A class of tricyclic compounds and their preparation and applications

Abstract

This invention relates to a class of tricyclic compounds and their preparation and applications. Specifically, the compounds of this invention have the structure shown in formula (I), wherein the definitions of each group and substituent are as described in the specification. This invention also discloses methods for preparing the compounds and their uses in regulating CDK2 kinase activity and / or preventing and / or treating CDK2-related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a class of tricyclic compounds used as CDK2 kinase inhibitors, and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to their uses, as well as their applications in regulating CDK2 kinase activity or preventing and / or treating CDK2-related diseases. Prior Art

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

[0003] Heterodimerization of CDKs with regulatory subunits (cyclins) enables their full activation and regulation of key cellular processes, including cell cycle progression and cell division. Uncontrolled proliferation is a hallmark of cancer cells. Aberrant regulation of CDK activity is associated with dysregulation of the cell cycle and is detected in nearly all forms of human cancer.

[0004] CDK2 plays a crucial role in the G1 / S transition and S phase progression. CDK2, in conjunction with the cyclin E (CCNE) complex, phosphorylates members of the retinoblastoma pocket protein family (p107, p130, and pRb), releasing the E2F transcription factor and promoting the G1 to S phase transition. This in turn activates CDK2 / cyclin A, phosphorylating endogenous substrates to allow DNA synthesis, replication, and centrosome duplication. The CDK2 pathway has been reported to influence tumorigenesis primarily through amplification and / or overexpression of CCNE1 and mutational inactivation of endogenous CDK2 inhibitors, such as p27.

[0005] Increased copy number and overexpression of CCNE1 have been demonstrated in ovarian, gastric, endometrial, breast, and other tumors and are associated with poor prognosis. CCNE1 amplification and / or overexpression have also been reported to contribute 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 growth.

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

[0007] The object of the present invention is to provide a compound represented by formula (I), a preparation method thereof, and use thereof as a CDK2 kinase inhibitor drug.

[0008] The first aspect of the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, in: Ring A is a saturated or partially saturated 5-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N, O or S; Ring B is selected from the following groups: C 5-6 aryl, 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; Each Ra, Rc, and Rd are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, =O, C1-4alkyl, C1-4heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C1-4alkyl, deuterated C1-4alkyl, halogenated C1-4heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C1-4alkoxy, halogenated C1-4alkoxy, and C3-4cycloalkyl; is a single bond or a double bond; p, q, t, w are each independently selected from the following group: 0, 1, 2, 3, 4; s is selected from the following groups: 1, 2; R 1 is selected from the following groups: -CONR 2R 3, -COOR 2, a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or a 7-10 membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl group, the 5-6 membered monocyclic heteroaryl group, or the 7-10 membered bicyclic heteroaryl group is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 R 4; X 1 is selected from the following group: CH 2, O; or X 1 is absent, such that Forming a four-membered cyclobutyl group ( ); X 2 is selected from the group consisting of O, -CH 2O-, NH, -CH 2NH-; R2 and R3 are each independently selected from the following group: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L-(C3-12 cycloalkyl), -L-(3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S), wherein the C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, =0, amino, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, -S(O)2-C1-4 alkyl, Alternatively, R 2 and R 3 together with the N to which they are attached form a 3-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-7 membered heterocycloalkyl group is 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, and halogenated C 1-4 alkoxy; L is a bond or C 1-6 alkylene, wherein the C 1-6 alkylene is optionally substituted by 0, 1, 2 or 3 substituents selected from the group consisting of deuterium, =O, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; Each R 4 is independently selected from the following group: deuterium, hydroxyl, halogen, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -SO 2R 5, -SO 2(NR 5R 6), -CO(OR 5), -CO(NR 5R 6), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, =O, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; R 5, R 6 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl; Each R 7 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl, and halogenated C 1-4 alkyl.

[0009] In another preferred embodiment, Selected from the following group: Each R a1, R b1, R c1, R d1 is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, =O, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-4 alkoxy, halogenated C 1-4 alkoxy, C 3-4 cycloalkyl; n, m, and r are each independently selected from the following group: 0, 1, 2, and 3.

[0010] In another preferred embodiment, the compound has a structure selected from the group consisting of: Among them, ring A, ring B, R 1, Ra, R c, R d, , p, q, t are as defined in claim 1.

[0011] In another preferred embodiment, the compound has a structure selected from the group consisting of: Among them, ring A, ring B, Ra, Rc, Rd, , p, q, t as defined in claim 1; R2 and R3 are each independently selected from the following group: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L-(C3-12 cycloalkyl), -L-(3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S), wherein the C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, =0, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, Alternatively, R 2 and R 3 together with the N to which they are attached form a 3-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-7 membered heterocycloalkyl group is 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, and halogenated C 1-4 alkoxy; L as defined in claim 1; Ring C is selected from the following group: a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or a 7-10 membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl group, the 5-6 membered monocyclic heteroaryl group, or the 7-10 membered bicyclic heteroaryl group is substituted by 0, 1, 2, 3, 4, 5 or 6 R 4 ; Each R 4 is independently selected from the following group: deuterium, hydroxyl, halogen, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -SO 2R 5, -SO 2(NR 5R 6), -CO(OR 5), -CO(NR 5R 6), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, =O, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; R 5 and R 6 are each independently selected from the following group: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, and halogenated C 1-4 alkyl.

[0012] In another preferred embodiment, the compound has a structure selected from the group consisting of: Among them, ring A, ring B, Ra, Rc, Rd, , p, q, t as defined in claim 1; R2 and R3 are each independently selected from the following group: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L-(C3-12 cycloalkyl), -L-(3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S), wherein the C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, =0, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, Alternatively, R 2 and R 3 together with the N to which they are attached form a 3-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-7 membered heterocycloalkyl group is 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, and halogenated C 1-4 alkoxy; L as defined in claim 1; Ring C is selected from the following group: a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or a 7-10 membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl group, the 5-6 membered monocyclic heteroaryl group, or the 7-10 membered bicyclic heteroaryl group is substituted by 0, 1, 2, 3, 4, 5 or 6 R 4 ; Each R 4 is independently selected from the following group: deuterium, hydroxyl, halogen, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -SO 2R 5, -SO 2(NR 5R 6), -CO(OR 5), -CO(NR 5R 6), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, =O, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; R 5 and R 6 are each independently selected from the following group: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, and halogenated C 1-4 alkyl.

[0013] In another preferred embodiment, Preferably .

[0014] In another preferred embodiment, Preferably .

[0015] In another preferred embodiment, Preferably .

[0016] In another preferred embodiment, Preferably .

[0017] In another preferred embodiment, Preferably .

[0018] In another preferred embodiment, Preferably .

[0019] In another preferred embodiment, Preferably .

[0020] In another preferred embodiment, Preferably .

[0021] In another preferred embodiment, Preferably .

[0022] In another preferred embodiment, Preferably .

[0023] In another preferred embodiment, Preferably .

[0024] In another preferred embodiment, Preferably .

[0025] In another preferred embodiment, Preferably .

[0026] In another preferred embodiment, Preferably .

[0027] In another preferred embodiment, Preferably .

[0028] In another preferred embodiment, Preferably .

[0029] In another preferred embodiment, Preferably .

[0030] In another preferred embodiment, the compound has a structure selected from the group consisting of: in, R 1 is selected from the following group: -CONR 2R 3, a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or a 7-10 membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl group, the 5-6 membered monocyclic heteroaryl group, or the 7-10 membered bicyclic heteroaryl group is substituted by 0, 1, 2, 3, 4, 5 or 6 R 4 ; R2 and R3 are each independently selected from the following group: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L-(C3-12 cycloalkyl), -L-(3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S), wherein the C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, =0, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, Alternatively, R 2 and R 3 together with the N to which they are attached form a 3-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-7 membered heterocycloalkyl group is 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, and halogenated C 1-4 alkoxy; L as defined in claim 1; Each R 4 is independently selected from the following group: deuterium, hydroxyl, halogen, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -SO 2R 5, -SO 2(NR 5R 6), -CO(OR 5), -CO(NR 5R 6), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, =O, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; R 5, R 6 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl; R a1 is selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 3-4 cycloalkyl; Each R c1 is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, =O, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halo C 1-4 alkyl, halo C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-4 alkoxy, halo C 1-4 alkoxy; Each R d1 is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-4 alkyl, halogenated C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-4 alkoxy, halogenated C 1-4 alkoxy; m and r are each independently selected from the following group: 0, 1, 2, 3.

[0031] In another preferred embodiment, R a1 is selected from the following group: C 1-4 alkyl, deuterated C 1-4 alkyl.

[0032] In another preferred embodiment, each R c1 is independently selected from the following group: hydrogen, halogen, hydroxyl, =0.

[0033] In another preferred embodiment, each R d1 is independently selected from the following group: hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl.

[0034] In another preferred embodiment, the compound has a structure selected from the group consisting of: in, R 1 is selected from the following group: -CONR 2R 3, a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or a 7-10 membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl group, the 5-6 membered monocyclic heteroaryl group, or the 7-10 membered bicyclic heteroaryl group is substituted by 0, 1, 2, 3, 4, 5 or 6 R 4 ; R2 and R3 are each independently selected from the following group: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L-(C3-12 cycloalkyl), -L-(3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S), wherein the C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, =0, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, Alternatively, R 2 and R 3 together with the N to which they are attached form a 3-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-7 membered heterocycloalkyl group is 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, and halogenated C 1-4 alkoxy; L as defined in claim 1; Each R 4 is independently selected from the following group: deuterium, hydroxyl, halogen, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -SO 2R 5, -SO 2(NR 5R 6), -CO(OR 5), -CO(NR 5R 6), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, =O, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; R 5, R 6 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl; R a1 is selected from the group consisting of: hydrogen, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S; Each R c1 is independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, cyano, =O, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halo C 1-4 alkyl, halo C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-4 alkoxy, halo C 1-4 alkoxy; Each R d1 is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-4 alkyl, halogenated C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-4 alkoxy, halogenated C 1-4 alkoxy; m and r are each independently selected from the following group: 0, 1, 2, 3.

[0035] In another preferred embodiment, R 1 is -CONR 2R 3.

[0036] In another preferred embodiment, R 1 is a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S.

[0037] In another preferred embodiment, R 1 is a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S.

[0038] In another preferred embodiment, R a1 is selected from the following group: C 1-4 alkyl, deuterated C 1-4 alkyl.

[0039] In another preferred embodiment, R a1 is -CH 3.

[0040] In another preferred embodiment, Ra1 is -CD3.

[0041] In another preferred embodiment, R c1 is selected from the following group: hydrogen, halogen, hydroxyl, =0.

[0042] In another preferred embodiment, R c1 is hydrogen.

[0043] In another preferred embodiment, R c1 is halogen.

[0044] In another preferred embodiment, R c1 is F.

[0045] In another preferred embodiment, R c1 is ═O.

[0046] In another preferred embodiment, R d1 is selected from the following group: hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl.

[0047] In another preferred embodiment, R d1 is hydrogen.

[0048] In another preferred embodiment, R d1 is -CH 3.

[0049] In another preferred embodiment, R d1 is -CF 3.

[0050] In another preferred embodiment, R d1 is -CHF 2.

[0051] In another preferred embodiment, m is 0.

[0052] In another preferred embodiment, m is 1.

[0053] In another preferred embodiment, m is 2.

[0054] In another preferred embodiment, r is 0.

[0055] In another preferred embodiment, r is 1.

[0056] In another preferred embodiment, the compound has a structure selected from the group consisting of: in, R 1 is selected from the following group: -CONR 2R 3, a 3-6 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, a 5-6 membered monocyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or a 7-10 membered bicyclic heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the 3-6 membered heterocycloalkyl group, the 5-6 membered monocyclic heteroaryl group, or the 7-10 membered bicyclic heteroaryl group is substituted by 0, 1, 2, 3, 4, 5 or 6 R 4 ; R2 and R3 are each independently selected from the following group: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L-(C3-12 cycloalkyl), -L-(3-12 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S), wherein the C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3 or 4 substituents selected from the following group: deuterium, hydroxyl, halogen, cyano, =0, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, Alternatively, R 2 and R 3 together with the N to which they are attached form a 3-7 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the 3-7 membered heterocycloalkyl group is 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, and halogenated C 1-4 alkoxy; L as defined in claim 1; Each R 4 is independently selected from the following group: deuterium, hydroxyl, halogen, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, deuterated C 1-6 alkyl, C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -SO 2R 5, -SO 2(NR 5R 6), -CO(OR 5), -CO(NR 5R 6), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, halogenated C 1-6 alkyl, halogenated C 1-6 heteroalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, =O, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy; R 5, R 6 are each independently selected from the group consisting of: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl; Each R d1 is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, halogenated C 1-4 alkyl, halogenated C 1-4 heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C 1-4 alkoxy, halogenated C 1-4 alkoxy; r is selected from the following group: 0, 1.

[0057] In another preferred embodiment, the structure Selected from the following group: 、 、 .

[0058] In another preferred embodiment, each R d1 is independently selected from the following group: hydrogen, C 1-4 alkyl, and halogenated C 1-4 alkyl.

[0059] In another preferred embodiment, the compound is selected from the following group: .

[0060] The second aspect of the present invention provides a pharmaceutical composition comprising a preventively and / or therapeutically effective amount of one or more compounds described in the first aspect of the present invention and a pharmaceutically acceptable carrier.

[0061] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a medicament for regulating CDK activity or for preventing and / or treating CDK-related diseases.

[0062] In another preferred embodiment, the CDK is CDK2.

[0063] In another preferred embodiment, the CDK-related disease is a disease in which CDK2 is highly expressed.

[0064] In another preferred embodiment, the CDK-related disease is a disease caused by abnormal expression or amplification of Cyclin E.

[0065] In another preferred embodiment, the CDK-related disease is cancer.

[0066] In another preferred embodiment, the cancer is a cancer caused by abnormal expression or amplification of Cyclin E.

[0067] In another preferred embodiment, 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, and pediatric tumor.

[0068] The fourth aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a medicament for preventing and / or treating cell cycle protein-related diseases.

[0069] In another preferred embodiment, the cell cycle protein is cyclin E.

[0070] In another preferred embodiment, the cyclin E is selected from the following group: cyclin E1 and cyclin E2.

[0071] In another preferred embodiment, the cell cycle protein-related disease is cancer.

[0072] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. Implementation Method

[0073] After extensive and intensive research, the inventors unexpectedly developed a class of tricyclic compounds with excellent CDK kinase inhibitory activity. Specifically, through structural optimization, the inventors obtained a class of compounds with excellent selective CDK2 inhibitory activity. Based on this, the inventors completed the present invention. [the term]

[0074] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0075] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0076] In the present invention, "C 1-6 alkyl" refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or the like. The term "C 1-4 alkyl" has a similar meaning.

[0077] In the present invention, the term "C 3-12 cycloalkyl" refers to a cyclic alkyl group having 3-12 carbon atoms in the ring, wherein the ring includes C 3-6 monocycloalkyl, C 5-12 bicycloalkyl, C 5-10 bridged ring group, C 6-10 spirocyclic group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, .

[0078] In the present invention, the term "C 1-4 alkoxy" refers to a straight chain or branched chain alkoxy group having 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy.

[0079] In the present invention, the term “C 1-6 alkylene” refers to a straight or branched alkylene structure comprising 1 to 6 carbon atoms, for example, -CH 2-, -CH 2CH 2CH 2-, -CH 2CH 2CH 2CH 2-, -CH 2CH 2CH 2CH 2-, -CH 2CH 2CH 2CH 2CH 2-, -CH 2CH 2CH 2CH 2CH 2-, -CH 2CH 2CH 2CH 2CH 2CH 2-.

[0080] In the present invention, the term "C 1-6 heteroalkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms containing 1 to 4 heteroatoms selected from N, O or S, including but not limited to methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, -CH 2OH, -CH 2NH 2, -CH 2NHCH 3, -CH 2N(CH 3) 2, -CH 2CH 2OCH 3, -CH 2CH 2NHCH 3, -CH 2CH 2N(CH 3) 2, etc. The similar term "C 1-4 heteroalkyl" has a similar meaning.

[0081] In the present invention, the term "deuterated C1-4 alkyl" refers to an alkyl group comprising 1 to 4 carbon atoms in which the hydrogen atoms on the straight or branched carbon atoms are optionally replaced by one, more or all deuterium atoms, for example, -CD3, -CH2CD3, -CH(CH3)CD3, etc.

[0082] In the present invention, the term "heterocycloalkyl" refers to a saturated or partially saturated 3-12 membered heterocycloalkyl group containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. The heterocycle includes a 3-6 membered monocyclic heteroalkyl group, a 5-12 membered bicyclic heteroalkyl group, a 5-10 membered heterobridged ring group, and a 6-10 membered heterospirocyclic group, including (but not limited to) the following groups: 、 、 、 、 、 、 .

[0083] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C 5-6 aryl group". The term "C 5-6 aryl group" refers to an aromatic ring group with 5-6 carbon atoms and no heteroatoms in the ring, such as phenyl.

[0084] In the present invention, the terms "aromatic heterocycle" and "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. For example, a "5- to 6-membered heteroaryl" refers to an aromatic heterocycle containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen, and one to five carbon atoms. Non-limiting examples include furanyl, thienyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, and tetrazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0085] In the present invention, the term "monocyclic heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms and having only one ring. For example, a "5- to 6-membered monocyclic heteroaryl" refers to a monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from O, S, and N, and 1 to 5 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted.

[0086] In the present invention, the term "bicyclic heteroaryl" refers to a heteroaromatic group having two rings and containing one or more heteroatoms. For example, a "7-10 membered bicyclic heteroaryl" refers to a bicyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from O, S, and N and 3 to 9 carbon atoms. Non-limiting examples include: etc. The heteroaryl group may be optionally substituted or unsubstituted.

[0087] In the present invention, the term "halo" means substituted with halogen.

[0088] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Specific substituents are those described above or in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specified group at any substitutable position on the group; the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. Examples of such substituents include (but are not limited to) deuterium, halogen, hydroxyl, cyano, amine, =0, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 halocycloalkyl, 3-10 membered heterocyclyl, aryl, heteroaryl, C2-C10 acyl, and C2-C10 ester groups.

[0089] In the present invention, the term 1-4 refers to 1, 2, 3 or 4. Other similar terms have similar meanings.

[0090] In the present invention, "-CO-" refers to -(C=O)-.

[0091] In the present invention, "-SO2-" refers to .

[0092] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. In other words, the term "selected from the group:" has the same meaning as the term "independently selected from the group:". [Compound]

[0093] The present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, Among them, ring A, ring B, , R 1, R 7, Ra, R c, R d, p, q, t, X 1, X 2, s, and w are as defined above.

[0094] In another preferred embodiment, in the compound, ring A, ring B, Any one of R 1, R 7, Ra, R c, R d, p, q, t, X 1, X 2, s, and w is independently a corresponding specific group in the specific compound.

[0095] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0096] Another preferred salt type is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0097] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0098] In addition, the compounds of the present invention also include prodrugs of the compounds represented by formula (I). The term "prodrug" includes compounds that may be biologically active or inactive, and when administered by appropriate methods, undergo metabolism or chemical reactions in the human body to transform into a compound of formula (I), or a salt or solution composed of a compound of formula (I). Such prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfonate, sulfonite, amino compound, carbamate, azo compound, phosphamide, glucoside, ether, acetal, and other forms of the compounds.

[0099] 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. Such combinations can be easily performed by those skilled in the art to which the present invention relates.

[0100] 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 through commercial channels unless otherwise specified. [Drug composition and administration method]

[0101] The present invention also provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of one or more compounds of the present invention and a pharmaceutically acceptable carrier.

[0102] 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.

[0103] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg per dose. Preferably, "one dose" refers to one capsule or tablet.

[0104] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels suitable for human use, and must be of sufficient purity and sufficiently low toxicity. "Compatibility" in this context refers to the ability of the components of the composition to be compatible with the compounds of the invention, and with each other, without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free water.

[0105] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0106] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0107] 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, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffering agent.

[0108] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a specific portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0109] 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 inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.

[0110] Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0111] In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0112] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0113] 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.

[0114] The compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0115] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0116] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0117] Compared with the prior art, the present invention has the following main advantages: 1) The compound has excellent CDK2 inhibitory activity; 2) The compound has excellent CDK2 selective inhibitory activity; 3) The compounds selectively inhibit cancers caused by abnormal expression or amplification of CyclinE; 4) The compound has excellent pharmacokinetic properties.

[0118] The present invention is further illustrated below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit its scope. Experimental procedures in the following examples, where specific conditions are not specified, were generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or in accordance with manufacturer recommendations. Unless otherwise noted, percentages and parts are by weight.

[0119] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only. [Example Synthesis Route]

[0120] Unless otherwise stated, the absolute stereochemistry of all chiral atoms is defined below. In the structural formula, the symbol "&" indicates that the compound is a cis racemate; the symbol "or" indicates that the compound is a single-configuration compound, but the absolute configuration is unknown; the symbol "abs" indicates that the absolute configuration of the compound is the indicated structure; and the symbol "rac" indicates that the compound is a racemate. [Synthesis of intermediates] [Intermediate] [int1] [Synthesis:] 1. Synthesis of int1-2

[0121] Int1-1 (10 g, 64.0 mmol) was dissolved in 150 mL of methanol. Under nitrogen protection, NaBH₄ (2.44 g, 64.0 mmol) was added portionwise in an ice-water bath. The reaction solution was then warmed to room temperature and stirred for 2 hours. After completion, the reaction was quenched by slowly adding 1 M dilute hydrochloric acid solution under ice-water cooling. The solvent, methanol, was evaporated under reduced pressure and then diluted with water. The mixture was extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 8.27 g of crude product. Ms [M+Na] + was 181.1. 2. Synthesis of int1-3

[0122] Int1-2 (8.27 g, 52.33 mmol) was dissolved in 100 mL of ethanol, followed by the addition of imidazole (10.67 g, 157.0 mmol). TBDPSCl (15.83 g, 57.58 mmol) was slowly added dropwise under nitrogen in an ice-water bath. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 16 hours. After the reaction, the ethanol solvent was evaporated under reduced pressure. The residue was then diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 19.86 g of the product. Ms [M+H] +: 397.2. 1HNMR (400 MHz, CDCl 3) δ 7.73-7.58 (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=5.6 Hz, 2H), 1.86-1.70 (m, 2H), 1.64-1.53​​ (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.05 (s, 9H). 3. Synthesis of int1-4

[0123] Under nitrogen, n-butyllithium (88 mL, 2.5 M in hexane) was added to 500 mL of anhydrous tetrahydrofuran. The system was cooled to -65°C, and acetonitrile (9.2 g, 224.8 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 1 hour. A solution of int1-3 (44.7 g, 112.4 mmol) in anhydrous tetrahydrofuran (100 mL) was then slowly added dropwise, and stirring was continued at this temperature for 2 hours. After the reaction was completed, water was added dropwise at -65°C to quench the reaction. After stirring and warming to room temperature, the reaction solution was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 49.0 g of crude product. Ms [M+H] +: 392.2. 4. Synthesis of int1-5

[0124] Dissolve tert-butylhydrazine hydrochloride (9.35 g, 75.0 mmol) and triethylamine (10.43 mL, 75.0 mmol) in 150 mL of ethanol and stir for 0.5 hour. Add a 50 mL solution of int1-4 (19.6 g, 50.0 mmol) in ethanol. Heat the reaction system to 75°C and stir for 16 hours. After completion of the reaction, cool the reaction mixture to room temperature, concentrate, dilute with water, and extract with ethyl acetate. The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 19.1 g. Ms [M+H] +:462.3 1H NMR (400 MHz, CDCl 3) δ 7.70-7.66 (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). 5. Synthesis of int1-6

[0125] Int1-5 (19.12 g, 41.0 mmol) was dissolved in 160 mL of acetonitrile and cooled in an ice-water bath. Benzyl chloroformate (11.7 mL, 82.0 mmol) was added dropwise. After complete addition, the mixture was warmed to room temperature and stirred for 2 h. NaHCO₃ (11.02 g, 130.0 mmol) was then added and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 21.2 g. Ms [M+H]⁺: 596.4. 6. Synthesis of int1-7

[0126] Int1-6 (21.0 g, 35.0 mmol) was dissolved in 150 mL of anhydrous tetrahydrofuran with stirring at room temperature. Glacial acetic acid (4.2 mL, 70.0 mmol) and tetrabutylammonium fluoride (35.0 mL, 1 M in THF) were added sequentially. The mixture was heated to 40°C and stirred for 23 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified to yield 4.41 g. Ms [M+H] +: 358.2. 1H NMR (400 MHz, DMSO-d6) δ 9.06(s, 1H), 7.59-7.22(m, 5H), 5.92(s, 1H), 5.12(s, 2H), 4.57(d, J=4.4 Hz, 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). 7. Synthesis of int1-8

[0127] Int1-7 (4.41 g, 12.35 mmol) was dissolved in 80 mL of dichloromethane. p-Nitrophenyl chloroformate (3.73 g, 18.53 mmol), pyridine (2.93 g, 37.05 mmol), and DMAP (149 mg, 1.24 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction solution was washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to yield 4.34 g of the product. Ms [M+H] +: 523.2. 8. Synthesis of int1-9

[0128] Dissolve int1-8 (4.34 g, 8.31 mmol) in 80 mL of tetrahydrofuran, then add isopropylamine (1.07 mL, 12.47 mmol) and diisopropylethylamine (4.33 mL, 24.93 mmol) sequentially. Stir at room temperature overnight. After completion of the reaction, dilute the reaction system with water, extract with ethyl acetate, and combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify to yield 1.17 g of the product. Ms [M+H] +: 443.3. 9. Synthesis of int1, int1A, and int1B

[0129] Int1-9 (1.07 g, 2.42 mmol) was dissolved in a mixture of 10 mL of methanol and 10 mL of ethyl acetate. Pd / C (214 mg, 20 mol%) was then added and stirred at room temperature under a hydrogen atmosphere for 5 h. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified to yield 640 mg of int1. Chiral preparative chromatography revealed int1A (300 mg) with an elution time of 28.878 min and int1B (291 mg) with an elution time of 33.753 min. The chromatography column used was a Phenomenex Lux® 3 μm Cellulose-4 column with a mobile phase of 90:10 hexane:isopropanol at 30°C. [Intermediate] [int1C] [、] [int1D] [Synthesis:] 1. Synthesis of int1C-1

[0130] The following method was used for chiral separation of int1-7: Agilent high performance liquid chromatography separation, and the preparation and separation conditions were as follows: chromatography column: Phenomenex Lux® 5 μm Cellulose-4; mobile phase: n-hexane:isopropanol = 90:10; flow rate: 1 mL / min, detection wavelength: 220 nm; column temperature: 30°C, solvent: isopropanol, and the sample with a peak time of 24.6 min was collected, concentrated and lyophilized to obtain the product int1C-1, and the peak time of the other configuration was 21.8 min. 2. Synthesis of int1C

[0131] Dissolve intC1-1 (2.2 g, 6.2 mmol) in 40 mL of dichloromethane, followed by the addition of p-nitrophenyl chloroformate (1.86 g, 9.26 mmol), pyridine (1.47 g, 18.5 mmol), and DMAP (74.5 mg). Stir at room temperature for 16 hours. After completion of the reaction, the reaction solution was washed several times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified to yield 2.21 g of the product. 3. Synthesis of int1D-1

[0132] Int1C (2.0 g, 1.0 eq) was added to a 50 mL single-necked flask, followed by formic acid (40 mL) at room temperature. The reaction was allowed to react at 80°C for 2 h. The reaction was monitored by TLC. The pH was adjusted to near neutral with saturated sodium bicarbonate and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 1.2 g of the product. 4. Synthesis of int1D

[0133] Int1D-1 (4.66 g, 1.0 eq), dichloromethane (100 mL), and DHP (1.68 g) were added to a 250 mL single-necked flask. 344 mg of p-toluenesulfonic acid was added dropwise at room temperature. The mixture was reacted at 40°C overnight. The mixture was diluted with water and extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 5.23 g of the product. [Intermediate] [int2] [Synthesis:] 1. Synthesis of int2-2

[0134] To a 1000 mL three-necked flask, add tetrahydrofuran (240 mL). Under nitrogen, add 60% NaH (4.3 g, 2 eq). Stir for 5 minutes, then slowly add diethyl malonate (21.27 g, 2.5 eq) dropwise. Stir at room temperature for 30 minutes, then add int2-1 (10 g, 1 eq) in tetrahydrofuran (120 mL) dropwise. Keep the mixture at 80°C for 16 hours. After completion, add 400 mL of saturated ammonium chloride to the reaction mixture, extract with ethyl acetate (100 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 8.3 g of int2-2.

