CN118063469A

CN118063469A - Cycloalkenyl-pyridine group-containing compound

Info

Publication number: CN118063469A
Application number: CN202311563709.8A
Authority: CN
Inventors: 任景; 张晓平; 黄永康; 王磊; 张寅生
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2022-11-22
Filing date: 2023-11-21
Publication date: 2024-05-24

Abstract

The application belongs to the field of pharmaceutical chemistry, and relates to a compound containing cycloalkenyl pyridine, in particular to a compound shown in a formula I or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in treating diseases (such as cancers).

Description

Cycloalkenyl-pyridine group-containing compound

Technical Field

The present application relates to compounds containing cycloalkenyl-pyridinium groups, methods for their preparation, pharmaceutical compositions containing the compounds, and their use in the treatment of related diseases, such as cancer.

Background

Wee1 protein is a cell cycle regulatory protein, which is one of important members of serine/threonine protein kinase family, and by regulating the phosphorylation state of CDK1, wee1 protein affects the binding of CDK1 to cyclin B to block the transition from G2 phase to M phase, thereby ensuring DNA replication accuracy and chromatin integrity. Thus, the Wee1 protein is a key protein kinase involved in the G2/M checkpoint and DNA damage repair process of the cell cycle. On the other hand, during normal cell cycle progression, p53 protein can also monitor genome integrity by regulating G1/S phase and DNA damage examination, but p53 gene deletion in most tumor cells results in defective cell cycle G1/S checkpoints. Therefore, these p 53-deleted tumor cells are more dependent on the G2/M checkpoint during DNA replication and damage repair, resulting in high expression of Wee1 protein kinase. Theoretically, by inhibiting the activity of Wee1 protein kinase, DNA damage of these p 53-deleted tumor cells cannot be repaired in time to enter M phase, so that genome instability and chromosome deletion are caused, mitosis disasters are caused, and tumor cells are caused to die.

Detailed Description

The present application relates to compounds of formula I or a pharmaceutically acceptable salt thereof,

Wherein,

Represents a single bond or a double bond;

X ¹、X² or X ³ are each independently selected from N or C;

r ¹ is selected from hydrogen, halogen, -OH, -NH ₂、-CN、C_1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, or C _3-10 cycloalkyl-C _1-10 alkyl-, said C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, or C _3-10 cycloalkyl-C _1-10 alkyl-optionally substituted with one or more halogen, -OH, -NH ₂, or-CN;

R ² is each independently selected from halogen, -OH, -NH ₂、-CN、＝O、C_1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, or C _1-10 alkyl substituted with one or more groups selected from halogen, -OH, -NH ₂, or-CN;

p is selected from 0,1, 2 or 3;

Ring E is selected from C _5-10 cycloalkenyl or 5-10 membered heterocycloalkenyl;

The ring Cy is selected from C _6-10 aryl, C _3-10 cycloalkyl or 3-20 membered heterocyclic group;

R ³ is each independently selected from halogen, =O, -OH, -CN, -NH ₂、C_1-10 alkyl, C _1-10 alkoxy, -NHC _1-10 alkyl, -N (C _1-10 alkyl) ₂、-NHCOC_1-10 alkyl, -OCOC _1-10 alkyl, C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl, said C _1-10 alkyl, C _1-10 alkoxy, -NHC _1-10 alkyl, -N (C _1-10 alkyl) ₂、-NHCOC_1-10 alkyl, -OCOC _1-10 alkyl, C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted by halogen, =o, -OH, -CN, -NH ₂、C_1-10 alkyl, C _1-6 alkoxy, -COC _1-10 alkyl, -COOC _1-10 alkyl, -CONH ₂、-CONHC_1-10 alkyl, -CON (C _1-10 alkyl) ₂、-S(O)₂C_1-8 alkyl, -S (O) ₂OC_1-8 alkyl, -S (O) ₂NHC_1-8 alkyl, C _3-10 cycloalkyl, 3-10 heterocycloalkyl, C _6-10 aryl, or 5-10 membered heteroaryl;

m is selected from 0,1, 2, 3 or 4;

r ⁴ is independently selected from halogen, -OH, -NH ₂、-CN、C_1-10 alkyl, C _1-10 alkoxy, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl, said C _1-10 alkyl, C _1-10 alkoxy, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl optionally substituted with halogen, -OH, -NH ₂, or-CN;

n is selected from 0,1, 2, 3 or 4;

When (when) Selected fromThe ring Cy is selected from 3-20 membered heterocyclic groups containing boron or phosphorus atoms;

Optionally, the composition may be used in combination with,

The compound of formula I is not selected from the following compounds:

In some embodiments, the compounds of formula I satisfy the following conditions:

When (when) For When the ring Cy is not selected fromAnd R ³ is not selected from

a) When (when) ForWhen the ring Cy is not selected fromAnd R ³ is not selected from

B) When (when)ForWhen the ring Cy is not selected fromAnd R ³ is not selected from

In some embodiments, the moietyIs not selected from

In some embodiments, at least one of X ¹、X²、X³ is selected from C.

In some embodiments, X ³ is selected from C, X ² is selected from N, and X ¹ is selected from C or N.

In some embodiments, X ¹ and X ² are selected from N and X ³ is selected from C.

In some embodiments, X ¹ and X ³ are selected from C and X ² is selected from N.

In some embodiments, R ¹ is selected from hydrogen, halogen, -OH, -NH ₂、-CN、C_1-6 alkyl, C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, or C _3-8 cycloalkyl-C _1-6 alkyl-, said C _1-6 alkyl, C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, or C _3-8 cycloalkyl-C _1-6 alkyl-optionally substituted with one or more halogen, -OH, -NH ₂, or-CN.

In some embodiments, R ¹ is selected from hydrogen, halogen, -OH, -NH ₂、-CN、C_1-4 alkyl, C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C _3-6 cycloalkyl-C _1-4 alkyl-, said C _1-4 alkyl, C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C _3-6 cycloalkyl-C _1-4 alkyl-optionally substituted with one or more halogen, -OH, -NH ₂, or-CN.

In some embodiments, R ¹ is selected from hydrogen, C _1-4 alkyl, C _3-6 alkenyl, C _3-6 cycloalkyl, or C _3-4 cycloalkyl-C _1-2 alkyl-, said C _1-4 alkyl, C _3-6 alkenyl, C _3-6 cycloalkyl, or C _3-4 cycloalkyl-C _1-2 alkyl-optionally substituted with one or more halogens, -OH, -NH ₂, or-CN.

In some embodiments, R ¹ is selected from hydrogen, C _1-3 alkyl, C _3-4 alkenyl, C _3-4 cycloalkyl, or C _3-4 cycloalkyl-C _1-2 alkyl-, said C _3-4 alkenyl being optionally substituted with one or more halogens.

In some embodiments, R ¹ is selected from hydrogen, methyl, ethyl, isopropyl,Cyclopropyl or

In some embodiments, R ² is each independently selected from halogen, -OH, -NH ₂、-CN、＝O、C_1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, or C _1-6 alkyl substituted with one or more groups selected from halogen, -OH, -NH ₂, or-CN;

In some embodiments, R ² is each independently selected from halogen, -OH, -NH ₂、-CN、＝O、C_1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl.

In some embodiments, R ² is each independently selected from halogen, -OH, -NH ₂、-CN、＝O、C_1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl.

In some embodiments, R ² is each independently selected from halogen, -OH, -NH ₂, -CN, =o, or C _1-4 alkyl

In some embodiments, R ² is each independently selected from F, cl, br, -CN, =o, or C _1-3 alkyl.

In some embodiments, R ² is each independently selected from F, =o, or-CN.

In some embodiments, p is selected from 0,1, or 2.

In some embodiments, p is selected from 0 or 1.

In some embodiments, p is selected from 2. In some embodiments, p is selected from 1. In some embodiments, p is selected from 0.

In some embodiments, ring E is selected from C _5-8 cycloalkenyl or 5-8 membered heterocycloalkenyl.

In some embodiments, ring E is selected from C _5-6 cycloalkenyl or 5-6 membered heterocycloalkenyl. In some embodiments, ring E is selected from C _5-6 cycloalkenyl.

In some embodiments, ring E is selected from cyclopentenyl, cyclohexenyl, or oxacyclopentenyl. In some embodiments, ring E is selected from cyclopentenyl or cyclohexenyl.

In some embodiments, ring E is selected from cyclopentenyl.

In some embodiments, the moietySelected fromIn some embodiments, the moietySelected fromIn some embodiments, the moietySelected from

In some embodiments, the ring Cy is selected from C _6-8 aryl, C _3-8 cycloalkyl, or a 6-17 membered heterocyclyl.

In some embodiments, the ring Cy is selected from phenyl or a 9-17 membered heterocyclyl.

In some embodiments, the ring Cy is selected from phenyl or a 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, or 17-membered heterocyclyl. Or the ring Cy is selected from phenyl or 9-16 membered heterocyclyl. Or the ring Cy is selected from phenyl or 9-15 membered heterocyclic group. Or the ring Cy is selected from phenyl or 9-14 membered heterocyclyl. Or the ring Cy is selected from phenyl or 9-13 membered heterocyclyl. Or the ring Cy is selected from phenyl or 9-12 membered heterocyclyl. Or the ring Cy is selected from phenyl or 9-11 membered heterocyclyl. Or the ring Cy is selected from phenyl or 9-10 membered heterocyclyl. In some embodiments, the ring Cy is selected from 9-17 membered heterocyclyl. Or the ring Cy is selected from a 9-16 membered (e.g., 9-, 10-, 11-, 12-, 13-, 14-, 15-, or 16-membered) heterocyclic group.

In some embodiments, the ring Cy is selected from C _3-8 cycloalkyl, or a 5-17 membered heterocyclyl containing a boron or phosphorus atom. In some embodiments, the ring Cy is selected from a 5-17 membered heterocyclyl containing a boron or phosphorus atom; in some embodiments, the ring Cy is selected from a 5-17 membered partially saturated heterocyclic group containing a boron or phosphorus atom.

In some embodiments, ring Cy is selected from phenyl or a 5-17 membered partially saturated heterocyclyl. In some embodiments, ring Cy is selected from phenyl or a 9-17 membered partially saturated heterocyclyl. In some embodiments, ring Cy is selected from phenyl or a 9-10 membered partially saturated heterocyclyl.

