Macrocyclic compound as well as preparation and application thereof

Abstract

The invention relates to a macrocyclic compound as well as a preparation method and application thereof. Specifically, the macrocyclic compound disclosed by the invention has a structure as shown in a formula (I), and the definitions of all groups and substituent groups are described in the specification. The invention also discloses a preparation method of the compound and application of the compound in the aspects of regulating CDK2 kinase activity and / or preventing and / or treating CDK2 related diseases. # imgabs0 #

Description

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 vital role in G1 / S transition and S phase progression. CDK2 and cyclin E (CCNE) complex phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), releases E2F transcription factor, and promotes the transition from G1 phase to S phase (Henley, sa and FADick, Cell Div, 2012, 7 (1): 10). CDK2 / cyclin A is then activated to phosphorylate endogenous substrates, thereby allowing DNA synthesis, replication and centrosome duplication (Ekholm, SV and S.I. 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). It has been reported that CCNE1 amplification and / or overexpression can also 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 apoptosis and inhibit tumor proliferation.

[0006] However, due to the high similarity of the ATP-binding domains of CDKs family kinases, there is currently a lack of selective inhibitors for CDK2. Most small molecules can often inhibit multiple CDK kinase subtypes and even other non-CDK family kinases at the same time. Such off-target effects not only bring about potent cell killing or inhibition, but also bring about significant side effects. Therefore, the development of new selective CDK2 kinase inhibitors has broad application prospects. Summary of the invention

[0007] An object of the present invention is to provide a macrocyclic compound as a CDK2 kinase inhibitor and its use.

[0008] In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,

[0009]

[0010] in:

[0011] 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 aC(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;

[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 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;

[0013] 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;

[0014] 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;

[0015] 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;

[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- 2NR 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)ORb 、-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 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 ,

[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, 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;

[0020] R a are independently selected from the group consisting of hydrogen, C 1-4 Alkyl, halogenated C 1-4Alkyl, deuterated C 1-4 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 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,

[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 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;

[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, hydroxyl, halogen, cyano, =O, C 1-4 Alkyl, C 1-4 Alkoxy, deuterated C 1-4Alkyl, halogenated C 1-4 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 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.

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

[0026]

[0027]

[0028] wherein Ring A, X1, X2, L1, and R are as defined herein;

[0029] 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.

[0030] In another preferred embodiment, ring A has a structure selected from the following group:

[0031]

[0032] in,

[0033] Y1 is selected from the following group: N, CH;

[0034] Y2 is selected from the following group: N, CH;

[0035] Y3 is selected from the following group: NH, NR1, O, CH2;

[0036] R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, =O, -(CH2) 0-2 ORb 、-(CH2) 0- 2NR 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 ;

[0037] m is selected from the following group: 0, 1, 2, 3, 4, 5, 6;

[0038] 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.

[0039] In another preferred embodiment, ring A is

[0040] In another preferred embodiment, ring A is

[0041] In another preferred embodiment, ring A is

[0042] In another preferred embodiment, ring A is

[0043] In another preferred embodiment, ring A is selected from the following group:

[0044] 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.

[0045] In another preferred embodiment, L1 is O or S; preferably L1 is O.

[0046] 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.

[0047] 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.

[0048] In another preferred embodiment, ring A has one oxo (=O) substituent.

[0049] In another preferred embodiment, X2 has a structure selected from the following group:

[0050]

[0051] In another preferred embodiment, ring C has a structure selected from the following group:

[0052]

[0053] In another preferred embodiment, R1 is independently selected from the following group: 1-3 Alkyl, halogenated C 1-3 Alkyl and C 3-6 Cycloalkyl; more preferably methyl, ethyl, isopropyl, CF2CH2-, CF3CH2-, cyclopropyl.

[0054] In a second aspect, the present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,

[0055]

[0056] in,

[0057] 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;

[0058] X2 is a bond, substituted or unsubstituted C 1-6Alkylene, 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;

[0059] 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,

[0060] 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 S02R c 、-NR b C(O)OR c ;

[0061] 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;

[0062] 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;

[0063] R b , Rc 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 by 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,

[0064] 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.

[0065] In another preferred embodiment, X1 and L1 are each independently a bond, -O-, -S-, -NR a -, 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) 0-2 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 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;

[0066] 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;

[0067] 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,

[0068] 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 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 S02R c 、-NR b C(O)OR c ;

[0069] 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;

[0070] 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;

[0071] 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 by 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,

[0072] 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 1-4 Alkoxy, deuterated C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy.

[0073] In another preferred embodiment, the compound has a structure shown in Formula II-a or Formula III-a:

[0074]

[0075] Wherein, ring A, X1, X2, and L1 are as defined in the first aspect of the present invention.

[0076] 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.

[0077] In another preferred embodiment, ring A is selected from the following group: substituted or unsubstituted oxo 9-10 membered ring.

[0078] In another preferred embodiment, ring A is a structure selected from the following group:

[0079]

[0080] in,

[0081] Y1 is selected from the group consisting of N, CH;

[0082] Y2 is selected from the group consisting of N, CH;

[0083] Y3 is selected from the group consisting of NH, NR1, O, S, CH2;

[0084] 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 C3-6 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 ;

[0085] m is selected from the following group: 0, 1, 2, 3, 4, 5, 6;

[0086] 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.

[0087] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, and R1 are as shown in the second aspect of the present invention.

[0088] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, and R1 are as shown in the second aspect of the present invention.

[0089] In another preferred embodiment, ring A is Wherein, Y1, Y2, Y3, and R1 are as shown in the second aspect of the present invention.

[0090] 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.

[0091] In another preferred embodiment, X2 is selected from the group consisting of a bond, a substituted or unsubstituted C 1-6 Alkylene, substituted or unsubstituted C 2-6 Alkenylene, substituted or unsubstituted C 2-6Alkyne, substituted or unsubstituted C 3-6 Cycloalkylene, -(CH2) 0-4 (C 3-6 Cycloalkyl);

[0092] 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.

[0093] In another preferred embodiment, X2 is selected from the following group:

[0094]

[0095]

[0096] In another preferred embodiment, ring A is selected from the following group:

[0097]

[0098] X1 is selected from the group consisting of a bond, -O-, substituted or unsubstituted C 1-6 Alkylene;

[0099] L1 is selected from the group consisting of a bond, -O-, -S-, a substituted or unsubstituted C 1-6 Alkylene;

[0100] X2 is selected from the following group:

[0101]

[0102]

[0103] In another preferred embodiment,

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] 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.

[0116] In another preferred embodiment, in the composition, the compound accounts for 0.001-99.999wt% of the total weight of the composition; preferably 0.01-99.99wt%; more preferably 0.1-90wt%.

[0117] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0118] 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.

[0119] In another preferred embodiment, the CDK kinase is CDK2 kinase.

[0120] In another preferred embodiment, the CDK-related disease is cancer.

[0121] In another preferred embodiment, the cell cycle protein-related disease is cancer.

[0122] 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.

[0123] 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 cell cycle protein-related diseases.

[0124] In another preferred embodiment, the cell cycle protein is cyclin E.

[0125] In another preferred embodiment, the cyclin E is selected from the following group: cyclin E1 and cyclin E2.

[0126] In another preferred embodiment, the cell cycle protein-related disease is cancer.

[0127] 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.

[0128] 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.

[0129] In the sixth aspect of the present invention, a method for preventing and / or treating CDK-related diseases is provided, 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.

[0130] In another preferred embodiment, the subject is a human or a non-human mammal, such as a monkey, a rat and a mouse.

[0131] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0132] After extensive and in-depth research, the inventors have provided a macrocyclic compound with excellent CDK kinase inhibitory activity for the first time. Specifically, through structural optimization, the inventors have obtained a class of compounds with excellent CDK2 selective inhibitory activity. Based on this, the inventors have completed the present invention.

[0133] the term

[0134] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0135] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- includes -OCH2-.

[0136] In the present invention, the term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0137] 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.

[0138] 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.

[0139] In the present invention, the term "C 2-6The 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.

[0140] In the present invention, the term "C 2-6 The term "alkynyl" refers to a straight or branched 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.

[0141] 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. The term "C 1-4 "Alkoxy" has a similar meaning.

[0142] 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.

[0144] 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.

[0145] 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.

[0146] In the present invention, the term "C 1-6 “Alkylene” refers to a straight or branched alkylene structure comprising 1 to 6 carbon atoms, including but not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH(CH3)-, and the like.

[0147] In the present invention, the term "cycloalkyl" refers to a cyclic alkyl group containing 3 to 12 carbon atoms, including monocyclic alkyl groups and condensed cyclic alkyl groups. The condensed cyclic alkyl groups include cycloalkyl groups, bridged cycloalkyl groups, 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 includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0148]

[0149] 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 includes, but is not limited to, cyclopentyl, cyclohexyl, cycloheptyl,

[0150]

[0151]

[0152] 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 monocyclic heterocycloalkyl groups and fused-ring heterocycloalkyl groups. The fused-ring heterocycloalkyl groups include cyclic heterocycloalkyl groups, bridged-ring heterocycloalkyl groups, and spirocyclic heterocycloalkyl groups.