[0135] 1H NMR (400 MHz, CDCl 3) δ 8.58 (d, J = 5.8 Hz, 1H), 7.00 (d, J = 5.8 Hz, 1H), 4.95 (s, 1H), 4.28 (qd, J = 7.1, 1.1 Hz, 4H), 3.99 (s, 3H), 1.28 (t, J = 7.2 Hz, 6H). 2. Synthesis of int2-3

[0136] Int2-2 (8.3 g, 1.0 eq), methanol (83 mL), and Pd / C (0.83 g) were added to a 250 mL single-necked flask under a hydrogen atmosphere. The mixture was reacted at 30°C for 3 h. After completion, the reaction was filtered and rotary dried to yield 7.2 g of int2-3. 3. Synthesis of int2-4

[0137] Int2-3 (7.2 g, 1.0 eq), concentrated hydrochloric acid (50 mL), and water (50 mL) were added to a 250 mL three-necked flask and reacted at 100°C under nitrogen for 16 h. After completion of the reaction, the mixture was cooled to room temperature and adjusted to pH 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2.8 g of int2-4.

[0138] 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.01 (d, J = 5.8 Hz, 1H), 6.96 (d, J = 5.9 Hz, 1H), 3.87 (s, 3H), 3.56 (s, 2H). 4. Synthesis of int2-5

[0139] Int2-4 (1.2 g, 1.0 eq), DMSO (20 mL), DBU (2 g 2 eq), and Zn(OTf)2 (0.5 g 0.2 eq) were added to a 100 mL single-necked flask. Stir at 25°C for 5 min, followed by the addition of diphenyl(vinyl)cerium trifluoromethanesulfonate (2.36 g, 1 eq). The reaction was allowed to proceed at 25°C for 1.5 h. After completion of the reaction, saturated sodium chloride solution (60 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 600 mg of int2-5.

[0140] 1H NMR (400 MHz, CDCl 3) δ 8.08 (d, J = 5.9 Hz, 1H), 7.82 (q, J = 5.2, 4.1 Hz, 1H), 6.72 (d, J = 5.9 Hz, 1H), 3.94 (s, 3H), 1.89 – 1.83 (m, 2H), 1.80 – 1.74 (m, 2H). 5. Synthesis of int2-6

[0141] DMF (10 mL) and int2-5 (600 mg, 1 eq) were added to a 100 mL three-necked flask. The temperature was lowered to 0°C under nitrogen protection. NaH (60%) (188 mg, 1.5 eq) was added. After stirring for 5 min, iodomethane (892 mg, 2 eq) was slowly added dropwise. After stirring at room temperature for 2 h, the reaction was completed. 40 mL of saturated ammonium chloride was added to the reaction solution, and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 660 mg of int2-6.

[0142] 1H NMR (400 MHz, CDCl 3) δ 8.03 (d, J = 5.8 Hz, 1H), 6.72 (d, J = 5.9 Hz, 1H), 3.93 (s, 3H), 3.55 (s, 3H), 1.86 – 1.78 (m, 2H), 1.78 – 1.62 (m, 2H). 6. Synthesis of int2-7

[0143] Int2-6 (150 mg, 1 eq), dichloromethane (10 mL), and boron tribromide (5 mL) were added to a 100 mL three-necked flask. The temperature was lowered to 0°C under nitrogen protection, and boron tribromide (5 mL) was added. The mixture was stirred at 40°C for 8 h. After concentration under reduced pressure, the mixture was dissolved in dichloromethane and quenched with 1 mL of water. After drying, 300 mg of crude product int2-7 was obtained and directly carried out to the next step. 7. Synthesis of int2

[0144] Int2-7 and dichloromethane (10 mL) were added to a 100 mL three-necked flask. The temperature was lowered to 0°C under nitrogen protection, and trifluoromethanesulfonic anhydride (354 mg 1.5 eq) in dichloromethane (2 mL) was added. The mixture was stirred for 5 min. After the reaction was completed, saturated ammonium chloride (40 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative chromatography to obtain int2 (165 mg). [Intermediate] [int2A] [Synthesis:] 1. Synthesis of int2A-2

[0145] Dimethyl malonate (3.31 g, 1.2 eq) was dissolved in N,N-dimethylformamide (25 mL), heated to 40°C, and NaH (0.82 g, 1.2 eq) was added. After stirring for 0.5 h, 4,6-dichloro-5-aminopyrimidine (2.25 g, 1 eq) was added and the temperature was slowly raised to 70°C. The reaction was maintained at this temperature for 3 h. After the reaction, the temperature was cooled to room temperature and the N,N-dimethylformamide was removed by distillation under reduced pressure. Water (20 mL) was added and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with water (25 mL x 2) and the combined aqueous phases were adjusted to pH 5-6 with concentrated hydrochloric acid. A yellow solid precipitated, which was filtered and dried to obtain 1.9 g of the product. 1H NMR (400 MHz, DMSO) δ = 10.98 (s, 1H), 8.03 (s, 1H), 4.15 (d, J=7.1, 2H), 1.18 (s, 3H). 2. Synthesis of int2A-3

[0146] Add int2A-2 (1.6 g) and acetic acid (80 mL) to a 250 mL reactor, add concentrated hydrochloric acid (80 mL) with stirring, then slowly raise the temperature to 100°C, keep stirring and react for 15 h, then cool the reaction solution to room temperature, rotary dry to obtain 1.3 g of crude product, which is directly used in the next step. 3. Synthesis of int2A-4

[0147] Int2A-3 (1.1 g, 1.0 eq), DMSO (20 mL), DBU (3.11 g, 4 eq), and Zn(OTf)2 (0.786 g, 0.4 eq) were added to a 100 mL single-necked flask and stirred at 25°C for 5 min. Diphenyl(vinyl)cerium trifluoromethanesulfonate (1.86 g, 1 eq) was then added and allowed to react at 25°C for 10 min. After completion of the reaction, saturated sodium chloride solution (60 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated under reduced pressure, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 400 mg of the product. 4. Synthesis of int2A

[0148] To a 100 mL three-necked flask, add N,N-dimethylformamide (10 mL) and int2A-4 (400 mg, 1 eq). The mixture was cooled to 0°C under nitrogen protection and cesium carbonate (1.37 g, 2 eq) was added. After stirring for 5 min, iodomethane (405 mg, 1.3 eq) was slowly added dropwise. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction, saturated ammonium chloride (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 240 mg of the product. 1H NMR (400 MHz, CDCl 3) δ = 8.54 (s, 1H), 3.64 (s, 3H), 1.98 (dd, J=8.7, 2.0, 4H). [Intermediate] [int2B] [Synthesis:] 1. Synthesis of int2B-2

[0149] Int2B-1 (10 g, 1.00 eq) and NN-dimethylformamide (100 mL) were added to a 250 mL flask. After stirring to dissolve, cesium carbonate (19.3 g, 0.9 eq) and iodomethane (11.2 g, 1.2 eq) were added. The reaction was allowed to react at room temperature for 3–5 hours. Once the reaction was complete, the product was quenched with water, extracted with ethyl acetate, and the layers separated. The organic phase was washed with saturated sodium chloride solution and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 5 g of the product. Ms [M+H] +: 167.0. 2. Synthesis of int2B-3

[0150] Int2B-2 (3.25 g, 1.00 eq) and tert-butanol (55 mL) were added to a 100 mL flask and stirred to dissolve. Sodium bicarbonate (4.94 g, 3.0 eq) was then added and stirred in an ice-water bath for 10 minutes. Bromine (5.76 g, 6.0 eq) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 1 hour until completion. The product was quenched with water, extracted with ethyl acetate, and the layers separated. The organic phase was washed with saturated sodium chloride solution and separated. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to yield 1.78 g of the product. Ms [M+H] +: 338.8. 3. Synthesis of int2B-4

[0151] Int2B-3 (1.78 g, 1.00 eq) and acetic acid (36 mL) were added to a 100 mL flask and stirred in an ice-water bath for 10 minutes. Zinc powder (1.73 g, 5.0 eq) was slowly added. The reaction was allowed to proceed at room temperature for 15 minutes until complete. The product was filtered, the filter cake rinsed with methanol, and the filtrate concentrated. Purification on a silica gel column afforded 0.75 g of the product. Ms [M+H] +: 183.0. 4. Synthesis of int2B

[0152] Int2B-4 (0.75 g, 1.00 eq), diphenyl(vinyl)arsenium trifluoromethanesulfonate (1.49 g, 1.00 eq), and dichloromethane (7.5 mL) were added to a 50 mL flask and stirred to dissolve. Zinc trifluoromethanesulfonate (0.3 g, 0.2 eq) was then added and stirred at room temperature for 3 minutes. A mixture of DBU (1.25 g, 2.0 eq) in dichloromethane (7.5 mL) was then added. The reaction was allowed to proceed at room temperature for 10 minutes until completion. Saturated ammonium chloride solution was added to the system, stirred, and the phases separated. The organic phase was washed with saturated sodium chloride solution, separated, and concentrated. The product (0.49 g) was purified on a silica gel column. Ms [M+H] +: 209.0. [Intermediate] [int2C] [Synthesis:] 1. Synthesis of int2C-1

[0153] Int2 (760 mg, 1.00 eq), int1-5 (1.09 g, 1.00 eq), cesium carbonate (2.31 g, 3.00 eq), Xantphos (273 mg, 0.20 eq), palladium acetate (53 mg, 0.10 eq), and 1,4-dioxane (15 mL) were added to a 100 mL single-necked flask. The reaction was heated to 100°C under a nitrogen atmosphere for 2 h, and the reaction was complete. The mixture was cooled, filtered, and the solid was washed with ethyl acetate. The organic filtrate was collected and washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification on a silica gel column afforded 200 mg of the product. Ms [M+H] +: 634.3. 2. Synthesis of int2C-2

[0154] Int2C-1 (200 mg, 1 eq) and methanol (5 mL) were added to a 50 mL single-necked flask. Concentrated hydrochloric acid (0.25 mL) was added to the solution, and the reaction mixture was stirred at 40°C for 2 h until the reaction was complete. The reaction mixture was concentrated, and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to yield 200 mg of the product. Ms [M+H] +: 396.2. 3. Synthesis of int2C-3

[0155] Int2C-2 (200 mg), N-methylmorpholine (511 mg, 10 eq), and dichloromethane (20 mL) were added to a 50 mL single-necked vial. A solution of phenyl p-nitrochloroformate (204 mg, 2 eq) in dichloromethane (10 mL) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 2 min until the reaction was complete. Water was added to the reaction mixture at 0°C to quench the reaction. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and concentrated. Purification by preparative thin-layer chromatography yielded 120 mg of the product. Ms [M+H] +: 561.3. 4. Synthesis of int2C

[0156] In a 25 mL single-necked vial, int2C-3 (110 mg, 1 eq) and formic acid (5 mL) were added. The reaction mixture was heated to 80°C for 1.5 h, cooled, concentrated, and used directly in the next step. Ms [M+H] +: 505.2. [Intermediate] [int2D] [Synthesis:] 1. Synthesis of int2D-2

[0157] Int2B (4 g, 1.00 eq), int2D-1 (1.8 g, 1.00 eq), cesium carbonate (8.5 g, 3.00 eq), Xantphos (1 g, 0.20 eq), palladium acetate (0.2 g, 0.10 eq), and 1,4-dioxane (40 mL) were added to a 100 mL flask. The mixture was heated to 100°C under a nitrogen atmosphere for 2 h, and the reaction was complete. The mixture was cooled, filtered, and the solid was washed with ethyl acetate. The organic phase was diluted with a large amount of ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification on a silica gel column yielded 5.17 g of the product. Ms [M+H] +: 634.3. 2. Synthesis of int2D-3

[0158] Int2D-2 (5 g, 1 eq) and methanol (50 mL) were added to a 100 mL flask. Concentrated hydrochloric acid (1 mL) was added to the solution and stirred at 40°C for 5–6 hours. Saturated aqueous sodium bicarbonate was added to adjust the pH to a weakly alkaline state, and the excess methanol was removed by vacuum concentration. The solution was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification with a silica gel column afforded 2.71 g of the product. Ms [M+H] +: 396.2. 3. Synthesis of int2D-4

[0159] Int2D-3 (2.71 g, 1.0 eq), N-methylmorpholine (6.9 g, 10 eq), and dichloromethane (110 mL) were added to a 100 mL flask. Phenyl p-nitrochloroformate (2.76 g, 2 eq) was slowly added to the reaction mixture at 0°C. The mixture was allowed to react at room temperature for 2 min until the reaction was complete. The reaction mixture was quenched by adding water at 0°C. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and concentrated. Purification on a silica gel column afforded 3.22 g of the product. Ms [M+H] +: 561.2. 4. Synthesis of int2D

[0160] Int2D-4 (3.22 g, 1.0 eq) and formic acid (32 mL) were added to a 100 mL flask. The reaction was heated to 80°C for 1.5 h, cooled, concentrated, and then water was added. Saturated sodium bicarbonate solution was added to the system to adjust the pH to a weak base. The product was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column afforded 1.2 g of the product. Ms [M+H] +: 505.1. [Intermediate] [int2E] [Synthesis:] 1. Synthesis of int2E-2

[0161] Compound int2E-1 (500 mg, 2.97 mmol) was dissolved in N,N-dimethylformamide (25 mL) and cooled to 0°C. A solution of sodium hydride (714 mg, 17.86 mmol) in N,N-dimethylformamide was added dropwise. After completion of the addition, the mixture was stirred at 0°C for 15 min. A solution of 1,2-dibromoethane (1.68 g, 8.93 mmol) in N,N-dimethylformamide was then added dropwise. The temperature was slowly warmed to room temperature and stirred for 3 h until the reaction was complete. The reaction was cooled, quenched with water, and concentrated under reduced pressure. Purification by column chromatography afforded 527 mg of the product, Ms [M+H] +: 195.0. 2. Synthesis of int2E

[0162] Compound int2E-2 (470 mg, 2.42 mmol) was dissolved in N,N-dimethylformamide (15 mL), cooled to 0°C, and a solution of sodium hydride (116 mg, 2.91 mmol) in N,N-dimethylformamide was added dropwise. After completion of the addition, the mixture was stirred at 0°C for 15 min. Ethyl iodide (1.13 g, 7.27 mmol) was then added dropwise. The mixture was slowly warmed to room temperature and stirred for 2 h. The reaction was complete. The mixture was cooled and quenched with water. The mixture was then concentrated under reduced pressure and purified by preparative thin-layer chromatography to yield 233 mg of the product, Ms [M+H] +: 223.1. [Intermediate] [int2F] [Synthesis:] 1. Synthesis of int2F-2

[0163] To a 250 mL single-necked flask, add Raney nickel (2.50 g) and replace the water with methanol. Then, add int2F-1 (5.00 g, 1 eq), methanol (50 mL), and tetrahydrofuran (50 mL) to replace the hydrogen atmosphere. The reaction mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. The reaction was complete. The reaction mixture was filtered, washed with methanol, and the organic phase was concentrated under reduced pressure. Purification on a silica gel column afforded 3.9 g of pure product. Ms [M+H] +: 177.0. 2. Synthesis of int2F-3

[0164] Compound int2F-2 (3.90 g, 1.00 eq), cuprous iodide (211 mg, 0.05 eq), and triethylamine (80 mL) were added to a 250 mL single-necked flask. Trimethylsilylacetylene (3.26 g, 1.50 eq) and bis(triphenylphosphine)palladium dichloride (778 mg, 0.05 eq) were added at room temperature, and the atmosphere was replaced with nitrogen. The reaction was allowed to proceed at 80°C for 2 h under a nitrogen atmosphere. The reaction was complete. The reaction mixture was cooled to room temperature, filtered, and the residue was washed with ethyl acetate. The organic phase was diluted with ethyl acetate, washed with water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column afforded 4 g of pure product. Ms [M+H] +: 239.1. 3. Synthesis of int2F-4

[0165] Compound int2F-3 (3.50 g, 1.00 eq) and acetonitrile (60 mL) were added to a 250 mL single-necked flask. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (14.71 mL, 1.50 eq) was added dropwise under an ice bath. The reaction was allowed to react at room temperature for 2 h. The reaction was complete. The reaction solution was diluted with a large amount of ethyl acetate, washed with water, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column afforded 2 g of pure product. Ms [M+H] +: 167.0. 4. Synthesis of int2F-5

[0166] Dissolve int2F-4 (500 mg, 1.00 eq) in ultra-dry N,N-dimethylformamide (10 mL). Cool to 0°C, add sodium hydride (180 mg, 1.50 eq), and react on ice for 30 min. Add iodomethane (515 mg, 1.2 eq) dropwise. Allow to react at room temperature for 1 h. The reaction is complete. Quench the reaction with ice water on ice, extract the aqueous phase with ethyl acetate, and separate the layers. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to yield 600 mg of crude product. Ms [M+H] +: 181.0. 5. Synthesis of int2F-6

[0167] Compound int2F-5 (542 mg, 1.00 eq), sodium bicarbonate (759 mg, 3.00 eq), and tert-butanol (10 mL) were added to a 50 mL single-necked flask and stirred at room temperature for 10 min. Bromine (2.89 g, 6.00 eq) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction was complete. The reaction was quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The layers were separated. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column afforded 800 mg of pure product. Ms [M+H] +: 352.9. 6. Synthesis of int2F-7

[0168] Dissolve int2F-6 (750 mg, 1.00 eq) in glacial acetic acid (7 mL) and add zinc powder (692 mg, 5.00 eq) at room temperature. Allow to react at room temperature for 1 h. The reaction is complete. Dilute the reaction solution with methanol, filter, and wash the residue with methanol. Concentrate the filtrate under reduced pressure to yield 500 mg of crude product. Ms [M+H] +: 197.0. 7. Synthesis of int2F

[0169] Int2F-7 (417 mg, 1.00 eq), diphenyl(vinyl)arsenium trifluoromethanesulfonate (771 mg, 1.00 eq), and zinc trifluoromethanesulfonate (155 mg, 0.20 eq) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 3 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (648 mg, 2.00 eq) was slowly added dropwise to the mixture. The reaction was allowed to proceed at room temperature for 10 min. The reaction was complete. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column afforded 350 mg of pure product. Ms [M+H] +: 223.1. [Intermediate] [int2G] [Synthesis:] 1. Synthesis of int2G-2

[0170] Dissolve int2G-1 (4 g, 1.00 eq) in ultra-dry N,N-dimethylformamide (10 mL). Cool to 0°C, add 60% sodium hydride (1.57 g, 1.50 eq), and react on ice for 30 min. Then, add iodomethane (4.47 g, 1.2 eq) dropwise to the reaction system. Allow to react at room temperature for 1 h. The reaction is complete. Quench the reaction with ice water on ice, extract the aqueous phase with ethyl acetate, and separate the layers. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to yield 5.39 g of crude product. Ms [M+H] +: 167.0. 2. Synthesis of int2G-3

[0171] Compound int2G-2 (5.39 g, 1.00 eq), sodium bicarbonate (8.15 g, 3.00 eq), and tert-butanol (250 mL) were added to a 500 mL single-necked flask and stirred at room temperature for 10 min. Bromine (31.0 g, 6.00 eq) was slowly added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction was complete. The reaction was quenched by adding water, and the aqueous phase was extracted with ethyl acetate. The layers were separated. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column afforded 2.167 g of pure product. Ms [M+H] +: 418.7. 3. Synthesis of int2G-4

[0172] Dissolve int2G-3 (2.15 g, 1.00 eq) in glacial acetic acid (100 mL) and add iron powder (1.44 g, 5.00 eq) at room temperature. Allow to react for 4 h at room temperature. The reaction is complete. Dilute the reaction solution with methanol, filter, and wash the residue with methanol. The filtrate is concentrated under reduced pressure and purified by column chromatography to yield 893 mg of the product. Ms [M+H] +: 260.9. 4. Synthesis of int2G

[0173] Int2G-4 (300 mg, 1.00 eq), diphenyl(vinyl)arsenium trifluoromethanesulfonate (414.5 mg, 1.00 eq), and zinc trifluoromethanesulfonate (83.1 mg, 0.20 eq) were dissolved in dichloromethane (10 mL) and stirred at room temperature for 3 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (348.1 mg, 2.00 eq) was slowly added dropwise to the mixture. The reaction was allowed to proceed at room temperature for 10 min. The reaction was complete. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column yielded 285 mg of the product. Ms [M+H] +: 286.9. [Intermediate] [int4] [Synthesis:] 1. Synthesis of int4-2

[0174] Compound int4-1 (10 g, 76.8 mmol) was dissolved in 80 mL of N,N-dimethylformamide. Imidazole (15.7 g, 230.4 mmol) was then added and the mixture was cooled and stirred in an ice bath. TBDPSCl (23.2 g, 84.5 mmol) was slowly added dropwise, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction was complete. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography to yield 24.12 g of compound int4-2. Ms [M+H] +: 369.1. 2. Synthesis of compound int4-3

[0175] Under nitrogen, n-BuLi (52 mL, 2.5 mol / L) and tetrahydrofuran (70 mL) were added to a flask and cooled with stirring in a dry ice bath. Acetonitrile (5.3 g, 128.4 mmol) was added dropwise, maintaining the internal temperature at -55°C. After completion, the mixture was stirred for 1 hour. A solution of compound int4-2 (23.62 g, 64.2 mmol) in tetrahydrofuran (47 mL) was then added dropwise. After completion, the mixture was stirred at -78°C for 2 hours. The reaction was complete. Water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to yield 28.66 g of compound int4-3. This was used directly in the next step. Ms [M+H] +: 378.2. 3. Synthesis of compound int4-4

[0176] Add tert-butylhydrazine hydrochloride (14.2 g, 114 mmol) and 143 mL of ethanol to a flask, followed by triethylamine (11.52 g, 114 mmol). Stir at room temperature for 30 minutes. Add a solution of compound int4-3 (28.66 g, 76 mmol) in ethanol (143 mL). Heat to 75°C and allow to react overnight.