In some embodiments, the ring Cy is selected from phenyl or benzo 5-13 membered heterocycloalkenyl. In some embodiments, the ring Cy is selected from phenyl or a benzo 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered heterocycloalkenyl. In some embodiments, the ring Cy is selected from phenyl or benzo 5-6 membered heterocycloalkenyl. In some embodiments, the heterocyclyl in Cy is selected from benzoheterocyclyl; in some embodiments, the heteroatom of the heterocyclyl or heterocyclenyl in the Cy is selected from a boron atom, a nitrogen atom, an oxygen atom, or a sulfur atom; or the heteroatom is selected from boron, nitrogen or oxygen atoms; or the heteroatom is selected from boron or oxygen atoms; the number of the hetero atoms is selected from 1, 2, 3, 4 or 5; or the number of heteroatoms is selected from 1, 2 or 3; or the number of heteroatoms is selected from 2 or 3. The hetero atom of the heterocyclic group or the heterocyclic alkenyl group in the Cy is 1 boron atom and 1 oxygen atom, and optionally, additionally contains 1 nitrogen atom or oxygen atom.

In some embodiments, the ring Cy is selected from

In some embodiments, R ³ is each independently selected from halogen, =o, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, -OCOC _1-6 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl, said C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, -OCOC _1-6 alkyl, C _3-8 cycloalkyl or 3-8 membered heterocycloalkyl optionally substituted by halogen, =o, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, -COC _1-6 alkyl, -COOC _1-6 alkyl, -CONH ₂、-CONHC_1-6 alkyl, -CON (C _1-6 alkyl) ₂、-S(O)₂C_1-6 alkyl, -S (O) ₂OC_1-6 alkyl, -S (O) ₂NHC_1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ aryl or 5-6 membered heteroaryl.

In some embodiments, R ³ is each independently selected from halogen, =o, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, -OCOC _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 heterocycloalkyl, said C _3-6 cycloalkyl or 3-6 heterocycloalkyl being optionally substituted with halogen, = O, OH, CN, NH ₂、C_1-6 alkyl, -COC _1-6 alkyl, -COOC _1-6 alkyl, -CONH ₂、-CONHC_1-6 alkyl, -CON (C _1-6 alkyl) ₂、-S(O)₂C_1-6 alkyl, or-S (O) ₂OC_1-6 alkyl.

In some embodiments, R ³ is each independently selected from halogen, =o, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, -OCOC _1-6 alkyl, or 5-6 membered heterocycloalkyl, optionally substituted with halogen, = O, C _1-6 alkyl, -COC _1-6 alkyl, or-S (O) ₂C_1-6 alkyl.

In some embodiments, R ³ is each independently selected from halogen (F, cl, br, I), -OH, C _1-6 alkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, or 5-6 membered heterocycloalkyl, optionally substituted with = O, C _1-6 alkyl, -COC _1-6 alkyl, or-S (O) ₂C_1-6 alkyl. In some embodiments, R ³ is each independently selected from halogen (F, cl, br, I), -OH, C _1-6 alkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂, or-NHCOC _1-6 alkyl.

In some embodiments, R ³ is each independently selected from halogen (F, cl, br, I), -OH, C _1-3 alkyl, -NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、-NHCOC_1-3 alkyl, or 6 membered heterocycloalkyl optionally substituted with = O, C _1-3 alkyl, -COC _1-3 alkyl, or-S (O) ₂C_1-3 alkyl.

In some embodiments, R ³ is each independently selected from halogen (F, cl, br, I), -OH, C _1-3 alkyl, -NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、-NHCOC_1-3 alkyl, or 6 membered heterocycloalkyl, optionally substituted with =o, methyl, -COCH ₃, or-S (O) ₂CH₃.

In some embodiments, the heteroatom of the heterocycloalkyl group in R ³ is selected from nitrogen, boron, phosphorus, or oxygen; or a heteroatom selected from nitrogen, phosphorus or oxygen; the number of the hetero atoms is selected from 1, 2, 3, 4 or 5; or the number of heteroatoms is selected from 1, 2 or 3; or the heterocycloalkyl group contains 2 heteroatoms selected from nitrogen, boron, phosphorus or oxygen.

In some embodiments, R ³ is each independently selected from F, -OH, -CH ₃、-NHCH₃、-N(CH₃)₂、-NHCOCH₃,

In some embodiments, m is selected from 0, 1, 2, or 3.

In some embodiments, m is selected from 1, 2, or 3.

In some embodiments, R ⁴ is each independently selected from halogen, -OH, -NH ₂、-CN、C_1-6 alkyl, C _1-6 alkoxy, or C _3-6 cycloalkyl, the C _1-6 alkyl, C _1-6 alkoxy, or C _3-6 cycloalkyl being optionally substituted with halogen, -OH, -NH ₂, or-CN.

In some embodiments, R ⁴ is each independently selected from halogen, -OH, -NH ₂、-CN、C_1-4 alkyl, C _1-4 alkoxy, or C _3-4 cycloalkyl, the C _1-4 alkyl, C _1-4 alkoxy, or C _3-4 cycloalkyl being optionally substituted with halogen, -OH, -NH ₂, or-CN.

In some embodiments, R ⁴ is each independently selected from halogen, -OH, -NH ₂、-CN、C_1-4 alkyl, or C _3-4 cycloalkyl, the C _1-4 alkyl optionally substituted with one or more fluoro, chloro, bromo, iodo, -OH, -NH ₂, or-CN.

In some embodiments, R ⁴ is each independently selected from halogen, -OH, -NH ₂、-CN、C_1-3 alkyl, or C _3-4 cycloalkyl, the C _1-3 alkyl optionally substituted with one or more fluoro.

In some embodiments, each R ⁴ is independently selected from-OH, -NH ₂、-CH₃, ethyl, -CF ₃、-CHF₂, or cyclopropyl.

In some embodiments, R ⁴ is each independently selected from-OH or C _1-6 alkyl. In some embodiments, R ⁴ is each independently selected from-OH or C _1-3 alkyl.

In some embodiments, R ⁴ is each independently selected from-OH or ethyl.

In some embodiments, n is selected from 1, 2, 3, or 4.

In some embodiments, n is selected from 1, 2, or 3.

In some embodiments, n is selected from 1 or 2.

In some embodiments, n is selected from 2.

In some embodiments, whenSelected fromThe ring Cy is selected from 9-11 membered heterocyclic groups containing boron heteroatoms; or the ring Cy is selected from 5-7 membered heterocyclic groups which are benzo containing boron heteroatoms; or the ring Cy is selected from 5-7 membered heterocyclic groups which contain boron and oxygen heteroatoms.

In some embodiments, whenSelected fromThe ring Cy is selected from phenyl, 9-17 membered heterocyclic group containing boron heteroatom; or the ring Cy is selected from phenyl; or the ring Cy is selected from 5-13 membered heterocyclic groups which are benzo containing boron heteroatoms; or the ring Cy is selected from 5-13 membered heterocyclic groups which contain boron and oxygen heteroatoms; or the ring Cy is selected from 5-13 membered heterocyclic groups which are benzo containing boron, oxygen and nitrogen heteroatoms.

In some embodiments, the moietySelected from In some embodiments, the moietySelected from In some embodiments, the moietySelected fromIn some embodiments, the moietySelected from

In some embodiments, the moietySelected from

In some embodiments, the moietySelected from In some embodiments, the moietySelected from the group consisting of In some embodiments, the moietySelected from

In some embodiments, the moietySelected from

The compound of formula I or pharmaceutically acceptable salt thereof is selected from the group consisting of formula I-1, formula I-2, formula IA, formula IB, formula IA-1, formula IB-1, formula IC-1, formula ID-1, formula IE, formula IF, formula IG or formula IH or pharmaceutically acceptable salt thereof,

Wherein R ¹,R²,R³,R⁴,X¹,X²,X³, cy, E, m, n and p are defined in the application.

The present application provides a compound or a pharmaceutically acceptable salt thereof,

In another aspect, the present application relates to a pharmaceutical composition comprising the compound of the present application or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

In another aspect, the application relates to the use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disease associated with wee 1.

The present application relates to a method of treating or preventing a wee 1-associated disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the application as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present application relates to a method for treating or preventing a disease associated with wee1 comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the application as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In another aspect, the application relates to the use of a compound as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a disease associated with wee 1.

In some embodiments, the above-described Wee 1-related disease is selected from the group consisting of disorders treated by degradation or inhibition of the Wee1 protein; in some embodiments, the Wee 1-related disease described above is selected from cancer.

In some embodiments, the application encompasses the variables defined above and embodiments thereof, as well as any combination thereof.

Technical effects

The compounds of the application can inhibit the activity of Wee1 kinase, and have selective inhibition activity on Wee1 kinase compared with Myt1 and PLK1 kinase. The compound of the application has proliferation inhibition activity on A427 cells and LoVo cells; has CDK1 phosphorylation inhibitory activity against U2OS cells; stable in vitro metabolism, and good in vivo pharmacokinetic property and in vivo efficacy.

Definition of the definition

The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

In some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH ₂CH₃), monosubstituted (e.g., CH ₂CH₂ F), polysubstituted (e.g., CHFCH ₂F、CH₂CHF₂, etc.), or fully substituted (CF ₂CF₃). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

Herein, C _m-n is that portion having an integer number of carbon atoms in the given range. For example, "C _1-6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group contains 2R's, then each R has an independent option.

When a bond is cross-linked to two atoms of a ring (including monocyclic, fused or spiro), such bond may be bonded to any atom on the ring (including monocyclic, fused or spiro).

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxy" refers to an-OH group.

The term "amino" refers to the-NH ₂ group.

The term "alkyl" refers to a hydrocarbon group of the formula C _nH_2n+1. The alkyl group may be linear or branched. For example, the term "C _1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as above.

The term "alkoxy" refers to an-O-alkyl group.

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.C-CH 3), 2-propynyl (-CH 2-C.ident.CH), 1, 3-butanediynyl (-C.ident.C-C.ident.CH), and the like.