[0153] 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:

[0154]

[0155] 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:

[0156]

[0157] The "saturated or partially saturated heterocycloalkyl" refers to a cycloalkyl group with or without 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:

[0158] In the present invention, the term "a 5-6-membered cycloalkyl or a 5-6-membered heterocycloalkyl and a 5-6-membered heteroaryl 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, the ring structure having 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:

[0159]

[0160]

[0161] In the present invention, the term "oxo 9-10 membered ring" refers to a ring structure containing 9 or 10 atoms substituted by a functional group "=O", and the ring structure can be a saturated ring, an aromatic ring, or a partially saturated ring. The term "a 5-6 membered heteroaryl or a phenyl 5-6 membered heterocycloalkyl 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 heteroaryl 5-6 membered heterocycloalkyl or a phenyl 5-6 membered heterocycloalkyl structure, including but not limited to:

[0162]

[0163] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "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: furanyl, thienyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group may be optionally substituted or unsubstituted.

[0164] In the present invention, the term "deuterated" means substituted with deuterium.

[0165] 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, C3-6 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.

[0166] In the present invention, the term 1-4 means 1, 2, 3 or 4. Other similar terms have similar meanings.

[0167] In the present invention, "-SO2-" means

[0168] In the present invention, "-C(O)-" means

[0169] It should be understood that when a group is present in multiple different positions of a compound at the same time, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the following group:" has the same meaning as the term "independently selected from the following group:".

[0170] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (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 conformational isomers) are all within the scope of the present invention.

[0171] The compounds of the present application can be prepared by a variety of synthesis 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 substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0172] Compound

[0173] The invention provides a macrocyclic compound with CDK kinase inhibitory activity, which is used for inducing cell apoptosis and inhibiting tumor proliferation.

[0174] Specifically, the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated product thereof,

[0175]

[0176] Wherein, Ring A, Ring B, X1, X2, X3, and L1 are as defined above.

[0177] Alternatively, the compound is a compound of formula Ia, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof,

[0178]

[0179] Ia wherein Ring A, X1, X2, and L1 are as defined above.

[0180] 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.

[0181] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by 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.

[0182] Another preferred salt is a salt of the compound of the present invention and 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.

[0183] 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.

[0184] The term "deuterated compound" refers to the compounds of the present invention in which the hydrogen atoms attached to carbon atoms can be optionally replaced by deuterium atoms to form deuterium-containing compounds.

[0185] 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 combination can be easily performed by a person skilled in the art to which the present invention belongs.

[0186] 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.

[0187] Pharmaceutical compositions and methods of administration

[0188] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention or, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof.

[0189] 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.

[0190] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0191] "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 ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0192] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0193] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0194] 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 starch 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.

[0195] Solid dosage forms such as tablets, pills, 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 opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0196] 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, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0197] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0198] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0199] Compositions for parenteral injection may include 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.

[0200] Dosage forms for topical administration of the compounds of the 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.

[0201] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0202] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0203] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0204] Compared with the prior art, the main advantages of the present invention include:

[0205] 1) The compound has excellent CDK2 inhibitory activity.

[0206] 2) The compound can be used to induce cell apoptosis and inhibit tumor proliferation.

[0207] 3) The compound has excellent selectivity in inhibiting CDK subtypes.

[0208] 4) The compounds of the present invention have excellent pharmacokinetic and pharmacodynamic properties and good drugability.

[0209] 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 where specific conditions are not specified are 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 under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0210] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0211] Example Synthesis Route

[0212] Unless otherwise stated, the absolute stereochemistry of all chiral atoms is defined as follows. The "&" symbol in the structural formula indicates that the compound is a cis racemate; the "or1" symbol indicates that the compound is a single-configuration compound, but the absolute configuration is unknown; 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 "abs" symbol indicates that the absolute configuration of the compound is the structure shown; the "rac" symbol indicates that the compound is a racemate; the "S" or "R" symbol indicates that the chirality of the carbon at that position of the compound is the known configuration marked. ()

[0213] Synthesis of intermediate int1:

[0214]

[0215] 1. Synthesis of int1-2

[0216] Dissolve int1-1 (10 g, 64.0 mmol) in 150 mL of methanol, add NaBH4 (2.44 g, 64.0 mmol) in batches under nitrogen protection and ice-water bath cooling, then heat the reaction solution to room temperature and stir for 2 hours. After the reaction is completed, slowly add 1 M dilute hydrochloric acid solution under ice-water bath cooling to quench the reaction, concentrate under reduced pressure to evaporate the solvent methanol, then dilute with water, extract with dichloromethane, separate the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 8.27 g of crude product. Ms[M+Na] + :181.1

[0217] 2. Synthesis of int1-3

[0218] Dissolve int1-2 (8.27 g, 52.33 mmol) in 100 mL of ethanol, then add imidazole (10.67 g, 157.0 mmol), slowly dropwise add TBDPSCl (15.83 g, 57.58 mmol) under nitrogen protection in an ice-water bath, and after the addition is complete, warm the reaction solution to room temperature and stir for 16 hours. After the reaction is completed, evaporate the solvent ethanol under reduced pressure, then dilute the residue with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and column chromatograph to obtain 19.86 g of the product. Ms[M+H] + 397.2.1 HNMR(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).

[0219] 3. Synthesis of int1-4

[0220] Under nitrogen protection, n-butyl lithium (88 mL, 2.5 M in hexane) was added to 500 mL of anhydrous tetrahydrofuran, the system was cooled to -65 ° C, and then acetonitrile (9.2 g, 224.8 mmol) was slowly added dropwise. After the addition was completed, the temperature was maintained and stirred for 1 hour. Then, an anhydrous tetrahydrofuran solution (100 mL) of int1-3 (44.7 g, 112.4 mmol) was slowly added dropwise, and the temperature was maintained and stirred for 2 hours. After the reaction was completed, water was added dropwise at -65 ° C to quench the reaction, and then stirred and heated 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

[0221] 4. Synthesis of int1-5

[0222] Dissolve tert-butylhydrazine hydrochloride (9.35 g, 75.0 mmol) and triethylamine (10.43 mL, 75.0 mmol) in 150 mL of ethanol, stir for 0.5 hours, then add ethanol solution (50 mL) of int1-4 (19.6 g, 50.0 mmol), and then heat the reaction system to 75 ° C and stir for 16 hours. After the reaction, the reaction solution was cooled to room temperature, concentrated, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 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).

[0223] 5. Synthesis of int1-6

[0224] Dissolve int1-5 (19.12 g, 41.0 mmol) in 160 mL of acetonitrile, add benzyl chloroformate (11.7 mL, 82.0 mmol) dropwise under ice-water cooling, warm to room temperature and stir for 2 h, then add NaHCO3 (11.02 g, 130.0 mmol) and stir at room temperature for 16 h. After the reaction is completed, filter the reaction solution, wash the filter cake with ethyl acetate several times, concentrate the filtrate under reduced pressure, dilute with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure and purify to obtain 21.2 g. Ms[M+H] + :596.4

[0225] 6. Synthesis of int1-7

[0226] Int1-6 (21.0 g, 35.0 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran under stirring at room temperature, and glacial acetic acid (4.2 mL, 70.0 mmol) and tetrabutylammonium fluoride (35.0 mL, 1 M in tetrahydrofuran) were added in sequence. 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, concentrated under reduced pressure, and the residue was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to obtain 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).

[0227] 7. Synthesis of int1-8

[0228] The following method was used for chiral separation of int1-7: Agilent high performance liquid chromatography separation, the preparation and separation conditions were as follows: Chromatographic column: Phenomenex 5μm Cellulose-4, mobile phase: n-hexane:isopropanol=90:10; collect the sample with the peak time at 24.6min, concentrate and freeze-dry to obtain the product int1-8 (1.07g), the peak time of another configuration is 21.8min.

[0229] 8. Synthesis of int1

[0230] Int1-8 (1.07 g, 2.42 mmol) was dissolved in a mixed solvent of 10 mL methanol and 10 mL ethyl acetate, and then Pd / C (214 mg, 20 mol%) was added and stirred at room temperature for 5 h under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified to obtain 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).

[0231] Synthesis of intermediate int2:

[0232]

[0233] 1. Synthesis of int2-2

[0234] 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.

[0235] 2. Synthesis of int2-3

[0236] 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.

[0237] 3. Synthesis of int2

[0238] Int2-3 (500 mg), Pd / C (200 mg) and methanol (10 ml) were added to a 50 mL single-mouth bottle and reacted at room temperature for 2 h. After the reaction was completed, the product was filtered and concentrated to obtain 340 mg.

