may be optionally replaced by a deuterium atom to form a deuterium-containing compound.

[0150] It should be understood that the specific preparation method of the compound of formula (I) of the present invention does not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0151] Typically, the compounds of the present invention can be prepared by the process described in the examples, wherein the raw materials and reagents used can be purchased from commercial sources unless otherwise specified.

[0152] Pharmaceutical compositions and methods of administration

[0153] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds of the present invention or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof.

[0154] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0155] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0156] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0157] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0158] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0159] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0160] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0161] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0162] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0163] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0164] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0165] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0166] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0167] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0168] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0169] Compared with the prior art, the main advantages of the present invention include:

[0170] 1) The compound has excellent CDK2 inhibitory activity.

[0171] 2) The compound can be used to induce cell apoptosis and inhibit tumor proliferation.

[0172] 3) The compound has excellent selectivity in inhibiting CDK isoforms.

[0173] 4) The compounds of the present invention have excellent pharmacokinetic and pharmacodynamic properties and are very druggable.

[0174] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0175] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0176] Example Synthesis Route

[0177] Unless otherwise stated, the absolute stereochemistry of all chiral atoms is defined as follows. The compound marked with the "&" symbol in the structural formula indicates that the compound is a cis racemate; the compound marked with the "or1" symbol indicates that the compound is a single-configuration compound, but the absolute configuration is unknown; the compound marked with the "or2" symbol indicates that the compound is a single-configuration compound, which is an enantiomer of the "or1" structure, but the absolute configuration is unknown; the compound marked with the "abs" symbol indicates that the absolute configuration of the compound is the structure shown; the compound marked with the "rac" symbol indicates that the compound is a racemate; the compound marked with the "S" or "R" symbol indicates that the chirality of the carbon at that position in the compound is the known configuration marked. ()

[0178] Synthesis of intermediate int1:

[0179] 1. Synthesis of int1-2

[0180] Dissolve int1-1 (10 g, 64.0 mmol) in 150 mL of methanol. Under nitrogen protection, add NaBH4 (2.44 g, 64.0 mmol) in portions. Then, warm the reaction mixture to room temperature and stir for 2 hours. After completion, quench the reaction by slowly adding 1 M dilute hydrochloric acid solution while cooling in an ice-water bath. Concentrate under reduced pressure to remove the methanol solvent, then dilute with water and extract with dichloromethane. The organic phase is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 8.27 g of crude product. Ms[M+Na] + :181.1

[0181] 2. Synthesis of int1-3

[0182] Int1-2 (8.27 g, 52.33 mmol) was dissolved in 100 mL of ethanol, followed by the addition of imidazole (10.67 g, 157.0 mmol). TBDPSCl (15.83 g, 57.58 mmol) was slowly added dropwise under nitrogen in an ice-water bath. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 16 hours. After the reaction was completed, the ethanol solvent was evaporated under reduced pressure. The residue was then diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 19.86 g of the product. Ms[M+H] + 397.2. 1HNMR(400MHz, CDCl3)δ7.73-7.58(m,4H),7.43-7.33(m,6H),4.31-4.20(m,1H),4.18-4.03(m,2H),2.71-2.55(m,1H) ,2.19-2.08(m,1H),2.01(d,J=5.6Hz,2H),1.86-1.70(m,2H),1.64-1.53(m,1H),1.25(t,J=7.1Hz,3H),1.05(s,9H).

[0183] 3. Synthesis of int1-4

[0184] Under nitrogen, n-butyllithium (88 mL, 2.5 M in hexane) was added to 500 mL of anhydrous tetrahydrofuran. The system was cooled to -65°C, and acetonitrile (9.2 g, 224.8 mmol) was slowly added dropwise. After the addition was complete, the temperature was maintained and stirred for 1 hour. A solution of int1-3 (44.7 g, 112.4 mmol) in anhydrous tetrahydrofuran (100 mL) was then slowly added dropwise, and the temperature was maintained and stirred for another 2 hours. After the reaction was completed, water was added dropwise at -65°C to quench the reaction. After stirring and warming to room temperature, the reaction solution was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 49.0 g of crude product. Ms[M+H] + :392.2

[0185] 4. Synthesis of int1-5

[0186] Dissolve tert-butylhydrazine hydrochloride (9.35 g, 75.0 mmol) and triethylamine (10.43 mL, 75.0 mmol) in 150 mL of ethanol and stir for 0.5 hours before adding a 50 mL solution of int1-4 (19.6 g, 50.0 mmol) in ethanol. Heat the reaction system to 75°C and stir for 16 hours. After completion of the reaction, cool the reaction solution to room temperature, concentrate, dilute with water, and extract with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 19.1 g. Ms[M+H] + :462.3 1 HNMR(400MHz, CDCl3)δ7.70-7.66(m,4H),7.40-7.31(m,6H),5.46(s,1H),5.19(s,1H),4.46-4.27(m,1H ),3.55-3.27(m,2H),2.90-2.81(m,1H),2.29-2.04(m,1H),1.93-1.64(m,4H),1.57(s,9H),1.06(s,9H).

[0187] 5. Synthesis of int1-6

[0188] Int1-5 (19.12 g, 41.0 mmol) was dissolved in 160 mL of acetonitrile and cooled in an ice-water bath. Benzyl chloroformate (11.7 mL, 82.0 mmol) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. NaHCO₃ (11.02 g, 130.0 mmol) was then added and stirred at room temperature for 16 hours. After the reaction, the reaction mixture was filtered and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 21.2 g. Ms[M+H] + :596.4

[0189] 6. Synthesis of int1-7

[0190] Int1-6 (21.0 g, 35.0 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran with stirring at room temperature. Glacial acetic acid (4.2 mL, 70.0 mmol) and tetrabutylammonium fluoride (35.0 mL, 1 M in tetrahydrofuran) were added sequentially. The mixture was heated to 40°C and stirred for 23 hours under a nitrogen atmosphere. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 4.41 g. Ms[M+H] + :358.2. 1 HNMR(400MHz,DMSO-d6)δ9.06(s,1H),7.59-7.22(m,5H),5.92(s,1H),5.12(s,2H),4.57(d,J=4.4Hz,1H),4 .22-4.09(m,1H),2.99-2.78(m,1H),2.23-2.14(m,1H),1.90-1.79(m,1H),1.77-1.64(m,3H),1.47(s,9H).

[0191] 7. Synthesis of int1-8

[0192] The following method was used for chiral separation of int1-7: Agilent high performance liquid chromatography separation, the preparative separation conditions were as follows: Chromatographic column: Phenomenex 5μm Cellulose-4, mobile phase: n-hexane:isopropanol = 90:10; collect the sample with a peak time of 24.6 min, concentrate and freeze-dry to obtain the product int1-8 (1.07 g), and the peak time of another configuration is 21.8 min.

[0193] 8. Synthesis of int1

[0194] Int1-8 (1.07 g, 2.42 mmol) was dissolved in a mixture of 10 mL of methanol and 10 mL of ethyl acetate. Pd / C (214 mg, 20 mol%) was then added and stirred at room temperature under a hydrogen atmosphere for 5 h. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified to afford Int1 (640 mg). 1 H NMR (400MHz, DMSO-d6) δ5.24(s,1H),4.69(s,2H),4.65(d,J=4.8Hz,1H),4.17-4.06(m,1H),2.77(p,J=8.4Hz,1H),2.13-2.06(m,1H),1.82 -1.49(m,5H),1.48(s,9H).

[0195] Synthesis of intermediate int2:

[0196] 1. Synthesis of int2-2

[0197] Int2-1 (1 g), tetrahydrofuran (30 ml), water (6 ml), and LiOH (382 mg) were added to a 50 mL three-necked flask and stirred at room temperature for 1 h. After the reaction was completed, 50 ml of ethyl acetate was added, and the mixture was washed with 1 M aqueous sodium hydroxide solution (20 ml x 5), dried, and concentrated to obtain 640 mg of the product.

[0198] 2. Synthesis of int2-3

[0199] Int2-2 (640 mg), dichloromethane (64 ml), N-methylmorpholine (997 mg), and benzoyl chloride (1.17 g) were added to a 10 mL three-necked flask and stirred at 45 °C for 16 h. After the reaction was completed, 500 mg of the product was obtained after column purification.

[0200] 3. Synthesis of int2

[0201] Int2-3 (500 mg), Pd / C (200 mg), and methanol (10 ml) were added to a 50 mL single-necked bottle and reacted at room temperature for 2 h. After the reaction was complete, the mixture was filtered and concentrated to obtain 340 mg of the product.

[0202] Synthesis of intermediate int3:

[0203] 1. Synthesis of int3-2

[0204] To a 100 mL flask, add N,N-dimethylformamide (20 mL). NaH (2.25 g) was added at 0°C. Dimethyl malonate (9 g) was added at room temperature. After reacting at 40°C for 40 min, C91-1 was added and the temperature was raised to 100°C for another 16 h. After the reaction, concentrate to remove the N,N-dimethylformamide, add water (20 mL), and extract with ethyl acetate (4 x 20 mL) to remove impurities. The aqueous phase was retained and the pH was adjusted with concentrated H2SO4 until a large amount of solid precipitated. The solid was collected, washed with water several times, and dried to obtain 2.5 g of crude product, which was used directly in the next step.

[0205] 2. Synthesis of int3-3

[0206] Int3-2 crude product (2.3 g) was added to a 100 mL flask, and concentrated HCl (22 mL) and AcOH (16 mL) were added. The mixture was reacted at 100 °C for 6 h. After the reaction was completed, the mixture was concentrated to obtain 2.5 g of crude product, which was used directly in the next step.

[0207] 3. Synthesis of int3-4

[0208] Int3-3 (1.5 g) was added to a 50 mL flask, dissolved in anhydrous dichloromethane (20 mL) and stirred for 3-5 min. Zn(OTf)2 (0.6 g) and DBU (2.5 g) were added sequentially at room temperature, and finally diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.1 g) was added. The mixture was allowed to react at room temperature for 15 min. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 180 mg of the product.

[0209] 4. Synthesis of int3-5

[0210] Int3-4 (100 mg) was added to a 50 mL flask and dissolved in anhydrous N,N-dimethylformamide (5 mL). NaH (40 mg) was added at 0°C and the mixture was allowed to react for 0.5 h at 0°C. CHCl (100 mg) was then added and the reaction continued for 1.5 h. After the reaction, water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain 110 mg of the product.