The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a single ring, a bicyclic bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring (e.g., a 4 to 8 membered ring). Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

The term "cycloalkyl" refers to a carbocycle that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring (e.g., a 5 to 8 membered ring). Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a3 to 15 membered ring, a3 to 7 membered ring, a3 to 6 membered ring, or a3 to 5 membered ring containing 1 to 3 heteroatoms (preferably 1,2, or 3 heteroatoms) independently selected from boron, sulfur, oxygen, and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, mercaptoethane, cyclic aziridine, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thioxalkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepinyl, thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

The term "heterocycloalkenyl" includes cycloalkenyl groups in which up to 3 carbon atoms, or up to 2 carbon atoms, or 1 carbon atom is each independently replaced by boron, oxygen, S (O), or nitrogen, provided that at least one cycloalkenyl carbon-carbon double bond is maintained. The cyclic group, which may be present as a single ring, a bridged ring or a spiro ring, may be a 3 to 13 membered ring (e.g., 5 to 13 membered ring, 5 to 8 membered ring). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrole, tetrahydropyridine, tetrahydroazepine, or azaspirooctene. For example, a heterocycloalkenyl group may be of the structure:

unless otherwise indicated, the carbocycle is typically a 4 to 10 membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.

The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocycle is typically a3 to 20 membered (or 3 to 17 membered, or 3 to 13 membered, or 3 to 7 membered) ring containing 1 to 3 heteroatoms (preferably 1,2 or 3 heteroatoms) independently selected from boron, phosphorus, sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like. The heterocyclyl may be, for example, heterocyclenyl, heterocycloalkyl, or benzoheterocyclenyl (not fully saturated heteroaromatics), and specifically, for example, the heterocyclyl or benzoheterocyclenyl may be of the structure:

The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and 1,2,3, 4-tetrahydronaphthalene, and the like. The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from nitrogen, oxygen, S, the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

The term "treatment" means administration of a compound or formulation of the application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;

(ii) The disease or condition is alleviated, even if the disease or condition subsides.

The term "preventing" means that the compound or formulation of the application is administered to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or a disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state, but has not been diagnosed as having the disease state.

The term "therapeutically effective amount" means an amount of a compound of the application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.

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

As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.

The compounds and intermediates of the application may also exist in different tautomeric forms and all such forms are included within the scope of the application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine isomerisation. A specific example of a proton tautomer is an imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include tautomers by recombination of some bond-forming electrons.

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

Certain isotopically-labeled compounds of the present application (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as ¹⁵O、¹³N、¹¹ C and ¹⁸ F are useful in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

Furthermore, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution being that at least one hydrogen is substituted by at least one deuterium.

The compounds of the application may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. In particular, for exampleIncluding but not limited to Or mixtures thereof (including racemates) in any ratio. The compounds of the application containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds of formula I described herein, the daily dosage is from 0.01 to 200mg/kg body weight, either alone or in divided doses.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.

The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.

An important consideration in the art of synthetic route planning is the selection of suitable protecting groups for reactive functionalities (such as amino groups in the present application), for example, reference may be made to Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc.

The compounds of the present application can be prepared by the following route, in combination with techniques known in the art:

Preparing a general formula 1:

preparing a general formula 2:

y ¹、Y²、Z¹, or Z ² are each independently selected from halogen, a boric acid group or a borate group, preferably Cl, br, I, -B (OH) ₂ or

R ¹,R²,R³,R⁴,X¹,X³, cy, E, m, n, p are as defined in the application.

The application adopts the following abbreviations:

DMF represents N, N-dimethylformamide; EA represents ethyl acetate; DCM represents dichloromethane; etOH stands for ethanol; meCN represents acetonitrile; DMA stands for N, N-dimethylacetamide; NMP represents N-methylpyrrolidone; selectfluor represents 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate); pd ₂dba₃ or Pd ₂(dba)₃ represents tris (dibenzylideneacetone) dipalladium; xphos represents 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl; xantphos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; XPhos Pd G2 represents chloro (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II); THF represents tetrahydrofuran; PBS represents phosphate buffered saline; cbz represents benzyloxycarbonyl; MOM stands for methoxymethyl ether.

The application is further illustrated by examples, which are not intended to limit the scope of the application, for clarity. All reagents used in the present application are commercially available and can be used without further purification.

Detailed Description

EXAMPLE 1 Synthesis of Compound 1

Step 1: synthesis of intermediate 1b

To a single-necked flask, intermediate 1a (3 g), acetonitrile (100 mL), acetic acid (20 mL) and selectfluor (6.92 g) were sequentially added, and the mixture was heated to 70℃under the protection of N ₂ to react. After the reaction, the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate was added to the system to adjust the system to be weakly alkaline, and 50mL of ethyl acetate was added to extract. The organic phases were separated, the aqueous phase was extracted with ethyl acetate and the organic phases were combined. Dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate under reduced pressure, and the crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate) to give the target intermediate 1b (0.55 g).

MS(ESI,[M+H]⁺)m/z：172.12

¹H NMR(500MHz,DMSO-d₆)δ12.30(s,1H),9.04(s,1H),7.65(t,J＝2.6Hz,1H).

Step 2: synthesis of intermediate 1c

To a microwave tube, intermediate 1B (200 mg), (R) -2-bromo-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (212 mg), cuprous iodide (183 mg), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (124 mg), potassium carbonate (363 mg) and 1, 4-dioxane (5 mL) were added in this order, and after stirring with nitrogen for 1 minute, the mixture was placed in a microwave reactor and heated to 110℃for reaction. After the reaction, the reaction solution was cooled to room temperature, and 30mL of ethyl acetate and 50mL of water were added to the system to extract. The organic phase was separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate) to give the target intermediate 1c (240 mg).

MS(ESI,[M+H]⁺)m/z：333.15

¹H NMR(500MHz,DMSO-d₆)δ9.21(s,1H),8.41(d,J＝1.9Hz,1H),8.29(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),5.07(s,1H),2.97(ddd,J＝16.6,8.6,5.4Hz,1H),2.80(ddd,J＝15.5,8.4,5.5Hz,1H),2.22(ddd,J＝13.7,8.5,5.4Hz,1H),2.09–2.00(m,1H),1.92(dt,J＝14.7,7.5Hz,1H),1.73(dq,J＝14.6,7.4Hz,1H),0.91(t,J＝7.4Hz,3H).

Step 3: synthesis of Compound 1

To a single-necked flask, intermediate 1c (150 mg), 4- (4-methylpiperazine) aniline (86 mg), pd ₂dba₃ (83 mg), xphos (86 mg), potassium carbonate (187 mg) and t-butanol (10 mL) were successively added, and the mixture was heated to 100℃under the protection of N ₂ to react. The reaction was cooled to room temperature, and 30mL of methylene chloride and 50mL of water were added to the system for extraction. The organic phase was separated, the aqueous phase was extracted 2 times with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the concentrate was purified by column chromatography to give compound 1 (100 mg).

MS(ESI,[M+H]⁺)m/z：488.39

¹H NMR(500MHz,DMSO-d₆)δ9.55(s,1H),8.89–8.81(m,1H),8.53(d,J＝8.2Hz,1H),7.97–7.85(m,2H),7.69–7.59(m,2H),7.01–6.91(m,2H),5.06–4.98(m,1H),3.18–3.05(m,4H),2.96(ddd,J＝15.3,8.5,5.2Hz,1H),2.78(ddd,J＝15.6,8.4,5.2Hz,1H),2.56–2.50(m,4H),2.26(s,3H),2.20(ddd,J＝13.4,8.4,5.2Hz,1H),2.04(ddd,J＝13.2,8.4,5.2Hz,1H),1.92(dq,J＝14.1,7.5,7.0Hz,1H),1.73(dq,J＝14.1,7.3Hz,1H),0.96–0.87(m,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.24,157.60,149.35,148.59,147.57,146.75,145.05,143.08,135.73,133.61,132.89,120.80,116.33,114.75,106.07,105.83,104.02,81.16,55.12,49.21,46.13,37.12,32.00,26.60,8.86.

EXAMPLE 2 Synthesis of Compound 2

Step 1: preparation of intermediate 2b

To the reaction flask were successively added 2a (10 g), ethynyl cyclopropane (3.11 g), bis (triphenylphosphine) palladium dichloride (2.75 g), cuprous iodide (0.895 g), triethylamine (11.88 g) and MeCN (100 mL), and the mixture was heated to 80 g under nitrogen atmosphere to react. After the completion of the reaction, the mixture was cooled to room temperature, 300mL of ethyl acetate and 500mL of water were added for extraction, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and purified by column chromatography to give 2b (10.1 g).

MS(ESI,[M+H]⁺)m/z：194.09。

Step 2: preparation of intermediate 2c

2B (7.58 g), potassium t-butoxide (7.03 g), and DMA (150 mL) were added sequentially to the flask, and the mixture was heated to 100deg.C to react. After the completion of the reaction, the mixture was cooled to room temperature, 300mL of ethyl acetate and 500mL of water were added thereto, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and purified by column chromatography to give 2c (2.01 g).

MS(ESI,[M+H]⁺)m/z：194.10。

Step 3: preparation of intermediate 2d

The reaction flask was charged with intermediate 2c (300 mg), (R) -2-bromo-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (450 mg), (1R, 2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine (331 mg), cuprous iodide (325 mg), potassium phosphate (987 mg) and 1, 4-dioxane (10 mL), and the mixture was heated to 100 ℃ under N ₂ protection to react. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was purified by a silica gel column to obtain the objective intermediate 2d (400 mg).

MS(ESI,[M+H]⁺)m/z：355.24。

Step 4: preparation of Compound 2

To the reaction flask, intermediate 2d (75 mg), 4- (4-methylpiperazin-1-yl) aniline (48 mg), pd ₂(dba)₃ (38 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (20 mg), potassium carbonate (88 mg) and t-butanol (10 mL) were added in this order, and the mixture was heated to 100℃under the protection of N ₂ to react. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective compound 2 (80 mg).

MS(ESI,[M+H]⁺)m/z：510.42.

¹H NMR(500MHz,DMSO-d6)δ9.07(s,1H),8.57(s,1H),7.95(d,J＝7.9Hz,1H),7.68–7.52(m,3H),6.88–6.74(m,2H),6.23(s,1H),5.01(s,1H),3.04(dt,J＝10.0,5.8Hz,5H),2.84(ddd,J＝16.3,8.6,5.0Hz,1H),2.47(d,J＝5.0Hz,4H),2.30–2.15(m,5H),2.06(ddd,J＝13.4,8.6,5.1Hz,1H),1.89(dt,J＝14.7,7.3Hz,1H),1.74(dt,J＝13.6,7.3Hz,1H),0.86(t,J＝7.4Hz,3H),0.83–0.54(m,4H).