[0239] Synthesis of intermediate int3:

[0240]

[0241] 1. Synthesis of int3-2

[0242] Add N,N-dimethylformamide (20 mL) to a 100 mL flask, add NaH (2.25 g) at 0°C, add dimethyl malonate (9 g) at room temperature, react at 40°C for 40 min, then add C91-1 and heat to 100°C to continue reacting for 16 h. After the reaction is completed, concentrate to remove N,N-dimethylformamide, add water (20 mL), extract with ethyl acetate (4*20 mL) to remove impurities, retain the aqueous phase, add concentrated H2SO4 to adjust the pH until a large amount of solid precipitates, collect the solid, wash with water several times, and finally dry to obtain 2.5 g of crude product, which is directly used in the next step.

[0243] 2. Synthesis of int3-3

[0244] In a 100 mL flask, add crude int3-2 (2.3 g), concentrated HCl (22 mL) and AcOH (16 mL), react at 100 °C for 6 h. After the reaction is complete, concentrate to obtain 2.5 g of a crude product, which is directly used in the next step.

[0245] 3. Synthesis of int3-4

[0246] 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 in turn at room temperature, and finally diphenyl (vinyl) sulfonium trifluoromethanesulfonate (1.1 g) was added, and the reaction was allowed to react for 15 min at room temperature. After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with dichloromethane three times. 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.

[0247] 4. Synthesis of int3-5

[0248] Int3-4 (100 mg) was added to a 50 mL flask, dissolved in anhydrous N, N-dimethylformamide (5 mL), and NaH (40 mg) was added at 0°C. The mixture was reacted at 0°C for 0.5 h, and then CH3I (100 mg) was added and the reaction was continued for 1.5 h. After the reaction was completed, water was added to the reaction solution, and then extracted three times with ethyl acetate, the organic phases were combined, washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain 110 mg of the product.

[0249] 5. Synthesis of int3

[0250] In a 50 mL flask, int3-5 (1.5 g) and carbon tetrachloride (20 mL) were added and stirred to dissolve, and azobisisobutyronitrile (95 mg) was added. Then N-bromosuccinimide (1.3 g) was added, and the mixture was reacted at 75°C for 2 hours under nitrogen protection, and concentrated and subjected to thin layer chromatography to obtain 1.1 g of the product.

[0251] Synthesis of intermediate int4:

[0252]

[0253] 1. Synthesis of int4-2

[0254] Under nitrogen protection, compound int4-1 (2g, 1.00eq) and tetrahydrofuran (80mL) were added to a 250mL three-necked flask, cooled to -78°C, and 1M vinylmagnesium bromide tetrahydrofuran solution (40mL, 3.7eq) was slowly added dropwise. After the addition, the temperature was slowly raised to -20°C and the reaction was continued for 4h. Saturated ammonium chloride aqueous solution was slowly added dropwise to the reaction system 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. 0.8g of the product was obtained after purification on a silica gel column. 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

[0255] 2. Synthesis of int4-3

[0256] 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 for 30 min in an ice bath. Then slowly add iodomethane (730 mg, 1.2 eq) to the reaction system in an ice bath. Slowly warm to room temperature and react for 1 h. 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 860 mg of the product. Ms[M+H] + 181.06

[0257] 3. Synthesis of int4-4

[0258] Add compound int4-3 (860 mg, 1.00 eq), sodium bicarbonate (1.2 g, 3.00 eq) and tert-butanol (17 mL) to a 100 mL single-mouth bottle and stir at room temperature for 10 min. Then slowly add bromine (4.58 g, 6.00 eq) to the reaction system and react at room temperature for 1 h. Add water to quench the reaction, extract the aqueous phase with ethyl acetate, and separate the layers. Combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 1.3 g of the product. Ms[M+H] + 352.86

[0259] 4. Synthesis of int4-5

[0260] 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. React at room temperature for 1 h. Add methanol to the reaction solution for dilution, filter and wash the filter residue with methanol. Concentrate the filtrate under reduced pressure to obtain 615 mg of crude product. Ms[M+H] + 197.04

[0261] 5. Synthesis of int4-6

[0262] 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), 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 reacted 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 a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 550 mg of pure product was obtained after purification by 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

[0263] 6. Synthesis of int4

[0264] Compound int4-6 (550 mg, 1.00 eq), N-bromosuccinimide (484 mg, 1.1 eq) and carbon tetrachloride (12 mL) were added to a 100 mL glass flask, and azobisisobutyronitrile (44 mg, 0.10 eq) was added at room temperature. The reaction solution was reacted at 75 ° C for 2 h in a nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated. After purification on a silica gel column, 300 mg of the product was obtained. 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

[0265] Synthesis of intermediate int5:

[0266]

[0267] 1. Synthesis of int5-2

[0268] Dissolve int5-1 (20g, 1.0eq) in dichloromethane (200mL), cool to 0°C, add carbonyldiimidazole (29g, 2.0eq) in batches, stir for 20 minutes, add dimethylhydroxylamine hydrochloride (13.1g, 1.5eq) and triethylamine (35mL, 3.0eq), naturally warm to room temperature and stir for 2h. After the reaction is completed, add saturated brine to the reaction system, separate the liquids, add dichloromethane to the aqueous phase and extract twice, combine and dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography to obtain 20.2g of the product.

[0269] 2. Synthesis of int5-3

[0270] Dissolve int5-2 (17.43 g, 1.0 eq) in dry tetrahydrofuran (240 mL), protect with nitrogen, cool to -5 ° C, then add 3M methylmagnesium bromide solution (54.6 mL, 2.5 eq), and naturally warm to room temperature for 16 hours. After the reaction is completed, add saturated ammonium chloride aqueous solution to the reaction solution at 0 ° C to quench, then add saturated brine, separate the liquids, extract the aqueous phase with ethyl acetate once, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography to obtain 13.6 g of the product.

[0271] 3. Synthesis of int5-4

[0272] (R)-methyl-CBS-oxazolidinone (3.1g, 1.0eq) was dissolved in dry tetrahydrofuran (25mL), nitrogen was protected, and then 1M borane tetrahydrofuran solution (13.5mL, 1.2eq) was added. After the addition was completed, the tetrahydrofuran solution (20mL, 2h) of int5-3 (2.5g, 1.0eq) was added dropwise with a microinjection pump. After the addition was completed, the reaction was allowed to react at room temperature for 10 minutes. After the reaction was completed, 5mL of methanol was added dropwise at 0°C to quench, and then water was added. The mixture was extracted with ethyl acetate twice, and the ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 2.2g of the product was obtained by column chromatography.

[0273] 4. Synthesis of int5

[0274] Int5-4 (2.2 g, 1.0 eq) was dissolved in methanol (25 mL), and Pd / C (500 mg) and di-tert-butyl dicarbonate (2.58 g, 1.2 eq) were added at room temperature, and the mixture was reacted for 3 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure. Purification by column chromatography gave 1.4 g of the product.

[0275] Synthesis of intermediate int6:

[0276]

[0277] 1. Synthesis of int6-2

[0278] Dissolve int6-1 (4.18 g, 1.0 eq) in dichloromethane (120 mL), cool to 0 ° C, add Dess-Martin reagent (11.87 g, 1.4 eq) in batches, and naturally warm to room temperature and stir to react for 16 hours. After the reaction is completed, filter and concentrate, 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 directly used in the next step.

[0279] 2. Synthesis of int6-3

[0280] NaH (0.386 g, 2.0 eq) was added to dimethyl sulfoxide (15 mL), and trimethylsulfur oxide iodide (2.12 g, 2.0 eq) was added in batches under water bath conditions. After addition, the reaction 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 above reaction solution. After addition, the reaction was allowed to react at room temperature for 2 h. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added dropwise to the reaction solution at 0°C to quench, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, dried, filtered, and concentrated under reduced pressure. 402 mg of the product was obtained by column chromatography.

[0281] 3. Synthesis of int6-4

[0282] Int6-3 (300 mg, 1.0 eq) was dissolved in triethylamine trihydrofluoride (4 mL) and reacted at 105°C for 16 h under nitrogen protection. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, and water was added. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, dried, filtered, concentrated under reduced pressure, and separated by a thin layer preparation plate to obtain 71 mg of the product.

[0283] 4. Synthesis of int6

[0284] 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, and react for 3 h under a hydrogen atmosphere. After the reaction is complete, filter and concentrate under reduced pressure. Purify by column chromatography to obtain 56 mg of the product.