[0211] 5. Synthesis of int3

[0212] Int3-5 (1.5 g) and carbon tetrachloride (20 mL) were added to a 50 mL flask and stirred to dissolve. Azobisisobutyronitrile (95 mg) was then added. N-bromosuccinimide (1.3 g) was then added. The mixture was reacted at 75°C under nitrogen for 2 hours. The mixture was concentrated and subjected to thin-layer chromatography to obtain 1.1 g of the product.

[0213] Synthesis of intermediate int4:

[0214] 1. Synthesis of int4-2

[0215] Under nitrogen, compound int4-1 (2 g, 1.00 eq) and tetrahydrofuran (80 mL) were added to a 250 mL three-necked flask. The temperature was cooled to -78°C, and a 1 M solution of vinylmagnesium bromide in tetrahydrofuran (40 mL, 3.7 eq) was slowly added dropwise. After completion of the addition, the temperature was slowly raised to -20°C and the reaction was allowed to react for 4 h. The reaction was quenched by slowly adding a saturated aqueous solution of ammonium chloride dropwise to the reaction system. The aqueous phase was extracted with ethyl acetate, and the layers were separated. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column yielded 0.8 g of the product. 1 H NMR(400MHz,Chloroform-d)δppm 9.27(s,1H),7.37(t,J=2.8Hz,1H),7.29(s,1H),6.50(dd,J=3.2,2.0Hz,1H),2.58(s,3H).Ms[M+H] + 167.03

[0216] 2. Synthesis of int4-3

[0217] Dissolve int4-2 (710 mg, 1.00 eq) in ultra-dry N,N-dimethylformamide (20 mL), cool to 0°C, add sodium hydride (188 mg, 1.10 eq), and react on ice for 30 min. Then, slowly add iodomethane (730 mg, 1.2 eq) dropwise to the reaction system on ice. Slowly warm to room temperature and react for 1 h. Quench the reaction with ice water on ice, extract the aqueous phase with ethyl acetate, and separate the layers. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to yield 860 mg of the product. Ms[M+H] + 181.06

[0218] 3. Synthesis of int4-4

[0219] Compound int4-3 (860 mg, 1.00 eq), sodium bicarbonate (1.2 g, 3.00 eq), and tert-butanol (17 mL) were added to a 100 mL single-necked bottle and stirred at room temperature for 10 min. Bromine (4.58 g, 6.00 eq) was then slowly added dropwise to the reaction system and allowed to react at room temperature for 1 h. Water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, and the layers were separated. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column afforded 1.3 g of the product. Ms[M+H] + 352.86

[0220] 4. Synthesis of int4-5

[0221] Dissolve int4-4 (1.3 g, 1.00 eq) in glacial acetic acid (26 mL) and add iron powder (1.03 g, 5.00 eq) at room temperature. Allow to react for 1 h at room temperature. Dilute the reaction solution with methanol, filter, and wash the residue with methanol. Concentrate the filtrate under reduced pressure to obtain 615 mg of crude product. Ms[M+H] + 197.04

[0222] 5. Synthesis of int4-6

[0223] Int4-5 (615 mg, 1.00 eq), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.13 g, 1.00 eq), and zinc trifluoromethanesulfonate (228 mg, 0.20 eq) were dissolved in dichloromethane (15 mL) and stirred at room temperature for 3 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (954 mg, 2.00 eq) was slowly added dropwise to the reaction system and allowed to react at room temperature for 10 min. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 550 mg of pure product was obtained after purification on a silica gel column. 1 H NMR(400MHz,Chloroform-d)δppm 6.57(s,1H),3.62(s,3H),2.48(s,3H),1.87(q,J=4.4Hz,2H),1.60(q,J=4.4Hz,2H).Ms[M+H] + 223.06

[0224] 6. Synthesis of int4

[0225] To a 100 mL glass flask, compound int4-6 (550 mg, 1.00 eq), N-bromosuccinimide (484 mg, 1.1 eq), and carbon tetrachloride (12 mL) were added. Azobisisobutyronitrile (44 mg, 0.10 eq) was then added at room temperature. The reaction mixture was incubated at 75°C under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature and concentrated. Purification on a silica gel column yielded 300 mg of the product. 1 H NMR(400MHz,Chloroform-d)δppm 6.87(s,1H),4.48(s,2H),3.65(s,3H),1.93(q,J=4.4Hz,2H), 1.69(q,J=4.4Hz,2H).Ms[M+H] + 300.97

[0226] Synthesis of intermediate int5:

[0227] 1. Synthesis of int5-2

[0228] Int5-1 (20 g, 1.0 eq) was dissolved in dichloromethane (200 mL), cooled to 0°C, and carbonyldiimidazole (29 g, 2.0 eq) was added in portions. After stirring for 20 minutes, dimethylhydroxylamine hydrochloride (13.1 g, 1.5 eq) and triethylamine (35 mL, 3.0 eq) were added. The mixture was naturally warmed to room temperature and stirred for 2 hours. After the reaction was complete, saturated brine was added to the reaction system, the liquids were separated, and the aqueous phase was extracted twice with dichloromethane. After combining, the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave 20.2 g of the product.

[0229] 2. Synthesis of int5-3

[0230] Int5-2 (17.43 g, 1.0 eq) was dissolved in dry tetrahydrofuran (240 mL) under nitrogen protection, cooled to -5 ° C, and then 3M methylmagnesium bromide solution (54.6 mL, 2.5 eq) was added dropwise. After the dropwise addition, the mixture was naturally warmed to room temperature and reacted for 16 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added dropwise to the reaction solution at 0 ° C to quench the reaction, and then saturated brine was added. The liquid was separated, and the aqueous phase was extracted once with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography gave 13.6 g of the product.

[0231] 3. Synthesis of int5-4

[0232] (R)-Methyl-CBS-oxazaborolidine (3.1 g, 1.0 eq) was dissolved in dry tetrahydrofuran (25 mL) under nitrogen atmosphere. A 1 M borane solution in tetrahydrofuran (13.5 mL, 1.2 eq) was then added. After stirring for 20 minutes, a solution of int5-3 (2.5 g, 1.0 eq) in tetrahydrofuran (20 mL, 2 h) was added dropwise using a microsyringe pump. The mixture was allowed to react at room temperature for 10 minutes. After completion, the reaction was quenched by the addition of 5 mL of methanol at 0°C. Water was then added and the mixture was extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography afforded 2.2 g of the product.

[0233] 4. Synthesis of int5

[0234] Int5-4 (2.2 g, 1.0 eq) was dissolved in methanol (25 mL). Pd / C (500 mg) and di-tert-butyl dicarbonate (2.58 g, 1.2 eq) were added at room temperature. The mixture was reacted under a hydrogen atmosphere for 3 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. Purification by column chromatography afforded 1.4 g of the product.

[0235] Synthesis of intermediate int6:

[0236] 1. Synthesis of int6-2

[0237] Dissolve int6-1 (4.18 g, 1.0 eq) in dichloromethane (120 mL), cool to 0°C, and add Dess-Martin reagent (11.87 g, 1.4 eq) in portions. After addition, warm to room temperature and stir for 16 h. After the reaction is complete, filter, concentrate, and add methyl tert-butyl ether to the residue. Wash twice with saturated sodium thiosulfate and sodium bicarbonate (1:1), dry, filter, and concentrate under reduced pressure to obtain 3.5 g of crude product, which is used directly in the next reaction.

[0238] 2. Synthesis of int6-3

[0239] NaH (0.386 g, 2.0 eq) was added to dimethyl sulfoxide (15 mL). Trimethylsulfuryl iodide (2.12 g, 2.0 eq) was added portionwise in a water bath. The mixture was allowed to react at room temperature for 1 h. A solution of int6-2 (1.01 g, 1.0 eq) in dimethyl sulfoxide (5 mL) was added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, saturated aqueous ammonium chloride was added dropwise to the reaction mixture at 0°C to quench the mixture. The mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded 402 mg of the product.

[0240] 3. Synthesis of int6-4

[0241] Int6-3 (300 mg, 1.0 eq) was dissolved in triethylamine trihydrofluoride (4 mL) and reacted at 105°C for 16 h under nitrogen. The reaction was monitored by TLC. After cooling to room temperature, water was added and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The product was isolated on a preparative thin-layer plate to yield 71 mg.

[0242] 4. Synthesis of int6

[0243] Dissolve int6-4 (71 mg, 1.0 eq) in methanol (2 mL). Add Pd / C (30 mg) and di-tert-butyl dicarbonate (78 mg, 1.2 eq) at room temperature. React under a hydrogen atmosphere for 3 h. After completion, filter, and concentrate under reduced pressure. Purify by column chromatography to yield 56 mg of the product.

[0244] Synthesis of intermediate int7

[0245] 1. Synthesis of int7-2

[0246] Int7-1 (204 mg, 1.0 eq) was added to tetrahydrofuran (10 mL), followed by p-nitrobenzoic acid (424 mg, 3.0 eq) and triphenylphosphine (888 mg, 4.0 eq). The mixture was cooled to 0°C and diisopropyl azodicarboxylate (684 mg, 4.0 eq) was added dropwise. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 h. After completion, the reaction was quenched with a saturated sodium bicarbonate solution at 0°C and extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded 576 mg of the product.

[0247] 2. Synthesis of int7-3

[0248] Int7-2 (576 mg, 1.0 eq) was added to methanol (10 mL). The temperature was cooled to 0°C, and potassium carbonate (407 mg, 2.0 eq) was added portionwise. After addition, the mixture was stirred at 0°C for 1 h. After completion of the reaction, the mixture was quenched with ice water at 0°C and extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded 195 mg of the product.

[0249] 3. Synthesis of int7

[0250] Int7-3 (180 mg, 1.0 eq) was added to methanol (5 mL). Di-tert-butyl dicarbonate (195 mg, 1.2 eq) and Pd / C were added at room temperature. The atmosphere was purged with nitrogen three times, then replaced with hydrogen three times. The mixture was hydrogenated under a hydrogen balloon and stirred at room temperature for 2 h. After completion of the reaction, the mixture was filtered, the filter cake was washed three times with methanol, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with petroleum ether, filtered, and dried to yield 119 mg of the product.