EXAMPLE 3 Synthesis of Compound 3

Step 1: preparation of intermediate 3a

To the reaction flask, intermediate 2c (3.06 g), acetonitrile (100 mL) and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (6.16 g) were successively added, and the mixture was reacted at room temperature for 4 hours. After the completion of the reaction, 200mL of ethyl acetate and 200mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective intermediate 3a (400 mg).

MS(ESI,[M+H]⁺)m/z：212.1。

¹H NMR(500MHz,DMSO-d6)δ12.07(s,1H),8.83(s,1H),2.07(tt,J＝8.6,5.1Hz,1H),1.09–1.04(m,2H),0.98–0.92(m,2H).

Step 2: preparation of intermediate 3b

To the reaction flask, intermediate 3a (400 mg), (R) -2-bromo-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (502 mg), (1R, 2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine (316 mg), cuprous iodide (310 mg), potassium phosphate (943 mg) and 1, 4-dioxane (10 mL) were added in this order, and the mixture was heated to 100 ℃ under protection of N ₂ to react for 3 hours. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective intermediate 3b (453 mg).

MS(ESI,[M+H]⁺)m/z：373.2。

Step 3: preparation of intermediate 3

To the reaction flask, intermediate 3b (100 mg), 4- (4-methylpiperazine) aniline (62 mg), pd ₂(dba)₃ (49 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (26 mg), potassium carbonate (111 mg) and t-butanol (5 mL) were added in this order, and the mixture was heated to 100℃under the protection of N ₂ and reacted for 3 hours. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective compound 3 (42 mg).

MS(ESI,[M+H]⁺)m/z：528.50。

¹H NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.70(s,1H),7.95(d,J＝7.9Hz,1H),7.64(d,J＝8.1Hz,1H),7.57(d,J＝8.5Hz,2H),6.83(d,J＝8.6Hz,2H),4.99(s,1H),3.15–2.96(m,5H),2.90–2.78(m,1H),2.50(s,4H),2.26(s,4H),2.12–2.01(m,2H),1.89(dd,J＝13.9,7.2Hz,1H),1.72(dd,J＝13.8,7.2Hz,1H),0.86(t,J＝7.4Hz,4H),0.75(dt,J＝10.0,5.3Hz,1H),0.65(dq,J＝14.1,8.3,6.6Hz,1H),0.55(dq,J＝9.9,5.2Hz,1H). EXAMPLE 4 Synthesis of Compound 4

Step 1: preparation of intermediate 4a

4-Amino-2-chloro-5-iodopyrimidine (10.1 g), 3-methyl-1-butyne (2.93 g), cuprous iodide (0.89 g), triethylamine (11.88 g), tetraphenylphosphine palladium (4.52 g) and NMP (100 mL) are added in sequence, and the temperature is raised to 85 ℃ under the protection of nitrogen to react. After the completion of the reaction, 200mL of ethyl acetate and 200mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective intermediate 4a (4.55 g).

MS(ESI,[M+H]⁺)m/z：195.9。

1H NMR(500MHz,DMSO-d6)δ8.05(s,1H),8.01(s,1H),7.05(s,1H),2.84(hept,J＝6.8Hz,1H),1.23(s,3H),1.21(s,3H).

Step 2: preparation of intermediate 4b

To the reaction flask, 4a (5.6 g), potassium t-butoxide (6.42 g) and DMA (60 mL) were added in this order, and the temperature was raised to 100℃to react. After the completion of the reaction, 100mL of ethyl acetate and 200mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective intermediate 4b (4.55 g).

MS(ESI,[M+H]⁺)m/z：196.1。

1H NMR(500MHz,DMSO-d6)δ12.24(s,1H),8.75(s,1H),6.32(d,J＝0.9Hz,1H),3.06(pd,J＝6.8,0.9Hz,1H),1.30(d,J＝6.9Hz,6H).

Step 3: preparation of intermediate 4c

4B (1.4 g), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (2.79 g) and DMA (30 mL) were sequentially added to the reaction flask, and the mixture was heated to 50℃to react. After the reaction, the reaction solution was poured into 100mL of water and suction-filtered. The filter cake was purified in reverse phase to give intermediate 4c (0.52 g).

MS(ESI,[M+H]⁺)m/z：214.2。

Step 4: preparation of intermediate 4d

To the reaction flask, intermediate 4c (400 mg), (R) -2-bromo-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (510 mg), (1R, 2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine (320 mg), cuprous iodide (306 mg), potassium phosphate (886 mg) and 1, 4-dioxane (10 mL) were added in this order, and the mixture was heated to 100 ℃ under protection of N ₂ to react. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give the objective intermediate 4d (453 mg).

MS(ESI,[M+H]⁺)m/z：375.1。

1H NMR(500MHz,DMSO-d6)δ9.06(s,1H),7.97(d,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),5.12(s,1H),3.08(ddt,J＝35.1,15.7,7.2Hz,2H),2.85(ddd,J＝16.0,8.5,5.0Hz,1H),2.24(ddd,J＝14.1,8.6,5.8Hz,1H),2.07(ddd,J＝13.4,8.5,4.9Hz,1H),1.86(dq,J＝14.7,7.4Hz,1H),1.73(dq,J＝14.4,7.3Hz,1H),1.33(d,J＝7.0Hz,3H),1.26(d,J＝7.1Hz,3H),0.86(t,J＝7.2Hz,3H).

Step 5: preparation of intermediate 4

To the reaction flask, intermediate 4d (50 mg), 4- (4-methylpiperazine) aniline (31 mg), pd ₂(dba)₃ (24 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (12 mg), potassium carbonate (55 mg) and t-butanol (5 mL) were added in this order, and the mixture was heated to 100℃under the protection of N ₂ to react. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give Compound 4 (30 mg).

MS(ESI,[M+H]⁺)m/z：530.43。

1H NMR(500MHz,DMSO-d6)δ9.28(s,1H),8.71(s,1H),7.97(d,J＝8.0Hz,1H),7.59(dd,J＝22.1,8.3Hz,3H),6.83(d,J＝8.6Hz,2H),5.04(s,1H),3.22(p,J＝6.9Hz,1H),3.17–3.06(m,4H),3.03(dd,J＝9.0,6.5Hz,1H),2.84(ddd,J＝16.4,8.6,4.9Hz,1H),2.70(s,4H),2.40(s,3H),2.23(ddd,J＝14.3,8.6,6.1Hz,1H),2.05(ddd,J＝13.4,8.6,4.9Hz,1H),1.87(dt,J＝14.6,7.2Hz,1H),1.74(dq,J＝14.4,7.3Hz,1H),1.34(d,J＝7.0Hz,3H),1.21(d,J＝6.9Hz,3H),0.85(t,J＝7.4Hz,3H).

EXAMPLE 5 Synthesis of Compound 5

Step 1: preparation of intermediate 5b

5A (10 g), 1-trimethylsilyl-1-butyne (5.93 g), bis (triphenylphosphine) palladium dichloride (1.37 g), cuprous iodide (0.74 g), triethylamine (16.37 mL), meCN (100 mL) and cesium fluoride (7.14 g) were added to the flask in this order, and the mixture was heated to 80 g under nitrogen protection to react. After the completion of the reaction, the mixture was cooled to room temperature, 300mL of ethyl acetate and 500mL of water were added thereto, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and purified by column chromatography to give 5b (6.55 g).

MS(ESI,[M+H]⁺)m/z：182.11。

Step 2: preparation of intermediate 5c

To the flask were added 5b (6.55 g), potassium t-butoxide (12 g) and DMA (100 mL) in this order, and the mixture was heated to 100deg.C to react. After the completion of the reaction, the mixture was cooled to room temperature, 300mL of ethyl acetate and 500mL of water were added thereto, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and purified by column chromatography to give 5c (5.6 g).

MS(ESI,[M+H]⁺)m/z：182.21。

Step 3: preparation of intermediate 5d

To the reaction flask, intermediate 5c (5 g), acetonitrile (100 mL) and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (10.5 g) were sequentially added, and the mixture was reacted at room temperature. After the completion of the reaction, 200mL of ethyl acetate and 200mL of water were added to the reaction mixture to extract, and the extract was purified by a silica gel column to obtain the objective intermediate 5d (1.52 g).

MS(ESI,[M+H]⁺)m/z：200.09。

¹H NMR(500MHz,DMSO-d6)δ12.26(s,1H),8.89(s,1H),2.78–2.74(m,2H),1.33–1.27(m,3H)。

Step 4: preparation of intermediate 5e

To the reaction flask, intermediate 5d (300 mg), (R) -2-bromo-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (450 mg), (1R, 2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine (300 mg), cuprous iodide (320 mg), potassium phosphate (987 mg) and 1, 4-dioxane (10 mL) were sequentially added, the mixture was heated to 100℃under the protection of N ₂, the reaction was completed, 100mL of ethyl acetate and 100mL of water were added to the reaction solution to extract, and the extract was concentrated and purified by a silica gel column to give the target intermediate 5e (380 mg).

MS(ESI,[M+H]⁺)m/z：361.21。

Step 5: preparation of Compound 5

To the reaction flask, 5e (70 mg), 4- (4-methylpiperazin-1-yl) aniline (47 mg), pd ₂(dba)₃ (35 mg), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (18 mg), potassium carbonate (80 mg) and t-butanol (10 mL) were added in this order, and the mixture was heated to 100℃under the protection of N ₂ to react. After the completion of the reaction, 100mL of ethyl acetate and 100mL of water were added to the reaction mixture to extract, and the extract was concentrated and purified by a silica gel column to give Compound 5 (35 mg).

MS(ESI,[M+H]⁺)m/z：516.24。

¹H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.72(s,1H),7.97(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.61–7.52(m,2H),6.88–6.79(m,2H),5.04(s,1H),3.14–2.99(m,5H),2.96(ddd,J＝15.0,7.5,1.7Hz,1H),2.84(ddd,J＝16.1,8.9,5.6Hz,2H),2.45(t,J＝4.9Hz,4H),2.30–2.16(m,4H),2.05(ddd,J＝13.4,8.6,5.0Hz,1H),1.94–1.84(m,1H),1.75(dt,J＝13.7,7.4Hz,1H),0.99(t,J＝7.4Hz,3H),0.86(t,J＝7.4Hz,3H).