[0285] Synthesis of intermediate Int7

[0286]

[0287] 1. Synthesis of int7-2

[0288] Add int7-1 (204 mg, 1.0 eq) to tetrahydrofuran (10 mL), add p-nitrobenzoic acid (424 mg, 3.0 eq) and triphenylphosphine (888 mg, 4.0 eq), cool to 0 ° C, add diisopropyl azodicarboxylate (684 mg, 4.0 eq) dropwise, and after addition, the reaction solution is heated to room temperature and stirred for 4 hours. After the reaction is completed, the reaction is quenched with a saturated sodium bicarbonate solution at 0 ° C, and extracted twice with ethyl acetate. Combine the organic phases, dry, filter, and concentrate under reduced pressure. Purify by column chromatography to obtain 576 mg of the product.

[0289] 2. Synthesis of int7-3

[0290] Add int7-2 (576 mg, 1.0 eq) to methanol (10 mL), cool to 0°C, add potassium carbonate (407 mg, 2.0 eq) in batches, stir at 0°C for 1 h. After the reaction is complete, quench the reaction with ice water at 0°C, and extract twice with ethyl acetate. Combine the organic phases, dry, filter, and concentrate under reduced pressure. Purify by column chromatography to obtain 195 mg of the product.

[0291] 3. Synthesis of int7

[0292] Add int7-3 (180 mg, 1.0 eq) to methanol (5 mL), add di-tert-butyl dicarbonate (195 mg, 1.2 eq) and Pd / C at room temperature, replace nitrogen three times, replace hydrogen three times, hydrogenate with a hydrogen balloon, and stir at room temperature for 2 hours. After the reaction is completed, filter, wash the filter cake with methanol three times, and concentrate under reduced pressure to obtain a crude product. The crude product is slurried with petroleum ether, filtered, and dried to obtain 119 mg of the product.

[0293] Synthesis of intermediate int8:

[0294]

[0295] 1. Synthesis of int8-2

[0296] Dissolve int8-1 (8g, 1.0eq) and benzyl bromide (40mL, 5.0eq) in N,N-dimethylformamide (120mL), add potassium carbonate (49.1g, 5.0eq) while stirring, and then heat to 100°C for 16h. The reaction is complete. After the reaction solution is cooled to room temperature, water is added, and then ethyl acetate is added for extraction twice. The ethyl acetate phases are combined and washed with saturated brine three times. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography gives 8.97g of the product.

[0297] 2. Synthesis of int8-3

[0298] Dissolve int8-2 (8.97 g, 1.0 eq) in ultra-dry tetrahydrofuran (90 mL), add DAST (5.55 g, 1.5 eq) at 0°C, and then warm to room temperature and react for 0.5 h. The reaction is complete. Add ice water to the reaction solution to quench, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 5.58 g of the product.

[0299] 3. Synthesis of int8-4

[0300] Int8-3 (5.58 g, 1.0 eq) was dissolved in methanol (60 mL), and then Pd / C (600 mg) was added and reacted at 60° C. for 16 h under a hydrogen atmosphere. After the reaction of the raw materials was complete, the product was filtered and concentrated to obtain 1.6 g.

[0301] 4. Synthesis of int8-5

[0302] 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 solution, then add petroleum ether:ethyl acetate = 5:1, stir for 0.5 h, filter, and collect the filter cake to obtain 750 mg of the product.

[0303] 5. Synthesis of int8

[0304] Dissolve int8-5 (750 mg, 1.0 eq) in ultra-dry tetrahydrofuran (15 mL), add 1N borane tetrahydrofuran (6.1 mL, 3.0 eq) at 0°C, and react at 65°C for 0.5 h. After the reaction is completed, add a small amount of water at room temperature to quench the reaction, and concentrate under reduced pressure. Purify by silica gel column chromatography to obtain 523 mg of the product.

[0305] Synthesis of intermediate int9:

[0306]

[0307] 1. Synthesis of int9-2

[0308] Dissolve int9-1 (25 g, 1.0 eq) in dichloromethane (700 mL), add imidazole (43.3 g, 3.0 eq) at room temperature, then add TBDPSCl (64 g, 1.1 eq), and react at room temperature for 1.5 h. The reaction is complete. Add water to the reaction solution, extract twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify with a silica gel column to obtain 70 g of the product.

[0309] 2. Synthesis of int9-3

[0310] Dissolve int9-2 (15 g, 1.0 eq) in ultra-dry dichloromethane (150 mL), protect with nitrogen, and add 1N diisobutylaluminum hydride (50.5 mL, 1.2 eq) dropwise at -70 ° C. After the addition, keep warm for 2 h. Add aqueous ammonium chloride to the reaction solution to quench, filter, add dichloromethane to the filtrate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by silica gel column to obtain 14.9 g of the product.

[0311] 3. Synthesis of int9-4

[0312] 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), protect with nitrogen, and stir at 40 ° C for 16 h. The reaction is complete. Add water to the reaction solution, filter, separate the filtrate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After purification on a silica gel column, 15 g of the product is obtained.

[0313] 4. Synthesis of int9-5

[0314] Dissolve int9-4 (8 g, 1.0 eq) in ultra-dry tetrahydrofuran (80 mL), protect with nitrogen, slowly add 3N methylmagnesium bromide (12.4 mL, 2.0 eq) at -40 ° C, and react at room temperature for 2 h. Add aqueous ammonium chloride to the reaction solution to quench, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 3.5 g of the product.

[0315] 5. Synthesis of int9-6

[0316] Dissolve int9-5 (2.0 g, 1.0 eq) in tetrahydrofuran (20 mL), add 1N tetrabutylammonium fluoride in tetrahydrofuran solution (6.74 mL) at room temperature, stir at room temperature for 1 h. The reaction is complete. Add water to the reaction solution, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 530 mg of the product.

[0317] 6. Synthesis of int9-7

[0318] 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 solution, then add ethyl acetate and stir for 15 min, filter, and collect the filter cake to obtain 290 mg.

[0319] 7. Synthesis of int9

[0320] 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 to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 470 mg of the product

[0321] Synthesis of intermediate int10:

[0322]

[0323] 1. Synthesis of int10-1

[0324] Dissolve int9-4 (13.9 g, 1.0 eq) in tetrahydrofuran (140 mL), add sodium borohydride (2.45 g, 2.0 eq) in batches at 0°C, and react at room temperature for 2 h. Add water to the reaction solution to quench, then add ethyl acetate to extract twice. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a silica gel column to obtain 7.75 g of the product.

[0325] 2. Synthesis of int10-2

[0326] Dissolve int10-1 (7.75 g, 1.0 eq) in tetrahydrofuran (80 mL), add 1N tetrabutylammonium fluoride tetrahydrofuran solution (25.8 mL) at room temperature, stir at room temperature for 1 h. Add water to the reaction solution, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 3.1 g of the product.

[0327] 3. Synthesis of int10-3

[0328] 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 solution, then add ethyl acetate and stir for 15 min, filter, and collect the filter cake to obtain 120 mg of the product.

[0329] 4. Synthesis of int10

[0330] Dissolve int10-3 (120 mg, 1.0 eq) in tetrahydrofuran (5 mL), add triethylamine (410 mg, 3.0 eq) and di-tert-butyl dicarbonate (400 mg, 1.5 eq), and stir at room temperature for 2 h. Add water to the reaction solution, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 180 mg of the product.

[0331] Synthesis of intermediate int11:

[0332]

[0333] 1. Synthesis of int11-2

[0334] Dissolve int11-1 (10 g, 1.0 eq) in dichloromethane (100 mL), add imidazole (17.3 g, 3.0 eq) at room temperature, then add TBDPSCl (25.6 g, 1.1 eq), and react at room temperature for 1.5 h. Add water to the reaction solution, extract twice with dichloromethane, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 29.6 g of the product.

[0335] 2. Synthesis of int11-3

[0336] Int11-2 (10 g, 1.0 eq) was dissolved in ultra-dry dichloromethane (100 mL), and 1N diisobutylaluminum hydride (22 mL, 1.2 eq) was added dropwise at -70 ° C under nitrogen protection. After the addition, the mixture was kept warm for 2 h. After the reaction was completed, an aqueous solution of ammonium chloride was added to the reaction solution to quench it, and the mixture was filtered. Dichloromethane was added to the filtrate to extract the mixture twice, and 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.

[0337] 3. Synthesis of int11-4

[0338] 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), protect with nitrogen, and stir at 40 ° C for 16 h. Add water to the reaction solution, filter, separate the filtrate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. After purification on a silica gel column, 12.1 g of the product was obtained.

[0339] 4. Synthesis of int11-5

[0340] Dissolve int11-4 (12.1 g, 1.0 eq) in tetrahydrofuran (120 mL), add sodium borohydride (2.1 g, 2.0 eq) in batches at 0°C, and react at room temperature for 2 h. Add water to the reaction solution to quench, then add ethyl acetate to extract twice. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a silica gel column to obtain 6.9 g of the product.