[0251] Synthesis of intermediate int8:

[0252] 1. Synthesis of int8-2

[0253] Int8-1 (8 g, 1.0 eq) and benzyl bromide (40 mL, 5.0 eq) were dissolved in N,N-dimethylformamide (120 mL). Potassium carbonate (49.1 g, 5.0 eq) was added with stirring, and the mixture was heated to 100°C for 16 h. The reaction was complete. After cooling the reaction solution to room temperature, water was added, followed by extraction with ethyl acetate twice. The combined ethyl acetate phases were washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 8.97 g of the product.

[0254] 2. Synthesis of int8-3

[0255] Int8-2 (8.97 g, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (90 mL). DAST (5.55 g, 1.5 eq) was added at 0°C and allowed to react for 0.5 h after warming to room temperature. The reaction was complete. Ice water was added to the reaction solution to quench the mixture, followed by extraction twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 5.58 g of the product.

[0256] 3. Synthesis of int8-4

[0257] Int8-3 (5.58 g, 1.0 eq) was dissolved in methanol (60 mL), and then Pd / C (600 mg) was added. The mixture was reacted at 60°C under a hydrogen atmosphere for 16 h. After the reaction was complete, the reaction mixture was filtered and concentrated to obtain 1.6 g of the product.

[0258] 4. Synthesis of int8-5

[0259] Dissolve int8-4 (1.0 g, 1.0 eq) in methanol (10 mL), add di-tert-butyl dicarbonate (2.7 g, 1.5 eq), and stir at 50°C for 16 h. The reaction is complete. Concentrate the reaction mixture, then add petroleum ether:ethyl acetate (5:1), stir for 0.5 h, and filter to obtain the filter cake (750 mg).

[0260] 5. Synthesis of int8

[0261] Int8-5 (750 mg, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (15 mL). 1N borane in tetrahydrofuran (6.1 mL, 3.0 eq) was added at 0°C. The reaction was allowed to react at 65°C for 0.5 h. After completion, a small amount of water was added to quench the reaction at room temperature and the mixture was concentrated under reduced pressure. Purification by silica gel column chromatography afforded 523 mg of the product.

[0262] Synthesis of intermediate int9:

[0263] 1. Synthesis of int9-2

[0264] Int9-1 (25 g, 1.0 eq) was dissolved in dichloromethane (700 mL). Imidazole (43.3 g, 3.0 eq) was added at room temperature, followed by TBDPSCl (64 g, 1.1 eq). The reaction was allowed to react at room temperature for 1.5 h. The reaction was complete. Water was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 70 g of the product.

[0265] 2. Synthesis of int9-3

[0266] Int9-2 (15 g, 1.0 eq) was dissolved in ultra-dry dichloromethane (150 mL) under nitrogen protection. 1N diisobutylaluminum hydride (50.5 mL, 1.2 eq) was added dropwise at -70°C. After completion of the addition, the mixture was kept warm for 2 h. The reaction solution was quenched by adding aqueous ammonium chloride, filtered, and extracted twice with dichloromethane to the filtrate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column gave 14.9 g of the product.

[0267] 3. Synthesis of int9-4

[0268] Dissolve int9-3 (14.9 g, 1.0 eq) and S-tert-butylsulfenamide (8.35 g, 1.5 eq) in ultra-dry dichloromethane (150 mL). Then add tetraethyl titanate (21 g, 2.0 eq). Stir under nitrogen at 40°C for 16 h. The reaction is complete. Add water to the reaction mixture, filter, separate the filtrate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 15 g of the product.

[0269] 4. Synthesis of int9-5

[0270] Int9-4 (8 g, 1.0 eq) was dissolved in ultra-dry tetrahydrofuran (80 mL) under nitrogen protection. 3N methylmagnesium bromide (12.4 mL, 2.0 eq) was slowly added at -40°C. After addition, the mixture was allowed to react at room temperature for 2 h. The reaction solution was quenched with aqueous ammonium chloride, then extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column gave 3.5 g of the product.

[0271] 5. Synthesis of int9-6

[0272] Dissolve int9-5 (2.0 g, 1.0 eq) in tetrahydrofuran (20 mL) and add 1N tetrabutylammonium fluoride in tetrahydrofuran (6.74 mL) at room temperature. Stir at room temperature for 1 hour. The reaction is complete. Add water to the reaction solution, then extract twice with ethyl acetate. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a silica gel column to obtain 530 mg of the product.

[0273] 6. Synthesis of int9-7

[0274] Dissolve int9-6 (530 mg, 1.0 eq) in hydrochloric acid / 1,4-dioxane (5 mL) and stir at room temperature for 1.5 h. The reaction is complete. Concentrate the reaction mixture, then add ethyl acetate and stir for 15 min. Filter and collect the filter cake to yield 290 mg.

[0275] 7. Synthesis of int9

[0276] Dissolve int9-7 (290 mg, 1.0 eq) in tetrahydrofuran, add triethylamine (633 mg, 3.0 eq) and di-tert-butyl dicarbonate (684 mg, 1.5 eq), and stir at room temperature for 2 h. The reaction is complete. Add water to the reaction solution, then add ethyl acetate and extract twice. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purify on a silica gel column to obtain 470 mg of the product.

[0277] Synthesis of intermediate int10:

[0278] 1. Synthesis of int10-1

[0279] Int9-4 (13.9 g, 1.0 eq) was dissolved in tetrahydrofuran (140 mL). Sodium borohydride (2.45 g, 2.0 eq) was added portionwise at 0°C. The mixture was allowed to react at room temperature for 2 h. The reaction mixture was quenched with water and then extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 7.75 g of the product.

[0280] 2. Synthesis of int10-2

[0281] Dissolve int10-1 (7.75 g, 1.0 eq) in tetrahydrofuran (80 mL) and add 1N tetrabutylammonium fluoride in tetrahydrofuran (25.8 mL) at room temperature. Stir at room temperature for 1 hour. Add water to the reaction mixture, then extract twice with ethyl acetate. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a silica gel column to obtain 3.1 g of the product.

[0282] 3. Synthesis of int10-3

[0283] Dissolve int10-2 (1.1 g, 1.0 eq) in hydrochloric acid / 1,4-dioxane (10 mL) and stir at room temperature for 1.5 h. Concentrate the reaction mixture, then add ethyl acetate and stir for 15 min. Filter and collect the filter cake to obtain 120 mg of the product.

[0284] 4. Synthesis of int10

[0285] Int10-3 (120 mg, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), and triethylamine (410 mg, 3.0 eq) and di-tert-butyl dicarbonate (400 mg, 1.5 eq) were added. The mixture was stirred at room temperature for 2 h. Water was added to the reaction solution, followed by extraction twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column afforded 180 mg of the product.

[0286] Synthesis of intermediate int11:

[0287] 1. Synthesis of int11-2

[0288] Int11-1 (10 g, 1.0 eq) was dissolved in dichloromethane (100 mL). Imidazole (17.3 g, 3.0 eq) was added at room temperature, followed by TBDPSCl (25.6 g, 1.1 eq). The mixture was allowed to react at room temperature for 1.5 h. Water was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 29.6 g of the product.

[0289] 2. Synthesis of int11-3

[0290] Int11-2 (10 g, 1.0 eq) was dissolved in ultra-dry dichloromethane (100 mL) under nitrogen protection, and 1N diisobutylaluminum hydride (22 mL, 1.2 eq) was added dropwise at -70 ° C. After the addition, the mixture was kept warm for 2 h. After the reaction was completed, an aqueous ammonium chloride solution was added to the reaction solution to quench the reaction, filtered, and the filtrate was extracted with dichloromethane twice. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification on a silica gel column, 9.1 g of the product was obtained.

[0291] 3. Synthesis of int11-4

[0292] Dissolve int11-3 (9.1 g, 1.0 eq) and R-tert-butylsulfenamide (5.06 g, 1.5 eq) in ultra-dry dichloromethane (90 mL). Then add tetraethyl titanate (12.7 g, 2.0 eq). Stir under nitrogen at 40°C for 16 h. Add water to the reaction mixture, filter, separate the filtrate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 12.1 g of the product.

[0293] 4. Synthesis of int11-5

[0294] Int11-4 (12.1 g, 1.0 eq) was dissolved in tetrahydrofuran (120 mL). Sodium borohydride (2.1 g, 2.0 eq) was added portionwise at 0°C. The mixture was allowed to react at room temperature for 2 h. The reaction mixture was quenched with water and then extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 6.9 g of the product.

[0295] 5. Synthesis of int11-6

[0296] Dissolve int11-5 (6.9 g, 1.0 eq) in tetrahydrofuran (70 mL) and add a 1N tetrabutylammonium fluoride solution in tetrahydrofuran (19.1 mL, 1.2 eq) at room temperature. Stir at room temperature for 1 hour. Add water to the reaction mixture, then extract twice with ethyl acetate. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a silica gel column to obtain 2.28 g of the product.

[0297] 6. Synthesis of int11-7

[0298] Dissolve int11-6 (1.13 g, 1.0 eq) in hydrochloric acid / 1,4-dioxane (10 mL) and stir at room temperature for 1.5 h. The reaction is complete. After concentration, the product is used directly in the next step.

[0299] 7. Synthesis of int11

[0300] Int11-7 (1.3 g, 1.0 eq) was dissolved in tetrahydrofuran, and triethylamine (1.2 g, 3.0 eq) and di-tert-butyl dicarbonate (1.9 g, 1.5 eq) were added. The mixture was stirred at room temperature for 2 h. Water was added to the reaction solution, followed by extraction twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 659 mg of the product.

[0301] Synthesis of intermediate int12:

[0302] 1. Synthesis of C12-2

[0303] C12-1 (5.0 g, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (1.23 g, 1.1 eq) was added under ice-water bath. The reaction mixture was stirred at room temperature for 0.5 h, and then a solution of iodomethane (1.92 mL, 1.1 eq) in tetrahydrofuran was added to the reaction mixture, followed by stirring at room temperature for 2 h. After completion of the reaction, water was added under ice-water bath to quench the reaction, followed by extraction with ethyl acetate twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5.20 g of the product.

[0304] 2. Synthesis of C12-3

[0305] C12-2 (5.2 g, 1.0 eq) was dissolved in methanol (50 mL), followed by the addition of a methanol solution of potassium hydroxide (1.67 g, 1.1 eq). The reaction mixture was stirred at room temperature for 4 h. Benzylamine (8.69 g, 3.0 eq) was then added to the reaction mixture, which was heated to 55°C and stirred for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dissolved in water, and the pH was adjusted to acidic with 5N hydrochloric acid. The mixture was then extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 4.93 g of the product.