[0177] The reaction was complete. The system was concentrated until no liquid was distilled out, water was added, stirred, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain 28.77 g of compound int4-4. Ms [M+H] +: 448.3. 4. Synthesis of compound int4-5

[0178] Under nitrogen, compound int4-4 (24.27 g, 54.3 mmol) was dissolved in 170 mL of acetonitrile and cooled with stirring in an ice bath. Cbz-Cl (18.5 g, 108.6 mmol) was slowly added dropwise. After complete addition, the mixture was stirred at room temperature for 1-2 hours. Sodium bicarbonate (14.6 g, 174 mmol) was added, and the temperature was slowly raised to room temperature and stirred overnight. The reaction was complete. The system was filtered, and the filtrate was concentrated until no liquid was distilled out. Water was added, stirred, and extracted with ethyl acetate. The mixture was dried, concentrated, and purified by column chromatography to obtain 24.88 g of compound int4-5. Ms [M+H] +: 582.3. 5. Synthesis of compound int4-6

[0179] Dissolve compound int4-5 (8.28 g, 14.2 mmol) in 82.8 mL of methanol and cool with stirring in an ice bath. Slowly add concentrated hydrochloric acid (1.7 mL) dropwise. Stir at room temperature overnight after the addition is complete. The reaction is complete. Adjust the pH to alkaline by adding sodium bicarbonate solution, and remove excess methanol under reduced pressure. Extract with ethyl acetate, dry, concentrate, and purify by column chromatography to obtain 3.57 g of compound int4-6. Ms [M+H] +: 344.2. 6. Synthesis of compound int4-8

[0180] Dissolve compound int4-6 (3 g, 8.74 mmol) and compound int4-7 (2.64 g, 13.11 mmol) in 60 mL of dichloromethane. Slowly add pyridine (2.07 g, 26.22 mmol) and 4-dimethylaminopyridine (0.11 g, 0.874 mmol). Allow to react at room temperature for 5 hours. The reaction is complete. Add water to the system and wash the separated liquid. Add saturated sodium chloride solution to the organic phase and wash the separated liquid five times. Concentrate the organic phase and purify by column chromatography to obtain 4.16 g of compound int4-8. Ms [M+H] +: 509.2. 7. Synthesis of compound int4-9

[0181] Compound int4-8 (4.16 g, 8.2 mmol) and isopropylamine (726 mg, 12.3 mmol) were dissolved in 83 mL of tetrahydrofuran. N,N-diisopropylethylamine (3.2 g, 24.6 mmol) was added and the mixture was allowed to react at room temperature for 5 hours. The reaction was complete. Water was added to the system, and the liquid phase was extracted with ethyl acetate. Saturated sodium chloride solution was added to the organic phase and the liquid phase was washed. The organic phase was concentrated and purified by column chromatography to obtain 2.67 g of compound int4-9. Ms [M+H] +: 429.2. 8. Synthesis of compound int4

[0182] Dissolve compound int4-9 (2.67 g, 6.2 mmol) in 26 mL of methanol / 26 mL of ethyl acetate. Add palladium on carbon (0.534 g) and stir overnight under a hydrogen atmosphere. The reaction is complete. Filter, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 1.85 g of compound int4. Ms [M+H] +: 295.2. [Intermediate] [int4A] [Synthesis:] 1. Synthesis of int4A-2

[0183] Int4A-1 (4.30 g, 1.0 eq), (S)-tert-butylsulfenamide (6.06 g, 1.0 eq), tetraisopropyl titanate (22.8 g, 2.0 eq), and tetrahydrofuran (86 mL) were added to a 250 mL single-necked flask and reacted at 70°C under nitrogen for 16 hours. After the reaction was complete and cooled to room temperature, the reaction solution was slowly poured into a mixture of saturated sodium bicarbonate and ethyl acetate. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 5.20 g of the product. 2. Synthesis of int4A-3

[0184] Methyllithium (10 mL, 3.0 eq) and tetrahydrofuran (15 mL) were added to a 50 mL single-necked flask. After cooling to -70°C, a solution of int4A-2 (1.00 g, 1.0 eq) in tetrahydrofuran (5 mL) was added dropwise. After the addition, the mixture was incubated at -70°C for 1 hour, then naturally warmed to room temperature and allowed to react for 16 hours. After the reaction was complete and cooled to 0°C, the reaction solution was slowly poured into a mixture of saturated sodium bicarbonate and ethyl acetate. Extraction was performed with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 272 mg of the product. Ms [M+H] +: 206.3. 3. Synthesis of int4A

[0185] Int4A-3 (272 mg, 1.0 eq) and dichloromethane (2 mL) were added to a 50 mL single-necked flask. After cooling to 0°C, HCl / dioxane (2 mL) was added dropwise. After warming to room temperature, the mixture was reacted for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and slurried with ethyl acetate to yield 147 mg of the crude product. Ms [M+H] +: 102.1. [Intermediate] [int4B] [Synthesis:] 1. Synthesis of int4B-2

[0186] Int4B-1 (4.30 g, 1.0 eq), (S)-tert-butylsulfenamide (6.06 g, 1.0 eq), tetraisopropyl titanate (22.8 g, 2.0 eq), and tetrahydrofuran (86 mL) were added to a 250 mL single-necked flask and reacted at 70°C under nitrogen for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and slowly poured into a mixture of saturated sodium bicarbonate and ethyl acetate. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 5.32 g of the product. MS: 190.3 [M+1]. 2. Synthesis of int4B-3

[0187] Methyllithium (20 mL, 3.0 eq) and tetrahydrofuran (30 mL) were added to a 50 mL single-necked flask. After cooling to -70°C, a solution of int4B-2 (2.00 g, 1.0 eq) in tetrahydrofuran (5 mL) was added dropwise. After the addition, the mixture was incubated at -70°C for 1 hour, then naturally warmed to room temperature and reacted for 16 hours. After the reaction was complete and cooled to 0°C, the reaction solution was slowly poured into a mixture of saturated sodium bicarbonate and ethyl acetate. Extraction was performed with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 1.50 g of the product. 3. Synthesis of int4B

[0188] Int4B-3 (1.50 g, 1.0 eq) and dichloromethane (3 mL) were added to a 50 mL single-necked flask. After cooling to 0°C, HCl / dioxane (3 mL) was added dropwise. After warming to room temperature, the mixture was reacted for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and slurried with ethyl acetate to yield 1.0 g of the crude product. Ms [M+H] +: 102.1. [Intermediate] [int4C] [Synthesis:] 1. Synthesis of int4C-2

[0189] In a 250 mL single-necked flask, compound int4C-1 (10 g, 1.00 eq) was dissolved in dichloromethane (100 mL). Ethyl acetate (13.05 g, 1.15 eq) was added, and CbzCl (19.14 g, 1.00 eq) was added dropwise in an ice bath. The mixture was warmed to room temperature and reacted overnight. After completion of the reaction, the mixture was concentrated, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 14 g of the product, Ms [M+H] +: 224.1. 2. Synthesis of int4C-3

[0190] In a 25 mL single-necked flask, compound int4C-2 (500 mg, 1.00 eq) was dissolved in tetrahydrofuran (5 mL). Ethyl acetate (906.4 mg, 4.00 eq) was added, and the temperature was lowered to -20°C. MsCl (641.6 mg, 2.5 eq) was added dropwise. The temperature was raised to room temperature and the reaction was allowed to react overnight. After completion of the reaction, water was added to the reaction solution, and the product was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 742 mg of a crude product with Ms [M+H] +: 302.1. 3. Synthesis of int4C-4

[0191] Compound int4C-3 (742 mg, 1.00 eq), tert-butanol (7 mL), and cesium fluoride (2244.0 g, 6.00 eq) were added to a 25 mL single-necked flask and reacted at 75°C overnight. After the reaction was complete, water and ethyl acetate were added and extracted three times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 225 mg of the product. 4. Synthesis of int4C

[0192] In a 25 mL single-necked bottle, compound int4C-4 (225 mg, 1.00 eq) was dissolved in tetrahydrofuran (5 mL), and palladium on carbon (50 mg) was added. The mixture was reacted at room temperature under hydrogen for 2 hours. After completion of the reaction, the crude product was used directly in the next reaction. [Intermediate] [int4D] [Synthesis:] 1. Synthesis of int4D-2

[0193] Dissolve int4D-1 (5 g, 1.00 eq) in tetrahydrofuran (120 mL), add tetraethyl titanate (24.6 g, 1.81 eq), and stir at room temperature for 10 minutes. Then add (S)-tert-butylsulfenamide (7.2 g, 1.00 eq) and stir at room temperature for 18 hours. The reaction system was concentrated in vacuo until no liquid was distilled out. Ethyl acetate was added, the fraction was washed with sodium bicarbonate solution, filtered, and concentrated to yield 9.5 g, which was directly used in the next step. 1H NMR (300 MHz, CDCl 3) δ: ppm 1.15 (s, 9H), 2.15 – 2.03 (m, 2H), 3.12 - 3.03 (m, 2H), 3.27 - 3.11 (m, 1H), 3.50 - 3.39 (m, 1H). 2. Synthesis of int4D-4

[0194] Dissolve int4D-3 (5 g, 1.00 eq) in chloroform (100 mL). Add diethylaminosulfur trifluoride (23 g, 4.0 eq) under nitrogen and stir at 60°C for 18 h. Add the reaction system dropwise to a saturated sodium bicarbonate solution at 0°C. Extract the mixture three times with dichloromethane and concentrate to yield 7.26 g of crude product, which was used directly in the next step. 1H NMR (300 MHz, CDCl 3) δ: ppm 5.62 (s, 1H), 5.80 (s, 1H), 7.35 - 7.26 (m, 3H), 7.51 - 7.43 (m, 2H). 3. Synthesis of int4D-5

[0195] Dissolve int4D-4 (5.07 g, 1.00 eq) in dichloromethane (50 mL). Add m-chloroperbenzoic acid (20.9 g, 3.4 eq) at 0°C and stir at room temperature for 18 h. Add the reaction system dropwise to a 0°C sodium thiosulfate solution. Extract the mixture three times with dichloromethane, concentrate, and purify by column chromatography to obtain 4.95 g of the product (Ms [M+H] +: 175.0). 4. Synthesis of int4D-6

[0196] Dissolve int4D-5 (4.8 g, 1.53 eq) in tetrahydrofuran (30 mL) and cool to -78°C under nitrogen. Slowly add n-butyllithium (11 mL, 1.53 eq) dropwise. Stir for 40 minutes. Add a solution of int4D-2 (3.12 g, 1.00 eq) in tetrahydrofuran dropwise at -78°C. Stir at room temperature for 18 hours. Quench the reaction system with water. Extract the mixture three times with dichloromethane, concentrate, and purify by column chromatography to obtain 2.8 g of the product (Ms [M+H] +: 348.1). 5. Synthesis of int4D-7

[0197] Int4D-6 (2.5 g, 1.00 eq) was dissolved in NN-dimethylformamide (450 mL). Under nitrogen, sodium acetate (37.8 g, 64 eq) and acetic acid (57.5 mL) were added and stirred at room temperature for 15 minutes. Magnesium (11.7 g, 67 eq) was added and the mixture was allowed to react at 65°C for 18 hours. The reaction system was filtered, and the filtrate was adjusted to a weakly alkaline pH by adding sodium bicarbonate. The filtrate was extracted with ethyl acetate and the layers separated. The separated layers were washed with saturated sodium chloride, and the organic phase was concentrated in vacuo until no liquid remained. The product was purified by column chromatography to yield 0.49 g, Ms [M+H] +: 208.1. 6. Synthesis of int4D

[0198] Dissolve int4D-7 (0.49 g, 1.00 eq) in methanol (5 mL) and add 4 M hydrogen chloride / 1.4-dioxane solution (5 mL). Stir at room temperature for 30 minutes. Concentrate the reaction mixture in vacuo until no liquid is distilled out. Add dichloromethane and methyl tert-butyl ether to prepare a slurry, and filter to obtain the product (0.22 g, Ms [M+H] +: 104.1). [Intermediate] [int4E] [Synthesis:] 1. Synthesis of int4E-2

[0199] Compound int4E-1 (30 g, 0.322 mol) was dissolved in 200 mL of ethanol, followed by the addition of potassium hydroxide (72.3 g, 1.289 mol) and 200 mL of water. The temperature was raised to 80°C and the reaction was allowed to proceed for 16 hours. The reaction was complete. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the system for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 37.4 g of the product, Ms [MH] +: 111.1. 2. Synthesis of int4E-3

[0200] Compound int4E-2 (10 g, 89.2 mmol) was dissolved in 50 mL of dichloromethane, and N,N'-carbonyldiimidazole (21.67 g, 133.8 mmol) was added. The mixture was allowed to react at room temperature for 10 minutes. Dimethylhydroxylamine hydrochloride (13 g, 133.8 mmol) and triethylamine (27.02 g, 267.5 mmol) were then added and allowed to react at room temperature for 2 hours. The reaction was complete. Water and dichloromethane were added to the system, and the liquids were extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 13.3 g of the product, Ms [M+H] +: 156.1. 3. Synthesis of int4E-4

[0201] Under nitrogen, n-butyllithium (137.1 mL, 2.5 M in hexane) was added to 300 mL of anhydrous tetrahydrofuran. The system was cooled to -65°C, and acetonitrile (15.8 g, 385.6 mmol) was slowly added dropwise. After complete addition, the mixture was stirred at this temperature for 1 hour. A solution of compound int4E-3 (13.3 g, 85.7 mmol) in anhydrous tetrahydrofuran (140 mL) was then slowly added dropwise, and stirring continued for 2 hours. After the reaction was complete, water was added dropwise at -65°C to quench the reaction. After stirring and warming to room temperature, the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 6.86 g of crude product, which was used directly in the next step. Ms [M+H] +: 136.1. 4. Synthesis of int4E-5

[0202] Dissolve tert-butylhydrazine hydrochloride (9.49 g, 76.1 mmol) in 70 mL of ethanol and add triethylamine (7.69 g, 76.1 mmol) dropwise in an ice bath. After addition, warm the mixture to room temperature and stir for 0.5 hour. Then, add a 20 mL solution of compound int4E-4 (6.86 g, 50.8 mmol) in ethanol. Heat the reaction system to 75°C and stir for 16 hours. After completion of the reaction, cool the reaction mixture to room temperature, concentrate, and extract with water and ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography yields 8.5 g of the product, Ms [M+H] +: 206.2. 5. Synthesis of int4E-6

[0203] Compound int4E-5 (8.5 g, 41.4 mmol) was dissolved in 100 mL of acetonitrile and cooled in an ice-water bath. Benzyl chloroformate (14.08 g, 82.8 mmol) was added dropwise. After complete addition, the mixture was warmed to room temperature and stirred for 2 h. Then, sodium bicarbonate (11.13 g, 132.48 mmol) was added portionwise and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography to yield 12.8 g (Ms [M+H] +: 340.2). 6. Synthesis of int4E-7

[0204] Under nitrogen, compound int4E-6 (1 g, 3 mmol) was dissolved in 10% tetrahydrofuran and borane dimethyl sulfide solution (1.5 mL) was added dropwise in an ice-salt bath. The mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, aqueous sodium hydroxide solution (5 mL) and then 30% hydrogen peroxide solution (1.7 mL) were added in an ice-salt bath, and the reaction was continued at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium sulfite solution (5 mL), diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and rotary dried. The product was purified by column chromatography to yield 1.06 g, Ms [M+H] +: 358.2. 7. Synthesis of int4E-8

[0205] Compound int4E-7 (1.06 g, 2.97 mmol) was dissolved in 20 mL of dichloromethane. p-Nitrophenyl chloroformate (896.3 mg, 4.45 mmol), pyridine (702.8 mg, 8.90 mmol), and DMAP (36.2 mg, 0.3 mmol) were added sequentially, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed 4-5 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 1.1 g of the product (Ms [M+H] +: 523.2). 8. Synthesis of int4E-9

[0206] Compound int4E-8 (500 mg, 0.96 mmol) was dissolved in 3 mL of tetrahydrofuran, and isopropylamine (84.84 mg, 1.44 mmol) and diisopropylethylamine (370 mg, 2.87 mmol) were added sequentially. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction system was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with 1 mol / L sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield 273 mg of the product (Ms [M+H] +: 443.2). 9. Synthesis of int4E

[0207] Compound int4E-9 (273 mg, 0.62 mmol) was dissolved in 10 mL of methanol, followed by the addition of wet Pd / C (60 mg, 20 mol%). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 h. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 80 mg of the purified product (Ms [M+H] + : 309.2). [Intermediate] [int4F] [Synthesis:] 1. Synthesis of int4F-2

[0208] Compound int4F-1 (5.0 g, 22.42 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N,N'-carbonyldiimidazole (5.4 g, 33.63 mmol) was added. After stirring for 10 minutes, triethylamine (6.8 g, 67.26 mmol) and methoxymethylamine (4.4 g, 44.84 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was complete. An appropriate amount of water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. After purification by column chromatography, 6.0 g of the product was obtained, Ms [M+H] +: 267.1. 2. Synthesis of int4F-3

[0209] Compound int4F-2 (6.0 g, 22.56 mmol) was dissolved in tetrahydrofuran (50 mL). The atmosphere was replaced with nitrogen and the temperature was lowered to 0°C. Methyl Grignard reagent (47.37 mL, 47.37 mmol) was added dropwise. After addition, the mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction was cooled and quenched with saturated aqueous ammonium chloride. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded 2.84 g of the product (Ms [M+H] +: 222.2). 3. Synthesis of int4F-4

[0210] Dissolve compound int4F-3 (0.8 g, 3.62 mmol) in tetrahydrofuran (8 mL), cool to 0°C, and add sodium borohydride (150 mg, 3.98 mmol). After addition, stir at 0°C for 2 hours. Perform thin-layer chromatography (TLC) control. Cool the mixture and quench the reaction with saturated ammonium chloride. Extract the organic phase with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography to obtain 743 mg of the product (Ms [M+H] +: 224.2). 4. Synthesis of int4F

[0211] Dissolve compound int4F-4 (743 mg, 3.33 mmol) in methanol (15 mL) and add palladium on carbon (150 mg). Stir at room temperature for 1 hour. Thin-layer chromatography was performed. Filter through celite, concentrate under reduced pressure, and purify by column chromatography to yield 160 mg. [Intermediate] [int4G] [Synthesis:] 1. Synthesis of int4G-2

[0212] Compound int4G-1 (10 g, 1.0 eq) was dissolved in 40 mL of N-dimethylformamide. N,N'-carbonyldiimidazole (11 g, 1.5 eq) was added under ice-cooling and stirred for 10 minutes. Triethylamine (13.6 g, 3.0 eq) and dimethylhydroxylamine hydrochloride (8.8 g, 2.0 eq) were added and stirred at room temperature for 16 hours until the reaction was complete. Water was added to the system, and the liquids were extracted with ethyl acetate. The organic phase was then washed with saturated sodium chloride solution and concentrated in vacuo until liquid was eliminated. Purification by column chromatography yielded 11.78 g of the product. Ms [M+H] +: 289.1. 2. Synthesis of int4G-3

[0213] Compound int4G-2 (11.78 g, 1.0 eq) was dissolved in 236 mL of tetrahydrofuran. Under nitrogen, the mixture was cooled and stirred. At -5°C, 118 mL of 1 mol / L methylmagnesium bromide solution was slowly added dropwise. After addition, the temperature was slowly raised to room temperature and the reaction was allowed to proceed for 12 hours. The reaction was complete. Saturated ammonium chloride solution was added dropwise under an ice bath to quench the reaction, and the liquid phases were extracted with ethyl acetate. The organic phase was then washed with saturated sodium chloride solution, concentrated in vacuo until liquid was eliminated, and purified by column chromatography to yield 7.4 g of the product. Ms [M+H] +: 244.1. 3. Synthesis of int4G-4

[0214] Compound int4G-3 (1 g, 1.0 eq) was dissolved in 20 mL of tetrahydrofuran and 5 mL of methanol was added. The mixture was cooled with stirring in an ice bath, and sodium borohydride (188 mg, 1.1 eq) was slowly added. The reaction was allowed to react at 0°C for 1-2 hours. The reaction was complete. Saturated ammonium chloride solution was added dropwise in an ice bath to quench the reaction, and the phases were extracted with ethyl acetate. The organic phase was then washed with saturated sodium chloride solution and concentrated in vacuo until liquid was eliminated. The product was purified by column chromatography to yield 1.08 g, Ms [M+H] +: 224.1. 4. Synthesis of int4G

[0215] Dissolve compound int4G-4 (1.08 g, 1.0 eq) in 10 mL of methanol and add 0.01 g of palladium on carbon. After replacing the atmosphere with hydrogen three times, allow the mixture to react at room temperature for 1-2 hours. The reaction is complete. Filter the system and concentrate in vacuo to a complete liquid state, yielding 340 mg of the product (Ms [M+H] + 90.0). [use] [int1] [Synthesis method of the following intermediates:]

[0216] Method 1: Method 2: . Intermediate number structure int3 int5 int6 int7 int8 int9 int10 int11 int12 int13 int14 int15 int16 int17 int18 int19 int20 int21 int22 int23 int24 int25 int26 int27 int28 [Intermediate] [int1E] [Synthesis:] 1. Synthesis of int1E-1

[0217] Tetrahydrofuran (10 mL) was added to a 100 mL three-necked flask, int1D-1 (300 mg, 1 eq) was cooled to 0°C under N2 protection, DI ethyl acetate (332 mg, 4 eq) was added, and bicyclo[1.1.1]pentane-1-amine hydrochloride (115.48 mg, 1.5 eq) was added after stirring for 5 min. The mixture was stirred at 40°C for 6 h. After the reaction was completed, ethyl acetate (50 mL) was added to the reaction solution, which was washed with 1 M sodium hydroxide (30 mL x 3) and then with saturated sodium chloride (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to 260 mg. 2. Synthesis of int1E-2

[0218] To a 100 mL three-necked flask, dichloromethane (10 mL) and int1E-1 (260 mg, 1 eq) were added. The mixture was cooled to 0°C under N2 protection, and DI ethyl acetate (163.2 mg, 2 eq), (Boc)2O (179.3 mg, 1.3 eq) and DMAP (15.43 mg, 0.2 eq) were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, 20 mL of saturated sodium chloride and ethyl acetate (50 mL x 3) were added to the reaction solution and extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Pre-TLC purification yielded 220 mg. 3. Synthesis of int1E

[0219] Int1E-2 (220 mg, 1 eq), methanol (20 mL), and Pd / C (110 mg) were added to a 100 mL single-necked bottle. The mixture was stirred at 30°C for 2 h under a hydrogen atmosphere, filtered, and concentrated to obtain 180 mg of the product. [use] [int1E] [Synthesis method of the following intermediates:] Intermediate number structure int29 int30 int31 int32 int33 int34 int35 int36 int37 int38 int39 int40 int41 int42 int43 int44 int45 [Specific embodiment:] Example 1

[0220] Compounds of the present invention: .

[0221] The synthetic route and experimental process are as follows: . 1. Synthesis of C1-1

[0222] Int2 (165 mg, 1.0 eq), Pd(OAc)2 (15 mg, 0.1 eq), XantPhos (60 g, 0.2 eq), Cs2CO3 (334 mg, 3 eq), int1 (182 mg, 1.5 eq), and dioxane (8 mL) were added to a 100 mL sealed vial and reacted at 100°C for 2 h. After completion of the reaction, the product was filtered and rotary dried. Purification by preparative chromatography afforded 200 mg of C1-1. 2. C1 synthesis

[0223] To a 50 mL single-necked flask, add C1-1 (200 mg, 1.0 eq), followed by formic acid (10 mL) at room temperature. The reaction was allowed to react at 80°C for 2 h. Completion of the reaction was monitored by thin-layer chromatography. The pH was adjusted to near neutral with saturated sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative chromatography to yield 50 mg of C1. [M+H] +: 425.2, 1H NMR (400 MHz, CDCl 3) δ:ppm 7.94 (d, J = 5.9 Hz, 1H), 7.13 (d, J = 5.9 Hz, 1H), 6.39 (s, 1H), 5.87 (s, 1H), 5.21 (s, 1H), 4.58 (s, 1H), 3.81 (s, 1H), 3.65 (s, 3H), 3.20 (t, J = 8.2 Hz, 1H), 2.58 – 2.46 (m, 1H), 2.15 (dt, J = 12.9, 6.1 Hz, 1H), 2.00 – 1.94 (m, 2H), 1.88 (s, 2H), 1.84 (s, 2H), 1.79 (t, J = 3.8 Hz, 2H), 1.15 (dd, J = 6.6, 3.3 Hz, 6H). Example 2

[0224] Compounds of the present invention: .

[0225] The synthetic route and experimental process are as follows: . [ , , ]

[0226] 1. Compound C1 50 mg was prepared by the following chiral resolution method: Chromatography was performed on a Phenomenex Lux® 5 μm Cellulose-4 column (250 × 30 mm). The mobile phase was hexane:isopropanol (0.1% TFA) = 60:40 at a flow rate of 15 mL / min and a column temperature of 25°C. The following products were obtained: C3 (11 mg, 25.7 min, [M+H] + : 425.2) and C2 (12 mg, 34.4 min, [M+H] + : 425.2). Example 3

[0227] Compounds of the present invention: .

[0228] The synthetic route and experimental process are as follows: . 1. Synthesis of C4-1

[0229] To a 100 mL three-necked flask, add N,N-dimethylformamide (10 mL) and int2-5 (200 mg, 1 eq). The mixture was cooled to 0°C under nitrogen protection, and NaH (60%) (73.2 mg, 1.5 eq) was added. After stirring for 5 min, deuterated iodomethane (353.6 mg, 2 eq) was slowly added dropwise. The mixture was stirred at room temperature for 2 h. After the reaction was complete, saturated ammonium chloride (40 mL) was added to the reaction solution, which was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 195 mg of the product.

[0230] 1H NMR (400 MHZ CDCl 3) δ ppm 8.04 (d 5.9,1H, 6.73 (d 5.9,1H), 3.93 (,3H), 1.83 (,2H), 1.76 (t3.5,2H). 2. Synthesis of C4-2

[0231] C4-1 (195 mg, 1 eq) and dichloromethane (10 mL) were added to a 100 mL three-necked flask. The temperature was lowered to 0°C under nitrogen protection, and boron tribromide (5 mL) was added. After stirring at 40°C for 8 h, the pressure was reduced and the product was dissolved in dichloromethane after concentration. 1 mL of water was added to quench the solution. After concentration, 300 mg of crude product was obtained and the product was directly used for the next step. 3. Synthesis of C4-3

[0232] C4-2, dichloromethane (10 mL), and triethylamine (306 mg, 3 eq) were added to a 100 mL three-necked flask. The temperature was lowered to 0°C under nitrogen protection, and trifluoromethanesulfonic anhydride (427.38 mg, 1.5 eq) / dichloromethane (2 mL) was added. The mixture was stirred for 5 min. After the reaction was completed, saturated ammonium chloride (40 mL) was added to the reaction solution, which was then extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified using a thin layer preparative plate to obtain 100 mg of the product. 4. Synthesis of C4-4

[0233] To a 100 mL sealed vial was added C4-3 (100 mg, 1.0 eq), Pd(OAc)2 (6.89 mg, 0.1 eq), XantPhos (35.57 mg, 0.2 eq), Cs2CO3 (301 mg, 3 eq), int1 (113.72 mg, 1.5 eq), and dioxane (8 mL). The mixture was reacted at 100°C for 2 h. After completion, the reaction was filtered, concentrated, and purified using a preparative thin-layer plate to yield 97 mg of the product. 5. Synthesis of C4

[0234] C4-4 (97 mg, 1.0 eq) was added to a 50 mL single-necked bottle, and then formic acid (10 mL) was added at room temperature and reacted at 80°C for 2 h. After completion of the reaction, the pH was adjusted to near neutral with saturated sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by TLC to give 32 mg of the product. 1H NMR (400 MHz, CDCl 3) δ ppm 7.94 (d, J=5.7, 1H), 7.09 (d, J=5.7, 1H), 6.30 (s, 1H), 5.86 (s, 1H), 5.22 (s, 1H), 4.58 (s, 1H), 3.81 (s, 1H), 3.26 – 3.15 (m, 1H), 2.52 (s, 1H), 2.15 (d, J=6.4, 1H), 1.95 (s, 2H), 1.92 – 1.79 (m, 4H), 1.76 (dd, J=7.5, 3.6, 2H), 1.15 (d, J=6.4, 6H).