[0341] 5. Synthesis of int11-6

[0342] Dissolve int11-5 (6.9 g, 1.0 eq) in tetrahydrofuran (70 mL), add 1N tetrabutylammonium fluoride tetrahydrofuran solution (19.1 mL, 1.2 eq) at room temperature, stir at room temperature for 1 h. Add water to the reaction solution, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 2.28 g of the product.

[0343] 6. Synthesis of int11-7

[0344] 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, it is directly used in the next step.

[0345] 7. Synthesis of int11

[0346] Dissolve int11-7 (1.3 g, 1.0 eq) in tetrahydrofuran, add triethylamine (1.2 g, 3.0 eq) and di-tert-butyl dicarbonate (1.9 g, 1.5 eq), and stir at room temperature for 2 h. Add water to the reaction solution, then add ethyl acetate to extract twice, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 659 mg of the product.

[0347] Synthesis of intermediate int12:

[0348]

[0349] 1. Synthesis of C12-2

[0350] C12-1 (5.0 g, 1.0 eq) was dissolved in tetrahydrofuran (50 mL), sodium hydride (1.23 g, 1.1 eq) was added under ice-water bath, and the reaction was stirred at room temperature for 0.5 h, and then iodomethane (1.92 mL, 1.1 eq) in tetrahydrofuran was added to the reaction solution, and then stirred at room temperature for 2 h. After the reaction was completed, water was added under ice-water bath to quench the reaction, and then extracted with ethyl acetate twice, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 5.20 g of product.

[0351] 2. Synthesis of C12-3

[0352] C12-2 (5.2 g, 1.0 eq) was dissolved in methanol (50 mL), and then a methanol solution of potassium hydroxide (1.67 g, 1.1 eq) was added. After stirring at room temperature for 4 h, benzylamine (8.69 g, 3.0 eq) was added to the reaction solution, and the temperature was raised to 55°C, and the reaction was stirred for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then water was added to dissolve it, and the pH was adjusted to acidic with a 5N hydrochloric acid solution, and then ethyl acetate was added for extraction twice, and the ethyl acetate phase was dried with anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to obtain 4.93 g of the product.

[0353] 3. Synthesis of C12-4

[0354] C12-3 (4.93 g, 1.0 eq) was added to a three-necked flask, anhydrous tetrahydrofuran (50 mL) was added, nitrogen was protected, the temperature was cooled to 0°C, borane dimethyl sulfide (43 mL, 4.0 eq) was added dropwise, and the mixture was stirred at room temperature for 4 h, and then the temperature was raised to 65°C and stirred for 16 h. After the reaction was completed, the temperature was lowered to 0°C, water was added dropwise to quench until no foam was generated, and then 5N hydrochloric acid solution was added to adjust the pH to acidic, ethyl acetate was added to extract twice, and then the aqueous phase was adjusted to alkaline with 50% sodium hydroxide solution, and ethyl acetate was added to extract twice. After the ethyl acetate phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain 4.12 g of the product.

[0355] 4. C12 synthesis

[0356] C12-4 (610 mg, 1.0 eq) was dissolved in methanol (10 mL), and then Pd / C (305 mg) and ammonium formate (1.95 g, 10.0 eq) were added. The mixture was stirred at 65 ° C for 16 h under nitrogen protection. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure, and then water was added to dissolve the mixture. A 5N hydrochloric acid solution was added to adjust the pH to acidic. Ethyl acetate was added to extract the mixture twice, and then the aqueous phase was adjusted to alkaline with a 50% sodium hydroxide solution. Then, a tetrahydrofuran solution of di-tert-butyl dicarbonate (1.01 g, 1.5 eq) was added and the mixture was reacted at room temperature for 2 h. After the reaction was completed, ethyl acetate was added to extract the mixture twice, and the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 472 mg of the product.

[0357] Synthesis of intermediate int13:

[0358]

[0359] 1. Synthesis of int13-1

[0360] Dissolve C1-4 (4.95 g, 1.0 eq) in anhydrous N,N-dimethylformamide (30 mL), cool to 0°C, add 60% sodium hydride (1.78 g, 1.5 eq) in batches and stir for 15 minutes, then add iodoethane (2.87 mL, 1.2 eq), and then stir at room temperature for 1-2 hours. Quench the reaction with ice water at 0°C, and extract the aqueous phase with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Purify the product by silica gel column chromatography to obtain 4.87 g.

[0361] 2. Synthesis of int13-2

[0362] Int13-1 (4.67 g, 1.0 eq) was dissolved in a mixed solvent of tert-butyl alcohol (80 mL) and water (4 mL), and N-bromosuccinimide (12.85 g, 3.0 eq) was added in batches, and the mixture was stirred at room temperature for 1 h. Water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the organic phase was directly spin-dried to obtain 11.38 g of crude product.

[0363] 3. Synthesis of int13-3

[0364] 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, and the reaction solution was stirred at room temperature for 1-2 h. Filtered with diatomaceous earth, the filter cake was washed with ethyl acetate several times, concentrated, and purified by silica gel column chromatography to obtain 5.45 g of the product.

[0365] 4. Synthesis of int13-4

[0366] 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 after stirring for ten minutes, 1,8-diazabicyclo [5.4.0] undec-7-ene (7.89 g, 2.0 eq) was slowly added, and then reacted at room temperature for 0.5 h. The reaction was quenched by adding 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.

[0367] 5. Synthesis of int13-5

[0368] 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), heated to 75 ° C under nitrogen atmosphere, stirred and reacted overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.05 g of the product.

[0369] 6. Synthesis of int13-6

[0370] 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, and the mixture was stirred at room temperature for 3-4 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain 1.54 g of a crude product.

[0371] 7. Synthesis of int13

[0372] 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)imidazole-2-ene (14 mg, 0.02 eq) were added at room temperature, and then stirred at room temperature for 4 h under nitrogen atmosphere. After adding 2N dilute hydrochloric acid aqueous solution 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. Specific embodiment:

[0374] Example 1

[0375]

[0376] The synthetic route and experimental process are as follows:

[0377]

[0378] 1. Synthesis of C1-2

[0379] Add Raney nickel (1.7 g) to a 1000 mL single-mouth bottle and replace water with methanol. Add C1-1 (17 g, 1 eq), methanol (340 mL) and tetrahydrofuran (340 mL) to replace hydrogen. Stir the reaction solution at room temperature for 12 h in a hydrogen atmosphere. Filter the reaction solution, 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.

[0380] 2. Synthesis of C1-3

[0381] 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-mouth bottle. Trimethylsilyl acetylene (8.4 g, 1.50 eq) and bis(triphenylphosphine)palladium dichloride (2 g, 0.05 eq) were added at room temperature to replace nitrogen. React 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. After purification on a silica gel column, 8.4 g of the product was obtained. Ms[M+H] + 239.0.

[0382] 3. Synthesis of C1-4

[0383] Add compound C1-3 (8.3 g, 1.00 eq) and acetonitrile (166 mL) to a 250 mL single-mouth bottle, and add 1 M potassium tert-butoxide tetrahydrofuran solution (52 mL, 1.50 eq) dropwise under an ice bath. React at room temperature for 2 h. Dilute the reaction solution with a large amount of ethyl acetate, wash with water and separate the layers. Wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 5.86 g of the product. Ms[M+H] + 167.1.

[0384] 4. Synthesis of C1-5

[0385] Dissolve C1-4 (5.76 g, 1.00 eq) in ultra-dry N,N-dimethylformamide (58 mL), cool to 0 degrees Celsius, add 60% sodium hydride (2.08 g, 1.50 eq), and react for 30 minutes in an ice bath. Then, add iodomethane (5.91 g, 1.2 eq) dropwise at the same temperature. React at room temperature for 1 hour. 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. Obtain 6.35 g of crude product. Ms[M+H] + 181.0.

[0386] 5. Synthesis of C1-6

[0387] Add compound C1-5 (6.35 g, 1.00 eq), sodium bicarbonate (8.9 g, 3.00 eq) and tert-butyl alcohol (127 mL) to a 250 mL single-mouth bottle and stir at room temperature for 10 min. Slowly add bromine (34 g, 6.00 eq) dropwise. React at room temperature for 1 h. Add water to quench the reaction, 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 8.8 g of the product. Ms[M+H] + 352.9.

[0388] 6. Synthesis of C1-7

[0389] 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. React at room temperature for 15 minutes. Add methanol to the reaction solution for dilution, filter and wash the filter residue with methanol. Concentrate the filtrate under reduced pressure and purify it on a silica gel column to obtain 5.47 g of the product. Ms[M+H] + 197.0.

[0390] 7. Synthesis of C1-8

[0391] Dissolve 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) in dichloromethane (55 mL), stir at room temperature for 3 min, and slowly drop 1,8-diazabicyclo [5.4.0] undec-7-ene (8.5 g, 2.00 eq) into the system. React at room temperature for 10 min. Add saturated ammonium chloride aqueous solution to the reaction solution, separate the layers, and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 2.56 g of the product. Ms[M+H] + 223.0.