[0306] 3. Synthesis of C12-4

[0307] C12-3 (4.93 g, 1.0 eq) was added to a three-necked flask, and anhydrous tetrahydrofuran (50 mL) was added. Under nitrogen protection, the temperature was cooled to 0°C, and borane dimethyl sulfide (43 mL, 4.0 eq) was added dropwise. After stirring at room temperature for 4 hours, the temperature was raised to 65°C and stirred for 16 hours. After the reaction was completed, the temperature was lowered to 0°C, and water was added dropwise to quench until no foam was generated. Then, 5N hydrochloric acid solution was added to adjust the pH to acidic, and ethyl acetate was added to extract twice. Then, the aqueous phase was adjusted to alkaline with 50% sodium hydroxide solution, and ethyl acetate was added to extract twice. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4.12 g of product.

[0308] 4. C12 synthesis

[0309] C12-4 (610 mg, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of Pd / C (305 mg) and ammonium formate (1.95 g, 10.0 eq). The reaction was stirred at 65°C under nitrogen for 16 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure. Water was then added to dissolve the mixture, and the pH was adjusted to acidic by adding 5N hydrochloric acid solution. The mixture was extracted twice with ethyl acetate, and the aqueous phase was then made alkaline with 50% sodium hydroxide solution. A solution of di-tert-butyl dicarbonate (1.01 g, 1.5 eq) in tetrahydrofuran was then added, and the mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the mixture was extracted twice with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to yield 472 mg of the product.

[0310] Synthesis of intermediate int13:

[0311] 1. Synthesis of int13-1

[0312] C1-4 (4.95 g, 1.0 eq) was dissolved in anhydrous N,N-dimethylformamide (30 mL), cooled to 0°C, and 60% sodium hydride (1.78 g, 1.5 eq) was added portionwise. After stirring for 15 minutes, iodoethane (2.87 mL, 1.2 eq) was added, and the mixture was stirred at room temperature for 1-2 hours. The reaction was quenched with ice water at 0°C, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography afforded 4.87 g of the product.

[0313] 2. Synthesis of int13-2

[0314] Int13-1 (4.67 g, 1.0 eq) was dissolved in a mixed solvent of tert-butanol (80 mL) and water (4 mL). N-bromosuccinimide (12.85 g, 3.0 eq) was added portionwise and stirred at room temperature for 1 h. The reaction was quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The organic phase was directly spin-dried to obtain 11.38 g of crude product.

[0315] 3. Synthesis of int13-3

[0316] Int13-2 (10.38 g, 1.0 eq) was dissolved in acetic acid (110 mL), and reduced iron powder (7.94 g, 5.0 eq) was added. The reaction mixture was stirred at room temperature for 1-2 h. Filtered through celite, the filter cake was washed several times with ethyl acetate, concentrated, and purified by silica gel column chromatography to yield 5.45 g of the product.

[0317] 4. Synthesis of int13-4

[0318] Compound int13-3 (5.45 g, 1.0 eq) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (9.39 g, 1.0 eq) were dissolved in dichloromethane (60 mL). Zinc trifluoromethanesulfonate (1.88 g, 0.2 eq) was added and stirred for 10 minutes. 1,8-diazabicyclo[5.4.0]undec-7-ene (7.89 g, 2.0 eq) was then slowly added and allowed to react at room temperature for 0.5 h. The reaction was quenched with saturated aqueous ammonium chloride solution, the aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 4.35 g of the product.

[0319] 5. Synthesis of int13-5

[0320] Compound int13-4 (2.0 g, 1.0 eq), N-bromosuccinimide (1.66 g, 1.1 eq), and azobisisobutyronitrile (139 mg, 0.1 eq) were dissolved in carbon tetrachloride (30 mL). Under a nitrogen atmosphere, the mixture was heated to 75°C and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.05 g of the product.

[0321] 6. Synthesis of int13-6

[0322] Compound int13-5 (1.7 g, 1.0 eq) was dissolved in acetonitrile (30 mL), and N-methylmorpholine oxide (2.53 g, 4.0 eq) was added. The mixture was stirred at room temperature for 3-4 h. The reaction was quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1.54 g of the crude product.

[0323] 7. Synthesis of int13

[0324] Compound int13-6 (440 mg, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). (Trifluoromethyl)trimethylsilane (874 mg, 3.5 eq) and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ene (14 mg, 0.02 eq) were added at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. After adding 2N dilute hydrochloric acid and stirring for 20 min, the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 365 mg of the product.

[0325] Specific embodiment:

[0326] Example 1

[0327] The synthetic route and experimental process are as follows:

[0328] 1. Synthesis of C1-2

[0329] To a 1000 mL single-necked flask, add Raney nickel (1.7 g) and replace the water with methanol. Add C1-1 (17 g, 1 eq), methanol (340 mL), and tetrahydrofuran (340 mL) to replace the hydrogen atmosphere. Stir the reaction mixture at room temperature under a hydrogen atmosphere for 12 h. Filter the reaction mixture, wash with methanol, and concentrate the organic phase under reduced pressure. Purify on a silica gel column to obtain 14.9 g of the product. Ms[M+H] + 177.0.

[0330] 2. Synthesis of C1-3

[0331] Compound C1-2 (10 g, 1.00 eq), cuprous iodide (0.541 g, 0.05 eq), and triethylamine (200 mL) were added to a 250 mL single-necked flask. Trimethylsilyl acetylene (8.4 g, 1.50 eq) and bis(triphenylphosphine)palladium dichloride (2 g, 0.05 eq) were added at room temperature, and the atmosphere was replaced with nitrogen. The reaction was allowed to proceed at 80°C for 2 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filter residue was washed with ethyl acetate. The organic phase was diluted with ethyl acetate, washed with water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 8.4 g of the product. Ms[M+H] + 239.0.

[0332] 3. Synthesis of C1-4

[0333] Compound C1-3 (8.3 g, 1.00 eq) and acetonitrile (166 mL) were added to a 250 mL single-necked flask. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (52 mL, 1.50 eq) was added dropwise under an ice bath. The reaction mixture was allowed to react at room temperature for 2 h. The reaction solution was diluted with a large amount of ethyl acetate, washed with water, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column yielded 5.86 g of the product. Ms[M+H] + 167.1.

[0334] 4. Synthesis of C1-5

[0335] Dissolve C1-4 (5.76 g, 1.00 eq) in ultra-dry N,N-dimethylformamide (58 mL), cool to 0°C, add 60% sodium hydride (2.08 g, 1.50 eq), and react in an ice bath for 30 min. Iodomethane (5.91 g, 1.2 eq) is then added dropwise at the same temperature. Reaction is continued at room temperature for 1 h. The reaction is quenched with ice water in an ice bath, and the aqueous phase is extracted with ethyl acetate. The layers are separated. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 6.35 g of crude product. Ms[M+H] + 181.0.

[0336] 5. Synthesis of C1-6

[0337] Compound C1-5 (6.35 g, 1.00 eq), sodium bicarbonate (8.9 g, 3.00 eq), and tert-butanol (127 mL) were added to a 250 mL single-necked flask and stirred at room temperature for 10 min. Bromine (34 g, 6.00 eq) was slowly added dropwise. The reaction was allowed to react at room temperature for 1 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The layers were separated. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column yielded 8.8 g of the product. Ms[M+H] + 352.9.

[0338] 6. Synthesis of C1-7

[0339] Dissolve C1-6 (8.8 g, 1.00 eq) in glacial acetic acid (160 mL) and add zinc powder (8 g, 5.00 eq) at room temperature. Allow to react at room temperature for 15 minutes. Dilute the reaction solution with methanol, filter, and wash the residue with methanol. Concentrate the filtrate under reduced pressure and purify on a silica gel column to obtain 5.47 g of the product. Ms[M+H] + 197.0.

[0340] 7. Synthesis of C1-8

[0341] C1-7 (5.47 g, 1.00 eq), diphenyl (vinyl) sulfonium trifluoromethanesulfonate (10.1 g, 1.00 eq) and zinc trifluoromethanesulfonate (2.03 g, 0.20 eq) were dissolved in dichloromethane (55 mL) and stirred at room temperature for 3 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (8.5 g, 2.00 eq) was slowly added dropwise to the system. The reaction was allowed to react at room temperature for 10 min. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column gave 2.56 g of the product. Ms[M+H] + 223.0.

[0342] 8. Synthesis of C1-9

[0343] C1-8 (2.5 g, 1.00 eq) and carbon tetrachloride (50 mL) were added to a 250 mL flask, stirred and dissolved, and azobisisobutyronitrile (185 mg, 0.10 eq) was added. N-bromosuccinimide (2.2 g, 1.1 eq) was then added and the mixture was allowed to react at 75°C under nitrogen for 2 hours. The system was concentrated in vacuo until no liquid was distilled out. Thin-layer chromatography yielded 2 g of the product, [M+H] + 301.0.

[0344] 9. Synthesis of C1-10

[0345] Dissolve N-Boc-trans-3-aminocyclobutanol (1.373 g, 1.10 eq) in ultra-dry tetrahydrofuran (20 mL), cool to 0°C, add 60% sodium hydride (0.29 g, 1.10 eq), and react in an ice bath for 30 min. Slowly add C1-9 (2 g, 1.0 eq) in tetrahydrofuran (20 mL) dropwise to the reaction system and react at room temperature for 1.5 hours. Quench the reaction with ice water in an ice bath, extract the aqueous phase with ethyl acetate, and separate the layers. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 1.88 g of the product. Ms[M+H] + 408.1.

[0346] 10. Synthesis of C1-11

[0347] To a 50 mL flask, add C1-10 (1 g, 1.00 eq), SM3 (0.55 g, 1.00 eq), cesium carbonate (2.45 g, 3.00 eq), Xantphos (289 mg, 0.20 eq), palladium acetate (56 mg, 0.10 eq), and 1,4-dioxane (10 mL). The mixture was heated to 100°C under a nitrogen atmosphere and reacted for 1-2 hours. The reaction mixture was cooled, filtered, concentrated, and purified by column chromatography to yield 0.77 g of the product. Ms[M+H] + 595.3.