[0235] The products were prepared using the following chiral separation method: chromatography column: Phenomenex Lux® 5 μm Cellulose-4 (250 x 30 mm), mobile phase: n-hexane:isopropanol (0.1% TFA) = 60:40, flow rate: 15 mL / min, column temperature: 25°C, and the products prepared were: C6 (11.6 mg, 26.2 min) and C5 (11.2 mg, 35.2 min). Example 4

[0236] Compounds of the present invention: .

[0237] The synthetic route and experimental process are as follows: . 1. Synthesis of C7-1

[0238] To a 100 mL sealed vial, add int2 (150 mg, 1.0 eq), Pd(OAc)2 (11.27 mg, 0.1 eq), XantPhos (53.85 mg, 0.2 eq), cesium carbonate (303 mg, 2 eq), int3 (179 mg, 1.5 eq), and dioxane (8 mL). React at 100°C for 2 h. After completion, filter, concentrate, and purify using a preparative thin-layer plate to obtain 100 mg of the product. 2. Synthesis of C7 and C8

[0239] C7-1 (100 mg, 1.0 eq) was added to a 50 mL single-necked flask, followed by formic acid (10 mL) at room temperature and the reaction was allowed to proceed at 80°C for 2 h. After completion of the reaction, the pH was adjusted to near neutral with saturated sodium bicarbonate and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified using a thin-layer preparative plate to obtain the product C7-2 (40 mg). This was prepared using the following chiral separation method: chromatography column: Phenomenex Lux® 5 μm Cellulose-4 (250 x 30 mm), mobile phase: n-hexane:isopropanol (0.1% TFA) = 60:40, flow rate: 15 mL / min, column temperature: 25°C, to obtain the product: C8 (12 mg, 29.4 min), 1H NMR (400 MHz, CDCl 3) δ ppm 7.94 (d, J=5.7, 1H), 7.07 (d, J=5.7, 1H), 6.46 (s, 1H), 5.85 (s, 1H), 5.21 (s, 1H), 5.01 (s, 1H), 4.13 (s, 1H), 3.63 (s, 3H), 3.25 – 3.14 (m, 1H), 2.50 (s, 1H), 2.31 (s, 2H), 2.14 (s, 1H), 1.96 (d, J=10.1, 2H), 1.85 – 1.72 (m, 6H), 1.71 – 1.59 (m, 4H).

[0240] C7 (11 mg, 41.9 min), 1H NMR (400 MHz, CDCl 3) δ ppm 7.94 (d, J=5.8, 1H), 7.07 (d, J=5.3, 1H), 6.40 (s, 1H), 5.85 (s, 1H), 5.20 (s, 1H), 5.01 (s, 1H), 4.16 (s, 1H), 3.63 (s, 3H), 3.26 – 3.13 (m, 1H), 2.50 (s, 1H), 2.31 (s, 2H), 2.14 (s, 1H), 1.94 (s, 2H), 1.86 – 1.76 (m, 6H), 1.72 – 1.63 (m, 4H). Example 5

[0241] The compounds of the present invention: .

[0242] The synthesis route and experimental process are as follows: . 1. Synthesis of C9-1

[0243] Int-2 (150 mg, 1 eq), int4 (137 mg, 1 eq), Cs2CO3 (456 mg, 3 eq), Xantphos (54 mg, 0.2 eq), Pd(OAc)2 (10 mg, 0.1 eq), and 1,4-dioxane (10 mL) were added to a 25 mL sealed glass tube. The mixture was heated to 100°C under a nitrogen atmosphere for 2 h. The reaction was monitored until complete. The mixture was cooled, filtered, and washed three times with ethyl acetate. The organic phase was concentrated. Purification by column chromatography and concentration afforded 150 mg of the product. Ms [M+H] + 467. 2. Synthesis of C9

[0244] To a 5 mL sealed glass tube, add C9-1 (150 mg, 1 eq) and formic acid (2 mL). Heat to 80°C and react for 80 min. Monitor the reaction for completion. Cool and concentrate. Dissolve in ethyl acetate, adjust the pH to neutral with saturated sodium bicarbonate solution, and extract three times with ethyl acetate. Dry the organic phase over anhydrous sodium sulfate and concentrate. Thin-layer chromatography yields 24 mg of the product. 1HNMR (400 MHz, CDCl 3) δ ppm 7.94 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.34 (s, 1H), 5.89 (s, 1H), 5.04-4.87 (m, 1H), 4.52 (s, 1H), 3.86-3.73 (m, 1H), 3.64 (s, 3H), 3.15-3.03 (m, 1H), 2.91-2.80 (m, 2H), 2.28-2.16 (m, 2H), 1.86-1.80 (m, 2H), 1.79-1.74 (m, 2H), 1.16 (d, J = 6.4 Hz, 6H). Ms [M+H] +411. Example 6

[0245] Compounds of the present invention: .

[0246] The synthetic route and experimental process are as follows: . 1. Synthesis of C10-1

[0247] To a 25 mL single-necked vial were added int2 (150 mg, 1.00 eq), int5 (156.6 mg, 1.0 eq), Pd(OAc)2 (10.4 mg, 0.1 eq), Xantphos (53.8 mg, 0.2 eq), cesium carbonate (303.5 mg, 2.0 eq), and 1,4-dioxane (3 mL). The reaction was heated to 100°C under nitrogen for 2 hours. The reaction was monitored for completion, filtered, concentrated, and purified on a preparative thin-layer plate to yield 93 mg of the product. Ms [M+H] +509. 2. Synthesis of C10-2

[0248] Compound C10-1 (93 mg, 1.00 eq) and formic acid (3 mL) were added to a 25 mL single-necked flask. The temperature was raised to 80°C and the reaction was allowed to react for 1 hour. The reaction was monitored for completion and concentrated under reduced pressure. Aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8. The solution was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a preparative thin-layer plate to yield 31 mg of the product. Ms [M+H] +: 453.25. 3. Synthesis of C10 and C11

[0249] C10-2 (31 mg) was prepared by the following chiral separation method: chromatography column: Phenomenex Lux® 5 μm Amylose-1 (250 x 21.2 mm), mobile phase: n-hexane:ethanol = 7:3, flow rate: 20 mL / min, column temperature: 25°C, to obtain the product: C10(7.3 mg,17.6 min),Ms [M+H] +:453.25, 1H NMR (400 MHz, CDCl 3) δ ppm 7.94-7.92 (d, J = 8 Hz, 1H), 7.10-7.09 (d, J = 4 Hz, 1H), 6.40 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.46-4.49 (d, J = 12 Hz, 1H), 3.64 (s, 3H), 3.47 (s, 1H), 3.15-3.29 (m, 1H), 2.57-2.49 (m, 1H), 2.12-2.19 (m, 1H), 1.94-2.01 (m, 2H), 1.90-1.75 (m, 6H), 1.49-1.58 (m, 2H), 1.32-1.40 (m, 2H), 0.89 (m, 6H).

[0250] C11(7.5 mg, 26.0 min), Ms [M+H] +:453.25, 1H NMR (400 MHz, CDCl 3) δ ppm 7.94-7.92 (d, J = 8 Hz, 1H), 7.10-7.09 (d, J = 4 Hz, 1H), 6.40 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.46-4.49 (d, J = 12 Hz, 1H), 3.64 (s, 3H), 3.47 (s, 1H), 3.15-3.29 (m, 1H), 2.57-2.49 (m, 1H), 2.12-2.19 (m, 1H), 1.94-2.01 (m, 2H), 1.90-1.75 (m, 6H), 1.49-1.58 (m, 2H), 1.32-1.40 (m, 2H), 0.89 (m, 6H). Example 7

[0251] The compounds of the present invention: .

[0252] The synthesis route and experimental process are as follows: . 1. Synthesis of C12-1

[0253] To a 100 mL sealed vial were added int2 (190 mg, 1.0 eq), Pd(OAc)2 (22.4 mg, 0.1 eq), XantPhos (117.4 mg, 0.2 eq), cesium carbonate (975 mg, 3 eq), int6 (483 mg, 1.5 eq), and 1,4-dioxane (6 mL). The mixture was reacted at 100°C for 16 h under nitrogen. After completion of the reaction, the mixture was cooled to room temperature, filtered, and concentrated to obtain the crude product. Purification by preparative thin-layer chromatography yielded 210 mg of the product, Ms [M+H] +: 495.6. 2. Synthesis of C12-2

[0254] To a 50 mL single-necked flask, add C12-1 (190 mg, 1.0 eq), followed by formic acid (10 mL) at room temperature and react at 80°C for 2 h. Monitor the reaction until completion, adjust the pH to 7-8 with saturated sodium bicarbonate, and extract with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a preparative thin-layer plate to yield 80 mg of the product, Ms [M+H] +: 439.5. 3. Synthesis of C12 and C13

[0255] C12-2 (80 mg) was prepared by the following chiral separation method: chromatography column: Phenomenex Lux® 5 μm Cellulose-4 (250 × 30 mm), n-hexane:isopropanol (0.1% TFA) = 60:40, flow rate: 15 mL / min, column temperature: 25°C, to prepare the product: C12 (30 mg,24.3 min),Ms [M+H] +:439.5, 1H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (s, 1H), 7.84 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 7.24 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.76 (s, 1H), 4.99 (s, 1H), 3.46 (s, 3H), 3.38 (dd, J = 14.6, 7.7 Hz, 1H), 3.05 (q, J = 8.5 Hz, 1H), 2.48 – 2.38 (m, 1H), 2.07 – 1.98 (m, 1H), 1.88 (d, J = 12.5 Hz, 1H), 1.73 (d, J = 8.4 Hz, 2H), 1.66 – 1.57 (m, 3H), 1.54 (q, J = 4.3, 3.6 Hz, 2H), 1.39 – 1.30 (m, 2H), 1.00 (d, J = 6.6 Hz, 3H), 0.79 (t, J = 7.4 Hz, 3H)。

[0256] C13 (25 mg, 30.0 min), Ms [M+H] +:439.5, 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H), 7.84 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 7.24 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.76 (d, J = 1.5 Hz, 1H), 4.99 (s, 1H), 3.46 (s, 3H), 3.39 (dt, J = 14.0, 6.1 Hz, 1H), 3.14 – 2.97 (m, 1H), 2.47 – 2.40 (m, 1H), 2.04 (d, J = 13.9 Hz, 1H), 1.93 – 1.84 (m, 1H), 1.78 – 1.68 (m, 2H), 1.67 – 1.57 (m, 3H), 1.54 (q, J = 4.2, 3.6 Hz, 2H), 1.34 (d, J = 7.4 Hz, 2H), 0.99 (d, J = 6.6 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H). The following compounds were synthesized using the above synthesis method: Compound Ms [M+H] + 1H NMR 439.2 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J = 5.8 Hz, 1H), 7.09 (d, J = 5.8 Hz, 1H), 6.30 (s, 1H), 5.86 (s, 1H), 5.20 (s, 1H), 4.50 (s, 1H), 3.64 (s, 3H), 1.82 (t, J = 3.4 Hz, 3H), 1.77 (d, J = 2.9 Hz, 2H), 1.42 (s, 3H), 1.13 (d, J = 6.6 Hz, 5H), 0.86 (dd, J = 7.2, 1.4 Hz, 8H) 439.2 1H NMR (400 MHz, CDCl 3) δ ppm 7.93 (d, J = 5.8 Hz, 1H), 7.09 (d, J = 5.8 Hz, 1H), 6.29 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.49 (s, 1H), 3.64 (s, 3H), 1.86 – 1.80 (m, 3H), 1.76 (t, J = 3.4 Hz, 2H), 1.42 (s, 3H), 1.12 (d, J = 6.6 Hz, 5H), 0.88 – 0.84 (m, 8H). 451.2 1H NMR (400 MHz, CDCl 3) δ = 7.94 (d, J=6.1, 1H), 7.24 (d, J=6.2, 1H), 7.00 (s, 1H), 5.88 (s, 1H), 5.20 (s, 1H), 5.05 (s, 1H), 3.66 (s, 3H), 3.26 – 3.16 (m, 1H), 2.52 (s, 1H), 2.29 (s, 2H), 2.16 (dd, J=12.1, 6.0, 1H), 2.05 – 1.99 (m, 2H), 1.97 (dd, J=8.9, 4.3, 4H), 1.89 – 1.75 (m, 6H), 1.42 (s, 3H). 451.2 1H NMR (400 MHz, CDCl 3) δ = 7.94 (d, J=6.0, 1H), 7.20 (d, J=6.0, 1H), 6.82 (s, 1H), 5.88 (s, 1H), 5.19 (d, J=5.9, 1H), 5.00 (s, 1H), 3.63 (d, J=14.3, 3H), 3.24 – 3.15 (m, 1H), 2.52 (s, 1H), 2.29 (s, 2H), 2.20 – 2.10 (m, 1H), 2.02 – 1.90 (m, 6H), 1.91 – 1.77 (m, 6H). 1.42 (s, 3H) 487.2 1H NMR (400 MHz, CDCl 3) δ 7.94 (d, J=5.8 Hz, 1H), 7.10 (d, J = 5.9 Hz, 1H), 6.59 (s, 1H), 5.85 (s, 1H), 5.36 – 5.17 (m, 2H), 3.62 (s, 3H), 3.21 (p, J = 8.3 Hz, 1H), 2.93 (d, J = 14.0 Hz, 3H), 2.58 (q, J = 12.3, 11.2 Hz, 5H), 2.16 (dt, J = 12.5, 7.1 Hz, 2H), 1.96 (dd, J = 9.5, 4.7 Hz, 3H), 1.79 (q, J = 4.3, 3.8 Hz, 2H), 1.25 (s, 3H). 487.2 1H NMR (400 MHz, CDCl 3) δ 7.94 (d, J = 5.8 Hz, 1H), 7.10 (d, J = 5.9 Hz, 1H), 6.75 (s, 1H), 5.84 (s, 1H), 5.26 (d, J = 33.5 Hz, 2H), 3.61 (s, 3H), 3.21 (p, J = 8.2 Hz, 1H), 3.02 – 2.82 (m,3H), 2.58 (td, J = 13.4, 7.6 Hz, 5H), 2.17 (dq, J = 12.5, 5.7 Hz, 2H), 2.01 – 1.92 (m, 3H), 1.79 (q, J = 4.5, 3.8 Hz, 2H), 1.25 (s, 3H). 493.5 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.8 Hz, 1H), 7.10 (d, J= 5.8 Hz, 1H), 6.36 (s, 1H), 5.86 (s, 1H), 5.28 – 5.15 (m, 1H), 4.84 (s, 1H), 4.05 (s, 1H), 3.63 (s, 3H), 3.19 (p, J= 8.2 Hz, 1H), 2.60 – 2.48 (m, 1H), 2.42 (s, 1H), 2.24 (d, J= 14.7 Hz, 1H), 2.16 (dt, J= 12.3, 6.0 Hz, 1H), 1.99 – 1.93 (m, 2H), 1.90 – 1.80 (m, 5H), 1.79 – 1.76 (m, 2H), 1.28 (d, J= 6.9 Hz, 3H). 493.5 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.7 Hz, 1H), 7.09 (d, J= 5.8 Hz, 1H), 6.45 (s, 1H), 5.85 (s, 1H), 5.22 (d, J= 6.5 Hz, 1H), 5.02 (s, 1H), 4.02 (d, J= 27.5 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.63 (s, 3H), 3.21 (t, J= 8.3 Hz, 1H), 2.49 (d, J= 15.4 Hz, 1H), 2.39 (d, J= 12.9 Hz, 1H), 2.25 (td, J= 16.1, 15.0, 5.4 Hz, 1H), 2.16 (dq, J= 12.6, 6.2, 5.7 Hz, 1H), 1.96 (d, J= 7.1 Hz, 2H), 1.90 – 1.81 (m, 4H), 1.77 (q, J= 4.5, 3.8 Hz, 2H), 1.29 (d, J= 7.0 Hz, 3H). 493.5 1H NMR (400 MHz, CDCl 3) δ 7.94 (d, J= 5.8 Hz, 1H), 7.12 (d, J= 5.8 Hz, 1H), 6.39 (br, 1H), 5.86 (m, 1H), 5.26-5.18 (m, 1H), 4.89-4.78 (m, 1H), 4.15-3.92 (m, 2H), 3.63 (s, 3H), 3.26-3.13 (m, 1H), 2.60-2.12 (m, 4H), 1.99-1.86 (m, 2H), 1.85-1.78 (m, 4H), 1.77-1.74 (m, 2H), 1.26 (d, J= 6.9 Hz, 3H). 493.5 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.8 Hz, 1H), 7.10 (d, J= 5.8 Hz, 1H), 6.36 (br, 1H), 5.86 (m, 1H), 5.28-5.15 (m, 2H), 4.89-4.78 (m, 2H), 4.15-3.89 (m, 2H), 3.63 (s, 3H), 3.26-3.13 (m, 2H), 2.60-2.48 (m, 4H), 2.42-2.12 (m, 3H), 1.99-1.86 (m, 2H), 1.28 (d, J= 6.9 Hz, 3H). 451.2 1H NMR (400 MHz, DMSO- d 6) δ ppm 12.02 (s, 1H), 7.90 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.36-7.16 (m, 1H), 5.78-5.74 (m, 1H), 5.08-5.00 (m, 1H), 3.82-3.70 (m, 1H), 3.46 (s, 3H), 3.26-3.20 (m, 2H), 3.14-3.06 (m, 1H), 2.47-2.37 (m, 1H), 2.10-1.99 (m, 1H), 1.95-1.87 (m, 2H), 1.81-1.74 (m, 3H), 1.74-1.68 (m, 2H), 1.67-1.62 (m, 2H), 1.57-1.53 (m, 2H), 1.50-1.43 (m, 1H), 1.09-1.04 (m, 3H). 451.2 1H NMR (400 MHz, DMSO- d 6) δ ppm 12.0 (s, 1H), 7.88 (s, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.30-7.16 (m, 1H), 5.76-5.73 (m, 1H), 5.05-5.00 (m, 1H), 3.84-3.68 (m, 1H), 3.46 (s, 3H), 3.27-3.20 (m, 2H), 3.13-3.05 (m, 1H), 2.47-2.36 (m, 1H), 2.08-1.99 (m, 1H), 1.97-1.86 (m, 2H), 1.83-1.74 (m, 3H), 1.74-1.66 (m, 2H), 1.66-1.61 (m, 2H), 1.57-1.52 (m, 2H), 1.50-1.43 (m, 1H), 1.11-1.02 (m, 3H). 453.2 1HNMR (400 MHz, CDCl 3) δppm 7.94 (d, J= 5.6 Hz, 1H), 7.10 (d, J= 5.6 Hz, 1H), 6.35 (s, 1H), 5.87 (s, 1H), 5.29-5.08 (m, 2H), 4.80 (s, 2H), 4.46 (s, 2H), 3.63 (s, 3H), 3.29-3.12 (m, 1H), 2.61-2.45 (m, 1H), 2.21-2.12 (m, 1H), 2.01-1.92 (m, 2H), 1.91-1.82 (m, 4H), 1.80-1.73 (m, 3H), 1.62 (s, 3H). 453.2 1HNMR (400 MHz, CDCl 3) δppm 7.94 (d, J= 5.6 Hz, 1H), 7.10 (d, J= 5.6 Hz, 1H), 6.35 (s, 1H), 5.87 (s, 1H), 5.29-5.08 (m, 2H), 4.80 (s, 2H), 4.47 (s, 2H), 3.63 (s, 3H), 3.29-3.12 (m, 1H), 2.61-2.45 (m, 1H), 2.21-2.12 (m, 1H), 1.92-1.82 (m, 4H), 1.79-1.71 (m, 3H), 1.62 (s, 3H). 449.2 1H NMR (400 MHz, CDCl 3) δ = 7.93 (d, J=5.8, 1H), 7.09 (d, J=5.8, 1H), 6.35 (s, 1H), 5.86 (s, 1H), 5.34 – 5.13 (m, 2H), 3.82 – 3.74 (m, 1H), 3.70 – 3.58 (m, 3H), 3.27 – 3.07 (m, 1H), 2.52 (s, 1H), 2.42 (s, 1H), 2.15 (d, J=6.3, 1H), 2.09 – 1.93 (m, 7H), 1.85 (dd, J=7.6, 3.7, 4H), 1.77 (t, J=3.4, 2H). 449.2 1H NMR (400 MHz, CDCl 3)δ = 7.94 (d, J=5.8, 1H), 7.08 (d, J=5.8, 1H), 6.34 (s, 1H), 5.85 (s, 1H), 5.36 – 5.13 (m, 2H), 3.82 – 3.73 (m, 1H), 3.67 – 3.60 (m, 3H), 3.20 (dd, J=16.3, 8.5, 1H), 2.52 (s, 1H), 2.42 (s, 1H), 2.15 (d, J=6.1, 1H), 2.06 – 1.94 (m, 7H), 1.90 – 1.80 (m, 4H), 1.77 (dt, J = 8.7, 4.4, 2H) 451.2 1HNMR(400 MHz, CDCl 3)δ 7.93 (d, J= 5.9 Hz, 1H), 7.11 (d, J= 5.8 Hz, 1H), 6.38 (s, 1H), 5.87 (s, 1H), 5.21 (ddd, J= 9.7, 6.4, 3.8 Hz, 1H), 3.65 (s, 3H), 3.38 (s, 4H), 3.20 (p, J= 8.1 Hz, 1H), 2.54 (ddd, J= 14.9, 9.0, 6.4 Hz, 1H), 2.22 – 2.11 (m, 1H), 2.02 – 1.95 (m, 2H), 1.93 – 1.84 (m, 4H), 1.77 (q, J= 4.5, 3.8 Hz, 2H), 1.53 (d, J= 20.5 Hz, 6H). Example 8

[0257] The compounds of the present invention: .

[0258] The synthesis route and experimental process are as follows: . 1. Synthesis of C31-1

[0259] Int15 (150 mg, 1.00 eq), int2B (231 mg, 1.0 eq), palladium acetate (16 mg, 0.1 eq), XantpHos (83 mg, 0.2 eq), cesium carbonate (715 mg, 3.0 eq) and 1,4-dioxane (23 mL) were added to a 25 mL single-necked bottle. The temperature was raised to 100°C under nitrogen protection and the reaction was carried out for 2 hours. After the reaction was completed, the mixture was filtered, concentrated, and purified by thin-layer chromatography preparative plate to obtain 230 mg of the product, Ms [M+H] +: 493.2. 2. Synthesis of C31-2

[0260] Compound C31-1 (230 mg, 1.00 eq) and formic acid (23 mL) were added to a 25 mL single-necked flask. The temperature was raised to 80°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate was added to the reaction solution to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to obtain 97 mg of the product, Ms [M+H] +: 437.2. 3. Preparation of C31 and C32

[0261] C31-2 (97 mg) was separated by chiral HPLC to obtain the product. The separation conditions were as follows: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Amylose-1 (250 × 21.2 nm); Mobile phase: n-hexane:ethanol = 6:4; Flow rate: 20 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; C31(14.4 min, 13.95 mg) 1H NMR (400 MHz, CDCl 3) δ ppm7.92 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 6.39 (s, 1H), 5.85 (s, 1H), 5.15 (d, J = 37.2 Hz, 2H), 3.63 (s, 3H), 3.19 (s, 1H), 2.52 (dt, J = 15.2, 8.0 Hz, 1H), 2.14 (s, 1H), 1.94 (s, 2H), 1.84 (q, J = 3.6, 2.8 Hz, 3H), 1.76 (q, J = 4.8, Ms [M+H] +:437.2.

[0262] C32(20.6 min, 15.76 mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.92 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 6.40 (s, 1H), 5.85 (s, 1H), 5.36 - 5.01 (m, 2H), 3.63 (s, 3H), 3.19 (s, 1H), 2.52 (dt, J = 14.8, 8.0 Hz, 1H), 2.14 (s, 1H), 1.94 (s, 2H), 1.87 - 1.80 (m, 3H), 1.78 - 1.72 (m, 2H), 1.35 (s, 3H), 1.26 (ddd, J = 7.2, 5.6, 2.0 Hz, 1H), 0.88 - 0.82 (m, 1H), 0.74 (t, J = 3.2 Hz, 2H), 0.61 (s, 2H). Ms [M+H] +:437.2. Example 9

[0263] The compounds of the present invention: .

[0264] The synthetic route and experimental process are as follows: . 1. Synthesis of C35-1

[0265] To a 25 mL reaction vial, int2B (150 mg, 1.0 eq), int16 (300 mg, 1.3 eq), palladium acetate (17 mg, 0.1 eq), XantPHos (83 mg, 0.2 eq), carbonic acid (700 mg, 3.0 eq), and 1,4-dioxane (15 mL) were added and reacted at 100°C for 3 h. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain 200 mg of the product. 2. Synthesis of C35-2

[0266] To a 25 mL reaction flask, add C35-1 (200 mg, 1.0 eq) and formic acid (5 mL). Incubate at 80°C for 2 h. After completion of the reaction, slowly add saturated sodium bicarbonate solution to adjust the pH to 8-9. Extract three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to yield 55 mg of the product. 3. Synthesis of C35 and C36

[0267] C35-2 (55 mg) was chiral resolved according to the following separation conditions: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Amylose-1 (250 × 21.2 nm); Mobile phase: n-hexane:ethanol = 6:4; Flow rate: 15 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; C36(27.1 min, 18 mg) 1H NMR (400 MHz, CDCl 3) δ ppm7.92 (d, J = 5.6 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 6.72-6.55 (m, 1H), 5.85 (s, 1H), 5.87-5.12(m, 2H), 4.91-4.77 (m, 1H), 3.66 (s, 3H), 3.31-3.21 (m, 1H), 2.81-2.48 (m, 3H), 2.26-1.73 (m, 8H), 0.92-0.73 (m, 4H). Ms [M+H] +:423.4.