EXAMPLE 6 Synthesis of Compound 6

Step 1: preparation of intermediate 6a

To the reaction flask, p-nitroiodobenzene (500 mg), 1, 4-oxaphosphine (240 mg), N, N-diisopropylethylamine (390 mg), pd ₂(dba)₃ (92 mg) and Xantphos (116 mg) were successively added, and after replacing nitrogen, the mixture was heated to 110℃under nitrogen protection to react. After the reaction, ethyl acetate and water were added to the reaction mixture to extract, the organic phase was concentrated, and the crude product was purified by silica gel column chromatography to give intermediate 6a (95 mg).

MS(ESI,[M+H]⁺)m/z：242.0

¹H NMR(500MHz,DMSO-d6)δ8.39–8.31(m,2H),8.19–8.11(m,2H),4.06–3.95(m,2H),3.95–3.83(m,2H),2.48–2.40(m,2H),2.10–1.98(m,2H).

Step 2: preparation of intermediate 6b

To the reaction flask, intermediate 6a (95 mg), reduced iron powder (100 mg), ammonium chloride (100 mg), water (1 mL) and ethanol (6 mL) were sequentially added, and reacted at 80 ℃. After the reaction, the mother liquor is concentrated by suction filtration, and the crude product is purified by column chromatography to obtain an intermediate 6b (70 mg)

MS(ESI,[M+H]⁺)m/z：212.0.

Step 3: preparation of Compound 6

To the reaction flask, intermediate 1c (66 mg), intermediate 6b (42 mg), pd ₂(dba)₃ (36 mg), xphos (38 mg), potassium carbonate (82 mg) and t-butanol (10 mL) were sequentially added, and after replacing nitrogen, the mixture was heated to 100℃under nitrogen protection for reaction. After the completion of the reaction, methylene chloride and water were added to the reaction mixture to extract, and the organic phase was concentrated and chromatographed on a silica gel column to give Compound 6 (35 mg).

MS(ESI,[M+H]⁺)m/z：508.2

¹H NMR(500MHz,DMSO-d6)δ10.17(s,1H),8.98(s,1H),8.48(d,J＝8.2Hz,1H),8.04–7.99(m,3H),7.97(d,J＝8.2Hz,1H),7.82–7.74(m,2H),5.04(s,1H),4.04–3.93(m,2H),3.93–3.81(m,2H),3.04–2.94(m,1H),2.85–2.75(m,1H),2.41–2.30(m,2H),2.27–2.17(m,1H),2.10–2.01(m,1H),1.97–1.85(m,3H),1.79–1.68(m,1H),0.92(t,J＝7.4Hz,3H).

EXAMPLE 7 Synthesis of Compound 7

Step 1: synthesis of intermediate 7a

To a single-necked flask, intermediate 9c (200 mg), formaldehyde (75 mg), tetrahydrofuran (5 mL) and sodium triacetoxyborohydride (529 mg) were successively added, and the mixture was reacted at room temperature. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product was separated by column chromatography (eluent: dichloromethane/methanol) to give the target intermediate 7a (150 mg).

MS(ESI,[M+H]⁺)m/z：255.11

¹H NMR(500MHz,DMSO-d₆)δ8.38–8.32(m,2H),8.17–8.08(m,2H),2.83–2.68(m,4H),2.38–2.20(m,5H),1.99(dddt,J＝17.7,15.1,5.8,2.5Hz,2H).

Step 2: synthesis of intermediate 7b

To a single-necked flask, intermediate 7a (140 mg), methanol (5 mL) and 10% Pd/C (70 mg) were sequentially added, and the mixture was reacted at room temperature by replacing 3 times with hydrogen. After the completion of the reaction, palladium on carbon was removed by filtration of the reaction mixture through a funnel, the cake was washed 3 times with methanol, and the solvent was distilled off from the filtrate under reduced pressure to give the objective intermediate 7b (120 mg).

MS(ESI,[M+H]⁺)m/z：225.19

¹H NMR(500MHz,DMSO-d₆)δ7.41–7.32(m,2H),6.67–6.58(m,2H),5.73(d,J＝29.9Hz,2H),2.67(ddt,J＝17.3,9.6,5.2Hz,4H),2.23(s,3H),2.08(ddt,J＝14.8,9.8,5.8Hz,2H),1.81–1.70(m,2H).

Step 3: synthesis of Compound 7

To a single-necked flask, intermediate 1c (100 mg), intermediate 7b (67.4 mg), pd ₂(dba)₃ (55.0 mg), xphos (57.3 mg), potassium carbonate (125 mg) and t-butanol (5 mL) were successively added, and the mixture was heated to 100℃under the protection of N ₂ to react. After the reaction, the reaction solution was cooled to room temperature, and 50mL of methylene chloride and 100mL of water were added to the system to extract. The organic phase was separated, the aqueous phase was extracted with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the concentrate was purified by column chromatography to give compound 7 (100 mg).

MS(ESI,[M+H]⁺)m/z：521.40

¹H NMR(500MHz,DMSO-d₆)δ10.14(s,1H),8.97(s,1H),8.47(d,J＝8.3Hz,1H),8.05–7.93(m,4H),7.74(dd,J＝10.8,8.4Hz,2H),5.05(s,1H),2.98(ddd,J＝14.8,8.7,5.5Hz,1H),2.85–2.66(m,5H),2.29–2.18(m,6H),2.05(ddd,J＝13.5,8.6,5.4Hz,1H),1.97–1.82(m,3H),1.74(dq,J＝14.5,7.3Hz,1H),0.92(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.46,156.74,149.46,148.39,146.98,144.81,144.03,142.84,135.87,134.05,131.43,118.66,118.56,115.04,107.49,107.26,105.05,104.90,81.17,51.83,46.34,37.12,31.98,28.34,27.82,26.63,8.86.

EXAMPLE 8 Synthesis of Compound 8

Step 1: preparation of intermediate 8a

To the reaction flask was added intermediate 9c (190 mg), acetyl chloride (93 mg), triethylamine (160 mg) and dichloromethane (30 mL), and the mixture was reacted at 25℃for 1h. The reaction solution was slowly poured into a mixed solution of saturated aqueous citric acid (2 mL) and water (20 mL), dichloromethane was added to extract the layers, the organic phase was washed with saturated sodium bicarbonate solution, the layers were separated, and the solvent was distilled off from the organic phase under reduced pressure to obtain 205mg of Compound 8a.

MS(ESI,[M+H]⁺)m/z:283.10

¹H NMR(500MHz,DMSO-d₆)δ8.40–8.32(m,2H),8.20–8.11(m,2H),4.23(ddt,J＝23.0,12.7,4.7Hz,1H),3.91(dd,J＝21.3,15.4Hz,1H),3.73(dtd,J＝14.5,11.4,2.9Hz,1H),3.43(tdd,J＝13.5,11.2,2.9Hz,1H),2.43(ddt,J＝15.4,10.3,4.8Hz,1H),2.19(ddt,J＝15.6,10.3,4.8Hz,1H),2.12–1.89(m,5H).

Step 2: preparation of intermediate 8b

To the flask was added intermediate 8a (205 mg), 10% palladium on carbon (205 mg) and methanol (50 mL), and the mixture was reacted at 25℃for 2 hours under hydrogen gas. The reaction solution was filtered off with suction, and the solvent was distilled off from the filtrate under reduced pressure to obtain 189mg of Compound 8b.

MS(ESI,[M+H]⁺)m/z:253.13

¹H NMR(500MHz,DMSO-d₆)δ7.41(dd,J＝11.0,8.2Hz,2H),6.63(dd,J＝8.5,2.4Hz,2H),5.74(s,2H),4.10(dt,J＝21.2,9.2Hz,1H),3.85–3.72(m,1H),3.67(qd,J＝11.4,5.4Hz,1H),3.45–3.35(m,1H),2.19(ddt,J＝15.4,10.4,4.9Hz,1H),2.08(s,3H),1.96(td,J＝10.7,5.6Hz,1H),1.86–1.66(m,2H).

Step 3: preparation of Compound 8

To the reaction flask was added intermediate 1c (90 mg), intermediate 8b (102 mg), tris (dibenzylideneacetone) palladium (49 mg), 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl (51 mg), potassium carbonate (112 mg) and t-butanol (10 mL), and reacted at 100℃for 3 hours. The reaction solution was directly concentrated, and the crude product was purified by column chromatography and then reversed phase column purification to obtain 109mg of Compound 8.

MS(ESI,[M+H]⁺)m/z:549.35

¹H NMR(500MHz,DMSO-d₆)δ10.15(s,1H),8.98(s,1H),8.48(d,J＝8.2Hz,1H),8.05–7.98(m,3H),7.95(d,J＝8.3Hz,1H),7.78(dd,J＝10.9,8.4Hz,2H),5.04(s,1H),4.17–4.07(m,1H),3.89–3.67(m,2H),3.48(tdd,J＝13.4,10.5,2.9Hz,1H),2.98(ddd,J＝16.4,8.6,5.4Hz,1H),2.80(ddd,J＝16.0,8.5,5.4Hz,1H),2.32(ddt,J＝15.2,10.3,4.7Hz,1H),2.25–2.09(m,5H),2.05(ddd,J＝13.6,8.6,5.5Hz,1H),1.95(ddd,J＝21.1,9.9,5.4Hz,2H),1.84(dddd,J＝14.5,12.0,5.9,2.9Hz,1H),1.74(dq,J＝14.5,7.4Hz,1H),0.92(t,J＝7.4Hz,3H).

EXAMPLE 9 Synthesis of Compound 9

Step 1: synthesis of intermediate 9b

1-Iodo-4-nitrobenzene (1.190 g), 1-benzyl-1, 4-azaphosphine 4-oxide (1 g), DMF (80 mL), N, N-diisopropylethylamine (0.927 g), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.219 g), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.277 g) were added under N ₂ -protection, and the mixture was stirred at 110℃for 3 hours. At the end of the reaction, 100mLEA and 200mL of water were added. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography to give 1.35g of intermediate 9b.

MS(ESI,[M+H]⁺)m/z：331.01.

¹H NMR(500MHz,DMSO-d₆)δ8.38–8.31(m,2H),8.17–8.08(m,2H),7.39–7.31(m,4H),7.27(qt,J＝5.3,2.4Hz,1H),3.64(s,2H),2.91–2.75(m,4H),2.32(ddt,J＝14.9,10.7,5.7Hz,2H),2.05–1.93(m,2H).