[0348] 11. Synthesis of C1-12

[0349] C1-11 (770 mg, 1.00 eq) was added to a 50 mL flask and dissolved in dichloromethane (10 mL). Pyridine (308.1 mg, 3.00 eq), 4-dimethylamino (16 mg, 0.10 eq), and p-nitrophenyl chloroformate (393 mg, 1.5 eq) were added and reacted at room temperature for 30 minutes. Water was added to the system to quench the reaction, and the mixture was extracted with dichloromethane and separated. The organic phase was washed with saturated sodium chloride solution 3 times and concentrated in vacuo until no liquid was distilled out. Purification by column chromatography gave 0.92 g of the product, [M+H] + 760.3.

[0350] 12. Synthesis of C1-13

[0351] C1-12 (0.92 g, 1.00 eq) and dichloromethane (45 mL) were added to a 50 mL flask. Trifluoroacetic acid (1.5 mL) was then added and the mixture was allowed to react at room temperature for 5 h. The reaction system was concentrated in vacuo until no liquid was distilled out, yielding 0.78 g of the product, [M+H] + 660.3.

[0352] 13. Synthesis of C1-14

[0353] C1-13 (0.78 g, 1.00 eq) and acetonitrile (78 mL) were added to a 250 mL flask. Triethylamine (0.23 g, 2.00 eq) was then slowly added dropwise and allowed to react at room temperature for 30 minutes. The reaction system was concentrated in vacuo until no liquid was distilled out and purified by column chromatography to give 0.53 g of the product, [M+H] + 521.3.

[0354] 14. Synthesis of C1

[0355] C1-14 (330 mg, 1.00 eq) and formic acid (30 mL) were added to a 100 mL flask. The temperature was then raised to 80°C and the reaction was allowed to react for 35 minutes. The reaction system was concentrated in vacuo until no liquid was distilled out, and dichloromethane was added to dissolve it. The pH was adjusted to a weakly alkaline state with sodium bicarbonate solution, and the layers were separated. The organic phase was concentrated until no liquid was distilled out, yielding 30.87 mg of the product, [M+H] + :465.2. 1 H NMR(400MHz,DMSO-d6)δppm 12.12(s,1H),8.00(s,1H),7.08(s,2H),5.86(s,1H),5.05(s,1H),4.29(d,J=12.8Hz ,1H),4.21(d,J=17.2Hz,1H),3.97(s,1H),3.54(s,3H),3.25-3.14(m,1H),2.45-2.33 (m,1H),2.10(t,J=8.9Hz,3H),2.00(dd,J=14.8,7.1Hz,2H),1.82(t,J=13.2Hz,3H),1 .72-1.64(m,1H),1.61(q,J=3.6,2.8Hz,2H),1.52(q,J=4.0,3.2Hz,2H),1.23(s,1H).

[0356] Example 2

[0357] The synthetic route and experimental process are as follows:

[0358] 1. Synthesis of C2-1

[0359] Dissolve N-(tert-Butyloxycarbonyl)ethanolamine (0.59 g) in ultra-dry tetrahydrofuran (10 mL), cool to 0°C, add 60% sodium hydride (0.147 g), and react in an ice-water bath for 30 minutes. Slowly add C1-9 (1 g) in tetrahydrofuran (10 mL) dropwise to the reaction system and react at room temperature for 1.5 hours. The reaction is complete. Quench the reaction with ice water in an ice-water bath, extract the aqueous phase with ethyl acetate, and separate the layers. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 1.3 g of pure product. Ms[M+H] + :382.1.

[0360] 2. Synthesis of C2-2

[0361] C2-1 (1.3 g), int1 (0.76 g), cesium carbonate (3.33 g), Xantphos (390 mg), palladium acetate (76 mg), and 1,4-dioxane (13 mL) were added to a 50 mL flask. The mixture was heated to 100°C under a nitrogen atmosphere and allowed to react for 1-2 hours. The reaction was complete. The reaction mixture was cooled, filtered, concentrated, and purified by column chromatography to yield 1.0 g of the product. Ms[M+H] + :569.4.

[0362] 3. Synthesis of C2-3

[0363] C2-2 (1 g) was added to a 50 mL flask, and dichloromethane (20 mL) was stirred to dissolve. N-methylmorpholine (3.59 g) was added. P-nitrochloroformic acid phenyl ester (5.3 g) was slowly added and reacted at room temperature for 30 minutes. Water was added to the system to quench, and the mixture was extracted with dichloromethane and separated. The organic phase was washed with saturated sodium chloride solution 3 times and the organic phase was concentrated in vacuo until no liquid was distilled. Purification by column chromatography gave 1.0 g of pure product, Ms[M+H] + :734.3.

[0364] 4. Synthesis of C2-4

[0365] C2-3 (300 mg) and trifluoroacetic acid (3 mL) were added to a 50 mL flask and reacted at 100°C for 50 minutes. The reaction system was concentrated in vacuo until no liquid was distilled out to obtain 260 mg of crude product. Ms[M+H] + : 578.2. It was used directly in the next reaction.

[0366] 5. Synthesis of C2

[0367] C2-4 (260 mg) and acetonitrile (2.6 mL) were added to a 50 mL flask. Triethylamine (91 mg) was then slowly added dropwise and allowed to react at room temperature for 30 minutes. The reaction system was concentrated in vacuo until no liquid was distilled out, and 14.09 mg of the product was obtained by HPLC.

[0368] Ms[M+H] + :439.3 1H NMR(400MHz,DMSO-d6)δppm 12.02(s,1H),7.97(s,1H),7.09(s,1H),6.98-6.92(m,1H),5.89(s,1H),4.93(s,1H) ,4.39(d,J=12.8Hz,1H),4.26(d,J=12.8Hz,1H),3.53(s,3H),3.50(d,J=6.0Hz,1H), 3.44-3.39(m,1H),3.22(d,J=8.4Hz,2H),2.94-2.88(m,1H),2.27(d,J=11.6Hz,1H), 2.14(d,J=9.2Hz,1H),1.83(d,J=16.8Hz,4H),1.61-1.55(m,2H),1.54-1.48(m,2H).

[0369] Example 3

[0370] The synthetic route and experimental process are as follows:

[0371] 1. Synthesis of C8-1

[0372] In a 100 mL single-necked bottle, N-Boc-trans-3-aminocyclobutanol (402 mg 1.3 eq) and acetonitrile (10 ml) were added and stirred to dissolve. NaH (86 mg 1.3 eq) was added and stirred at room temperature for 1 h. Then int3 (500 mg 1 eq) was added and stirred at room temperature for 1 h. After the reaction was completed, 20 ml of saturated sodium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 450 mg of the product after column purification.

[0373] 2. Synthesis of C8-2

[0374] C8-1 (340 mg), int2 (296 mg), and dimethyl sulfoxide (10 ml) were added to a 100 mL single-necked bottle and stirred to dissolve. Potassium tert-butoxide (280 mg) was then added and stirred at room temperature for 20 min. After the reaction was completed, saturated sodium chloride (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml*3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and directly subjected to the next step.

[0375] 3. Synthesis of C8-3

[0376] The above C8-2 methanol (30 ml), water (6 ml) and LiOH (175 mg) were added to a 50 mL three-necked flask and stirred at room temperature for 1 h. After the reaction was completed, 10 ml of water was added and the mixture was extracted with ethyl acetate (20 ml * 5). The mixture was dried and purified by spin drying to obtain 230 mg of the product.

[0377] 4. Synthesis of C8-4

[0378] C8-3 (200 mg), dichloromethane (10 ml), N-methylmorpholine (320 mg), and nitrophenyl chloroformate (516 g) were added to a 50 mL three-necked flask and stirred at room temperature for 5 min. After the reaction was completed, 130 mg of the product was purified.

[0379] 5. Synthesis of C8

[0380] C8-4 (130 mg), dichloromethane (5 ml) and TFA (0.5 ml) were added to a 50 mL three-necked flask and stirred at room temperature for 30 min. After the reaction was completed, the temperature was lowered to 0°C and triethylamine (1 ml) was added dropwise. The reaction was allowed to proceed at room temperature for 10 min. After the reaction was completed, the mixture was washed with water (20 ml*3) and dried in a spin-drying machine to obtain 30 mg of the purified product. 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.52(s,1H),7.14(s,1H),6.56(s,1H),5.04(s,1H),4.23(d,J=17.6Hz,3 H),4.04(s,1H),3.56(s,3H),3.17(d,J=5.5Hz,1H),2.33(s,1H),2.23(s,1H),2.05(s,3H),1.89–1.60(m,9H).

[0381] Example 4

[0382] The synthetic route and experimental process are as follows:

[0383] 1. Synthesis of C 19-1

[0384] Dissolve int4 (300 mg, 1.00 eq) and tert-butyl N-(3-hydroxypropyl)carbamate (192 mg, 1.05 eq) in N,N-dimethylformamide (10 mL), cool to 0°C, and add 60% sodium hydride (44 mg, 1.10 eq) in portions. Stir at 0°C for 10 min. Then, warm to room temperature and allow to react for 1 h. Quench the reaction with ice water at 0°C, extract the aqueous phase with ethyl acetate, and dry and concentrate the organic phase. Purify on a silica gel column to obtain 225 mg of the product. Ms[M+H] + 396.16

[0385] 2. Synthesis of C19-2

[0386] C19-1 (212 mg, 1.00 eq), int1 (131 mg, 1.00 eq), palladium acetate (12 mg, 0.10 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg, 0.20 eq), and cesium carbonate (522 mg, 2.00 eq) were dissolved in 1,4-dioxane (7 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 2 h. The reaction solution was cooled to room temperature, filtered, and the filter residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification on a silica gel column gave 80 mg of the product. Ms[M+H] + 583.35

[0387] 3. Synthesis of C19-3

[0388] C19-2 (60 mg, 1.00 eq), N-methylmorpholine (104 mg, 10 eq), and dichloromethane (5 mL) were added to a 25 mL single-necked flask. A solution of p-nitrophenyl chloroformate (166 mg, 8 eq) in dichloromethane (2 mL) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 10 min. Water was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The organic phase was dried and concentrated. Purification on a silica gel column afforded 70 mg of the product. Ms[M+H] + 748.36

[0389] 4. Synthesis of C19-4

[0390] C19-3 (70 mg, 1.00 eq) and trifluoroacetic acid (2 mL) were added to a 25 mL single-necked bottle and heated to 80°C for 2 h. The reaction solution was cooled and concentrated to obtain 100 mg of crude product, which was used directly in the next step. Ms[M+H] + 592.24

[0391] 5. Synthesis of C19

[0392] Compound C19-4 (100 mg, crude) was dissolved in acetonitrile (3 mL). The temperature was lowered to 0°C, and triethylamine (164 mg, 12.00 eq) was slowly added dropwise. Stir at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with 1N aqueous sodium hydroxide. The organic phase was dried and concentrated. Purification by preparative chromatography yielded 3 mg of the product. 1H NMR(400MHz,DMSO-d6)δppm 11.77(s,1H),8.08(d,J=16.6Hz,1H),6.67(d,J=34.0Hz,2H),6.33(d,J=74.4Hz,1H),5.00(d,J=50.0Hz,1H),4.39(dd ,J=50.0,11.3Hz,1H),4.20(dd,J=28.8,11.2Hz,1H),3.54(s,3H),2.86(m,2H),2.06(m,2H),1.69(m,6H),1.59m,2H).