[0268] C35(37.2 min, 19 mg) 1H NMR (400 MHz, CDCl 3) δ ppm7.92 (d, J = 5.6 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 6.89-6.71 (m, 1H), 5.85 (s, 1H), 5.12-5.87 (m, 2H), 4.91-4.77 (m, 1H), 3.65 (s, 3H), 3.31-3.21 (m, 1H), 2.81-2.48 (m, 3H), 2.28-1.78 (m, 8H). Ms [M+H] +:423.4. Example 10

[0269] The compounds of the present invention: .

[0270] The synthesis route and experimental process are as follows: . 1. Synthesis of C63-1

[0271] Int2F (150 mg, 1.00 eq), int7 (225 mg, 1.00 eq), cesium carbonate (661 mg, 3.00 eq), XantpHos (78 mg, 0.20 eq), palladium acetate (15 mg, 0.10 eq), and 1,4-dioxane (5 mL) were added to a sealed glass tube and the atmosphere was replaced with nitrogen. The temperature was raised to 100°C and the reaction was allowed to proceed for 2 h. The reaction was complete. The reaction mixture was cooled, filtered, and the solid was washed with ethyl acetate. The filtrate was then concentrated under reduced pressure. Purification by preparative thin-layer chromatography afforded 250 mg of the pure product. Ms [M+H] +: 519.3. 2. Synthesis of C63

[0272] Compound C63-1 (200 mg, 1.00 eq) was dissolved in formic acid (6 mL), heated to 80°C, and stirred for 1.5 hours. The reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The product was redissolved in ethyl acetate, the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by preparative thin-layer chromatography yielded 57 mg of the product. 1H NMR (400 MHz, CDCl 3) δppm 6.93 (s, 1H), 6.23 (s, 1H), 5.83 (s, 1H), 5.33-5.14 (m, 2H), 3.59 (s, 3H), 3.26-3.14 (m, 1H), 2.58-2.47 (m, 1H), 2.41 (s, 1H), 2.40 (s, 3H), 2.20-2.09 (m, 1H), 2.07-1.91 (m, 7H), 1.90-1.76 (m, 4H), 1.75-1.69 (m, 2H), 1.68-1.62 (m, 1H). Ms [M+H] +:463.2. The following compounds were synthesized using the above-mentioned synthesis method: Compound Ms [M+H] + 1H NMR 451.2 1HNMR(400 MHz, DMSO- d 6) δ ppm 11.99 (s, 1H), 7.85 (s, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.32-7.13 (m, 1H), 5.76-5.72 (m, 1H), 5.07-4.99 (m, 1H), 3.84-3.70 (m, 1H), 3.45 (s, 3H), 3.29-3.18 (m, 2H), 3.14-3.05 (m, 1H), 2.48-2.35 (m, 1H), 2.07-1.99 (m, 1H), 1.97-1.86 (m, 2H), 1.83-1.74 (m, 3H), 1.74-1.66 (m, 2H), 1.65-1.60 (m, 2H), 1.56-1.51 (m, 2H), 1.51-1.43 (m, 1H), 1.11-1.01 (m, 3H). 451.2 1HNMR(400 MHz, DMSO- d 6) δ ppm 12.00 (s, 1H), 7.86 (s, 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.29-7.17 (m, 1H), 5.77-5.72 (m, 1H), 5.08-4.99 (m, 1H), 3.86-3.68 (m, 1H), 3.46 (s, 3H), 3.27-3.19 (m, 2H), 3.15-3.03 (m, 1H), 2.47-2.38 (m, 1H), 2.08-1.99 (m, 1H), 1.94-1.85 (m, 2H), 1.81-1.74 (m, 3H), 1.73-1.66 (m, 2H), 1.65-1.60 (m, 2H), 1.56-1.51 (m, 2H), 1.51-1.42 (m, 1H), 1.09-1.03 (m, 3H). 453.2 - 453.2 - 455.2 1H NMR (400 MHz, CDCl 3) δ = 7.92 (d, J=5.8, 1H), 7.08 (d, J=5.8, 1H), 6.46 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 5.05 (s, 1H), 3.87 (s, 1H), 3.64 (s, 3H), 3.40 – 3.29 (m, 5H), 3.25 – 3.15 (m, 1H), 2.57 – 2.46 (m, 1H), 2.15 (d, J=6.4, 1H), 1.95 (dd, J=12.8, 7.5, 2H), 1.90 – 1.80 (m, 4H), 1.78 – 1.72 (m, 2H), 1.16 (d, J=6.7, 3H) 450.5 1H NMR (400 MHz, CDCl 3)δ 7.93 (d, J= 5.8 Hz, 1H), 7.10 (d, J= 5.8 Hz, 1H), 6.34 (s, 1H), 5.86 (s, 1H), 5.23 (s, 1H), 3.64 (s, 3H), 3.19 (p, J= 8.2 Hz, 1H), 2.52 (s, 1H), 2.42 (s, 1H), 2.21 – 2.10 (m, 1H), 1.96 (t, J= 7.2 Hz, 3H), 1.85 (q, J= 3.8, 3.0 Hz, 4H), 1.79 – 1.75 (m, 3H), 1.64 (s, 4H) 463.5 1H NMR (400 MHz, CDCl 3) δppm 6.97 (s, 1H), 6.23 (br, 1H), 5.85 (s, 1H), 5.26-5.21 (m, 2H), 3.61 (s, 3H), 3.25-3.16 (m, 1H), 2.59-2.45 (m, 1H), 2.43 (s, 3H), 2.20-2.09 (m, 1H), 2.07-1.71 (m, 10H), 1.69-1.48 (m, 4H), 0.88-0.76 (m, 2H). 453.2 1HNMR(400MHz,DMSO-d6) δ 11.99 (s, 1H), 7.93 – 7.71 (m, 2H), 7.47 – 7.17 (m, 2H), 5.76 (s, 1H), 5.04 – 4.84 (m, 2H), 4.19 (q, J = 5.9 Hz, 1H), 3.99 (d, J = 6.3 Hz, 1H), 3.05 (d, J = 8.7 Hz, 1H), 2.45 (dd, J = 13.9, 7.1 Hz, 1H), 2.04 (t, J = 6.1 Hz, 4H), 1.90 (s, 1H), 1.72 (d, J = 9.5 Hz, 2H), 1.63 (q, J = 3.6, 3.0 Hz, 2H), 1.59 (d, J = 3.1 Hz, 1H), 1.54 (dt, J = 6.9, 2.9 Hz, 2H). 467.5 1H NMR (400 MHz, CDCl 3)δ 7.94 (d, J= 5.5 Hz, 1H), 7.07 (d, J= 5.8 Hz, 1H), 6.41 (s, 1H), 5.87 (s, 1H), 5.20 (s, 2H), 4.01 – 3.82 (m, 3H), 3.63 (s, 3H), 3.58 (dd, J= 9.1, 2.7 Hz, 1H), 3.27 – 3.16 (m, 1H), 2.50 (s, 1H), 2.25 (d, J= 6.3 Hz, 1H), 2.15 (d, J= 7.6 Hz, 2H), 1.93 (d, J= 11.0 Hz, 3H), 1.88 – 1.80 (m, 4H), 1.78 – 1.74 (m, 2H), 1.49 (s, 3H). 441.5 - 453.2 1HNMR(400MHz, DMSO- d6) δppm 11.98 (s, 1H), 7.88-7.81 (m, 2H), 7.33-7.22 (m, 2H), 5.77 (s, 1H), 5.07-4.90 (m, 2H), 3.80-3.67 (m, 1H), 3.47 (s, 3H), 3.45-3.38 (m, 1H), 3.13-2.99 (m, 1H), 2.48-2.36 (m, 3H), 2.07-1.97 (m, 1H), 1.95-1.83 (m, 1H), 1.78-1.67 (m, 4H), 1.66-1.61 (m, 2H), 1.61-1.57 (m, 1H), 1.57-1.51 (m, 2H). 466.2 1H NMR (400 MHz, CDCl 3) δ ppm 7.93-7.92 (d, J = 4 Hz, 1H), 7.09-7.08 (d, J = 4 Hz, 1H), 6.42 (s, 1H), 5.85 (s, 1H), 5.21-5.19 (d, J = 8 Hz, 1H), 5.02-5.00 (d, J = 8 Hz, 1H), 3.82-3.76 (m, 1H), 3.63 (s, 3H), 3.60-3.57 (m, 1H), 3.22(s,3H), 2.72-2.70 (m, 2H), 2.55-2.47 (m, 1H), 2.15-2.13 (m, 1H), 1.95-1.94(m, 2H), 1.84-1.74(m, 10H). 469.2 1H NMR (400 MHz, CDCl 3)δ 7.92 (d, J= 5.8 Hz, 1H), 7.06 (d, J= 5.8 Hz, 1H), 6.58 (s, 1H), 5.84 (s, 1H), 5.25 – 5.05 (m, 2H), 3.88 (qd, J= 6.3, 3.0 Hz, 1H), 3.61 (s, 3H), 3.23 (s, 1H), 2.53 – 2.38 (m, 1H), 2.27 – 2.08 (m, 1H), 2.02 – 1.87 (m, 4H), 1.84 (q, J= 3.9, 3.0 Hz, 2H), 1.76 (q, J= 4.7, 3.8 Hz, 2H), 1.58 (d, J= 18.9 Hz, 1H), 1.39 – 1.22 (m, 3H), 1.11 (d, J= 6.4 Hz, 3H), 0.95 (t, J= 7.3 Hz, 3H). 455.5 1H NMR (400 MHz, CDCl 3) δ 7.82 (d, J = 5.6 Hz, 1H), 7.26 (d, J = 5.6 Hz, 1H), 6.54 (br, 1H), 5.87-5.85 (m, 1H), 5.24-5.13 (m, 1H), 5.00-4.93 (m, 1H), 3.68 (s, 3H), 3.68-3.50 (m, 2H), 3.25-3.10 (m, 1H), 2.58-2.48 (m, 1H), 2.25-1.78 (m, 10H), 1.30-1.21 (m, 6H). 439.3 1HNMR(400MHz, DMSO- d6) δ ppm 11.95 (s, 1H), 7.76 (s, 1H), 7.15 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 5.00 (s, 1H), 3.58 (d, J = 8.0 Hz, 1H), 3.44 (s, 3H), 3.07 (t, J = 8.0 Hz, 1H), 2.27 (s, 3H), 2.08 -1.44 (m, 10H), 1.12 - 0.96 (m, 6H). Example 11

[0273] The compounds of the present invention: .

[0274] The synthesis route and experimental process are as follows: . 1. Synthesis of C37-1

[0275] Int2C (280 mg, 1.0 eq), tetrahydrofuran (10 mL), (S)-1-cyclopropylethylamine (95 mg, 2.0 eq), and N,N-diisopropylethylamine (285 mg, 4.0 eq) were added to a 50 mL flask and reacted at 50°C for 2 h. After the reaction, water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified to obtain 50 mg of the product. 2. Synthesis of C37 and C38

[0276] C37-1 (50 mg) was prepared by chiral resolution as follows: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Amylose-1 (250 × 21.2 nm); Mobile phase: n-hexane:ethanol = 6:4; Flow rate: 15 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; After chiral splitting, the following was obtained: C38(21.1 min, 16 mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.95 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.45 (br, 1H), 5.86 (s, 1H), 5.23 (m, 1H), 4.86 (m, 1H), 3.66 (s, 3H), 3.12 (q, J = 8.0 Hz, 1H), 3.10-3.05 (m, 1H), 2.59-2.30 (m, 2H), 2.14-1.58 (m, 8H), 0.95-0.79 (m, 4H), 0.52-0.23 (m, 4H). Ms [M+H] +:451.7.

[0277] C37(28.9 min, 17 mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.94 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 5.6 Hz, 1H), 6.45 (br, 1H), 5.86 (s, 1H), 5.22 (m, 1H), 4.86 (m, 1H), 3.66 (s, 3H), 3.12 (q, J = 8.0 Hz, 1H), 3.10-3.05 (m, 1H), 2.59-2.30 (m, 2H), 2.14-1.71 (m, 8H), 0.94-0.78 (m, 4H), 0.53-0.21 (m, 4H). Ms [M+H] +:451.7. Example 12

[0278] Compounds of the present invention: .

[0279] The synthetic route and experimental process are as follows: . 1. Synthesis of C61

[0280] In a 25 mL single-necked vial, compound int2D (80 mg, 1.00 eq), (S)-(+)-1-methoxy-2-propylamine (21.2 mg, 1.5 eq), and tetrahydrofuran (1.6 mL) were added, followed by N,N-diisopropylethylamine (61 mg, 3.00 eq). The reaction was heated to 50°C for 1–2 hours, and the reaction was complete. The system was rotary dried, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and separated by HPLC to yield 26.75 mg of the product, Ms [M+H] +: 455.3. 1H NMR (400 MHz, CDCl 3) δ ppm7.93 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.38 (s, 1H), 5.86 (s, 1H), 5.19 (dt, J = 6.4, 3.9 Hz, 1H), 4.94 (s, 1H), 3.87 (s, 1H), 3.64 (s, 3H), 3.35 (s, 5H), 3.20 (s, 1H), 2.51 (ddd, J = 15.1, 9.3, 6.4 Hz, 1H), 2.15 (d, J = 6.0 Hz, 1H), 1.94 (d, J = 6.0 Hz, 2H), 1.91 – 1.79 (m, 4H), 1.79 – 1.63 (m, 3H), 1.17 (d, J = 6.8 Hz, 3H). Example 13

[0281] Compounds of the present invention: .

[0282] The synthetic route and experimental process are as follows: . 1. Synthesis of Compound C101-1

[0283] Compounds int2D (150 mg, 1.0 eq) and int4G (40 mg, 1.5 eq) were dissolved in tetrahydrofuran (15 mL), followed by the addition of N,N-diisopropylethylamine (115 mg, 3.00 eq). The mixture was heated to 50°C for 20 minutes, then rotary dried and purified by preparative thin-layer chromatography to yield 100 mg of the product (Ms [M+H] +: 455.3). 2. Synthesis of C101 and C102

[0284] Compound C101-1 was prepared and split: The separation conditions are as follows: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Amylose-1 (250 × 21.2 nm); Mobile phase: n-hexane:ethanol = 60:40; Flow rate: 20 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; C101(35.2 min,42.34mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.88 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.65 (s, 1H), 5.83 (s, 1H), 5.34 – 5.10 (m, 2H), 3.87 (s, 1H), 3.80 – 3.65 (m, 1H), 3.59 (s, 3H), 3.25 – 3.09 (m, 1H), 2.56 – 2.36 (m, 1H), 2.12 (s, 1H), 2.03 – 1.67 (m, 9H), 1.29 – 0.96 (m, 7H). Ms [M+H] +:455.3.

[0285] C102(44.8 min,16.54mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.91 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 6.56 (s, 1H), 5.84 (s, 1H), 5.17 (d, Ms [M+H] +:455.3. Example 14

[0286] Compounds of the present invention: .

[0287] The synthetic route and experimental process are as follows: . 1. Synthesis of C117