[0392] 8. Synthesis of C1-9

[0393] C1-8 (2.5 g, 1.00 eq) and carbon tetrachloride (50 mL) were added to a 250 mL flask and stirred to dissolve. Azobisisobutyronitrile (185 mg, 0.10 eq) was added. Then N-bromosuccinimide (2.2 g, 1.1 eq) was added and reacted at 75 degrees for 2 hours under nitrogen protection. The system was vacuum concentrated until no liquid was distilled out. The product 2 g was prepared by thin layer chromatography, [M+H] + 301.0.

[0394] 9. Synthesis of C1-10

[0395] Dissolve N-Boc-trans-3-aminocyclobutanol (1.373 g, 1.10 eq) in ultra-dry tetrahydrofuran (20 mL), cool to 0 degrees Celsius, add 60% sodium hydride (0.29 g, 1.10 eq), and react for 30 minutes under ice bath. Slowly add tetrahydrofuran (20 mL) of C1-9 (2 g, 1.0 eq) to the reaction system and react at room temperature for 1.5 hours. Quench the reaction with ice water under ice bath, extract the aqueous phase with ethyl acetate, and separate the phases. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on silica gel column to obtain 1.88 g of the product. Ms[M+H] + 408.1.

[0396] 10. Synthesis of C1-11

[0397] 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) were added to a 50 mL flask. The temperature was raised to 100 °C in a nitrogen atmosphere and the reaction was carried out for 1 to 2 hours. The reaction solution was cooled, filtered, concentrated and purified by column chromatography to obtain 0.77 g of the product. Ms[M+H] + 595.3.

[0398] 11. Synthesis of C1-12

[0399] C1-11 (770 mg, 1.00 eq) was added to a 50 mL flask, and dichloromethane (10 mL) was stirred to dissolve. 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 the reaction was allowed to react at room temperature for 30 minutes. Water was added to the system to quench, and the dichloromethane was extracted and separated. The organic phase was washed with a saturated sodium chloride solution and the organic phase was concentrated in vacuo until no liquid was distilled out. Purification by column chromatography gave 0.92 g of the product, [M+H] + 760.3.

[0400] 12. Synthesis of C1-13

[0401] 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 reacted at room temperature for 5 h. The reaction system was concentrated in vacuo until no liquid was distilled out to obtain 0.78 g of the product, [M+H] + 660.3.

[0402] 13. Synthesis of C1-14

[0403] 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 reacted at room temperature for 30 minutes. The reaction system was concentrated in vacuo until no liquid was distilled out, and the product was purified by column chromatography to obtain 0.53 g, [M+H] + 521.3.

[0404] 14. Synthesis of C1

[0405] 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 degrees and the reaction was allowed to proceed for 35 minutes. The reaction system was vacuum concentrated until no liquid was distilled out, and dichloromethane was added to dissolve. The pH of the sodium bicarbonate solution was adjusted to a weak alkaline state, and the liquids were separated. The organic phase was concentrated until no liquid was distilled out, and 30.87 mg of the product was prepared, [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).

[0406] Example 2

[0407]

[0408] The synthetic route and experimental process are as follows:

[0409]

[0410] 1. Synthesis of C2-1

[0411] 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 min. Slowly drop C1-9 (1 g) in tetrahydrofuran (10 mL) into 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 phases. 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.

[0412] 2. Synthesis of C2-2

[0413] 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 temperature was raised to 100 °C in a nitrogen atmosphere and the reaction was carried out for 1 to 2 hours. The reaction was complete. The reaction solution was cooled, filtered, concentrated and purified by column chromatography to obtain 1.0 g of the product. Ms[M+H] + :569.4.

[0414] 3. Synthesis of C2-3

[0415] C2-2 (1 g) was added to a 50 mL flask, and dichloromethane (20 mL) was stirred to dissolve, and 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 dichloromethane was extracted and separated. The organic phase was washed with saturated sodium chloride solution 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.

[0416] 4. Synthesis of C2-4

[0417] 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。 Used directly in the next step reaction.

[0418] 5. Synthesis of C2

[0419] 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 reacted at room temperature for 30 minutes. The reaction system was vacuum concentrated until no liquid was distilled out, and 14.09 mg of the product was prepared by high performance liquid chromatography.

[0420] Ms[M+H] + :439.3 1 H 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).

[0421] Example 3

[0422]

[0423] The synthetic route and experimental process are as follows:

[0424]

[0425] 1. Synthesis of C8-1

[0426] In a 100mL single-mouth bottle, add N-Boc-trans-3-aminocyclobutanol (402mg 1.3eq) and acetonitrile (10ml), stir to dissolve, add NaH (86mg 1.3eq), stir at room temperature for 1h, then add int3 (500mg 1eq), stir at room temperature for 1h. After the reaction is completed, add saturated sodium chloride 20ml to the reaction solution, extract with ethyl acetate (20ml*3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain 450mg purified by column.

[0427] 2. Synthesis of C8-2

[0428] In a 100mL single-necked bottle, C8-1 (340mg), int2 (296mg) and dimethyl sulfoxide (10ml) were added, stirred to dissolve, and potassium tert-butoxide (280mg) was added. The mixture was stirred at room temperature for 20min. After the reaction was completed, saturated sodium chloride (50ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50ml*3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and directly subjected to the next step.

[0429] 3. Synthesis of C8-3

[0430] In a 50 mL three-necked flask, add the above C8-2 methanol (30 mL), water (6 mL), and LiOH (175 mg), and stir at room temperature for 1 h. After the reaction is complete, add 10 mL of water, extract with ethyl acetate (20 mL*5), dry and spin-dry to obtain 230 mg of the purified product.

[0431] 4. Synthesis of C8-4

[0432] 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.

[0433] 5. Synthesis of C8

[0434] C8-4 (130 mg), dichloromethane (5 ml) and TFA (0.5 ml) were added into 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 mixture was reacted 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).

[0435] Example 4

[0436]

[0437] The synthetic route and experimental process are as follows:

[0438] 1. Synthesis of C 19-1

[0439] 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, add 60% sodium hydride (44 mg, 1.10 eq) in batches, and stir at 0°C for 10 min. Then warm to room temperature and 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

[0440] 2. Synthesis of C19-2

[0441] 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), replaced with nitrogen, and heated 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. After purification on a silica gel column, 80 mg of the product was obtained. Ms[M+H] + 583.353, Synthesis of C19-3

[0442] C19-2 (60 mg, 1.00 eq), N-methylmorpholine (104 mg, 10 eq) and dichloromethane (5 mL) were added to a 25 mL single-mouth bottle. A solution of p-nitrochloroformic acid phenyl ester (166 mg, 8 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 10 min. Water was added to the reaction solution, the layers were separated, the aqueous phase was extracted with dichloromethane, and the organic phase was dried and concentrated. Purification by silica gel column gave 70 mg of the product. Ms[M+H] + 748.364, Synthesis of C19-4

[0443] C19-3 (70 mg, 1.00 eq) and trifluoroacetic acid (2 mL) were added to a 25 mL single-mouth 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] + 592.245, Synthesis of C19

[0444] Dissolve compound C19-4 (100 mg, crude) in acetonitrile (3 mL), cool to 0°C, slowly add triethylamine (164 mg, 12.00 eq), and stir at room temperature for 30 min. Dilute the reaction solution with ethyl acetate, and wash the organic phase with 1N sodium hydroxide aqueous solution. Dry and concentrate the organic phase. Purify by preparative chromatography to obtain 3 mg of the product. 1 H NMR (400MHz, DMSO-d6) δppm11.77(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).

[0445] Example 5

[0446]

[0447] The synthetic route and experimental process are as follows:

[0448]

[0449] 1. Synthesis of C20-2

[0450] Add compound C20-1 (600 mg, 1.00 eq) and tetrahydrofuran (20 mL) to a 100 mL three-necked flask, cool to -40 °C, and slowly drop 3M methylmagnesium bromide tetrahydrofuran solution (1.10 mL, 1.30 eq) at -40 °C. Slowly warm to room temperature and react for 1 h. The reaction is complete. Quench the reaction with saturated ammonium chloride solution, extract the aqueous phase with ethyl acetate, and dry and concentrate the organic phase. Purify on a silica gel column to obtain 470 mg of the product. Ms[M+H] + :253.1.

[0451] 2. Synthesis of C20-3

[0452] Dissolve C20-2 (390 mg, 1.00 eq) in N,N-dimethylformamide (15 mL), cool to 0°C, add 60% sodium hydride (93 mg, 1.50 eq) in batches, and stir at 0°C for 30 min. Slowly drop a tetrahydrofuran solution of N-Boc-3-aminopropyl bromide (917 mg, 2.50 eq) 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.