Step 2: synthesis of intermediate 9c

9B (1.2 g), 1, 2-dichloroethane (30 mL) and ice-water bath were added to the flask and stirred, 1-chloroethyl chloroformate (0.779 g) was added thereto, and after the reaction mixture was heated to reflux for 1h, methanol (8.15 g) was added thereto and the reflux reaction was continued for 4h. After the reaction was completed, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography to give 0.831g of intermediate 9c.

MS(ESI,[M+H]⁺)m/z：241.16.

¹H NMR(500MHz,DMSO-d₆)δ9.76(s,1H),8.43(dq,J＝9.0,2.2Hz,2H),8.20–8.11(m,2H),3.58–3.46(m,4H),2.79(ddt,J＝16.1,11.3,4.8Hz,2H),2.33(tq,J＝15.4,2.5Hz,2H).

Step 3: synthesis of intermediate 9d

N, N-diisopropylethylamine (336 mg), DCM (20 mL), 9c (250 mg) and methylsulfonic anhydride (363 mg) were added sequentially to a single flask in an ice-water bath, and stirred at room temperature for 1h after the addition. The reaction was completed. The reaction solution was poured into a mixed solvent of 100mLDCM and 100mL of water. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain 0.332g of intermediate 9d.

Step 4: synthesis of intermediate 9e

In a single-port flask, 10% palladium on carbon (10 mg) was added to a solution of 9d (250 mg) of MeOH (5 mL) and DCM (1 mL), the reaction mixture was replaced with nitrogen 2-3 times, then with hydrogen 2-3 times, and finally stirred at room temperature for 3.5h. After the reaction, the catalyst was removed by suction filtration. The solvent was distilled off from the filtrate under reduced pressure to obtain 0.223g of intermediate 9e.

MS(ESI,[M+H]⁺)m/z：289.11.

Step 5: synthesis of Compound 9

To a microwave tube, 1c (50 mg), 9e (43.3 mg), DMF (2 mL) and Pd ₂(dba)₃ (27.5 mg) were successively added, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (28.7 mg), potassium carbonate (62.3 mg) and the mixture was reacted at 100℃for 4 hours under the protection of N ₂. The reaction was completed. 100mLEA and 100mL of water were added, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography to give 0.03g of Compound 9.

MS(ESI,[M+H]⁺)m/z：585.341.

¹H NMR(500MHz,DMSO-d₆)δ10.18(s,1H),8.99(s,1H),8.48(d,J＝8.2Hz,1H),8.05–7.95(m,4H),7.86–7.75(m,2H),5.04(s,1H),3.73(ddd,J＝22.2,12.4,4.4Hz,2H),3.49(q,J＝11.2Hz,2H),3.00(s,3H),2.97(dt,J＝8.4,3.5Hz,1H),2.80(ddd,J＝16.1,8.4,5.4Hz,1H),2.34(ddd,J＝15.0,9.3,4.5Hz,2H),2.22(ddd,J＝13.7,8.5,5.5Hz,1H),2.10–1.96(m,3H),1.93(dt,J＝14.7,7.3Hz,1H),1.74(dq,J＝14.6,7.4Hz,1H),0.92(t,J＝7.4Hz,3H).

EXAMPLE 10 Synthesis of Compound 10

Step 1: preparation of Compound 10

To the reaction flask were successively added intermediate 1c (100 mg), 10a (67 mg), DMF (5 mL) and potassium tert-butoxide (101 mg), and the mixture was reacted at room temperature under nitrogen atmosphere. After completion of the reaction of intermediate 1c, 1M aqueous hydrochloric acid (450. Mu.l) was added thereto and stirred at room temperature. After the completion of the reaction, methylene chloride and water were added to the reaction mixture, followed by extraction, concentration of the organic phase, and purification of the crude product by C ₁₈ column chromatography to give compound 10 (30 mg).

MS(ESI,[M+H]⁺)m/z：446.2

¹H NMR(500MHz,DMSO-d6)δ9.83(s,1H),9.17(s,1H),8.90(s,1H),8.57(d,J＝8.3Hz,1H),8.17(d,J＝2.0Hz,1H),7.99(d,J＝1.8Hz,1H),7.85(d,J＝8.3Hz,1H),7.80(dd,J＝8.2,2.1Hz,1H),7.38(d,J＝8.2Hz,1H),5.02(s,1H),4.98(s,2H),3.00–2.90(m,1H),2.82–2.72(m,1H),2.25–2.16(m,1H),2.07–2.00(m,1H),1.96–1.86(m,1H),1.78–1.67(m,1H),0.91(t,J＝7.4Hz,3H).

EXAMPLE 11 Synthesis of Compound 11

Step 1: synthesis of Compound 11

To a single-necked flask, intermediate 1c (100 mg), intermediate 11a (98 mg), DMF (5 mL) and potassium tert-butoxide (101 mg) were successively added, and the mixture was reacted at room temperature under the protection of N ₂. At the end of the reaction, diluted hydrochloric acid was added to the reaction mixture to neutralize the excess base, the pH was adjusted to neutrality, 150mL of methylene chloride and 80mL of water were used for extraction, the aqueous phase was extracted with methylene chloride, the organic phases were combined, the solvent was removed by distillation under reduced pressure, and the concentrate was purified by column chromatography to give Compound 11 (40 mg).

MS(ESI,[M+H]⁺)m/z：460.30

¹H NMR(500MHz,DMSO-d₆)δ8.88(s,1H),8.56(d,J＝8.3Hz,1H),8.27–8.17(m,1H),8.01(s,1H),7.86(d,J＝8.3Hz,1H),7.70–7.60(m,1H),7.19(d,J＝8.2Hz,1H),4.10(t,J＝5.9Hz,2H),2.96(ddd,J＝15.2,8.7,5.4Hz,1H),2.85(t,J＝5.9Hz,2H),2.81–2.70(m,1H),2.21(ddd,J＝13.8,8.5,5.3Hz,1H),2.04(ddd,J＝13.7,8.6,5.5Hz,1H),1.92(dq,J＝14.7,7.4Hz,1H),1.73(dq,J＝14.5,7.3Hz,1H),0.90(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.14,157.49,149.47,148.45,147.32,144.95,142.98,139.62,138.59,136.10,133.61,127.30,123.89,122.74,114.86,106.19,104.38,81.17,63.94,49.07,37.11,32.02,26.59,8.86.

EXAMPLE 12 Synthesis of Compound 12

Step 1: preparation of Compound 12

To the reaction flask were successively added intermediate 1c (100 mg), 12a (128 mg), DMF (5 mL) and potassium tert-butoxide (135 mg), and the mixture was reacted at room temperature under nitrogen. After the reaction of intermediate 1c was completed, 1M aqueous hydrochloric acid (1.2 mL) was added and stirred at room temperature. After the completion of the reaction, methylene chloride and water were added to the reaction mixture, followed by extraction, and the organic phase was concentrated and purified by C ₁₈ column chromatography to give Compound 12 (30 mg).

MS(ESI,[M+H]⁺)m/z：474.2

¹H NMR(500MHz,DMSO-d6)δ9.81(s,1H),8.99(s,1H),8.90(s,1H),8.57(d,J＝8.3Hz,1H),8.08(d,J＝2.0Hz,1H),7.99(d,J＝1.7Hz,1H),7.86(d,J＝8.3Hz,1H),7.78(dd,J＝8.3,2.1Hz,1H),7.38(d,J＝8.2Hz,1H),5.02(s,1H),3.01–2.91(m,1H),2.82–2.72(m,1H),2.25–2.16(m,1H),2.08–1.99(m,1H),1.98–1.87(m,1H),1.78–1.67(m,1H),1.47(s,6H),0.91(t,J＝7.4Hz,3H).

EXAMPLE 13 Synthesis of Compound 13

Step 1: synthesis of Compound 13

To a single-necked flask, intermediate 1c (150 mg), intermediate 13a (151 mg), DMF (1 mL) and potassium tert-butoxide (152 mg) were sequentially added, and the mixture was reacted at room temperature under the protection of N ₂. At the end of the reaction, diluted hydrochloric acid was added to the reaction mixture to neutralize the excess base, the pH was adjusted to neutrality, 150mL of methylene chloride and 80mL of water were used for extraction, the aqueous phase was extracted with methylene chloride, the organic phases were combined, the solvent was removed by distillation under reduced pressure, and the concentrate was purified by column chromatography to give compound 13 (20 mg).

MS(ESI,[M+H]⁺)m/z：464.20

¹H NMR(500MHz,DMSO-d₆)δ9.37(s,1H),8.87(s,1H),8.43(d,J＝8.3Hz,1H),8.09(d,J＝7.9Hz,1H),8.02–7.96(m,1H),7.71(d,J＝8.3Hz,1H),7.37(d,J＝10.6Hz,1H),5.01(s,3H),2.92(ddd,J＝15.2,8.6,5.4Hz,1H),2.74(ddd,J＝15.8,8.5,5.5Hz,1H),2.18(ddd,J＝13.6,8.4,5.4Hz,1H),2.01(ddd,J＝13.6,8.7,5.5Hz,1H),1.90(dq,J＝14.5,7.3Hz,1H),1.71(dq,J＝14.5,7.2Hz,1H),0.89(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.11,158.06,151.73,149.47,148.46,144.92,142.94,135.57,133.57,127.95,127.27,114.73,109.45,109.28,106.31,104.82,81.15,70.04,49.07,37.06,32.00,26.56,8.83.

EXAMPLE 14 Synthesis of Compound 14

Step 1: synthesis of Compound 14

To a single-necked flask, intermediate 1c (140 mg), intermediate 14a (125 mg), DMF (1 mL) and potassium tert-butoxide (142 mg) were sequentially added, and the mixture was reacted at room temperature under the protection of N ₂. At the end of the reaction, diluted hydrochloric acid was added to the reaction mixture to neutralize the excess base, the pH was adjusted to neutrality, 150mL of methylene chloride and 80mL of water were used for extraction, the aqueous phase was extracted with methylene chloride, the organic phases were combined, the solvent was removed by distillation under reduced pressure, and the concentrate was purified by column chromatography to give compound 14 (45 mg).