[0393] Example 5

[0394] The synthetic route and experimental process are as follows:

[0395] 1. Synthesis of C20-2

[0396] Compound C20-1 (600 mg, 1.00 eq) and tetrahydrofuran (20 mL) were added to a 100 mL three-necked flask. The temperature was lowered to -40°C, and a 3M solution of methylmagnesium bromide in tetrahydrofuran (1.10 mL, 1.30 eq) was slowly added dropwise at -40°C. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 1 h. The reaction was complete. The reaction was quenched with saturated ammonium chloride solution, the aqueous phase was extracted with ethyl acetate, and the organic phase was dried and concentrated. Purification on a silica gel column yielded 470 mg of the product. Ms[M+H] + :253.1.

[0397] 2. Synthesis of C20-3

[0398] Dissolve C20-2 (390 mg, 1.00 eq) in N,N-dimethylformamide (15 mL), cool to 0°C, and add 60% sodium hydride (93 mg, 1.50 eq) portionwise. Stir at 0°C for 30 min. Slowly add a solution of N-Boc-3-aminopropyl bromide (917 mg, 2.50 eq) in tetrahydrofuran dropwise at 0°C. Warm to room temperature and react overnight. The reaction is complete. Quench the reaction with ice water at 0°C, extract the aqueous phase with ethyl acetate, and dry and concentrate the organic phase. Purify on a silica gel column to obtain 480 mg of the product.

[0399] 3. Synthesis of C20-4

[0400] C20-3 (480 mg, 1.00 eq), int1 (262 mg, 1.00 eq), palladium acetate (26 mg, 0.10 eq), Xantphos (136 mg, 0.20 eq), and cesium carbonate (765 mg, 2.00 eq) were dissolved in 1,4-dioxane (15 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 2 h. The reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification on a silica gel column yielded 480 mg of the product.

[0401] 4. Synthesis of C20-5

[0402] C20-4 (480 mg, 1.00 eq), N-methylmorpholine (407 mg, 5 eq), and dichloromethane (13 mL) were added to a 50 mL single-necked flask. A solution of p-nitrophenyl chloroformate (648 mg, 4 eq) in dichloromethane (2 mL) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 10 min. The reaction was complete. Water was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with dichloromethane. The organic phase was dried and concentrated. Purification on a silica gel column yielded 500 mg of the product.

[0403] 5. Synthesis of C20-6

[0404] To a 25 mL single-necked vial, add C20-5 (450 mg, 1.00 eq) and trifluoroacetic acid (5 mL). Heat to 80°C and react for 1.5 h. The reaction is complete. Cool the reaction mixture, concentrate, and use it directly in the next step.

[0405] 6. Synthesis of C20-7

[0406] Compound C20-6 (600 mg, crude) was dissolved in acetonitrile (20 mL). The temperature was lowered to 0°C, and triethylamine (717 mg, 12.00 eq) was slowly added dropwise. Stir at room temperature for 30 min. The reaction was complete. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with 1N aqueous sodium hydroxide solution. The organic phase was dried and concentrated. Purification by preparative thin-layer chromatography yielded 70 mg of the product.

[0407] 7. Preparation of C20 and C21

[0408] Compound C20-7 (70 mg) was prepared by chiral high performance liquid chromatography separation under the following conditions:

[0409] Column: Phenomenex 5 μm Amylose-1 (250×21.2 mm), mobile phase: n-hexane:ethanol=6:4, solvent: isopropanol, running time: 26 min.

[0410] The peak C20 appeared at 13.0 min. After concentration and freeze-drying, 19 mg of product was obtained.

[0411] 1 H NMR(400MHz,DMSO-d6)δppm 12.11(d,J=35.2Hz,1H),8.01(s,1H),6.98(d,J=25.2Hz,1H),6.60(d,J=108.8Hz,1H),5 .79(d,J=17.2Hz,1H),5.01(d,J=23.6Hz,1H),4.32-4.13(m,1H),3.54(s,3H),3.40-3.29 (m,3H),3.25-3.17(m,2H),3.11-3.00(m,1H),2.97-2.71(m,1H),2.45-2.28(m,1H),2.2 0-2.07(m,1H),1.94-1.70(m,4H),1.66-1.49(m,4H),1.33-1.17(m,3H).Ms[M+H]+467.2.

[0412] The peak C21 appeared at 23.4 min. After concentration and freeze-drying, 17 mg of product was obtained.

[0413] 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.11(d,J=16.0Hz,1H),7.96(s,1H),7.11-6.67(m,2H),5.81(d,J=7.6Hz,1 H),5.02(d,J=52.0Hz,1H),4.35-4.16(m,1H),3.53(s,3H),3.43-3.37(m,2H ),3.34-3.30(m,1H),3.28-2.98(m,3H),2.82-2.63(m,1H),2.47-2.32(m,1H ),2.10-1.93(m,1H),1.91-1.47(m,8H),1.27-1.16(m,3H).Ms[M+H]+467.2.

[0414] Example 6

[0415] The synthetic route and experimental process are as follows:

[0416] 1. Synthesis of C37-1

[0417] Dissolve C1-9 (800 mg, 1.0 eq) in acetonitrile (15 mL), then add sodium trifluoromethanesulfonate (622 mg, 1.5 eq). Stir under nitrogen at 80°C for 18 h. The reaction is complete. Filter, and concentrate the filtrate under reduced pressure. Purify by silica gel column chromatography to yield 811 mg of the product.

[0418] 2. Synthesis of C37-2

[0419] C37-1 (811 mg, 1.0 eq) was dissolved in N,N-dimethylformamide (15 mL), followed by the addition of N-fluorobisbenzenesulfonamide (1.58 g, 2.2 eq) and potassium phosphate (2.4 g, 5.0 eq). The reaction mixture was stirred at 25°C for 2 h. Saturated aqueous ammonium chloride was added to the reaction mixture, stirred for 0.5 h, and then extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 697 mg of the product.

[0420] 3. Synthesis of C37-3

[0421] C37-2 (636 mg, 1.0 eq) was dissolved in acetonitrile (10 mL), followed by the addition of lithium bromide (1.13 g, 8.0 eq). The mixture was reacted at 35°C for 16 h under a nitrogen atmosphere. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column afforded 284 mg of the product.

[0422] 4. Synthesis of C37-4

[0423] C37-3 (216 mg, 1.0 eq) and N-Boc-3-amino-1-propanol (121 mg, 1.0 eq) were dissolved in acetonitrile (5 mL). Sodium hydride (77 mg, 3.0 eq) was added at room temperature and stirred at 30°C for 16 h. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column yielded 46 mg of the product.

[0424] 5. Synthesis of C37-5

[0425] C37-4 (46 mg, 1.0 eq), int2 (38.1 mg, 1.0 eq), palladium acetate (2.4 mg, 0.1 eq), Xantphos (12.4 mg, 0.2 eq), and cesium carbonate (105 mg, 3.0 eq) were dissolved in 1,4-dioxane (3 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 2 h. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification on a silica gel column yielded 56 mg of the product.

[0426] 6. Synthesis of C37-6

[0427] C37-5 (56 mg, 1.0 eq) was dissolved in methanol (2 mL) and water (0.7 mL), and then LiOH (9.3 mg, 3.0 eq) was added and reacted at 40°C for 2 h. The mixture was concentrated under reduced pressure and purified on a silica gel column to obtain 49 mg of the product.

[0428] 7. Synthesis of C37-7

[0429] C37-6 (49 mg, 1.0 eq), N-methylmorpholine (38.3 mg, 5.0 eq), and dichloromethane (3 mL) were added to a 25 mL single-necked flask. Phenyl p-nitrochloroformate (61 mg, 4.0 eq) was added to the reaction mixture at room temperature, and the reaction mixture was stirred for 1 min. Saturated aqueous sodium bicarbonate was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Purification by preparative thin-layer chromatography yielded 60 mg of the product.

[0430] 8. Synthesis of C37-8

[0431] C37-7 (60 mg, 1.0 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was directly used in the next reaction.

[0432] 9. Synthesis of C37 and C38

[0433] Triethylamine (2 mL) was added to the reaction mixture of C37-8 and stirred at room temperature for 3 h. Liquid chromatography-mass spectrometry indicated complete reaction of the starting material. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded products C38 (1.12 mg) and C37 (3.2 mg).

[0434] Example 7

[0435] The synthetic route and experimental process are as follows:

[0436] 1. Synthesis of C41-1

[0437] NaH (53 mg, 1.2 eq) was dissolved in dimethyl sulfoxide (15 mL). Trimethylsulfoxide iodide (338 mg, 1.4 eq) was added portionwise at room temperature. After addition, the mixture was allowed to react at room temperature for 1 h. Then, a solution of C20-1 (260 mg, 1.0 eq) in dimethyl sulfoxide (3 mL) was added dropwise. After addition, the mixture was allowed to react at room temperature for 3 h. The reaction was quenched with ice water at 0°C, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 150 mg of the product.

[0438] 2. Synthesis of C41-2

[0439] C41-1 (150 mg, 1.0 eq) was added to water (10 mL) and reacted at 100°C for 4 h. After cooling to room temperature, the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 155 mg of crude product.

[0440] 3. Synthesis of C41-3

[0441] C41-2 (155 mg, 1.0 eq) and imidazole (99 mg, 2.5 eq) were dissolved in N,N-dimethylformamide (5 mL). The temperature was cooled to 0°C. TBDPSCl (97 g, 1.1 eq) was added all at 0°C. After addition, the mixture was allowed to warm to room temperature and allowed to react for 16 h. The reaction was quenched with ice water at 0°C, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 215 mg of the product.