[0288] Compound int4C (5 mL, 1.5 eq) was added with int2D (75 mg, 1.0 eq) and N,N-diisopropylethylamine (38.4 mg, 2.0 eq) and reacted at 50°C for 2 hours. Water was added to the system, extracted three times with ethyl acetate, washed three times with 1 M aqueous sodium hydroxide solution, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography preparative plate to give 35 mg of the product, Ms [M+H] +: 457.2, 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.93 – 7.75 (m, 2H), 7.26-7.27 (d, J = 4 Hz, 1H), 7.04-7.01 (d, J = 12 Hz, 1H), 5.77 (s, 1H), 5.01-4.99 (d, J = 7.1 Hz, 1H), 4.50-4.47 (t, J = 4 Hz, 1H), 4.38-4.35 (t, J = 4 Hz, 1H), 3.66-3.59 (m, 1H), 3.47 (s, 3H), 3.09-3.03 (m, 1H), 2.48-2.44(m, 1H), 2.07-1.91(m, 2H), 1.77-1.53​​ (m, 8H), 1.08-1.06 (m, 3H). The following compounds were synthesized using the above-mentioned synthesis method: Compound Ms [M+H] + 1H NMR 436.5 1HNMR (400 MHz, CDCl 3) δppm 7.92 (d, J= 5.6 Hz, 1H), 7.09 (d, J= 5.6 Hz, 1H), 6.40 (s, 1H), 5.87 (s, 1H), 5.20 (s, 1H), 4.40-4.30 (m, 1H), 3.88 (t, J= 7.6 Hz, 2H), 3.64 (s, 3H), 3.29-3.15 (m, 1H), 2.56-2.45 (m, 1H), 2.39-2.28 (m, 1H), 2.22-2.11 (m, 1H), 2.01-1.94 (m, 2H), 1.92-1.79 (m, 6H), 1.78-1.74 (m, 2H), 1.39 (d, J= 6.4 Hz, 3H). 436.5 1HNMR (400 MHz, CDCl 3) δppm 7.93 (d, J= 5.6 Hz, 1H), 7.10 (d, J= 5.6 Hz, 1H), 6.37 (s, 1H), 5.87 (s, 1H), 5.27-5.19 (m, 1H), 4.41-4.29 (m, 1H), 3.95-3.84 (m, 2H), 3.65 (s, 3H), 3.28-3.17 (m, 1H), 2.56-2.44 (m, 1H), 2.40-2.29 (m, 1H), 2.22-2.12 (m, 1H), 2.00-1.93 (m, 2H), 1.93-1.79 (m, 6H), 1.79-1.74 (m, 2H), 1.40 (d, J= 6.4 Hz, 3H). 451.2 1H NMR (400 MHz, CDCl 3) δ ppm 7.92 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 6.45 (s, 1H), 5.86 (s, 1H), 5.19 (dt, J = 8.4, 4.0Hz, 1H), 4.79 (s, 1H), 3.63 (s, 3H), 3.18 (q, J = 8.0 Hz, 1H), 3.10 (s, 1H), 2.59 - 2.45 (m, 1H), 2.14 (dt, J = 12.5, 6.2 Hz, 1H), 2.02 - 1.92 (m, 2H), 1.85 (dt, J = 6.8, 4.4 Hz, 4H), 1.76 (q, J = 4.8, 4.0 Hz, 2H), 1.18 (d, J = 6.4 Hz, 3H), 0.90 - 0.73 (m, 2H), 0.46 (ddt, J = 13.6, 8.8, 4.8 Hz, 2H), 0.34 (s, 1H), 0.19 (dd, J = 9.6, 4.8 Hz, 1H). 451.2 1H NMR (400 MHz, CDCl 3) δ ppm 7.93 (d, J = 5.8 Hz, 1H), 7.09 (d, J = 5.8 Hz, 1H), 6.38 (s, 1H), 5.86 (s, 1H), 5.20 (dt, J = 8.4, 4.2 Hz, 1H), 4.74 (s, 1H), 3.64 (s, 3H), 3.18 (q, J = 8.1 Hz, 1H), 3.10 (s, 1H), 2.52 (ddd, J = 15.0, 9.1, 6.4 Hz, 1H), 2.21 - 2.09 (m, 1H), 2.03 -1.93 (m, 2H), 1.92-1.81 (m, 4H), 1.79 - 1.73 (m, 2H), 1.20 (d, J = 6.6 Hz, 3H), 0.93-0.72 (m, 2H), 0.45 (dddd, J = 15.6, 8.0, 5.6, 4.4 Hz, 2H), 0.32 (dd, J = 9.6, 4.8 Hz, 1H), 0.19 (dt, J = 9.2, 4.8 Hz, 1H). 436.5 - 436.5 - 481.2 1H NMR(400 MHz, CDCl 3) δ ppm 7.92 (d, J = 5.8 Hz, 1H), 7.06 (d, J = 5.8 Hz, 1H), 6.38 (s, 1H), 5.85 (s, 1H), 5.19 (s, 1H), 4.89 (d, J = 6.2 Hz, 1H), 3.86 (q, J = 8.2 Hz, 1H), 3.62 (s, 3H), 3.24 – 3.10 (m, 1H), 2.59 (dt, J = 15.1, 7.8 Hz, 1H), 2.23 – 2.07 (m, 2H), 2.05 – 1.92 (m, 2H), 1.91 – 1.67 (m, 9H), 1.62 (d, J = 11.9 Hz, 2H), 1.40 – 1.24 (m, 2H), 1.17 (s, 3H). 481.2 1H NMR (400 MHz, CDCl 3) δ ppm 7.94 (d, J = 5.7 Hz, 1H), 7.09 (d, J = 5.8 Hz, 1H), 6.31 (s, 1H), 5.86 (s, 1H), 5.21 (s, 1H), 4.82 (s, 1H), 3.86 (q, J = 8.2 Hz, 1H), 3.63 (s, 3H), 3.21 (s, 1H), 2.53 (d, J = 7.5 Hz, 1H), 2.15 (d, J = 6.5 Hz, 2H), 1.98 (d, J = 17.9 Hz, 2H), 1.92 – 1.81 (m, 4H), 1.79 – 1.69 (m, 4H), 1.66 – 1.57 (m, 3H), 1.25 (s, 2H), 1.14 (s, 3H). 439.2 - 439.2 - 463.6 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.7 Hz, 1H), 7.09 (d, J= 5.8 Hz, 1H), 6.45 (s, 1H), 5.85 (s, 1H), 5.22 (d, J= 6.5 Hz, 1H), 5.02 (s, 1H), 4.02 (d, J= 27.5 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.63 (s, 3H), 3.21 (t, J= 8.3 Hz, 1H), 2.49 (d, J= 15.4 Hz, 1H), 2.39 (d, J= 12.9 Hz, 1H), 2.25 (td, J= 16.1, 15.0, 5.4 Hz, 1H), 2.16 (dq, J= 12.6, 6.2, 5.7 Hz, 1H), 1.96 (d, J= 7.1 Hz, 2H), 1.90 – 1.81 (m, 4H), 1.77 (q, J= 4.5, 3.8 Hz, 2H), 1.29 (d, J= 7.0 Hz, 3H). 463.6 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.8 Hz, 1H), 7.10 (d, J= 5.8 Hz, 1H), 6.36 (s, 1H), 5.86 (s, 1H), 5.28 – 5.15 (m, 1H), 4.84 (s, 1H), 4.05 (s, 1H), 3.63 (s, 3H), 3.19 (p, J= 8.2 Hz, 1H), 2.60 – 2.48 (m, 1H), 2.42 (s, 1H), 2.24 (d, J= 14.7 Hz, 1H), 2.16 (dt, J= 12.3, 6.0 Hz, 1H), 1.99 – 1.93 (m, 2H), 1.90 – 1.80 (m, 5H), 1.79 – 1.76 (m, 2H), 1.28 (d, J= 6.9 Hz, 3H). 454.2 1H NMR (400 MHz, DMSO) δ = 11.89 (s, 1H), 7.93 – 7.79 (m, 2H), 7.34 – 7.20 (m, 2H), 7.09 (d, J=7.8, 1H), 6.95 (s, 1H), 5.79 (s, 1H), 5.01 (s, 1H), 3.94 (s, 1H), 3.48 (s, 3H), 3.13 – 2.99 (m, 1H), 2.46 (dd, J=14.2, 7.4, 1H), 2.04 (d, J= 8.8, 1H), 1.89 (s, 1H), 1.74 (dd, J=19.0, 9.9, 2H), 1.68 – 1.56 (m, 3H), 1.55 (dd, J=7.5, 3.6, 2H), 1.18 (dt, J=7.1, 3.5, 3H). 465.2 1HNMR(400MHz, DMSO-d6) δ 11.99 (s, 1H), 7.93 – 7.79 (m, 2H), 7.70 (s, 1H), 7.26 (d, J = 5.8 Hz, 1H), 6.15 (s, 1H), 5.76 (s, 1H), 4.99 (s, 1H), 3.47 (s, 3H), 3.17 (d, J = 5.2 Hz, 1H), 3.13 – 2.99 (m, 1H), 2.02 (s, 1H), 1.93 (s, 7H), 1.72 (s, 2H), 1.64 (q, J = 3.6, 2.9 Hz, 2H), 1.59 (d, J = 3.2 Hz, 1H), 1.55 (q, J = 4.1, 3.5 Hz, 2H). 466.5 1H NMR (400 MHz, CDCl 3) δppm 7.92 (d, J= 5.6 Hz, 1H), 7.07 (d, J= 5.6 Hz, 1H), 6.40 (s, 1H), 5.85 (s, 1H), 5.36 (s, 1H), 5.25-5.16 (m, 1H), 3.62 (s, 3H), 3.24-3.12 (m, 1H), 2.59-2.46 (m, 1H), 2.41-2.24 (m, 6H), 2.21-2.09 (m, 1H), 2.00-1.91 (m, 2H), 1.90-1.80 (m, 4H), 1.79-1.73 (m, 2H). 464.6 1H NMR (400 MHz, CDCl 3) δppm 7.94 (d, J= 6.0 Hz, 1H), 7.13 (d, J= 6.0 Hz, 1H), 6.48 (s, 1H), 5.87 (s, 1H), 5.18 (s, 1H), 4.72 (s, 1H), 3.64 (s, 3H), 3.25-3.13 (m, 1H), 2.58-2.48 (m, 1H), 2.19-2.10 (m, 1H), 1.98-1.76 (m, 9H), 1.76-1.53 (m, 7H), 1.37 (s, 3H). 464.6 1H NMR (400 MHz, CDCl 3) δppm 7.94 (d, J= 6.0 Hz, 1H), 7.17 (d, J= 6.0 Hz, 1H), 6.69 (s, 1H), 5.87 (s, 1H), 5.18 (s, 1H), 4.77 (s, 1H), 3.65 (s, 3H), 3.24-3.14 (m, 1H), 2.58-2.46 (m, 1H), 2.19-2.09 (m, 1H), 2.00-1.76 (m, 9H), 1.75-1.51 (m, 7H), 1.37 (s, 3H). 483.2 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.8 Hz, 1H), 7.10 (d, J= 15.0 Hz, 1H), 6.45 (s, 1H), 5.86 (s, 1H), 5.19 (d, J= 25.2 Hz, 2H), 3.94 (d, J= 38.7 Hz, 2H), 3.62 (s, 3H), 3.58 – 3.44 (m, 2H), 3.38 (d, J= 12.9 Hz, 2H), 3.28 – 3.06 (m, 2H), 2.15 (s, 2H), 1.97 (s, 4H), 1.86 (q, J= 3.8, 3.0 Hz, 4H), 1.77 (q, J= 4.5, 3.7 Hz, 2H). 480.3 1H NMR (400 MHz, CDCl 3) δ ppm7.92 (d, J = 5.8 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 6.40 (s, 1H), 5.85 (s, 1H), 5.22 (d, J = 28.1 Hz, 2H), 3.64 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 3.00 (d, J = 9.2 Hz, 1H), 2.92 (t, J = 14.4 Hz, 1H), 2.47 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H), 2.35 (dd, J = 3.2, 1.6 Hz, 1H), 2.11 (q, J = 7.6, 6.6 Hz, 3H), 1.91 (d, J = 5.4 Hz, 4H), 1.85-1.79 (m, 3H), 1.78-1.71 (m, 2H), 1.49 (d, J = 12.6 Hz, 3H). 454.5 - 480.6 1H NMR (400 MHz, CDCl 3) δ ppm7.92 (d, J = 5.8 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 6.40 (s, 1H), 5.85 (s, 1H), 5.22 (d, J = 28.1 Hz, 2H), 3.64 (s, 3H), 3.19 (t, J = 8.5 Hz, 1H), 3.00 (d, J = 9.4 Hz, 1H), 2.92 (t, J = 14.6 Hz, 1H), 2.47 (d, J = 8.1 Hz, 2H), 2.37 (s, 3H), 2.35 (dd, J = 3.2, 1.6 Hz, 1H), 2.11 (q, J = 7.6, 6.5 Hz, 3H), 1.91 (d, J = 5.4 Hz, 4H), 1.85 – 1.79 (m, 3H), 1.78 – 1.71 (m, 2H), 1.49 (d, J = 12.6 Hz, 3H). 441.2 1H NMR (400 MHz, CDCl 3) δ ppm 7.92 (d, J = 5.7 Hz, 1H), 7.06 (d, J = 5.6 Hz, 1H), 6.47 (s, 1H), 5.84 (s, 1H), 5.18 (dd, J = 6.8, 3.6 Hz, 1H), 5.03 (s, 1H), 3.83 (s, 1H), 3.61 (s, 4H), 3.45 (dd, J = 11.2, 6.2 Hz, 1H), 3.24 (d, J = 9.2 Hz, 1H), 2.44 (m, 2H), 2.24-2.09 (m, 1H), 1.94 (s, 4H), 1.86-1.70 (m, 5H), 1.15 (d, J = 6.8 Hz, 3H). 455.3 1H NMR (400 MHz, CDCl 3) δ ppm 7.91 (d, J = 5.8 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 6.56 (s, 1H), 5.84 (s, 1H), 5.49 (s, 1H), 5.21 (s, 1H), 3.60 (s, 3H), 3.27-3.07 (m, 3H), 2.46 (m, 1H), 2.21-2.09 (m, 1H), 2.02 -1.86 (m, 4H), 1.85 -1.70 (m, 5H), 1.28 -1.15 (m, 7H). 467.5 1H NMR (400 MHz, CDCl 3) δ 7.93 (d, J= 5.7 Hz, 1H), 7.06 (t, J= 5.9 Hz, 1H), 6.51 (s, 1H), 5.85 (s, 1H), 5.21 (s, 2H), 4.00 – 3.84 (m, 3H), 3.62 (s, 3H), 3.57 (d, J= 9.1 Hz, 1H), 3.21 (p, J= 8.1 Hz, 1H), 2.55 – 2.43 (m, 1H), 2.25 (q, J= 9.3, 7.1 Hz, 1H), 2.14 (dt, J= 12.8, 6.6 Hz, 1H), 1.94 (h, J= 4.8 Hz, 3H), 1.83 (h, J= 4.6, 4.1 Hz, 4H), 1.76 (q, J= 4.4, 3.6 Hz, 3H), 1.49 (s, 3H). 467 1HNMR(400 MHz, DMSO- d 6) δ ppm 11.98 (s, 1H), 7.86 (s, 1H), 7.83 (d, J= 5.6 Hz, 1H), 7.32-7.21 (m, 1H), 7.12 (s, 1H), 5.76 (s, 1H), 5.02-4.95 (m, 1H), 4.91 (d, J= 6.0 Hz, 1H), 4.09-4.03 (m, 1H), 3.46 (s, 3H), 3.07-3.00 (m, 1H), 2.47-2.44 (m, 1H), 2.06-1.98 (m, 1H), 1.94-1.85 (m, 1H), 1.75-1.69 (m, 3H), 1.69-1.65 (m, 2H), 1.64-1.62 (m, 2H), 1.61-1.57 (m, 1H), 1.56-1.53 (m, 2H), 1.30 (s, 3H), 1.28-1.23 (m, 1H). 503.2 1H NMR (400 MHz, CDCl 3)δ ppm 7.93 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 6.36 (s, 1H), 5.86 (s, 1H), 5.20 (s, 2H), 4.36 – 4.21 (m, 1H), 3.63 (s, 3H), 3.25 (dd, J = 20.8, 7.6 Hz, 3H), 3.01 (s, 3H), 2.46 (s, 1H), 2.14 (q, J = 8.8, 7.2 Hz, 1H), 1.93 (d, J = 5.6 Hz, 4H), 1.82 (q, J = 3.6, 2.8 Hz, 2H), 1.76 (t, J = 3.2 Hz, 2H), 1.42 (d, J = 6.8 Hz, 3H), 1.25 (s, 1H). 479.2 1H NMR (400 MHz, CDCl 3)δ ppm 9.76 (s, 1H), 7.92 (d, J = 5.6 Hz, 1H), 7.07 (d, J = 5.6 Hz, 1H), 6.39 (s, 1H), 5.85 (s, 1H), 5.40 - 5.14 (m, 2H), 3.62 (s, 3H), 3.29 (s, 3H), 3.19 (p, J = 8.0 Hz, 1H), 2.52 (s, 1H), 2.15 (s, 6H), 1.95 (q, J = 5.2, 4.4 Hz, 2H), 1.92 - 1.82 (m, 3H), 1.79 - 1.73 (m, 2H), 1.68 (s, 2H). 450.2 1HNMR(400MHz, DMSO-d6) δ ppm 12.17 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.89-7.88 (d, J = 4.0 Hz, 1H), 7.41-7.39 (d, J = 8.0 Hz, 1H), 5.85 (s, 1H), 5.03 (s, 1H), 3.80 – 3.75 (m, 1H), 3.51 (s, 3H), 3.14-3.12 (m, 2H), 2.06-1.93 (m, 3H), 1.77-1.62 (m, 8H), 1.15-1.14(d, J = 8.0 Hz, 3H). 467.3 1H NMR (400 MHz,CDCl 3) δ ppm 7.93 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 6.33 (s, 1H), 5.86 (s, 1H), 5.20 (s, 1H), 4.93 (s, 1H), 4.18 - 4.04 (m, 1H), 3.62 (s, 3H), 3.20 (t, J = 8.4 Hz, 1H), 2.42 (t, J = 6.0 Hz, 4H), 2.21-2.09 (m, 1H), 1.95 (s, 2H), 1.83 (q, J = 3.6, 2.9 Hz, 3H), 1.76 (q, J = 4.4, 3.6 Hz, 2H), 1.57 (d, J = 55.2 Hz, 4H), 1.33 (s, 3H). 455.2 1HNMR(400 MHz, DMSO- d 6) δ 11.97 (s, 1H), 7.84 (s, 1H), 7.82 (d, J= 5.6 Hz, 1H), 7.34-7.15 (m, 1H), 6.76 (d, J= 8.4 Hz, 1H), 5.76 (s, 1H), 5.04-4.95 (m, 1H), 4.50 (d, J= 5.2 Hz, 1H), 3.46 (s, 3H), 3.46-3.41 (m, 1H), 3.31-3.25 (m, 1H), 3.11-3.01 (m, 1H), 2.49-2.42 (m, 1H), 2.06-1.98 (m, 1H), 1.94-1.85 (m 1H), 1.79-1.69 (m, 2H), 1.65-1.62 (m, 2H), 1.62-1.57 (m, 1H), 1.56-1.51 (m, 2H), 1.01-0.95 (m, 6H). 455.2. 1HNMR(400MHz, DMSO- d6) δppm 12.00 (s, 1H), 7.93-7.77 (m, 2H), 7.28 (s, 1H), 6.73 (d, J= 8.0 Hz, 1H), 5.78 (s, 1H), 5.06-4.93 (m, 1H), 4.65-4.48 (m, 1H), 3.69-3.55 (m, 1H), 3.47 (s, 3H), 3.28-3.21 (m, 1H), 3.12-2.98 (m, 1H), 2.50-2.42 (m, 3H), 2.10-1.98 (m 1H), 1.96-1.83 (m, 1H), 1.81-1.68 (m, 2H), 1.68-1.62 (m, 2H), 1.58-1.52 (m, 2H), 1.27-1.23 (m, 2H), 0.83 (t, J= 7.6 Hz, 3H). 481.5 1HNMR(400MHz, DMSO-d6) δ 11.99 (s, 1H), 8.00 – 7.74 (m, 2H), 7.21 (d, J = 40.1 Hz, 2H), 5.76 (s, 1H), 4.98 (s, 1H), 4.73 (s, 1H), 3.47 (s, 3H), 2.24 (d, J = 11.8 Hz, 2H), 2.08 – 1.96 (m, 2H), 1.90 (d, J = 12.5 Hz, 3H), 1.80 – 1.67 (m, 2H), 1.68 – 1.52 (m, 5H), 1.34 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H). 450.2 1HNMR(400MHz, DMSO- d6) δ 12.17 (s, 1H), 9.00 (s, 1H), 8.30 (s, 1H), 7.89-7.88 (d, J = 4 Hz, 1H), 7.41-7.39 (d, J = 8 Hz, 1H), 5.85 (s, 1H), 5.03 (s, 1H), 3.80 – 3.75 (m, 1H), 3.51 (s, 3H), 3.14-3.12 (m, 2H), 2.06-1.93 (m, 3H), 1.77-1.62 (m, 8H), 1.15-1.14(d, J = 8Hz, 3H). 467.5 1H NMR (400 MHz, CDCl 3)δ 7.93 (d, J= 5.7 Hz, 1H), 7.06 (t, J= 5.9 Hz, 1H), 6.51 (s, 1H), 5.85 (s, 1H), 5.21 (s, 2H), 4.00 – 3.84 (m, 3H), 3.62 (s, 3H), 3.57 (d, J= 9.1 Hz, 1H), 3.21 (p, J= 8.1 Hz, 1H), 2.55 – 2.43 (m, 1H), 2.25 (q, J= 9.3, 7.1 Hz, 1H), 2.14 (dt, J= 12.8, 6.6 Hz, 1H), 1.94 (h, J= 4.8 Hz, 3H), 1.83 (h, J= 4.6, 4.1 Hz, 4H), 1.76 (q, J= 4.4, 3.6 Hz, 3H), 1.49 (s, 3H). 455.3 1HNMR(400MHz, DMSO-d6) δ 12.06 (s, 1H), 7.99 (s, 1H), 7.87-7.85 (d, J = 6.0 Hz, 1H), 7.30 (s, 1H), 6.73-6.71 (d, J = 8.0 Hz, 1H), 5.80 (s, 1H), 4.99 (s, 1H), 4.57 (s, 1H), 3.48 (s, 3H), 3.26 – 3.23 (m, 1H), 3.10-3.03 (m, 1H), 2.47 – 2.44 (m, 1H), 2.06-2.00 (m, 1H), 1.92-1.90 (m, 1H), 1.77-1.69 (m, 4H), 1.64-1.58 (m, 2H), 1.54 – 1.49 (m, 1H), 1.28 - 1.18 (m, 1H), 0.82 - 0.76(t, J = 8.0Hz, 3H). 481.5 1HNMR(400MHz, DMSO-d6) δ 11.99 (s, 1H), 7.91 – 7.79 (m, 2H), 7.27 (d, J = 19.7 Hz, 2H), 5.77 (s, 1H), 4.99 (s, 1H), 3.69 (s, 1H), 3.47 (s, 3H), 3.09 (s, 3H), 2.23 (ddd, J = 9.7, 6.7, 2.6 Hz, 2H), 2.01 (d, J = 12.4 Hz, 3H), 1.87 (d, J = 21.2 Hz, 1H), 1.74 (d, J = 9.3 Hz, 2H), 1.63 (t, J = 3.6 Hz, 3H), 1.55 (q, J = 3.9, 3.4 Hz, 2H), 1.25 (d, J = 7.3 Hz, 5H). 482.2 1HNMR(400 MHz, DMSO- d 6) δ 11.98 (s, 1H), 7.86 (s, 1H), 7.82 (d, J= 5.6 Hz, 1H), 7.25 (d, J= 5.6 Hz, 1H), 7.22 (s, 1H), 5.76 (s, 1H), 5.03-4.92 (s, 1H), 3.83-3.76 (m, 1H), 3.46 (s, 3H), 3.07 (s, 3H), 3.06-3.01 (m, 1H), 2.47-2.43 (m, 1H), 2.09-1.98 (m, 1H), 1.96-1.82 (m, 1H), 1.77-1.69 (m, 4H), 1.65-1.62 (m, 2H), 1.61-1.56 (m, 1H), 1.55-1.52 (m, 2H), 1.30 (s, 3H). 455.2 1HNMR(400 MHz, DMSO- d 6) δ 11.98 (s, 1H), 7.84 (s, 1H), 7.82 (d, J= 5.6 Hz, 1H), 7.33-7.16 (m, 1H), 6.65 (d, J= 8.4 Hz, 1H), 5.76 (s, 1H), 5.03-4.95 (m, 1H), 4.49 (d, J= 5.2 Hz, 1H), 3.57-3.50 (m, 1H), 3.46 (s,3H), 3.45-3.40(m, 1H), 3.12-3.01 (m, 1H), 2.48-2.40 (m, 1H), 2.06-1.98 (m, 1H), 1.94-1.84 (m, 1H), 1.78-1.68 (m, 2H), 1.66-1.62 (m, 2H), 1.62-1.56 (m, 1H), 1.56-1.51 (m, 2H), 1.00-0.96 (m, 3H), 0.96-0.92 (m, 3H). Example 15

[0289] The compounds of the present invention: .

[0290] The synthetic route and experimental process are as follows: . 1. Synthesis of C14-1

[0291] To a 100 mL three-necked flask, N,N-dimethylformamide (10 mL) and int2A-4 (150 mg, 1 eq) were added. The mixture was cooled to 0°C under N2 protection and cesium carbonate (467 g, 2 eq) was added. After stirring for 5 min, deuterated iodomethane (156 mg, 1.3 eq) was slowly added dropwise and stirred at room temperature for 0.5 h. After the reaction was complete, saturated ammonium chloride (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 35 mg of the product. 2. Synthesis of C14

[0292] C14-1 (62 mg, 1 eq), int1E (35 mg, 1 eq), and DMSO (5 mL) were added to a 100 mL single-necked flask and stirred to dissolve. Potassium tert-butoxide (55.47 mg, 3 eq) was then added and stirred at room temperature for 20 min. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 9.5 mg of the product, Ms [M+H] +: 453.2, 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.53 (s, 1H), 8.30 (s, 1H), 7.78 (s, 1H), 6.27 (s, 1H), 5.01 (s, 1H), 3.09 (s, 1H), 2.35 (s, 1H), 2.04 (s, 1H), 1.91 (m, 8H), 1.75 (m, 4H), 1.65 (s, 3H). Example 16

[0293] Compounds of the present invention: .

[0294] The synthetic route and experimental process are as follows: . 1. Synthesis of C33-1

[0295] Compound int2E (130 mg, 0.57 mmol), int1 (176 mg, 0.57 mmol), palladium acetate (13 mg, 0.06 mmol), XantpHos (66 mg, 0.11 mmol), cesium carbonate (560 mg, 1.72 mmol) and 1,4-dioxane (15 mL) were heated to 100°C under nitrogen for 2 hours. After completion of the reaction, the mixture was filtered, concentrated, and purified by TLC preparative plate to obtain 325 mg of the product, Ms [M+H] +: 495.3. 2. Synthesis of C33-2

[0296] Compound C33-1 (180 mg, 0.36 mmol) was dissolved in formic acid solution (10 mL), heated to 80°C and stirred for 1.5 h. After completion of the reaction, the mixture was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate was added to the reaction solution to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to obtain 55 mg of the product, Ms [M+H] +: 439.2. 3. Preparation of C33 and C34

[0297] C33-2 (55 mg) was separated and prepared by chiral high performance liquid chromatography; The separation conditions are as follows: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Cellulose-4 (250 × 21.2 nm); Mobile phase: n-hexane:isopropanol (0.1% TFA) = 7:3; Flow rate: 20 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; C33 (17.9 min, 14.8 mg) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.81 (s, 1H), 7.22 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 5.75 - 5.73 (m, 1H), 5.02 - 4.96 (m, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.62 - 3.52 (m, 1H), 3.10 - 3.01 (m, 1H), 2.48 - 2.40 (m, 1H), 2.07 - 1.98 (m, 1H), 1.95 - 1.85 (m, 1H), 1.76 - 1.69 (m, 2H), 1.65 - 1.62 (m, 2H), 1.62 - 1.57 (m, 1H), 1.57 - 1.53 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H), 1.04 - 0.99 (m, 6H). Ms [M+H]+: 439.2.

[0298] C34 (28.4 min, 10.4 mg) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 7.81 (s, 1H), 7.22 (d, J = 5.6 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 5.75 - 5.73 (m, 1H), 5.03 - 4.94 (m, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.63 - 3.51 (m, 1H), 3.11 - 3.00 (m, 1H), 2.48 - 2.38 (m, 1H), 2.07 - 1.97 (m, 1H), 1.95 - 1.83 (m, 1H), 1.77 - 1.69 (m, 2H), 1.65 - 1.62 (m, 2H), 1.62 - 1.57 (m, 1H), 1.57 - 1.53 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H), 1.04 - 0.99 (m, 6H). Ms [M+H]+: 439.2. Example 17

[0299] Compounds of the present invention: .

[0300] The synthetic route and experimental process are as follows: . 1. Synthesis of C43-1

[0301] To a 25 mL single-necked vial were added int2B (126.3 mg, 1.00 eq), int4E (187 mg, 1.0 eq), palladium acetate (13.6 mg, 0.1 eq), XantpHos (70.2 mg, 0.2 eq), cesium carbonate (395.9 mg, 2.0 eq), and 1,4-dioxane (5 mL). The temperature was raised to 100°C under nitrogen for 2 hours. After completion, the reaction was filtered, concentrated, and purified by preparative thin-layer chromatography to afford 240 mg of the product. Ms [M+H] +: 481.3. 2. Synthesis of C43-2

[0302] Compound C43-1 (240 mg, 1.00 eq) and formic acid (6 mL) were added to a 25 mL single-necked flask. The temperature was raised to 100°C and the reaction was allowed to react for 30 minutes. After completion, the mixture was concentrated under reduced pressure. Aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to obtain 80 mg of the product. Ms [M+H] +: 425.2. 3. Synthesis of C43 and C44

[0303] C43-2 (80 mg) was prepared by chiral HPLC separation under the following conditions: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Amylose-1 (250 × 21.2 nm); Mobile phase: n-hexane:ethanol = 2:8; Flow rate: 15 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; C44(14.0 min,32 mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.91-7.89 (d, J = 8 Hz, 1H), 7.07-7.06 (d, J = 4 Hz, 1H), 6.67 (s, 1H), 5.84 (s, 1H), 4.60 (s, 1H), 4.09-4.07 (d, J = 8 Hz, 2H), 3.82-3.80 (m, 1H), 3.63 (s, 3H), 3.47-3.38 (m, 1H), 2.63 (m, 1H), 2.53-2.46 (m, J = 2H), 2.05-1.98(m, 2H), 1.84-1.79(m, 2H), 1.77-1.73 (m, 2H), 1.25 (s, 1H), 1.17-1.15 (d, J = 8 Hz, 6H). Ms [M+H] +:425.2.

[0304] C43(22.9 min,22 mg) 1H NMR (400 MHz, CDCl 3) δ ppm 7.94-7.92 (d, J = 8 Hz, 1H), 7.11-7.10 (d, J = 4 Hz, 1H), 6.43 (s, 1H), 5.92 (s, 1H), 4.55 (s, 1H), 4.17-4.15 (d, J = 8Hz, 2H), 3.83-3.81 (m, 1H), 3.64 (s, 1H), 3.60-3.51 (m, 1H), 2.72(m, 1H) 2.30-2.26 (m, 4H), 1.85-1.81 (m, 2H), 1.79-1.74 (m, 2H), 1.25 (m, 1H), 1.17-1.16 (d, J = 8 Hz, 6H). Ms [M+H] +:425.2. Example 18

[0305] The compounds of the present invention: .

[0306] The synthesis route and experimental process are as follows: . 1. Synthesis of C70-2

[0307] Compound C70-1 (3.00 g, 29.7 mmol) was dissolved in N,N-dimethylformamide (50 mL). The temperature was cooled to 0°C, and potassium carbonate (8.2 g, 59.4 mmol) and benzyl bromide (6.1 g, 35.6 mmol) were added. After addition, the mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was complete. The temperature was then lowered, and the reaction was quenched with water. The mixture was extracted three times with ethyl acetate. The ethyl acetate phase was washed with saturated brine and then concentrated under reduced pressure. Purification by column chromatography afforded 3.3 g of the product, Ms [M+H] +: 192.0. 2. Synthesis of C70-3

[0308] Compound C70-2 (2.0 g, 10.5 mmol) was dissolved in acetonitrile (23 mL), and N-bromosuccinimide (2.1 g, 11.5 mmol) was added. After addition, the mixture was stirred at room temperature for 3 days. The reaction was complete. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography afforded 1.93 g of the product, Ms [M+H] +: 270.0. 3. Synthesis of C70-4

[0309] Compound C70-3 (1.93 g, 7.17 mmol), cyclopropylboronic acid (6.17 g, 71.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (525 mg, 0.72 mmol), and cesium carbonate (4.68 g, 14.35 mmol) were dissolved in 1,4-dioxane / water (v:4:1, 12 mL). The temperature was raised to 100°C under nitrogen and the reaction was carried out for 12 hours. After the reaction was completed, the mixture was filtered, concentrated, and purified by thin-layer chromatography preparative plate to obtain 1.04 g of the product, Ms [M+H] +: 232.1. 4. Synthesis of C70-5

[0310] Compound C70-4 (1.04 g, 4.50 mmol) was dissolved in concentrated hydrochloric acid (12 mL) and heated to 50°C for 5 hours. The reaction was complete. The product was concentrated under reduced pressure and purified by reverse-phase column chromatography to yield 537 mg of the product, Ms [M+H] + : 142.0. 5. Synthesis of C70-6

[0311] Compound C70-5 (0.5 g, 3.55 mmol), int1-7 (1.26 g, 3.55 mmol), and triphenylphosphine (1.39 g, 5.32 mmol) were dissolved in tetrahydrofuran (50 mL). The mixture was cooled to 0°C and a solution of diisopropyl azodicarboxylate (1.07 g, 5.32 mmol) in tetrahydrofuran (10 mL) was added dropwise. After addition, the mixture was stirred at 0°C for 5 minutes, then heated to 50°C and stirred for 2 hours. The reaction was complete. The reaction was quenched with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Purification by column chromatography gave 2.30 g of the crude product, Ms [M+H] +: 481.2. 6. Synthesis of C70-7

[0312] Dissolve the crude compound C70-6 (1.00 g) in 1,4-dioxane / water (v / v:10:1, 10 mL). Add 50 mg (2.08 mmol) of lithium hydroxide (LiOH) and heat to 80°C with stirring for 5 hours. The reaction is complete. Concentrate under reduced pressure and purify by column chromatography to yield 471 mg of the product (M+H) + 347.2. 7. Synthesis of C70-8

[0313] Compound C70-7 (400 mg, 1.00 eq), int2B (240 mg, 1.00 eq), palladium acetate (103 mg, 0.40 eq), XantpHos (534 mg, 0.80 eq), cesium carbonate (1.13 g, 3.00 eq) and 1,4-dioxane (16 mL) were added to a 25 mL single-necked bottle. The temperature was raised to 100°C under nitrogen protection and the reaction was carried out for 2 hours. After the reaction was completed, the mixture was filtered, concentrated, and purified by thin-layer chromatography preparative plate to obtain 200 mg of the product, Ms [M+H] +: 519.3. 8. Synthesis of C70-9

[0314] Compound C70-8 (200 mg, 1.00 eq) and trifluoroacetic acid / water (10 mL, v: 20:1) were added to a 25 mL single-necked flask. The temperature was raised to 70°C and the reaction was allowed to react for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate was added to the reaction solution to adjust the pH to 7-8. The reaction solution was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative thin-layer chromatography to obtain 150 mg of the product, Ms [M+H] +: 463.2. 9. Synthesis of C70 and C71

[0315] C70-9 (150 mg) was separated and prepared by chiral HPLC using the following separation conditions: Instrument: Agilent 1260 Infinity II; Chromatography column: PHenomenex Lux® 5 μm Amylose-1 (250 × 21.2 nm); Mobile phase: n-hexane:isopropanol (0.1% TFA) = 7:3; Flow rate: 20 mL / min, detection wavelength: 254 nm; Column temperature: 25°C, solvent: isopropanol; C70(26.3 min,24.3 mg) 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 5.78 (s, 1H), 5.36-5.30 (m, 1H), 3.45 (s, 3H), 3.20-3.12 (m, 1H), 2.65-2.57 (m, 1H), 2.12-2.01 (m, 2H), 1.97-1.90 (m, 1H), 1.88-1.78 (m, 2H), 1.73-1.67 (m, 1H), 1.66-1.60 (m, 2H), 1.57-1.50 (m, 2H), 0.83-0.78 (m, 2H), 0.65-0.61(m, 2H). Ms [M+H] +:463.2.