MS(ESI,[M+H]⁺)m/z:446.18

¹H NMR(500MHz,DMSO-d₆)δ10.03(s,1H),9.01(s,1H),8.95(s,1H),8.50(d,J＝8.2Hz,1H),8.09(d,J＝1.6Hz,1H),8.00(d,J＝1.7Hz,1H),7.92(d,J＝8.3Hz,1H),7.65(d,J＝8.0Hz,1H),7.61(dd,J＝8.1,1.7Hz,1H),5.02(d,J＝8.5Hz,3H),2.98(ddd,J＝16.2,8.6,5.4Hz,1H),2.79(ddd,J＝16.1,8.5,5.4Hz,1H),2.21(ddd,J＝13.7,8.5,5.5Hz,1H),2.04(ddd,J＝13.6,8.7,5.5Hz,1H),1.93(dq,J＝14.7,7.4Hz,1H),1.78–1.68(m,1H),0.92(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.42,157.01,155.68,149.47,148.42,147.07,143.26,142.90,135.68,134.03,131.23,118.55,114.98,110.84,107.11,106.88,104.58,81.18,70.32,37.13,31.97,26.62,8.86.

EXAMPLE 15 Synthesis of Compound 15

Step 1: synthesis of Compound 15

To a single-necked flask, intermediate 1c (100 mg), intermediate 16e (98 mg), DMF (1 mL) and potassium tert-butoxide (101 mg) were sequentially added, and the mixture was reacted at room temperature under the protection of N ₂. At the end of the reaction, diluted hydrochloric acid was added to the reaction mixture to neutralize the excess base, the pH was adjusted to neutrality, 150mL of methylene chloride and 80mL of water were used for extraction, the aqueous phase was extracted with methylene chloride, the organic phases were combined, the solvent was removed by distillation under reduced pressure, and the concentrate was purified by column chromatography to give compound 15 (25 mg).

MS(ESI,[M+H]⁺)m/z：460.20

¹H NMR(500MHz,DMSO-d₆)δ9.94(s,1H),8.94(s,1H),8.53(d,J＝8.3Hz,1H),8.29(s,1H),8.01(d,J＝1.7Hz,1H),7.89(d,J＝8.3Hz,1H),7.84(d,J＝1.9Hz,1H),7.64(d,J＝8.0Hz,1H),7.56(dd,J＝8.1,2.0Hz,1H),5.02(d,J＝17.1Hz,1H),4.10(t,J＝5.9Hz,2H),2.97(ddd,J＝16.2,8.6,5.4Hz,1H),2.87(t,J＝5.9Hz,2H),2.79(ddd,J＝16.1,8.5,5.4Hz,1H),2.21(ddd,J＝13.7,8.5,5.5Hz,1H),2.04(ddd,J＝13.5,8.6,5.5Hz,1H),1.93(dq,J＝14.7,7.4Hz,1H),1.73(dq,J＝14.4,7.4Hz,1H),0.91(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.44,157.00,149.49,148.45,147.08,144.89,143.24,142.92,135.65,134.05,133.97,116.81,114.86,107.02,106.79,81.18,63.64,37.12,32.99,31.98,26.63,8.86.

EXAMPLE 16 Synthesis of Compound 16

Step1: synthesis of intermediate 16 b:

To a single-necked flask, (R) -2-bromo-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (1 g), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.197 g), 16a (0.531 g), cuprous iodide (0.132 g), 1, 4-dioxane (50 mL), dipotassium hydrogen phosphate (1.205 g), and N ₂ were added in this order, the mixture was heated to 95℃to react for 2 hours under protection of N ₂, the reaction was completed, the reaction liquid was cooled to room temperature, and 200mL of EA and 100mL of water were added. The organic phases were separated, the aqueous phase was extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to give 0.65g of intermediate 16b.

MS(ESI,[M+H]⁺)m/z：315.08

¹H NMR(500MHz,DMSO-d₆)δ9.07(s,1H),8.43(d,J＝3.8Hz,1H),8.31(d,J＝8.2Hz,1H),8.00–7.92(m,1H),6.95(d,J＝3.8Hz,1H),5.07(s,1H),2.98(dddd,J＝15.5,8.7,5.6,1.0Hz,1H),2.80(dddd,J＝16.2,8.6,5.4,1.0Hz,1H),2.22(ddd,J＝13.1,8.6,5.6Hz,1H),2.06(ddd,J＝13.1,8.7,5.4Hz,1H),2.01–1.88(m,1H),1.75(dq,J＝13.4,7.4Hz,1H),0.92(t,J＝7.4Hz,3H).

Step 2: synthesis of intermediate 16 d:

16c (2.5G), etOH (20 mL), tetrahydroxydiboron (2.73G), potassium acetate (2.99G) and XPhos Pd G2 (1.597G), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (0.484G), N ₂ were added to the flask, and the mixture was heated to 85℃and stirred for 2 hours. After the reaction, the mixture was suction-filtered, and the cake was washed with 50mLEA, and the filtrate was purified by column chromatography to give 0.770g of intermediate 16d.

¹H NMR(500MHz,DMSO-d₆)δ8.87(s,1H),8.15–8.04(m,2H),7.91(d,J＝7.9Hz,1H),4.12(t,J＝5.9Hz,2H),3.03(t,J＝5.9Hz,2H).

Step 3: synthesis of intermediate 16 e:

to a single-necked flask, 16d (300 mg), meOH (30 mL) and 10% palladium on carbon (30 mg) were sequentially added, and the reaction mixture was replaced with nitrogen for 2 to 3 times and then with hydrogen for 2 to 3 times, followed by stirring at room temperature for 60 minutes. The reaction was completed. The catalyst was removed by suction filtration. The filtrate was purified by column chromatography to give 0.17g of intermediate 16e.

Step 4: synthesis of Compound 16:

In a single flask, 16b (174 mg), 16e (90 mg), DMF (10 mL) and potassium tert-butoxide (186 mg) were successively added, and the mixture was reacted at room temperature for 1h under the protection of N ₂. To the reaction mixture was added 1M hydrochloric acid (1.105 mL) and the mixture was reacted for 30 minutes. After the reaction was completed, extracted with 150mL of DCM/meoh=10:1 and 100mL of water, the solution was separated, the aqueous phase was extracted 2 times with DCM/meoh=10:1, the organic phases were combined, the solvent was removed by distillation under reduced pressure, and purification by column chromatography gave 100mg of compound 16.

MS(ESI,[M+H]⁺)m/z：442.2

¹H NMR(500MHz,DMSO-d₆)δ9.74(s,1H),8.85(s,1H),8.57(d,J＝8.2Hz,1H),8.20(s,1H),8.13(d,J＝3.9Hz,1H),7.93–7.85(m,2H),7.65–7.54(m,2H),6.72(d,J＝3.9Hz,1H),5.04(s,1H),4.10(t,J＝5.9Hz,2H),2.99(ddd,J＝15.2,8.5,5.4Hz,1H),2.87(t,J＝5.9Hz,2H),2.80(ddd,J＝16.2,8.5,5.3Hz,1H),2.22(ddd,J＝13.9,8.5,5.6Hz,1H),2.05(ddd,J＝13.5,8.6,5.4Hz,1H),1.94(dq,J＝14.7,7.4Hz,1H),1.75(dq,J＝14.5,7.4Hz,1H),0.92(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ166.27,156.18,151.84,151.30,148.87,147.14,143.59,135.60,134.09,134.02,124.89,116.36,114.58,114.55,102.59,81.19,63.65,37.03,32.97,31.90,31.39,26.59,22.50,14.41.

EXAMPLE 17 Synthesis of Compound 17

Step 1: synthesis of intermediate 17a

To a single-necked flask, (R) -2-chloro-7-ethyl-6, 7-dihydro-5H-cyclopenta [ B ] pyridin-7-ol (1 g), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (0.288 g), sodium iodide (1.517 g) and cuprous iodide (0.193 g) were sequentially added, and the mixture was heated to 120℃under the protection of N ₂ to react with ultra-dry anisole (20 mL). After the completion of the reaction, the reaction mixture was cooled to room temperature, and the crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate) to give the target intermediate 17a (1.1 g).

MS(ESI,[M+H]⁺)m/z：289.96

¹H NMR(500MHz,DMSO)δ7.62(d,J＝7.8Hz,1H),7.38(dt,J＝7.8,1.1Hz,1H),5.09(s,1H),2.84(dddd,J＝16.5,8.7,5.6,1.1Hz,1H),2.66(dddd,J＝16.5,8.6,5.4,1.0Hz,1H),2.11(ddd,J＝13.3,8.7,5.6Hz,1H),2.01–1.89(m,1H),1.88–1.77(m,1H),1.63(dq,J＝13.5,7.4Hz,1H),0.84(t,J＝7.4Hz,3H).

Step 2: synthesis of intermediate 17b

To a 10mL microwave tube were successively added 2-chloro-7H-pyrrolo [2,3-D ] pyrimidine-5-carbonitrile (260 mg), intermediate 17a (421 mg), cuprous iodide (305 mg), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (249 mg), potassium t-butoxide (604 mg) and 1, 4-dioxane (10 mL), and after stirring with nitrogen for 1 minute, the mixture was placed in a microwave reactor and heated to 110℃for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the crude product was separated by column chromatography (eluent: dichloromethane/methanol) to give the objective intermediate 17b (180 mg).

MS(ESI,[M+H]⁺)m/z：340.12

¹H NMR(500MHz,DMSO-d₆)δ9.32(s,1H),9.28(s,1H),8.20(d,J＝8.1Hz,1H),8.01(d,J＝8.2Hz,1H),5.11(s,1H),3.01(ddd,J＝16.6,8.7,5.4Hz,1H),2.83(ddd,J＝16.5,8.6,5.6Hz,1H),2.24(ddd,J＝13.8,8.6,5.5Hz,1H),2.07(ddd,J＝13.1,8.7,5.6Hz,1H),1.94(dt,J＝14.8,7.3Hz,1H),1.75(dq,J＝14.6,7.5Hz,1H),0.91(t,J＝7.4Hz,3H).

Step 3: synthesis of Compound 17

To a single-necked flask, intermediate 17b (180 mg), intermediate 16e (86 mg), DMF (1 mL) and potassium tert-butoxide (178 mg) were sequentially added, and the mixture was reacted at room temperature under the protection of N ₂. At the end of the reaction, diluted hydrochloric acid was added to the reaction mixture to neutralize the excess base, the pH was adjusted to neutrality, 150mL of methylene chloride and 80mL of water were used for extraction, the aqueous phase was extracted with methylene chloride, the organic phases were combined, the solvent was concentrated by distillation under reduced pressure, and the concentrate was separated and purified by column chromatography to give compound 17 (30 mg).