[0442] 4. Synthesis of C41-4

[0443] C41-3 (215 mg, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0°C, and 60% sodium hydride (33.7 mg, 1.5 eq) was added portionwise at 0°C. The mixture was allowed to react at 0°C for 1 h. A solution of tert-butyl N-(3-bromopropyl)carbamate (332.6 mg, 2.5 eq) in N,N-dimethylformamide (2.5 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched with ice water at 0°C and extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 210 mg of the product.

[0444] 5. Synthesis of C41-5

[0445] To a 50 mL single-necked vial, add C41-4 (210 mg, 1.0 eq) and tetrahydrofuran (16 mL). Add a solution of tetrabutylammonium fluoride (1.15 mL, 3.0 eq) in tetrahydrofuran dropwise at room temperature. Allow to react at room temperature for 1 h. After cooling to 0°C, the reaction mixture was quenched with saturated ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 130 mg of the product.

[0446] 6. Synthesis of C41-6

[0447] C41-5 (130 mg, 1.0 eq) and tetrahydrofuran (13 mL) were added to a 50 mL single-necked vial. Diethylaminosulfur trifluoride (496.5 mg, 4.0 eq) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 16 h. The reaction mixture was cooled to 0°C and quenched with saturated ammonium chloride. The mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 76 mg of the product.

[0448] 7. Synthesis of C41-7

[0449] C41-6 (76 mg, 1.0 eq), int2 (63 mg, 1.0 eq), palladium acetate (4 mg, 0.10 eq), Xantphos (20.6 mg, 0.20 eq), and cesium carbonate (173.5 mg, 3.0 eq) were dissolved in 1,4-dioxane (6 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 2 h. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 115 mg of the product.

[0450] 8. Synthesis of C41-8

[0451] C41-7 (115 mg, 1.0 eq) was added to methanol (4 mL). A solution of LiOH.H2O (20 mg, 3.0 eq) in water (1.3 mL) was added dropwise at room temperature. After completion, the mixture was heated to 35°C and allowed to react for 2 h. The mixture was cooled to room temperature, and saturated sodium chloride and ethyl acetate were added to the reaction mixture. The layers were separated, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. 103 mg of crude product was obtained, which was used directly in the next step without purification.

[0452] 9. Synthesis of C41-9

[0453] To a 50 mL single-necked flask, C41-8 (103 mg, 1.0 eq), N-methylmorpholine (81 mg, 5.0 eq), and dichloromethane (6 mL) were added. Phenyl p-nitrochloroformate (129.3 mg, 4.0 eq) was added all at room temperature. The reaction mixture was stirred at room temperature for 20 min. Saturated aqueous sodium bicarbonate was added to the reaction mixture at 0°C. The layers were separated, and the aqueous phase was extracted once with dichloromethane. The combined organic phases were washed five times with saturated sodium bicarbonate, dried, filtered, concentrated, and purified by preparative thin-layer chromatography to yield 102 mg of the product.

[0454] 10. Synthesis of C41-10

[0455] C41-9 (102 mg, 1.0 eq) and dichloromethane (8 mL) were added to a 50 mL single-necked bottle. Trifluoroacetic acid (0.8 mL) was added dropwise at room temperature. After addition, the reaction was allowed to proceed at room temperature for 4 h. The product was used directly in the next step without purification.

[0456] 11. Synthesis of C41-11

[0457] The untreated solution was cooled to 0°C and triethylamine (2 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and react for 4 h. Saturated sodium bicarbonate and dichloromethane were added to the reaction solution, and the layers were separated. The aqueous phase was extracted once with dichloromethane. The resulting organic phases were combined, dried, filtered, concentrated, and purified on a preparative thin-layer chromatography plate to yield 42 mg of the product.

[0458] 12. Synthesis of C41 and C42

[0459] C41-11 was prepared by chiral HPLC separation under the following conditions: Chromatographic column: Phenomenex 5 μm Amylose-1 (250× 21.2 mm), mobile phase: n-hexane:ethanol = 6:4, solvent: isopropanol, running time: 31 min. C41 (8.2 mg) was obtained, with an elution time of 12.7 min. 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.06(s,1H),7.05(s,1H),6.73(s,1H),5.82(s,1H),5.04(s,1H),4.64–4.26(m,3H),3.55(s,3H) ,3.49–3.36(m,2H),3.26–3.17(m,1H),3.11–2.98(m,1H),2.88–2.76(m,1H),2.43–2.32(m,1H),2.18–2.08(m,1H),1.94–1.51(m,10H);

[0460] C42 (6.1 mg) was obtained, with a peak time of 26.5 min. 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.01(s,1H),7.07(s,1H),6.84(d,J=84.2Hz,1H),5.82(s,1H),5.03(d,J=58.3Hz,1H),4 .63–4.27(m,3H),3.67–3.48(m,1H),3.54(s,3H),3.41–3.03(m,3H),2.77(s,1H),2.42(d,J=18.9Hz,1H),2.08–1.50(m,11H).

[0461] Example 8

[0462] Compounds of the present invention

[0463] The synthetic route and experimental process are as follows:

[0464] Synthesis of C65-2

[0465] C65-1 (486.8 mg, 1.1 eq) and C1-9 (254 mg, 1.0 eq) were dissolved in N,N-dimethylformamide (12 mL), cooled to 0°C, and 60% sodium hydride (84.4 mg, 2.5 eq) was added portionwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 20 min. Liquid chromatography-mass spectrometry indicated complete reaction of the starting materials. The reaction was quenched with ice water at 0°C, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column afforded 362 mg of the product. MS [M+1] + :422.2,424.2

[0466] Synthesis of C65-3

[0467] C65-2 (360 mg, 1.0 eq), int1 (190.3 mg, 1.0 eq), palladium acetate (19.2 mg, 0.10 eq), Xantphos (98.7 mg, 0.20 eq), and cesium carbonate (831 mg, 3.0 eq) were dissolved in 1,4-dioxane (11 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 2 h. Liquid chromatography-mass spectrometry indicated that the starting materials had reacted completely. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification on a silica gel column yielded 340 mg of the product. MS [M+1] + :609.4

[0468] Synthesis of C65-4

[0469] C65-3 (340 mg, 1.0 eq), N-methylmorpholine (282 mg, 5.0 eq), and dichloromethane (25 mL) were added to a 50 mL single-necked flask. A solution of p-nitrophenyl chloroformate (450 mg, 4.0 eq) in dichloromethane (2 mL) was slowly added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 20 min. Liquid chromatography-mass spectrometry indicated complete reaction of the starting material. Saturated aqueous sodium bicarbonate was added to the reaction solution at 0°C. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Purification by preparative thin-layer chromatography yielded 397 mg of the product. MS [M+1] + :774.4

[0470] Synthesis of C65-5

[0471] C65-4 (390 mg, 1.0 eq) and trifluoroacetic acid (20 mL) were added to a 50 mL single-necked vial. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 h. LC / MS / MS monitoring indicated that the starting material reacted well. The reaction solution was cooled, concentrated, and used directly in the next step. MS [M+1] + :606.3

[0472] Synthesis of C65

[0473] Compound C65-5 (445 mg, 1.0 eq) was dissolved in dichloromethane (20 mL), and triethylamine (1.34 g, 12.00 eq) was added. The mixture was stirred at room temperature for 16 h. Liquid chromatography-mass spectrometry indicated that the starting material had reacted completely. The reaction solution was concentrated, dissolved in ethyl acetate, washed with water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification by TLC preparative plate, 92 mg of the product was obtained. The solid was slurried with 20 mL of petroleum ether:ethyl acetate = 3:1 to obtain 72 mg of C1. MS [M+1] + :479.2.

[0474] 1 H NMR (400MHz, DMSO-d6) δ12.13(s,1H),8.08(s,1H),7.20(s,1H),5.91(s,1H),5.09(s,1H),4.85(s,1H),4.33(s,2H),3.99(d,J=5.9Hz,1H ),3.56(s,3H),3.21(s,1H),2.77(s,3H),2.48–2.39(m,1H),2.38–2.23(m,2H),2.16–2.06(m,1H),2.04(s,2H),1.77(s,4H),1.54(s,4H).

[0475] The following compounds were synthesized using the above synthesis method:

[0476] Cell proliferation inhibition assay

[0477] 1. Experimental Materials

[0478] 2. Experimental Plan

[0479] 1. Cell plating

[0480] a) Preparation of cell suspension

[0481] b) removing the culture medium from the culture flask;

[0482] c) Rinse the cells once with PBS;

[0483] d) adding trypsin for digestion and collecting by centrifugation;

[0484] e) Resuspend in culture medium, count and adjust to the appropriate concentration.

[0485] f) Add 80 μL of the cell suspension to each well of a 96-well plate, with each cell type plated on one plate. Culture in a 37°C, 5% CO2 incubator overnight.

[0486] 2. Compound treatment

[0487] Compound dilution

[0488] a) Prepare test compound serial dilution solutions: Palbociclib and the example compounds were prepared at 10 mM stock solutions. 2.5 μL of the stock solution was then dissolved in 497.5 μL of DMSO-free culture medium. Three-fold serial dilutions were then performed in 0.1% DMSO culture medium for a total of nine concentrations. The compound concentrations after dilution were as follows:

[0489] 10000nM, 3333.33nM, 1111.11nM, 370.34nM, 123.45nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM

[0490] b) After thorough mixing, 20 μL of the compound solution was added to the cell culture plate containing 80 μL of cells, with 4 replicate wells for each concentration.

[0491] c) Transfer the cells to an incubator and incubate for 5 days.

[0492] 3. MTT assay

[0493] a) Remove the cell culture plate and add 10 μL of 5 mg / ml MTT to the hood.

[0494] b) Place the cell culture plate back into the incubator and continue incubating for 3 hours

[0495] c) The cell culture plate was removed and the culture medium was removed. 100 μL of isopropanol (0.4 mM HCl, 0.4% NP40) was added. The plate was shaken at room temperature for 30 minutes and the plate was read at 570 nm.