[0453] 3. Synthesis of C20-4

[0454] 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), nitrogen was replaced, and the temperature was raised to 100 ° C for 2 h. The reaction was complete. 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. After purification on a silica gel column, 480 mg of the product was obtained.

[0455] 4. Synthesis of C20-5

[0456] C20-4 (480 mg, 1.00 eq), N-methylmorpholine (407 mg, 5 eq) and dichloromethane (13 mL) were added to a 50 mL single-mouth bottle. A solution of p-nitrochloroformic acid phenyl ester (648 mg, 4 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 10 min. The reaction was complete. Water was added to the reaction solution, the layers were separated, the aqueous phase was extracted with dichloromethane, and the organic phase was dried and concentrated. After purification on a silica gel column, 500 mg of the product was obtained.

[0457] 5. Synthesis of C20-6

[0458] C20-5 (450 mg, 1.00 eq) and trifluoroacetic acid (5 mL) were added to a 25 mL single-necked bottle and the temperature was raised to 80 °C for 1.5 h. The reaction was complete. The reaction solution was cooled and concentrated and used directly in the next step.

[0459] 6. Synthesis of C20-7

[0460] Dissolve compound C20-6 (600 mg, crude) in acetonitrile (20 mL), cool to 0°C, slowly add triethylamine (717 mg, 12.00 eq), and stir at room temperature for 30 min. The reaction is complete. Dilute the reaction solution with ethyl acetate, and wash the organic phase with 1N sodium hydroxide aqueous solution. Dry and concentrate the organic phase. Purify on a thin layer chromatography plate to obtain 70 mg of the product.

[0461] 7. Preparation of C20 and C21

[0462] Compound C20-7 (70 mg) was prepared by chiral high performance liquid chromatography separation under the following conditions:

[0463] Column: Phenomenex 5 μm Amylose-1 (250×21.2 mm), mobile phase: n-hexane:ethanol=6:4, solvent: isopropanol, running time: 26 min.

[0464] The peak time of the front peak C20 was 13.0min. After concentration and freeze-drying, 19mg of the product was obtained.

[0465] 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.

[0466] The peak time of the latter peak C21 was 23.4 min. After concentration and freeze-drying, 17 mg of the product was obtained.

[0467] 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.

[0468] Example 6

[0469]

[0470] The synthetic route and experimental process are as follows:

[0471] 1. Synthesis of C37-1

[0472] Dissolve C1-9 (800 mg, 1.0 eq) in acetonitrile (15 mL), then add sodium trifluoromethanesulfonate (622 mg, 1.5 eq), protect with nitrogen, stir at 80°C for 18 h. The reaction is complete. Filter, concentrate the filtrate under reduced pressure. Purify by silica gel column chromatography to obtain 811 mg of the product.

[0473] 2. Synthesis of C37-2

[0474] C37-1 (811 mg, 1.0 eq) was dissolved in N,N-dimethylformamide (15 mL), and then N-fluorobisbenzenesulfonamide (1.58 g, 2.2 eq) and potassium phosphate (2.4 g, 5.0 eq) were added, and the mixture was stirred at 25°C for 2 h. Saturated aqueous ammonium chloride solution was added to the reaction solution and stirred for 0.5 h, and then ethyl acetate was added for extraction twice. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification on a silica gel column, 697 mg of the product was obtained.

[0475] 3. Synthesis of C37-3

[0476] Dissolve C37-2 (636 mg, 1.0 eq) in acetonitrile (10 mL), then add lithium bromide (1.13 g, 8.0 eq), protect with nitrogen, and react at 35 ° C for 16 h. Add water to the reaction solution, extract twice with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify on a silica gel column to obtain 284 mg of the product.

[0477] 4. Synthesis of C37-4

[0478] 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 the mixture was stirred at 30°C for 16 h. Water was added to the reaction solution to quench the mixture, and ethyl acetate was added to extract the mixture twice. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 46 mg of the product was obtained after purification on a silica gel column.

[0479] 5. Synthesis of C37-5

[0480] 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), nitrogen was replaced, 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. After purification on a silica gel column, 56 mg of the product was obtained.

[0481] 6. Synthesis of C37-6

[0482] 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 by silica gel column to obtain 49 mg of the product.

[0483] 7. Synthesis of C37-7

[0484] 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-mouth bottle. Phenyl chloroformate (61 mg, 4.0 eq) was added to the reaction solution at room temperature, and the reaction solution was stirred for 1 min. Saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the layers were separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. After purification on a thin layer chromatography preparative plate, 60 mg of the product was obtained.

[0485] 8. Synthesis of C37-8

[0486] C37-7 (60 mg, 1.0 eq) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2 h. The mixture was directly used for the next reaction.

[0487] 9. Synthesis of C37 and C38

[0488] Triethylamine (2 mL) was added to the reaction solution of C37-8 and stirred at room temperature for 3 h. Liquid quality monitoring showed that the raw material reacted completely. Water was added to the reaction solution and extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After purification on a thin layer chromatography preparative plate, products C38 (1.12 mg) and C37 (3.2 mg) were obtained.

[0489] Example 7

[0490]

[0491] The synthetic route and experimental process are as follows:

[0492]

[0493] 1. Synthesis of C41-1

[0494] NaH (53 mg, 1.2 eq) was dissolved in dimethyl sulfoxide (15 mL), and trimethyl sulfoxide iodide (338 mg, 1.4 eq) was added in batches at room temperature. After addition, the mixture was reacted 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 reacted 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. After purification on a thin layer chromatography preparative plate, 150 mg of the product was obtained.

[0495] 2. Synthesis of C41-2

[0496] 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 obtain 155 mg of a crude product.

[0497] 3. Synthesis of C41-3

[0498] Dissolve C41-2 (155 mg, 1.0 eq) and imidazole (99 mg, 2.5 eq) in N,N-dimethylformamide (5 mL), cool to 0°C, add TBDPSCl (97 g, 1.1 eq) at 0°C in one portion, and naturally warm to room temperature for 16 h. Quench the reaction with ice water at 0°C, and extract the aqueous phase with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a thin layer chromatography preparative plate to obtain 215 mg of the product.

[0499] 4. Synthesis of C41-4

[0500] Dissolve C41-3 (215 mg, 1.0 eq) in N, N-dimethylformamide (10 mL), cool to 0°C, add 60% sodium hydride (33.7 mg, 1.5 eq) in batches at 0°C, react at 0°C for 1 h, add dropwise N-(3-bromopropyl)carbamic acid tert-butyl ester (332.6 mg, 2.5 eq) in N, N-dimethylformamide (2.5 mL), add dropwise, and the reaction solution is naturally warmed to room temperature and stirred for 16 h. Quench the reaction with ice water at 0°C, and extract twice with ethyl acetate. Combine the organic phases, dry, filter, and concentrate under reduced pressure. Purify on a thin layer chromatography preparative plate to obtain 210 mg of the product.

[0501] 5. Synthesis of C41-5

[0502] C41-4 (210 mg, 1.0 eq) and tetrahydrofuran (16 mL) were added to a 50 mL single-mouth bottle. A tetrahydrofuran solution of tetrabutylammonium fluoride (1.15 mL, 3.0 eq) was added dropwise at room temperature. After addition, the mixture was reacted at room temperature for 1 h. After the reaction solution was cooled to 0°C, it was quenched with saturated ammonium chloride, extracted twice with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated under reduced pressure. Purification on a thin layer chromatography preparative plate gave 130 mg of the product.

[0503] 6. Synthesis of C41-6

[0504] C41-5 (130 mg, 1.0 eq) and tetrahydrofuran (13 mL) were added to a 50 mL single-mouth bottle, and diethylaminosulfur trifluoride (496.5 mg, 4.0 eq) was added dropwise at 0°C. After addition, the mixture was reacted at room temperature for 16 h. After the reaction solution was cooled to 0°C, it was quenched with saturated ammonium chloride, extracted twice with ethyl acetate, and the organic phases were combined, dried, filtered, and concentrated under reduced pressure. After purification on a thin layer chromatography preparative plate, 76 mg of the product was obtained.

[0505] 7. Synthesis of C41-7

[0506] 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), replaced with nitrogen, and heated 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. After purification on a thin layer chromatography preparative plate, 115 mg of the product was obtained.

[0507] 8. Synthesis of C41-8

[0508] C41-7 (115 mg, 1.0 eq) was added to methanol (4 mL), and LiOH.H2O was added dropwise at room temperature.

[0509] (20 mg, 3.0 eq) water (1.3 mL) solution, add dropwise, heat to 35 ° C for 2 h. Cool to room temperature, add saturated sodium chloride and ethyl acetate to the reaction solution, separate the liquids, extract the aqueous phase with ethyl acetate once, combine the organic phases, dry, filter, and concentrate under reduced pressure. The crude product 103 mg was obtained, which was used directly in the next step without purification.