[0316] C71(33.3 min,25.1 mg) 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 5.78 (s, 1H), 5.35-5.30 (m, 1H), 3.46 (s, 3H), 3.21-3.12 (m, 1H), 2.66-2.58 (m, 1H), 2.11-2.01 (m, 2H), 1.97-1.90 (m, 1H), 1.87-1.79 (m, 2H), 1.74-1.67 (m, 1H), 1.65-1.60 (m, 2H), 1.56-1.51 (m, 2H), 0.83-0.78 (m, 2H), 0.65-0.61 (m, 2H). Ms [M+H] +:463.2. Example 19

[0317] Compounds of the present invention: .

[0318] The synthetic route and experimental process are as follows: . 1. Synthesis of C85-2

[0319] Compound C85-1 (3.0 g, 14.22 mmol) was dissolved in N,N-dimethylformamide (50 mL). The temperature was cooled to 0°C, and sodium hydride (3.41 g, 85.31 mmol) was added portionwise. After addition, the mixture was stirred at 0°C for 15 minutes. A solution of 1,2-dibromoethane (7.9 g, 42.65 mmol) in N,N-dimethylformamide was then added dropwise. After completion of the addition, the temperature was slowly warmed to room temperature and stirred for 2 hours. The reaction was complete. The mixture was cooled, quenched with water, and then concentrated under reduced pressure. Purification by column chromatography afforded 948 mg of the product, Ms [M+H] +: 238.0. 2. Synthesis of C85-3

[0320] Compound C85-2 (940 mg, 3.95 mmol) was dissolved in N,N-dimethylformamide (40 mL). The temperature was cooled to 0°C, and sodium hydride (190 mg, 4.74 mmol) was added portionwise. After addition, the mixture was stirred at 0°C for 30 minutes. Then, iodomethane (1.7 g, 11.85 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was complete. The temperature was lowered, and the reaction was quenched with water. The mixture was then concentrated under reduced pressure and purified by preparative thin-layer chromatography to yield 968 mg of the product, Ms [M+H] +: 252.0. 3. Synthesis of C85-4

[0321] Compound C85-3 (150 mg, 0.60 mmol), int7 (158 mg, 0.49 mmol), palladium acetate (13 mg, 0.06 mmol), XantpHos (69 mg, 0.12 mmol), cesium carbonate (584 mg, 1.79 mmol) and 1,4-dioxane (15 mL) were heated to 100°C under nitrogen for 2 hours. After the reaction was completed, the mixture was filtered, concentrated, and purified by thin-layer chromatography preparative plate to obtain 264 mg of the product, Ms [M+H] +: 504.3. 4. Synthesis of C85

[0322] Compound C85-4 (219 mg, 0.44 mmol) was dissolved in acetic acid / water solution (v: 20:1) (15 mL), heated to 110°C and stirred for 2 days. After the reaction was completed, the mixture was concentrated under reduced pressure. An aqueous solution of sodium bicarbonate was added to the reaction solution to adjust the pH to 7-8. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer chromatography preparative plate to obtain 20 mg of the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 7.74 (s, 1H), 7.32 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 5.39 (s, 1H), 4.96 (s, 1H), 3.35 (s, 3H), 3.09-2.90 (m, 1H), 2.47-2.37 (m, 1H), 2.37-2.26 m, 1H), 2.03-1.93 (m, 1H), 1.92-1.80 (m, 7H), 1.73-1.61 (m, 2H), 1.59-1.45 (m, 5H). Ms [M+H] +:448.2. Example 20

[0323] Compounds of the present invention .

[0324] The synthetic route and experimental process are as follows: . 1. Synthesis of C89-2

[0325] To a 250 mL three-necked flask, water (10 mL), methylamine hydrochloride (9.2 mg, 2 eq), and sodium bicarbonate (11.4 g, 5 eq) were added. After stirring under N2 for 1 h, C89-1 (5 g, 1.3 eq) and butyl acetate (100 mL) were added. The mixture was stirred at 60°C for 15 h. After completion of the reaction, 40 mL of saturated ammonium chloride was added to the reaction solution, which was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1.8 g of the product. 2. Synthesis of C89-3

[0326] Dimethyl malonate (7.6 g, 5 eq) was dissolved in N,N-dimethylformamide (34 mL), heated to 40°C, and sodium hydride (1.9 g, 5 eq) was added. The mixture was stirred for 0.5 h, and then C89-2 (1.7 g, 1 eq) was added. The temperature was slowly raised to 100°C and kept for 16 h. After the reaction, the temperature was cooled to room temperature and N,N-dimethylformamide was removed by distillation under reduced pressure. Water (20 mL) was added and the organic phases were extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with water (25 mL x 2). The combined aqueous phases were adjusted to pH 5-6 with concentrated hydrochloric acid. The combined organic phases were extracted with ethyl acetate (100 mL x 3) and rotary dried to obtain 1 g of the product. 1H NMR (400 MHz, DMSO) δ = 10.98 (s, 1H), 8.03 (s, 1H), 4.15 (d, J=7.1, 2H), 1.18 (s, 3H). 3. Synthesis of C89-4

[0327] Add C89-3 (1 g) and acetic acid (10 mL) to a 50 mL reactor, add concentrated hydrochloric acid (10 mL) under stirring, then slowly raise the temperature to 100°C, keep stirring and react for 15 h, then cool the reaction solution to room temperature and rotary dry to obtain 800 mg of crude product, which was directly used in the next reaction. 4. Synthesis of C89-5

[0328] To a 100 mL single-necked flask, add C89-4 (800 mg, 1.0 eq), DMSO (20 mL), DBU (3.3 g, 4 eq), and Zn(OTf)2 (0.84 g, 0.4 eq). Stir at 25°C for 5 min, then add diphenyl(vinyl)cerium trifluoromethanesulfonate (1.98 g, 1 eq). Allow to react at 25°C for 10 min. After completion, add saturated sodium chloride solution (60 mL) and extract with ethyl acetate (100 mL x 3). The combined organic phases are concentrated under reduced pressure, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 70 mg of the product. 5. Synthesis of C89

[0329] To a 100 mL sealed vial, add C89-5 (45 mg, 1.0 eq), palladium acetate (10.42 mg, 0.2 eq), XantPHos (50 mg, 0.4 eq), t-BuOK (48.3 mg, 2 eq), int1E (97.4 mg, 1.2 eq), and dioxane (8 mL). React at 100°C for 2 h. After completion, filter, concentrate, and purify by HPLC to obtain 1.2 mg of the product. Example 21

[0330] Compounds of the present invention .

[0331] The synthetic route and experimental process are as follows: . 1. Synthesis of C90-1

[0332] Int2G (80 mg, 1.00 eq), int1E (105 mg, 1.00 eq), cesium carbonate (272 mg, 3.00 eq), XantpHos (32 mg, 0.20 eq), palladium acetate (6.2 mg, 0.10 eq), and 1,4-dioxane (5 mL) were added to a sealed glass tube and the atmosphere was replaced with nitrogen. The temperature was raised to 100°C and the reaction was allowed to proceed for 2 h. The reaction was complete. The reaction mixture was cooled, filtered, and the solid was washed with ethyl acetate. The filtrate was then concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography to yield 30 mg. Ms [M+H] +: 519.3. 2. Synthesis of C90

[0333] Compound C90-1 (30 mg, 1.00 eq) was dissolved in ethyl acetate (3 mL). A solution of hydrogen chloride in dioxane was added with stirring and the mixture was stirred at room temperature for 20 minutes. After the reaction was complete, ethyl acetate and water were added for extraction. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography to yield 31 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 5.92 (s, 1H), 4.99 (s, 1H), 3.18 (s, 3H), Ms [M+H] +:483.1. Example 22

[0334] Compounds of the present invention .

[0335] The synthetic route and experimental process are as follows: . 1. Synthesis of C91-2

[0336] To a 100 mL flask, add N,N-dimethylformamide (20 mL). NaH (2.25 g, 5.0 eq) was added at 0°C. Dimethyl malonate (9 g, 5.0 eq) was then added at room temperature. After reacting at 40°C for 40 min, C91-1 was added and the temperature was raised to 100°C for another 16 h. After the reaction, concentrate to remove the N,N-dimethylformamide, add water (20 mL), and extract with ethyl acetate (4 x 20 mL) to remove impurities. The aqueous phase was retained and the pH was adjusted with concentrated H₂SO₄ until a large amount of solid precipitated. The solid was collected, washed with water several times, and dried to obtain 2.5 g of crude product, which was used directly in the next step. 2. Synthesis of C91-3

[0337] In a 100 mL flask, add the crude product of C91-2 (2.3 g, 1.0 eq), concentrated HCl (22 mL) and AcOH (16 mL), and react at 100 °C for 6 h. After the reaction is complete, concentrate to obtain 2.5 g of crude product, which is used directly in the next step. 3. Synthesis of C91-4

[0338] C91-3 (1.5 g, 1.0 eq) was added to a 50 mL flask and dissolved in anhydrous dichloromethane (20 mL). The mixture was stirred for 3-5 min. Zn(OTf)2 (0.6 g, 0.2 eq) and DBU (2.5 g, 2.0 eq) were added sequentially at room temperature. Finally, diphenyl(vinyl)cerium trifluoromethanesulfonate (1.1 g, 0.4 eq) was added. The mixture was allowed to react at room temperature for 15 min. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 180 mg of the product. 4. Synthesis of C91-5

[0339] To a 50 mL flask, C91-4 (100 mg, 1.0 eq) was added and dissolved in anhydrous N,N-dimethylformamide (5 mL). NaH (40 mg, 2.0 eq) was added at 0°C and the reaction was allowed to proceed for 0.5 h. CHCl (100 mg, 1.5 eq) was then added and the reaction continued for 1.5 h. After the reaction, water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phases were combined, washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 110 mg of the purified product. 5. Synthesis of C91-6

[0340] To a 25 mL flask, C91-5 (50 mg, 1.0 eq), int1E (75 mg, 1.0 eq), and DMSO (3 mL) were added. Potassium tert-butoxide (63 mg, 2.5 eq) was added with stirring at room temperature and allowed to react for 20 min. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 17 mg of the product. 6. Synthesis of C91

[0341] To a 25 mL flask, C91-6 (17 mg, 1.0 eq) and ethyl acetate (3 mL) were added. A 1 M dioxane hydrochloride solution (1 mL) was added with stirring at room temperature. The mixture was allowed to react at room temperature for 10 min. After completion, the reaction mixture was added to a saturated aqueous sodium bicarbonate solution in an ice bath. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 8 mg of the product. Ms [M+H] +: 464.5. Example 23

[0342] Compounds of the present invention .

[0343] The synthetic route and experimental process are as follows: . 1. Synthesis of C95-2

[0344] Compound C95-1 (5.0 g, 42.37 mmol) was dissolved in N,N-dimethylformamide (40 mL). The temperature was cooled to 0°C, and sodium hydride (2.03 g, 50.85 mmol) was added. Stirring was continued at 0°C for 15 minutes. Methyl iodide (7.2 g, 50.85 mmol) was then added dropwise. After completion of the addition, the mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was complete. The temperature was then lowered, and the reaction was quenched with water. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain 5.6 g of the crude product (Ms [M+H] + : 133.1). 2. Synthesis of C95-3

[0345] Compound C95-2 (5.6 g, 42.4 mmol) was dissolved in tert-butanol (50 mL). Sodium bicarbonate (10.7 g, 127.27 mmol) was added and stirred for 10 minutes. The temperature was then cooled to 0°C. Bromine (40.7 g, 254.55 mmol) was then added dropwise. The mixture was slowly warmed to room temperature and stirred overnight. The temperature was then lowered and the reaction was quenched with water. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product (1.81 g, Ms [M+H] +: 382.8) was purified by column chromatography. 3. Synthesis of C95-4

[0346] Compound C95-3 (1.7 g, 4.45 mmol) was dissolved in acetic acid (25 mL). The temperature was lowered to 0°C, and zinc powder (1.46 g, 22.25 mmol) was added portionwise. After addition, the mixture was warmed to room temperature and stirred for 15 minutes. The reaction was complete. The product was filtered, concentrated under reduced pressure, and purified by column chromatography to yield 0.99 g of the product (Ms [M+H] +: 226.0). 4. Synthesis of C95-5

[0347] Compound C95-4 (0.95 g, 4.20 mmol) was dissolved in dichloromethane (25 mL). Diphenyl(vinyl)arsenium trifluoromethanesulfonate (1.52 g, 4.20 mmol) and zinc trifluoromethanesulfonate (305 mg, 0.84 mmol) were added and stirred at room temperature for 3 minutes. 1,8-Diazabisspiro[5.4.0]undec-7-ene (1.28 g, 8.40 mmol) was added and stirred at room temperature for 10 minutes. The reaction was complete. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 667 mg of the product, Ms [M+H] +: 253.0. 5. Synthesis of C95

[0348] Compound C95-5 (100 mg, 0.40 mmol), int1E (120 mg, 0.32 mmol), palladium acetate (18 mg, 0.08 mmol), XantpHos (68 mg, 12 mmol), cesium carbonate (388 mg, 1.19 mmol) and 1,4-dioxane (15 mL) were heated to 100 °C under nitrogen for 12 hours. After completion of the reaction, the mixture was filtered, concentrated, and purified by thin layer chromatography to obtain 9 mg of the product. 1H NMR (400 MHz, DMSO- d 6) δ 11.55 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.80-7.68 (m, 1H), 7.49 (s, 1H), 5.42 (s, 1H), 4.99-4.93 (m, 1H), 3.29 (s, 3H), 3.04-2.94 (m, 1H), 2.45-2.38 (m, 1H), 2.36-2.31 (m, 1H), 2.01-1.95 (m, 1H), 1.92-1.79 (m, 8H), 1.75-1.72 (m, 2H), 1.71-1.61 (m, 2H), 1.59-1.56 (m, 2H). Ms [M+H] +:449.3. Example 24

[0349] Compounds of the present invention: .

[0350] The synthetic route and experimental process are as follows: . 1. Synthesis of C59

[0351] In a 100 mL single-necked flask, int1E (150 mg, 1 eq), int2A (80 mg, 1 eq), and DMSO (5 mL) were added and stirred to dissolve. Potassium tert-butoxide (133.68 mg, 3 eq) was added and stirred at room temperature for 20 min. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 40 mg of the product. 1H NMR (400 MHz, DMSO) δ = 12.11 (s, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 7.78 (s, 1H), 6.26 (s, 1H), 5.01 (s, 1H), 3.50 (d, J=14.7, 3H), 3.08 (d, J=8.1, 1H), 2.46 (d, J=7.9, 1H), 2.35 (s, 1H), 2.04 (s, 1H), 1.91 (s, 7H), 1.82 – 1.69 (m, 4H), 1.65 (dd, J=7.8, 3.7, 3H). Ms [M+H] +:450.2. Example 25

[0352] Compounds of the present invention: .

[0353] The synthetic route and experimental process are as follows: . 1. Synthesis of C94

[0354] Int29 (150 mg, 1 eq), int2A (74 mg, 1 eq) and DMSO (5 mL) were added to a 100 mL single-necked bottle and stirred to dissolve. Potassium tert-butoxide (120 mg, 3 eq) was then added and stirred at room temperature for 20 min. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified to obtain 27 mg of the product. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.53 (s, 1H), 8.30 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 5.02 (s, 1H), 3.97 – 3.75 (m, 1H), 3.47 (s, 3H), 3.14 – 3.01 (m, 1H), 2.43 – 2.25 (m, 2H), 2.10 – 1.98 (m, 1H), 1.92 (s, 1H), 1.81 – 1.69 (m, 4H), 1.65 (q, J = 4.2, 3.6 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H). Ms [M+H] +:494.2. Example 26

[0355] Compounds of the present invention: .

[0356] The synthetic route and experimental process are as follows: . 1. Synthesis of C103-1

[0357] Compounds int31 (130 mg, 1.0 eq) and int2A (74.1 mg, 1.0 eq) were dissolved in dimethylsulfoxide (13 mL). A solution of potassium tert-butoxide (78 mg, 2.0 eq) in dimethylsulfoxide was slowly added dropwise under an ice-water bath. The mixture was allowed to react at room temperature for 20 minutes. Purified water was added dropwise under an ice-water bath, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated sodium chloride solution and concentrated in vacuo to a complete absence of liquid. Thin-layer chromatography was performed to obtain 100 mg of the product. Ms [M+H] +: 540.2. 2. Synthesis of C103

[0358] Dissolve compound C103-1 (100 mg, 1.0 eq) in 10 mL of ethyl acetate. Slowly add a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (2 mL) dropwise under an ice-water bath. Allow to react at room temperature for 10 minutes. Add the reaction system dropwise to a saturated sodium bicarbonate solution under an ice-water bath, and extract with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and concentrated in vacuo to give 7.39 mg of the product by thin layer chromatography. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 4.99 (s, 1H), 3.46 (s, 3H), 3.07 (t, J = 8.8 Hz, 1H), 2.67 (s, 1H), 2.33 (s, 1H), 2.09 – 1.98 (m, 1H), 1.90 (s, 1H), 1.82 – 1.56 (m, 6H), 1.43 – 1.17 (m, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H). Ms [M+H] +:440.2. Example 27

[0359] Compounds of the present invention: .

[0360] The synthetic route and experimental process are as follows: . 1. Synthesis of C104

[0361] In a 50 mL single-necked flask, int32 (146 mg, 1 eq), int2A (74.1 mg, 1.0 eq), and DMSO (5 mL) were added and stirred to dissolve. Potassium tert-butoxide (120 mg, 3 eq) was added and stirred at room temperature for 20 min. After completion of the reaction, saturated sodium chloride (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by high performance liquid chromatography to obtain 35 mg of the product. 1H NMR (400 MHz, Chloroform- d) δ 8.44 (s, 1H), 7.19 (s, 1H), 6.54 (s, 1H), 5.19 (q, J = 5.0, 4.6 Hz, 1H), 4.91 (s, 1H), 3.65 (s, 3H), 3.21 (p, J = 8.2 Hz, 1H), 2.54 (s, 1H), 2.29 (s, 2H), 2.14 (dd, J= 11.6, 6.3 Hz, 1H), 1.99 – 1.75 (m, 13H), 1.42 (s, 3H). Ms [M+H] +:452.5. Example 28

[0362] Compounds of the present invention: .

[0363] The synthetic route and experimental process are as follows: . 1. Synthesis of C106-1

[0364] Compound int2F (800 mg, 1.00 eq), N-bromosuccinimide (3.85 g, 4.00 eq), and carbon tetrachloride (30 mL) were added to a 100 mL glass flask. Azobisisobutyronitrile (59 mg, 0.10 eq) was then added at room temperature. The reaction mixture was allowed to react at 75°C under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, concentrated, and purified on a silica gel column to yield 600 mg of the product. Ms [M+H] +: 378.9. 2. Synthesis of C106-2

[0365] C106-1 (400 mg, 1.00 eq) and ethanol (12 mL) were added to a 50 mL single-necked flask. A solution of silver nitrate (630 mg, 3.50 eq) in water (8 mL) was added at room temperature. The reaction mixture was stirred at 80°C for 1 h. The mixture was filtered and the liquid phase was concentrated. The aqueous phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin-layer chromatography to yield 190 mg of the product. Ms [M+H] +: 237.0. 3. Synthesis of C106-3

[0366] C106-2 (190 mg, 1.00 eq) and dichloromethane (20 mL) were added to a 50 mL three-necked flask. The temperature was lowered to -50°C, and diethylaminosulfur trifluoride (518 mg, 4.00 eq) was slowly added dropwise. The reaction mixture was stirred at -50°C for 10 min, then slowly warmed to room temperature and allowed to react for 2 h. A saturated aqueous solution of sodium bicarbonate was slowly added at 0°C, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Purification by preparative thin-layer chromatography yielded 170 mg of the product. Ms [M+H] +: 259.0. 4. Synthesis of C106-4

[0367] To a 25 mL sealed glass tube were added C106-3 (80 mg, 1.00 eq), int7 (103 mg, 1.00 eq), cesium carbonate (303 mg, 3.00 eq), XantpHos (36 mg, 0.20 eq), palladium acetate (7 mg, 0.10 eq), and 1,4-dioxane (5 mL). The mixture was heated to 100°C under a nitrogen atmosphere for 2 h. The reaction mixture was cooled, filtered, and the residue was washed with ethyl acetate. The organic phase was concentrated under reduced pressure. Purification by preparative thin-layer chromatography afforded 100 mg of the product. Ms [M+H] +: 555.3. 5. Synthesis of C106

[0368] Compound C106-4 (90 mg, 1.00 eq) was dissolved in formic acid (4 mL) and heated to 80°C for 1.5 hours. The reaction mixture was cooled and concentrated. Dissolved in ethyl acetate and the pH was adjusted to alkaline with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product (14 mg) was prepared. 1H NMR (400 MHz, DMSO- d 6) δppm 12.10 (s, 1H), 8.09 (s, 1H), 7.83-7.69 (m, 2H), 6.76 (t, J= 55.2 Hz, 1H), 5.81 (s, 1H), 5.00 (s, 1H), 3.51 (s, 3H), 3.13-3.05 (m, 1H), 2.50-2.43 (m, 2H), 2.39-2.30 (m, 1H), 2.09-2.02 (m, 1H), 1.99-1.79 (m, 7H), 1.79-1.65 (m, 4H), 1.63-1.59 (m, 2H). Ms [M+H] +:499.2. Example 29

[0369] Compounds of the present invention: .

[0370] The synthetic route and experimental process are as follows: . 1. Synthesis of C107-1

[0371] Compound int2B (500 mg, 1.00 eq) and tetrahydrofuran (15 mL) were added to a 50 mL glass flask. The temperature was cooled to 0°C, and lithium aluminum hydride (110 mg, 1.20 eq) was added. The reaction mixture was heated to 60°C and stirred for 1 h. The reaction mixture was cooled to 0°C, quenched with ice water, filtered, and the residue washed with ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column afforded 150 mg of the product. Ms [M+H] +: 195.1. 2. Synthesis of C107-2

[0372] To a 25 mL sealed glass tube, add C107-1 (100 mg, 1.00 eq), int7 (171 mg, 1.00 eq), cesium carbonate (504 mg, 3.00 eq), XantpHos (60 mg, 0.20 eq), palladium acetate (12 mg, 0.10 eq), and 1,4-dioxane (5 mL). The mixture was heated to 100°C under a nitrogen atmosphere and reacted for 2 h. The mixture was cooled, filtered, and the organic phase was concentrated. Purification by preparative thin-layer chromatography afforded 150 mg of the product. Ms [M+H] +: 491.3. 3. Synthesis of C107

[0373] Compound C107-2 (130 mg, 1.00 eq) was dissolved in formic acid (4 mL), heated to 80°C for 1.5 hours, cooled, concentrated, dissolved in ethyl acetate, adjusted to alkaline pH with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product was prepared in an amount of 16 mg. 1H NMR (400 MHz, DMSO- d6) δppm 11.87 (s, 1H), 7.81-7.66 (m, 2H), 7.61 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 5.6 Hz, 1H), 5.76 (s, 1H), 4.99 (s, 1H), 3.38 (s, 2H), 3.11-2.96 (m, 1H), 2.77 (s, 3H), 2.49-2.42 (m, 2H), 2.38-2.30 (m, 1H), 2.06-1.97 (m, 1H), 1.89 (s, 6H), 1.78-1.64 (m, 2H), 1.63-1.52 (m, 1H), 1.01 (q, J= 3.6 Hz, 2H), 0.88 (q, J= 3.6 Hz, 2H). Ms [M+H] +:435.2. Example 30

[0374] Compounds of the present invention: .

[0375] The synthetic route and experimental process are as follows: . 1. Synthesis of C109-2

[0376] Compound C109-1 (2.00 g, 1.00 eq), sodium bicarbonate (3.11 g, 3.00 eq), and tert-butanol (40 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 10 min. Bromine (11.85 g, 6.00 eq) was slowly added dropwise. The reaction was allowed to react at room temperature for 1 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The layers were separated. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification on a silica gel column afforded 4.40 g of the product. Ms [M+H] +: 412.8. 2. Synthesis of C109-3

[0377] C109-2 (4.40 g, 1.00 eq) and methanol (80 mL) were added to a 250 mL single-necked flask. 10% Pd / C (4.00 g) was added at room temperature to displace the hydrogen atmosphere. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 24 h, filtered, and the filter cake was washed with methanol. The organic phase was concentrated to yield 3.20 g of crude product. Ms [M+H] +: 179.1. 3. Synthesis of C109-4

[0378] C109-3 (3.20 g, crude product), diphenyl(vinyl)arsenium trifluoromethanesulfonate (3.86 g, 1.00 eq), and zinc trifluoromethanesulfonate (775 mg, 0.20 eq) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 3 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (3.25 g, 2.00 eq) was slowly added dropwise. The reaction was allowed to react at room temperature for 10 min. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification on a silica gel column afforded 900 mg of the product. Ms[M+H] +: 205.1. 4. Synthesis of C109-5

[0379] To a 50 mL single-necked flask, C109-4 (550 mg, 1.00 eq), sodium iodide (809 mg, 2.00 eq), and acetonitrile (15 mL) were added. Trimethylsilyl chloride (588 mg, 2.00 eq) was added at room temperature to displace the hydrogen atmosphere. The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 16 h. The pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, filtered, and the liquid phase was concentrated. Purification on a silica gel column afforded 700 mg of the product. Ms [M+H] +: 191.1. 5. Synthesis of C109-6

[0380] C109-5 (300 mg, 1.00 eq), triethylamine (957 mg, 6.00 eq), and dichloromethane (15 mL) were added to a 50 mL single-necked flask. Trifluoromethanesulfonic anhydride (668 mg, 1.50 eq) was dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction system under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 minutes, then warmed to room temperature and stirred for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by preparative thin-layer chromatography afforded 147 mg of the product. Ms[M+H] +: 323.0. 6. Synthesis of C109-7

[0381] To a sealed glass tube, add C109-6 (110 mg, 1.00 eq), int7 (113 mg, 1.00 eq), cesium carbonate (334 mg, 3.00 eq), XantpHos (14 mg, 0.20 eq), palladium acetate (3 mg, 0.10 eq), and 1,4-dioxane (5 mL). The atmosphere was replaced with nitrogen. The mixture was heated to 100°C and reacted for 1 h. The mixture was then cooled, filtered, the solid washed with ethyl acetate, and concentrated under reduced pressure. The product was purified by preparative thin-layer chromatography to yield 90 mg. Ms [M+H] + : 505.3. 7. Synthesis of C109

[0382] Compound C109-7 (90 mg, 1.00 eq) was dissolved in formic acid (5 mL), heated to 80°C with stirring for 40 min, cooled to room temperature, and concentrated under reduced pressure. The mixture was redissolved in ethyl acetate, the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography to give 11 mg of the product. 1H NMR (400 MHz, CDCl 3) δppm 7.98 (d, J= 5.2 Hz, 1H), 6.84 (s, 1H), 6.45 (d, J= 5.2 Hz, 1H), 6.06 (s, 1H), 5.28 (s, 1H), 5.22-5.14 (m, 1H), 3.62 (s, 3H), 3.17 (p, J= 8.4 Hz, 1H), 2.56-2.44 (m, 1H), 2.40 (s, 1H), 2.16-2.07 (m, 1H), 2.02 (s, 6H), 1.96-1.90 (m, 2H), 1.90-1.81 (m, 4H), 1.62 (q, J= 4.0 Hz, 2H). Ms [M+H] +449.2. Example 31

[0383] Compounds of the present invention: .