[0496] 4. Data Analysis

[0497] The following formula was used to calculate the cell survival rate (%Cell Survival):

[0498] %Cell Survival=100%×(OD_Sample-OD_LCave) / (OD_HC-OD_LCave)

[0499] OD_HC: 0.1‰ DMSO control group cell reading

[0500] OD_Sample: Cell readings after compound addition

[0501] OD_LC: Blank culture medium reading

[0502] Analyzed by Prizm:Dose-response-Inhibition-Log(inhibitor) vs response(three parameters for the best fit).

[0503] The results of the cell proliferation inhibition test are shown in Table 1 below.

[0504] Table 1

[0505] The cell proliferation activity values ​​in the table are represented by A, B, C, and D, where A≤500nM, 500nM<B≤1000nM, 1000nM<C≤3000nM, and 3000nM<D.

[0506] The experimental results showed that the example compounds exhibited a good inhibitory effect on the CyclinE-amplified cell line OVCAR3, while the example compounds had no obvious inhibitory effect on the non-CyclinE-amplified cell line TOV21G, demonstrating good selectivity of the compounds.

[0507] Enzyme activity test

[0508] Prepare the compound:

[0509] 1. Prepare the test compound into a 0.5 nM DMSO solution;

[0510] 2. Use Echo550 to transfer 20 μL of the stock solution to a 384-well plate. Use DMSO as a blank control.

[0511] Experimental steps:

[0512] 1. Prepare 1.3X enzyme solution containing enzyme, substrate, and coenzyme factors according to the table below;

[0513] 2. Add 15uL of 1.3x enzyme solution to each well and incubate at room temperature for 30 minutes;

[0514] 3. Add 5 μL of 4x ATP solution to start the reaction. The final volume per well is 20 μL.

[0515] 4. After incubation at room temperature for 150 min, add 75 μL of stop buffer solution to terminate the experiment;

[0516] 5. Analyze the sample using the EZ reader.

[0517] Data Analysis:

[0518] Calculate the % inhibition using the following equation

[0519] The positive control (PC) was treated with DMSO.

[0520] The negative control (NC) was without enzyme.

[0521] % inhibition rate = 100-100*((CR PC -CR sample ) / (CR PC -CR NC ))

[0522] Table 2

[0523] The experimental results show that the compounds of the present invention have excellent selectivity and activity for CDK2 kinase.

[0524] The present invention provides a series of compounds with excellent CDK2 kinase activity and selectivity. The series of compounds have a good inhibitory effect on cell overproliferation caused by abnormal expression or amplification of Cycline E and have broad application prospects.

[0525] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof, in: X1 is a bond, -O-, -NR a -、-S-、C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, -(CH2) 1-2 O-, -(CH2) 1-2 NR a -、-(CH2) 1-2 S-, -C(O)-, -NR a C(O)-, or -C(O)NR a -, wherein the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; X2 is a bond, -O-, or -NR a -、-S-、C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, or a 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; X3 is a key, C 1-6 Alkylene, -NR-, C 3-6 Cycloalkyl, or a 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 1-6 Alkylene, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; L1 is a bond, -O-, -NR a -、-S-、C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, -(CH2) 1-2 O-, -(CH2) 1-2 NR a -、-(CH2) 1-2 S-, -C(O)-, -NR a C(O)-, or -C(O)NR a -, wherein the C 1-6 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Ring A is selected from the following group: C 4-6 Cycloalkyl, saturated or partially saturated 5-6-membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, 5-6-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or phenyl-5-6-membered heterocycloalkyl, 5-6-membered cycloalkyl containing 1-4 heteroatoms selected from N, O or S, or 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the group is optionally substituted by 0, 1, 2, 3 or 4 R1; Ring B is selected from the group consisting of: R is selected from the following group: H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, =O, -(CH2) 0-2 OR b 、-(CH2) 0-2 NR b R c , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b 、-C(O)NR b R c 、-NR b S02R c 、-OC(O)NR b R c 、-NR b C(O)OR c ,That In the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =0, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, -NR d R e 、-SO2R d 、-SO2NR d R e 、-C(O)OR d 、-C(O)NR d R e 、-NR d S02R e 、-OC(O)NR d R e 、-NR d C(O)OR e , Alternatively, two R1 attached to the same atom may be linked to each other to form a C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxyl, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; R a are independently selected from the group consisting of hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; R b , R c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (a 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxyl, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, Or, R b and R c Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and the 3-6 membered heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxyl, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; R d , R e are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (a 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxyl, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, Or, R d and R e Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, and the 3-6 membered heterocycloalkyl is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxyl, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

2. The compound according to claim 1, characterized in that The compound has a structure selected from the group consisting of: wherein ring A, X1, X2, L1, and R are as defined in claim 1; Ring C is selected from the group consisting of: C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

3. The compound according to claim 1, characterized in that Ring A has a structure selected from the group consisting of: in, Y1 is selected from the following group: N, CH; Y2 is selected from the following group: N, CH; Y3 is selected from the following group: NH, NR1, O, CH2; R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, =O, -(CH2) 0-2 OR b 、-(CH2) 0-2 NR b R c , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, phenyl, 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b 、-C(O)NR b R c 、-NR b S02R c 、-OC(O)NR b R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, Optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, =O, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, -NR d R e 、-SO2R d 、-SO2NR d R e 、-C(O)OR d 、-C(O)NR d R e 、-NR d S02R e 、-OC(O)NR d R e 、-NR d C(O)OR e ; m is selected from the following group: 0, 1, 2, 3, 4, 5, 6; It represents the connection position of ring A in the structure of formula I, one end of which is connected to NH and the other end of which is connected to X1.

4. The compound according to claim 1, characterized in that X2 has a structure selected from the group consisting of:

5. The compound according to claim 2, characterized in that Ring C has a structure selected from the group consisting of:

6. A compound of formula Ia, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, in, X1 and L1 are each independently a bond, -O-, -S-, -NR a -, substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-10 Alkenylene, substituted or unsubstituted C 2-10 Alkyne, substituted or unsubstituted C 3-6 Cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 O-, -(CH2) 0-4 S-, -(CH2) 0-4 NR a -、-C(O)-、-NR a C(O)-、-C(O)NR a -, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group being replaced by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; X2 is a bond, substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-6 Alkenylene, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-6 Cycloalkylene, substituted or unsubstituted 3-6 membered heterocycloalkylene containing 1-2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 (C 3-6 The substitution refers to the substitution of one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group by a substituent selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Ring A is selected from the following group: a substituted or unsubstituted saturated or partially saturated 5-6 membered heterocyclic group containing 1-4 heteroatoms independently selected from N, O or S, a substituted or unsubstituted oxo 9-10 membered ring, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3, 4, 5 or 6) on the group being replaced by R1, wherein R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, oxo (=O), -(CH2) 0-4 OR b 、-(CH2) 0-4 NR b R c , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O or S, -SO2R b 、-SO2NR b R c 、-C(O)OR b 、-NR b R c 、-C(O)NR b R c 、-NR b S02R c 、-OC(O)NR b R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O or S, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, phenyl, benzyl, -NR b R c 、-SO2R b 、-C(O)OR b 、-OC(O)NR b R c 、-SO2NR b R c 、-C(O)NR b R c 、-NR b SO2R c 、-NR b C(O)OR c ; Alternatively, two R1 on the same atom and the atom to which they are attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or a substituted or unsubstituted 3-6 membered heterocyclic group containing 1-2 heteroatoms independently selected from N, O or S, wherein the substitution refers to one or more hydrogen atoms (e.g., 1, 2, 3 or 4) on the group being replaced by a substituent selected from the group consisting of deuterium, hydroxyl, halogen, cyano, oxo (═O), C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R a are independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N, O or S; R b , R c are independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S, -(CH2) 0-4 (C 3-6 Cycloalkyl), -(CH2) 0-4 (a 3-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from N, O or S), wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of: Deuterium, hydroxyl, halogen, cyano, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, Or, R b and R c Together with the N to which it is attached, it forms a 3-6 membered heterocycloalkyl-containing 1, 2 or 3 heteroatoms selected from N, O or S, and the 3-6 membered heterocycloalkyl-is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, hydroxy, halogen, cyano, oxo (═O), C 1-4 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

7. The compound according to claim 6, characterized in that The compound has a structure shown in formula II-a or formula III-a: wherein ring A, X1, X2, and L1 are as defined in claim 1.

8. The compound according to claim 6, characterized in that Ring A is a structure selected from the following group: in, Y1 is selected from the group consisting of N, CH; Y2 is selected from the group consisting of N, CH; Y3 is selected from the group consisting of NH, NR1, O, S, CH2; R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, oxo (=O), -(CH2) 0-4 OR b 、-(CH2) 0-4 NR b R c , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O or S, 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O or S, phenyl, benzyl, -SO2R b 、-C(O)OR b 、-SO2NR b R c 、-OC(O)NR b R c 、-C(O)NR b R c 、-NR b S02R c 、-NR b C(O)OR c , wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzyl are optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, oxo (=O), hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O or S, -SO2R b 、-C(O)OR b 、-SO2NR b R c 、-OC(O)NR b R c 、-C(O)NR b R c 、-NR b S02R c 、-NR b C(O)OR c ; m is selected from the following group: 0, 1, 2, 3, 4, 5, 6; It represents the connection position of ring A in the structure of formula I, one end of which is connected to NH and the other end of which is connected to X1.

9. The compound according to claim 6, characterized in that X2 is selected from the following group:

10. The compound according to claim 6, characterized in that Ring A is selected from the following group: X1 is selected from the group consisting of a bond, -O-, substituted or unsubstituted C 1-6 Alkylene; L1 is selected from the group consisting of a bond, -O-, -S-, a substituted or unsubstituted C 1-6 Alkylene; X2 is selected from the following group:

11. The compound according to claim 1, characterized in that The compound is selected from the group consisting of:

12. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound according to any one of claims 1 to 11.

13. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, characterized in that: Used for preparing a drug or preparation, wherein the drug or preparation is used for (a) regulating CDK kinase activity, and / or (b) preventing and / or treating CDK-related diseases.

14. Use of the compound according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12, characterized in that: Used for preparing medicines or preparations, wherein the medicines or preparations are used for preventing and / or treating cell cycle protein related diseases.

15. The use according to claim 13 or 14, characterized in that The CDK-related disease is cancer, preferably the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), renal cancer (including RCC), skin cancer, glioblastoma, glioblastoma, mantle cell lymphoma (MCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), neuroblastoma, sarcoma, liposarcoma, chondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer, choriocarcinoma, pediatric tumor.

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