[0510] 9. Synthesis of C41-9

[0511] C41-8 (103 mg, 1.0 eq), N-methylmorpholine (81 mg, 5.0 eq) and dichloromethane (6 mL) were added to a 50 mL single-mouth bottle, and p-nitrophenyl chloroformate (129.3 mg, 4.0 eq) was added at room temperature all at once, and the reaction solution was stirred at room temperature for 20 min. Saturated sodium bicarbonate aqueous solution was added to the reaction solution at 0°C, the layers were separated, the aqueous phase was extracted once with dichloromethane, the organic phases were combined, washed 5 times with saturated sodium bicarbonate, dried, filtered, concentrated, and purified on a thin layer chromatography preparative plate to obtain 102 mg of the product.

[0512] 10. Synthesis of C41-10

[0513] 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 continued at room temperature for 4 h. The product was used directly in the next step without purification.

[0514] 11. Synthesis of C41-11

[0515] The untreated solution was cooled to 0°C, and triethylamine (2 mL) was added dropwise. After the addition was completed, the temperature was naturally raised to room temperature and the mixture was reacted for 4 h. Saturated sodium bicarbonate and dichloromethane were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted once with dichloromethane, and the organic phases were combined, dried, filtered, concentrated, and purified on a thin layer chromatography preparative plate to obtain 42 mg of the product.

[0516] 12. Synthesis of C41 and C42

[0517] C41-11 was prepared by chiral HPLC separation under the following conditions: Chromatographic column: Phenomenex 5μm Amylose-1 (250X 21.2mm), mobile phase: n-hexane: ethanol = 6:4, solvent: isopropanol, running time: 31min. C41 (8.2mg) was obtained, and the peak time was 12.7min 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);

[0518] 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).

[0519] Example 8

[0520] Compounds of the present invention

[0521]

[0522] The synthetic route and experimental process are as follows:

[0523]

[0524] Synthesis of C65-2

[0525] Dissolve C65-1 (486.8 mg, 1.1 eq) and C1-9 (254 mg, 1.0 eq) in N,N-dimethylformamide (12 mL), cool to 0°C, and add 60% sodium hydride (84.4 mg, 2.5 eq) in batches at 0°C. The reaction solution is heated to room temperature and stirred for 20 min. Liquid quality monitoring shows that the raw materials react completely. Quench the reaction with ice water at 0°C, and extract the aqueous phase with ethyl acetate. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Purify on a silica gel column to obtain 362 mg of the product. MS

[0526] [M+1] + :422.2,424.2

[0527] Synthesis of C65-3

[0528] 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), replaced with nitrogen, and heated to 100 ° C for 2 h. Liquid quality monitoring showed that the raw materials reacted completely. 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. The product was 340 mg after purification by silica gel column.

[0529] MS[M+1] +:609.4

[0530] Synthesis of C65-4

[0531] 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-mouth bottle. A solution of p-nitrochloroformic acid phenyl ester (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 quality monitoring showed that the raw material reacted completely. Saturated sodium bicarbonate aqueous solution was added to the reaction solution at 0°C, the layers were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. 397 mg of the product was obtained after purification on a thin layer chromatography preparative plate. MS [M+1] + :774.4

[0532] Synthesis of C65-5

[0533] Add C65-4 (390 mg, 1.0 eq) and trifluoroacetic acid (20 mL) to a 50 mL single-mouth bottle. Heat to 80 °C and react for 2 h. Liquid quality monitoring showed that the raw material reacted well. Cool the reaction solution, concentrate it and use it directly in the next step. MS [M+1] + :606.3

[0534] Synthesis of C65

[0535] Compound C65-5 (445 mg, 1.0 eq) was dissolved in dichloromethane (20 mL), triethylamine (1.34 g, 12.00 eq) was added, and the mixture was stirred at room temperature for 16 h. Liquid quality monitoring showed that the raw material 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, and the solid was slurried with 20 mL (petroleum ether: ethyl acetate = 3:1) to obtain 72 mg of C1. MS [M+1] + :479.2.

[0536] 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).

[0537] The following compounds were synthesized using the above synthesis method:

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552] Cell proliferation inhibition assay

[0553] 1. Experimental Materials

[0554] Cell lines supplier OVCAR3 Beina Biotechnology TOV21G Beina Biotechnology

[0555] 2. Experimental plan

[0556] 1. Cell plating

[0557] a) Preparation of cell suspension

[0558] b) removing the culture medium from the culture flask;

[0559] c) Rinse the cells once with PBS;

[0560] d) digest with trypsin and collect by centrifugation;

[0561] e) Resuspend in culture medium, count and adjust to appropriate concentration.

[0562] f) Add the cell suspension to a 96-well plate at a volume of 80 μL per well, place one plate for each cell type, and culture overnight in a 37°C, 5% CO2 incubator.

[0563] 2. Compound treatment

[0564] Compound dilution

[0565] a) Preparation of gradient dilution solutions of the test compounds: Palbociclib and the example compounds were prepared at 10 mM as stock solutions. Then 2.5 μL of the stock solution was dissolved in 497.5 μL of DMSO-free culture medium, and then 3-fold continuous gradient dilutions were performed with 0.1% DMSO culture medium, for a total of 9 concentrations. The compound concentrations after dilution were as follows:

[0566] 10000nM, 3333.33nM, 1111.11nM, 370.34nM, 123.45nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM

[0567] b) After thorough mixing, 20 μL of the culture compound solution was added to the cell culture plate containing 80 μL of cells, with 4 replicate wells for each concentration.

[0568] c) Transfer the cells to an incubator and incubate for 5 days.

[0569] 3. MTT assay

[0570] a) Take out the cell culture plate and add 10μL of 5mg / ml MTT into the hood.

[0571] b) Place the cell culture plate back into the incubator and continue incubating for 3 hours

[0572] c) Take out the cell culture plate and remove the culture medium, add 100uL of isopropanol (0.4mM HCl, 0.4% NP40), shake at room temperature for 30 minutes, and read the plate at 570nm.

[0573] 4. Data Analysis

[0574] The survival rate (%Cell Survival) was calculated using the following formula:

[0575] %Cell Survival=100%×(OD_Sample-OD_LCave) / (OD_HC-OD_

[0576] LCave)

[0577] OD_HC: 0.1‰ DMSO control group cell reading

[0578] OD_Sample: Cell reading after adding compound

[0579] OD_LC: Blank culture medium reading

[0580] Analyzed by Prizm:Dose-response-Inhibition-Log(inhibitor) vs response(three parameters for the best fit).

[0581] The results of the cell proliferation inhibition test are shown in Table 1.

[0582] Table 1

[0583]

[0584]

[0585]

[0586] The cell proliferation activity values ​​in the table are represented by A, B, C, and D, wherein A≤500nM, 500nM<B≤1000nM, 1000nM<C≤3000nM, and 3000nM<D.

[0587] The experimental results show that: for the CyclinE amplified cell line OVCAR3, the example compounds showed a good inhibitory effect, while for the non-CyclinE amplified cell line TOV21G, the example compounds had no obvious inhibitory effect, showing good selectivity of the compounds.

[0588] Enzyme activity test

[0589] Prepare the compound:

[0590] 1. Prepare the test compound into 0.5 nM DMSO solution;

[0591] 2. Use Echo550 to transfer 20 μL of the stock solution to a 384-well plate. Use DMSO as a blank control.

[0592] Experimental steps:

[0593] 1. Prepare 1.3X enzyme solution containing enzyme, substrate, and coenzyme factor according to the table below;

[0594] 2. Add 15uL of 1.3x enzyme solution to each well and incubate at room temperature for 30 minutes;

[0595] 3. Add 5 μL of 4x ATP solution to start the reaction. The final volume of each well is 20 μL;

[0596] 4. After incubation at room temperature for 150 min, add 75 μL of stop buffer solution to terminate the experiment;

[0597] 5. Analyze samples using EZ reader.

[0598]

[0599] Data Analysis:

[0600] Calculate the % inhibition using the following equation

[0601] The positive control (PC) was treated with DMSO

[0602] The negative control (NC) was without enzyme.

[0603] % inhibition rate = 100-100*((CR PC -CR sample ) / (CR PC -CR NC ))

[0604] Table 2

[0605] Compound CDK1(nM) CDK2(nM) C1 18 0.2 C65 15 2.1

[0606] The experimental results show that the compounds of the present invention have excellent selectivity and activity for CDK2 kinase.

[0607] The present invention provides a series of compounds with excellent CDK2 kinase activity and selectivity. The series of compounds have good inhibitory effects on excessive cell proliferation caused by abnormal expression or amplification of CyclineE and have broad application prospects.

[0608] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

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-, -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 , 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 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 by 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, 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- 4NR 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 SO2R 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-, a 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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