[0384] The synthetic route and experimental process are as follows: . 1. Synthesis of C120-1

[0385] In a 100 mL single-necked flask, compounds int40 (620 mg, 1.00 eq) and int2A (439 mg, 1.30 eq) were dissolved in DMSO (30 mL). A solution of potassium tert-butoxide (543 mg, 3.00 eq) in DMSO (3 mL) was added dropwise to the solution in a water bath. The mixture was allowed to react at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 780 mg of a crude product. Ms [M+H] +: 558.6. 2. Synthesis of C120

[0386] In a 100 mL single-necked flask, compound C120-1 (780 mg, 1.00 eq) was dissolved in dichloromethane (30 mL). Trifluoroacetic acid (1 mL) was added dropwise to the solution in a water bath. After addition, the mixture was allowed to react at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 415 mg of the crude product. The product was then slurried twice with ethyl acetate (30 mL) to obtain 275 mg of the product. 1H NMR (400 MHz, DMSO- d 6) δ 12.10 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.01 (d, J= 8.4 Hz, 1H), 6.26 (s, 1H), 5.01 (s, 1H), 4.48 (t, J= 5.9 Hz, 1H), 4.36 (t, J= 5.9 Hz, 1H), 3.63 (q, J= 7.0 Hz, 1H), 3.47 (s, 3H), 3.16 – 3.01 (m, 1H), 2.50 (s, 2H), 2.10 – 1.85 (m, 2H), 1.83 – 1.53 (m, 8H), 1.07 (d, J= 6.7 Hz, 3H), Ms[M+H] +:458.5. Example 32

[0387] Compounds of the present invention: .

[0388] The synthetic route and experimental process are as follows: . 1. Synthesis of C128-2

[0389] To a 25 mL sealed glass tube, compound int1D (700 mg, 1.00 eq), diisopropylethylamine (822 mg, 5.00 eq), and tetrahydrofuran (6 mL) were added, followed by the addition of C128-1 (248 mg, 1.40 eq) at room temperature. The reaction mixture was allowed to react at 55°C for 16 h. The mixture was then cooled to room temperature and a large amount of ethyl acetate was added. The organic phase was washed four times with 1 N aqueous sodium hydroxide solution. The organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. Purification on a silica gel column afforded 630 mg of the product, Ms[M+H] +: 515.3. 2. Synthesis of C128-3

[0390] C128-2 (300 mg, 1.00 eq) and methanol (15 mL) were added to a 100 mL single-necked flask. 10% Pd / C (80 mg) was added at room temperature to displace the hydrogen atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 h, filtered, and the filter cake was washed with methanol. The organic phase was concentrated to obtain 230 mg of the crude product. Ms [M+H] +: 381.2. 3. Synthesis of C128-4

[0391] C128-3 (230 mg, 1.00 eq), int2A (127 mg, 1.00 eq), and dimethylsulfoxide (5 mL) were added to a 25 mL glass flask. Potassium tert-butoxide (204 mg, 3.00 eq) was dissolved in DMSO (1 mL) and slowly added dropwise to the reaction system at room temperature. The reaction was stirred at room temperature for 30 min. Water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated. Purification by preparative thin-layer chromatography afforded 170 mg of the product. Ms [M+H] +: 554.3. 4. Synthesis of C128-5

[0392] Compound C128-4 (170 mg, 1.00 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 min, and the pH was adjusted to neutral with an aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The organic phase was purified by preparative thin-layer chromatography, slurried with ethyl acetate / petroleum ether, and filtered to obtain 80 mg of the product. Ms [M+H] +: 470.2. 5. Synthesis of C128 and C129

[0393] Compound C128-5 (80 mg) was prepared and isolated as follows: C129(47 mg) 1H NMR (400 MHz, DMSO) δppm 12.11 (s, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 7.43 (s, 1H), 6.27 (s, 1H), 5.08-4.85 (m, 2H), 3.47 (s, 3H), 3.16-3.00 (m, 1H), 2.50-2.48 (m, 1H), 2.47-2.31 (m, 4H), 2.08-1.99 (m, 1H), 1.96-1.85 (m, 1H), 1.81-1.69 (m, 4H), 1.69-1.58 (m, 3H), 1.25 (s, 3H). Ms[M+H] +:470.2.

[0394] C128(16 mg) 1H NMR (400 MHz, DMSO) δppm 12.10 (s, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 7.31 (s, 1H), 6.26 (s, 1H), 5.17-4.96 (m, 2H), 3.47 (s, 3H), 3.15-3.02 (m, 1H), 2.74-2.60 (m, 2H), 2.50-2.48 (m, 1H), 2.14-1.98 (m, 3H), 1.97-1.84 (m, 1H), 1.81-1.57 (m, 7H), 1.38 (s, 3H). Ms[M+H] +:470.2. The following compounds were synthesized using the above synthesis method: Compound Ms [M+H] + 1H NMR 466.3 1HNMR(400MHz, DMSO-d6) δ 12.09 (s, 1H), 8.64 – 8.36 (m, 1H), 8.30 (d, J = 3.6 Hz, 1H), 6.86 (s, 1H), 6.39 – 6.03 (m, 1H), 4.98 (s, 1H), 3.47 (d, J = 3.5 Hz, 3H), 3.07 (s, 1H), 2.03 (s, 1H), 1.91 (s, 3H), 1.75 (p, J = 4.9 Hz, 4H), 1.68 – 1.50 (m, 7H), 1.43 (s, 2H), 1.26 (d, J = 3.5 Hz, 3H). 454.5 1H NMR (400 MHz, CDCl 3) δ 8.44 (s, 1H), 7.13 (s, 1H), 6.54 (br, 1H), 5.21 (s, 1H), 4.51-4.36 (m, 1H), 3.66 (s, 3H), 3.51-3.62 (m, 1H), 3.26-3.18 (m, 1H), 2.61-2.49 (m, 1H), 2.24-2.15 (m, 1H), 2.04-1.78 (m, 8H), 1.52-1.45 (m, 2H), 1.40-1.26 (m, 3H), 0.96-0.79 (m, 6H). 440.2 1HNMR(400 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 6.76 (s, 1H), 6.24 (s, 1H), 5.02-4.93 (m 1H), 3.46 (s, 3H), 3.11-3.02 (m, 1H), 2.49-2.43 (m, 1H), 2.06-1.98 (m, 1H), 1.94-1.84 (m, 1H), 1.77-1.69 (m, 4H), 1.66-1.63 (m, 2H), 1.63-1.55 (m, 1H), 1.20 (s, 9H). 488.2 1HNMR(400MHz, DMSO- d6) δppm 12.10 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 7.60 (s, 1H), 6.26 (s, 1H), 5.02 (s, 1H), 3.47 (s, 3H), 3.16-3.02 (m, 1H), 2.92-2.74 (m, 2H), 2.59-2.51 (m, 2H), 2.50-2.46 (m, 2H), 2.10-1.99 (m, 1H), 1.98-1.85 (m, 1H), 1.84-1.71 (m, 4H), 1.66-1.61 (m, 2H), 1.38 (s, 3H). 452.2 1HNMR(400MHz, DMSO- d6) δ 12.09 (s, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.02-7.00 (d, J = 8 Hz, 1H), 6.23 (s, 1H), 4.99 (s, 1H), 3.48 (s, 3H), 3.05 – 2.97 (m, 2H), 2.06 – 1.86 (m, 2H), 1.73-1.67 (m, 8H), 1.09-1.077(d, J = 8 Hz, 2H)0.82 – 0.79 (m, 1H), 0.39 – 0.20 (m, 3H), 0.10-0.07 (m, 1H). 438.2 1HNMR(400 MHz, DMSO-d 6) δ 12.09 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 7.35 (s, 1H), 6.23 (s, 1H), 5.00 – 4.99 (m, 1H), 3.46(s, 3H),3.07(m, 1H), 2.07-1.56(m, 10H), 1.23 (s, 3H), 0.60-0.57 (m, 2H), 0.48-0.45 (m, 2H). 482.5 1HNMR(400 MHz, DMSO- d 6) δ 12.10 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 7.31 (s, 1H), 6.27 (s, 1H), 5.00 (s, 1H), 3.69 (t, J= 7.1 Hz, 1H), 3.47 (s, 3H), 3.09 (s, 4H), 2.48 (s, 1H), 2.24 (m, J= 9.6, 6.8, 2.9 Hz, 2H), 2.03 (s, 3H), 1.96 – 1.84 (m, 1H), 1.75 (p, J= 4.5 Hz, 4H), 1.65 (q, J= 4.2, 3.7 Hz, 3H), 1.27 (s, 3H). 482.5 1HNMR(400MHz, DMSO-d6) δ 12.09 (s, 1H), 8.56-8.45 (m, 1H), 8.30 (s, 1H), 7.22 (s, 1H), 6.26 (s, 1H), 4.99 (s, 1H), 3.84-3.74 (m, 1H), 3.47 (s, 3H), 3.10-3.02 (m, 1H), 3.07 (s, 3H), 2.49-2.40 (m, 3H), 2.08-1.99 (m, 1H), 1.94-1.85 (m, 1H), 1.77-1.70 (m, 6H), 1.66-1.57 (m, 3H), 1.31 (s, 3H). Ms [M+H]+ 482.2. 476.5 1HNMR(400MHz, DMSO-d6) δ 12.10 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.37 – 6.20 (m, 1H), 6.02 (tt, J = 56.4, 4.8 Hz, 1H), 5.02 (s, 1H), 3.77 – 3.61 (m, 1H), 3.47 (s, 3H), 3.10 (d, J = 9.5 Hz, 1H), 2.50 (d, J = 1.8 Hz, 2H), 2.12 – 1.82 (m, 4H), 1.70 (dq, J = 40.8, 4.0 Hz, 6H), 1.10 (d, J = 6.7 Hz, 3H). 472.5 1H NMR (400 MHz, CDCl 3)δ 7.07 (s, 1H), 6.42 (s, 1H), 5.21 (s, 1H), 4.55 (s, 1H), 3.80 (s, 1H), 3.61 (s, 3H), 3.23 (p, J= 8.1 Hz, 1H), 2.57 (s, 3H), 2.55 – 2.46 (m, 1H), 2.14 (dd, J= 11.5, 6.4 Hz, 1H), 2.08 – 1.74 (m, 9H), 1.21 (d, J= 6.7 Hz, 6H). 444.2 1HNMR(400 MHz, DMSO- d 6) δ ppm 12.08 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.25 (s, 1H), 5.08-4.96 (m, 1H), 4.30 (d, J= 4.8 Hz, 1H), 4.18 (d, J= 4.8 Hz, 1H), 3.84-3.66 (m, 1H), 3.46 (s, 3H), 3.12-3.02 (m, 1H), 2.48-2.41 (m, 1H), 2.08-1.99 (m, 1H), 1.96-1.86 (m, 1H), 1.80-1.71 (m, 4H), 1.67-1.56 (m, 3H), 1.04 (d, J= 6.0 Hz, 3H). 472.5 1H NMR (400 MHz, CDCl 3)δ 7.08 (s, 1H), 6.39 (s, 1H), 5.21 (s, 1H), 4.72 (s, 1H), 4.66 – 4.44 (m, 2H), 3.89 (s, 1H), 3.61 (s, 3H), 3.23 (p, J= 8.1 Hz, 1H), 2.57 (s, 3H), 2.55 – 2.46 (m, 1H), 2.14 (dd, J= 11.5, 6.4 Hz, 1H), 2.08 – 1.74 (m, 11H), 1.21 (d, J= 6.7 Hz, 3H). 471.2 1HNMR(400MHz, DMSO- d6) δppm 11.95 (s, 1H), 7.74 (s, 1H), 7.14 (s, 1H), 7.00 (d, J= 8.4 Hz, 1H), 5.74 (s, 1H), 5.00 (s, 1H), 4.48 (t, J= 6.0 Hz, 1H), 4.36 (t, J= 6.0 Hz, 1H), 3.68-3.56 (m, 1H), 3.43 (s, 3H), 3.11-2.99 (m, 1H), 2.48-2.40 (m, 1H), 2.26 (s, 3H), 2.08-1.98 (m, 1H), 1.97-1.86 (m, 1H), 1.81-1.66 (m, 4H), 1.64-1.53 ​​(m, 3H), 1.50 (q, J= 3.6, 3.2 Hz, 2H), 1.10-0.98 (m, 3H). 470.3 1HNMR(400 MHz, DMSO-d 6) δ ppm 12.08 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 7.42 (s, 1H), 6.26 (s, 1H), 5.00 (s, 1H), 4.53 (s, 1H), 4.41 (s, 1H), 3.46 (s, 3H), 3.13 - 3.03 (m, 1H), 2.09 (t, J = 9.6 Hz, 2H), 2.00 (ddd, J = 12.8, 7.6, 4.0 Hz, 3H), 1.90 (s, 2H), 1.80 - 1.69 (m, 6H), 1.65 (t, J = 4.0 Hz, 3H). [Cell proliferation inhibition test] 1. Experimental Materials [Cell lines] [Supplier] OVCAR3 Beina Biological TOV21G Beina Biological

[0395] The control compound is Palbociclib. 2. Experimental Plan 1. Cell plate culture a) preparing a cell suspension; b) Remove the culture medium from the culture flask; c) Rinse the cells once with PBS; d) digest with trypsin and collect by centrifugation; e) Resuspend in culture medium, count and adjust to the appropriate concentration; f) Add 80 μL of the cell suspension to each well of a 96-well culture plate, seeding one plate with each cell type. Incubate overnight in a 37°C, 5% CO2 incubator. 2. Compound treatment Compound dilution: a) Prepare a serial dilution of the test compound: Palbociclib and the example compounds were prepared as 10 mM stock solutions. 2.5 μL of the stock solution was then dissolved in 497.5 μL of DMSO-free culture medium. Three-fold serial dilutions were then performed in 0.1% DMSO culture medium, for a total of nine concentrations. The compound concentrations after dilution were as follows: 10000 nM, 3333.33 nM, 1111.11 nM, 370.34 nM, 123.45 nM, 41.15 nM, 13.72 nM, 4.57 nM, 1.52 nM; b) After thorough mixing, add 20 μL of the compound solution to each well containing 80 μL of cells in a cell culture dish, with four replicates per well. c) Transfer the cells to an incubator and incubate for 5 days. 3. MTT assay a) Remove the cell culture plate and add 10 μL of 5 mg / mL MTT into the hood; b) Place the cell culture dish back into the incubator and continue incubating for 3 hours; c) Remove the cell culture plate and discard the culture medium. Add 100 μL of isopropanol (0.4 mM HCl, 0.4% NP40) and incubate at room temperature in a shaking incubator for 30 minutes. Read the plate at 570 nm. 4. Data Analysis The % Cell Survival was calculated using the following formula: % Cell Survival=100%×(OD_Sample-OD_LCave) / (OD_HC-OD_LCave) OD_HC: 0.1‰ DMSO control group cell reading OD_Sample: Cell readings after compound addition OD_LC: Blank culture medium reading Analyzed by Prizm: Dose-response-Inhibition - Log(inhibitor) vs response (three parameters for the best fit).

[0396] The results of the cell proliferation inhibition test are shown in Table 1 below. Table 1 cell lines Compound OVCAR3 (IC50 nM) TOV21G (IC50 nM) Palbociclib (Palbociclib) D B(395.7) C1 B D C2 B D C10 B C C11 A A C12 B D C13 A C C15 B C C17 A B C18 A C C19 A B C20 A B C22 B C C23 A A C24 A B C25 B C C29 A B C30 A A C31 A C C32 A B C37 A B C38 B C C42 B B C53 B C C54 B B C59 A C C64 A B C65 A B C66 D D C67 D D C70 B B C74 A B C85 A B C94 B C C98 B C C104 B B C109 B B C110 C B C112 A B C113 B B C114 A C C115 B B C117 A C C118 B C C119 B D C120 B C C121 B C C125 B D C126 B D C127 B D C128 A C C129 A C A≤300 nM; 300 nM <B≤1000 nM; 1000 nM <C≤3000 nM; D>3000 nM

[0397] The experimental results showed that the example compounds showed good inhibitory effect on the CyclinE amplified cell line OVCAR3, while the example compounds had no obvious inhibitory effect on the non-CyclinE amplified cell line TOV21G, showing good selectivity of the compounds. [Enzyme activity test]

[0398] Prepare the compound: 1. Prepare the test compound and palbociclib into a 0.5 nM DMSO solution; 2. Use Echo550 to transfer 20 μL of the stock solution to a 384-well plate. Use DMSO as a blank control.

[0399] Experimental steps: 3. Prepare 1.3X enzyme solution containing enzyme, substrate, and coenzyme factors according to the table below; 4. Add 15 μL of 1.3x enzyme solution to each well and incubate at room temperature for 30 minutes; 5. Add 5 μL of 4x ATP solution to start the reaction. The final volume per well is 20 μL. 6. After incubation at room temperature for 150 min, add 75 μL of stop buffer solution to terminate the experiment; 7. Analyze the sample using the EZ reader. enzyme supplier Enzyme concentration (nM) ATP concentration (nM) Hostage Coenzyme factor Reaction time CDK1 / CycB1 Carna 1.40 50 FL-Peptide29 10 mM MgCl 2 120 minutes CDK2 / CycE1 Carna 0.63 100 FL-Peptide18 10 mM MgCl 2 120 minutes CDK4 / CycD1 Carna 1.50 200 FL-Peptide34 10 mM MgCl 2 120 minutes CDK6 / CycD3 Carna 1.50 300 FL-Peptide34 10 mM MgCl 2 120 minutes

[0400] Data Analysis: The % inhibition rate was calculated using the following equation: The cells treated with DMSO were used as positive control (PC); The one without enzyme was the negative control (NC); % inhibition rate = 100-100*((CR PC-CR sample) / (CR PC-CR NC)). Table 2 Compound CDK1 (nM) CDK2 (nM) CDK4 (nM) CDK6 (nM) Palbociclib (Palbociclib) >10000 5207.7 0.8 0.2 C1 C A C C C2 C A D C C3 D B D D C4 C A C C C5 C A D C C6 D A D D C7 C B / / C8 D B / / C9 C B / / C10 C A / / C11 B A / / C12 C A / / C13 C A / / C15 C A / / C16 D B / / C17 B A / / C18 B A / / C19 C A / / C20 C A / / C21 C A / / C22 B A / / C23 B A / / C24 C A / / C25 C A / / C26 C A / / C27 C A / / C28 C B / / C29 C A / / C30 B A / / C31 C A / / C32 B A / / C33 D B / / C35 C B / / C36 D B / / C37 C A / / C38 C A / / C39 C B / / C40 C B / / C41 C A / / C42 B A / / C44 C A / / C45 D B / / C46 C B / / C47 C B / / C48 C B / / C52 C B / / C53 C A / / C54 B A / / C55 C A / / C56 C A / / C59 C A / / C60 B A / / C61 D A / / C62 C A / / C63 C A / / C64 B A / / C65 B A / / C66 C A / / C68 D B / / C70 B A / / C71 C A / / C73 D B / / C76 C B / / C77 D B / / C78 D B / / C79 D A / / C80 D B / / C81 D B / / C82 D B / / C83 C A / / C84 D B / / C85 B A / / C86 C A / / C87 C B / / C91 C B / / C92 C A / / C93 C A / / C94 C A / / C95 D B / / C96 D B / / C97 D B / / C98 C A / / C99 C A / / C100 D B / / C101 D B / / C102 D B / / C103 D A / / C104 C A / / C105 C A / / C106 C B / / C107 C A / / C108 D A / / C109 C A / / C110 C A / / C111 D B / / C112 B A / / C113 C A / / C114 B A / / C115 D A / / C116 C A / / C117 C A / / C118 C A / / C119 D A / / C120 D A / / C121 C A / / C122 D B / / C123 D B / / C124 D B / / C125 C A / / C126 C A / / C127 C A / / C128 D A / / C129 C A / / C130 D B / / A≤10 nM; 10 nM <B≤50 nM; 50 nM <C≤500 nM; D>500 nM

[0401] The experimental results show that the compounds of the present invention have excellent selectivity and activity for CDK2 kinase.

[0402] The present invention provides a series of compounds with excellent CDK2 kinase activity and selectivity. This series of compounds has a good inhibitory effect on cell overproliferation caused by abnormal expression or amplification of Cyclin E and has broad application prospects.

[0403] All documents mentioned in this application are incorporated herein by reference, just as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents are also within the scope of the claims appended hereto.

Claims

1. A compound of formula (Ⅰ), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Selected from the following groups: ; Ra1 is selected from the following groups: C1-4 alkyl, deuterated C1-4 alkyl; Each Rc1 and Rd1 is independently selected from the following groups: hydrogen, deuterium, halogen, hydroxyl, cyano, C1-4 alkyl, halo-C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo-C1-4 alkoxy; m is 0; r is selected from the following groups: 0, 1, 2; w is selected from the following groups: 0, 1, 2; R1 is -CONR2R3; X1 is CH2; X2 is O; R2 and R3 are each independently selected from the group consisting of: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L- (C3-7 cycloalkyl), -L- (4-7 member heterocycloalkyl containing one or two heteroatoms selected from N and O), wherein the C1-6 alkyl, C3-7 cycloalkyl, and 4-7 member heterocycloalkyl are optionally substituted by 0, 1, 2, 3, or 4 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, cyano, =O, amino, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halo-C1-4 alkyl, halo-C1-4 alkoxy, -S(O)2-C1-4 alkyl. Alternatively, R2 and R3 together with the N atom to which they are attached form a 4-6 member monocyclic heterocyclic alkyl group containing one N atom and one optional O atom, wherein the 4-6 member monocyclic heterocyclic alkyl group is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, cyano, =O, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halo-C1-4 alkyl, halo-C1-4 alkoxy; L is a bond; each R7 is independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-4 alkyl, deuterated C1-4 alkyl, halo-C1-4 alkyl.

2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound has a structure selected from the group consisting of: wherein, R1 is -CONR2R3; R2 and R3 are each independently selected from the group consisting of: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L- (C3-7 cycloalkyl), -L- (4-7 member heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O), wherein the C1-6 alkyl, C3-7 cycloalkyl, and 4-7 member heterocycloalkyl are optionally substituted by 0, 1, 2, 3, or 4 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, cyano, =O, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halo-C1-4 alkyl, halo-C1-4 alkoxy. Alternatively, R2 and R3 together with the N atom to which they are attached form a 4-6 member monocyclic heterocyclic alkyl group containing one N atom and one optional O atom, wherein the 4-6 member monocyclic heterocyclic alkyl group is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, cyano, =O, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halo-C1-4 alkyl, halo-C1-4 alkoxy; L as defined in claim 1; Ra1 selected from the group consisting of: C1-4 alkyl, deuterated C1-4 alkyl; each Rc1 is independently hydrogen; each Rd1 is independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-4 alkyl, halo-C1-4 alkyl; m is 0; r is selected from the group consisting of: 0, 1, 2.

3. The compound of formula (I) as claimed in claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound has a structure selected from the group consisting of: wherein, R1 is -CONR2R3; R2 and R3 are each independently selected from the group consisting of: hydrogen, C1-6 alkyl, deuterated C1-6 alkyl, -L- (C3-7 cycloalkyl), -L- (4-7 member heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O), wherein the C1-6 alkyl, C3-7 cycloalkyl, and 4-7 member heterocycloalkyl are optionally substituted by 0, 1, 2, 3, or 4 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, cyano, =O, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halo-C1-4 alkyl, halo-C1-4 alkoxy. Alternatively, R2 and R3 together with the N atom to which they are attached form a 4-6 member monocyclic heterocyclic alkyl group containing one N atom and one optional O atom, wherein the 4-6 member monocyclic heterocyclic alkyl group is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of: deuterium, hydroxyl, halogen, cyano, =O, C1-4 alkyl, C1-4 alkoxy, deuterated C1-4 alkyl, halo-C1-4 alkyl, halo-C1-4 alkoxy; L as defined in claim 1; Ra1 selected from the group consisting of: C1-4 alkyl, deuterated C1-4 alkyl; each Rc1 is independently hydrogen; each Rd1 is independently selected from the group consisting of: hydrogen, halogen, C1-4 alkyl, halo-C1-4 alkyl; m is 0; r is selected from the group consisting of: 0, 1, 2.

4. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the compound is selected from the group consisting of compounds, or pharmaceutically acceptable salts or stereoisomers thereof: .

5. A pharmaceutical composition characterized in that it comprises a preventive and / or therapeutically effective amount of the compound of formula (I) as claimed in claim 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound of formula (I) as claimed in claim 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that it is used to prepare a medicament for modulating CDK activity or for preventing and / or treating CDK-related diseases.

7. Use of a compound of formula (I) as claimed in claim 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that it is used to prepare a medicament for the prevention and / or treatment of cyclin-related diseases.