MS(ESI,[M+H]⁺)m/z：467.20

¹H NMR(500MHz,DMSO-d₆)δ10.06(s,1H),9.03(s,1H),8.90(s,1H),8.43(d,J＝8.1Hz,1H),8.25(s,1H),7.97(d,J＝8.2Hz,1H),7.81(d,J＝1.9Hz,1H),7.63(d,J＝8.1Hz,1H),7.56(dd,J＝8.1,2.0Hz,1H),5.06(s,1H),4.09(t,J＝5.9Hz,2H),3.01(ddd,J＝16.5,8.7,5.5Hz,1H),2.86(t,J＝5.9Hz,2H),2.85–2.79(m,1H),2.23(ddd,J＝13.8,8.5,5.5Hz,1H),2.06(ddd,J＝13.6,8.7,5.6Hz,1H),1.95(dq,J＝14.7,7.4Hz,1H),1.75(dq,J＝14.5,7.3Hz,1H),0.92(t,J＝7.4Hz,3H).

¹³C NMR(126MHz,DMSO-d₆)δ167.00,157.49,151.66,151.08,147.52,147.08,143.02,135.90,135.87,134.05,133.80,116.92,116.86,115.54,114.69,112.07,86.33,81.16,63.63,37.08,32.97,31.93,26.73,8.86.

EXAMPLE 18 Synthesis of Compound 18

Step 1: synthesis of intermediate 18a

In a single-necked flask, 2-bromo-6-nitrobenzoic acid (22 g), toluene (100 mL) and thionyl chloride (21.28 g,12.97 mL) were sequentially added, and the mixture was heated to 100℃under the protection of N ₂ to react for 4 hours. After completion of the reaction, 1000mL of EA and 200mL of water were added to the reaction mixture. The organic phase was separated, washed with an aqueous sodium hydrogencarbonate solution, washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to give 21g of intermediate 18a.

¹H NMR(500MHz,DMSO-d₆)δ8.30(dd,J＝8.3,1.0Hz,1H),8.21(dd,J＝8.1,0.9Hz,1H),7.73(t,J＝8.2Hz,1H),3.93(s,3H).

Step 2: synthesis of intermediate 18b

In a single-necked flask, 18a (10 g), pinacol ester of diboronic acid (10.74 g), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (2.81 g) and potassium acetate (11.32 g) were sequentially added, and the mixture was heated to 105℃under the protection of N ₂ for reaction for 6 hours. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by column chromatography to obtain 9.5g of intermediate 18b.

Step 3: synthesis of intermediate 18c

To the reaction flask, lithium aluminum hydride (293 mg,3.13 mL) was added and THF (15 mL) was added under ice-bath. 18b (1 g) was dissolved in THF (15 mL), and then, the mixture was slowly dropped into a reaction flask, and the reaction was carried out under N ₂ under an ice-water bath for 2 hours. After the reaction was completed, the reaction mixture was quenched with 5mL of water, ph=4 was adjusted by adding 3M aqueous hydrochloric acid, 50mL of EA and 50mL of water were added for extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to give 0.135g of intermediate 18c.

¹H NMR(500MHz,DMSO-d₆)δ9.59(s,1H),8.34(dd,J＝8.1,1.0Hz,1H),8.17(dd,J＝7.1,1.0Hz,1H),7.70(t,J＝7.7Hz,1H),5.39(s,2H).

Step 4: synthesis of intermediate 18d

10% Palladium on carbon (21 mg) was added to a solution of 18c (120 mg) in MeOH (5 mL), and the reaction solution was replaced with nitrogen 2-3 times and then with hydrogen 2-3 times, followed by stirring overnight at room temperature. After the reaction, the catalyst was removed by suction filtration, and then 50mLDCM solvent was added for rinsing, the solvent was distilled off from the filtrate under reduced pressure, and then the mixture was purified by column chromatography to obtain 0.095g of intermediate 18d.

Step 5: synthesis of Compound 18

1C (200 mg), 18d (81 mg), DMF (20 mL) and a solution of potassium tert-butoxide in tetrahydrofuran (1.622 mL) were added in this order under N ₂ protection, replaced 3 times with N ₂, and then 1M hydrochloric acid (1.081 mL) was added dropwise to the mixture to react at 50℃for 1 hour, followed by stirring at room temperature for 10 minutes. After completion of the reaction, 50mL of DCM and 50mL of water were added to the reaction mixture and extracted 3 times, the organic phases were separated, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to give 0.04g of Compound 18.

MS(ESI,[M+H]⁺)m/z：446.09

¹H NMR(500MHz,DMSO-d₆)δ9.31(s,1H),9.17(s,1H),8.87(s,1H),8.41(d,J＝8.3Hz,1H),7.99(d,J＝1.7Hz,1H),7.91(d,J＝7.8Hz,1H),7.72(d,J＝8.3Hz,1H),7.51(dd,J＝7.2,0.9Hz,1H),7.41(t,J＝7.5Hz,1H),5.07(s,2H),5.01(s,1H),2.93(ddd,J＝16.4,8.7,5.5Hz,1H),2.75(ddd,J＝16.1,8.4,5.4Hz,1H),2.19(ddd,J＝13.8,8.5,5.5Hz,1H),2.02(ddd,J＝13.6,8.7,5.5Hz,1H),1.91(dq,J＝14.7,7.4Hz,1H),1.71(dq,J＝14.5,7.4Hz,1H),0.90(t,J＝7.4Hz,3H).

EXAMPLE 19 Synthesis of Compound 19

Step 1: preparation of intermediate 19b

60Wt% sodium hydride (7.16 g) was slowly added to a stirred solution of 2-bromo-4-nitrophenol (30.00 g) in DMF (200 mL) at 0deg.C, and after 0.5h of stirring reaction, bromomethyl ether (22.36 g) was added and the reaction was resumed at room temperature for 1h. The reaction solution was slowly poured into ice water, ethyl acetate was added to extract and layer, the solvent was distilled off under reduced pressure from the organic phase, and after purification by column chromatography of the crude product, 32.1g of intermediate 19b was obtained.

MS(ESI,[M+H]⁺)m/z:262.06

¹H NMR(500MHz,DMSO-d₆)δ8.45(d,J＝2.8Hz,1H),8.26(dd,J＝9.2,2.8Hz,1H),7.40(d,J＝9.2Hz,1H),5.47(s,2H),3.44(s,3H).

Step 2: preparation of intermediate 19c

To the reaction flask was added intermediate 19b (31.00 g), iron powder (65.40 g), ammonium chloride (62.60 g), ethanol: water=10:1 mixed solution (600 mL), reacted at 90 ℃ for 5h. After the completion of the reaction, the reaction mixture was suction-filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 27.60g of intermediate 19c.

MS(ESI,[M+H]⁺)m/z:232.08

¹H NMR(500MHz,DMSO-d₆)δ6.90(d,J＝8.7Hz,1H),6.80(d,J＝2.7Hz,1H),6.51(dd,J＝8.7,2.6Hz,1H),5.03(d,J＝6.5Hz,4H),3.40(s,3H).

Step 3: preparation of intermediate 19d

Under the preparation of 0, benzyl chloroformate (33 mL) was slowly dropped into a mixed solution of intermediate 19c (27 g), sodium acetate (16.61 g), tetrahydrofuran (270 mL) and water (108 mL), and after the completion of the dropping, the reaction was returned to 25℃for 0.5h. After the completion of the reaction, the reaction mixture was poured into a mixed solution of water (100 mL) and ethyl acetate (200 mL), the layers were separated by extraction, the solvent was distilled off under reduced pressure from the organic phase, and after purification by column chromatography of the crude product, 33.9g of intermediate 19d was obtained.

MS(ESI,[M+H]⁺)m/z:366.00

¹H NMR(500MHz,DMSO-d₆)δ9.80(s,1H),7.80–7.72(m,1H),7.44–7.33(m,6H),7.15(d,J＝8.9Hz,1H),5.20(s,2H),5.15(s,2H),3.40(s,3H).

Step 4: preparation of intermediate 19e

To the reaction flask was added intermediate 19d (33 g), pd (dba) ₂ (8.25 g), 1, 4-dioxane: water=1.6:1 mixed solution (v: v,400 mL), xphos (4.30 g), vinylboronic acid pinacol ester (23.59 g) and potassium carbonate (37.40 g) were reacted at 100℃for 12h. The solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography to give 28.48g of intermediate 19e.

MS(ESI,[M+H]⁺)m/z:314.02

Step 5: preparation of intermediate 19f

Under the preparation of 0, a 1M solution of borane in tetrahydrofuran (223 mL) was slowly dropped into a stirring solution of intermediate 19e (28.48 g) in tetrahydrofuran (180 mL), and after the completion of the dropping, the reaction was resumed at 25℃for 5 hours. After the reaction, water (140 mL) was added, tetrahydrofuran in the reaction solution was distilled off under reduced pressure, water was retained, methanol (140 mL) and 6M hydrochloric acid (100 mL) were added to the water, the reaction was continued for 16h at 25℃and ethyl acetate was added after the completion of the reaction, the mixture was separated by extraction, the solvent was distilled off from the organic phase under reduced pressure, and after purification by column chromatography, 6.76g of intermediate 19f was obtained.

MS(ESI,[M+H]⁺)m/z:298.12

¹H NMR(500MHz,DMSO-d₆)δ9.54(s,1H),8.86(s,1H),7.44–7.37(m,5H),7.22–7.16(m,2H),6.78(d,J＝8.7Hz,1H),5.12(s,2H),2.66(t,J＝7.8Hz,2H),1.00(t,J＝7.8Hz,2H).

Step 6: preparation of intermediate 19g

To the flask was added 19f (6.26 g), 10% Pd/C (1.00 g), ethyl acetate (150 mL), and the mixture was reacted at 25℃for 16h under hydrogen. The reaction solution was suction-filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 2.91g of an intermediate 19g.

MS(ESI,[M+H]⁺)m/z:164.14

¹H NMR(500MHz,DMSO-d₆)δ10.25(s,3H),9.07(s,1H),7.18–7.12(m,2H),6.95(d,J＝8.4Hz,1H),2.74(t,J＝7.8Hz,2H),1.03(t,J＝7.8Hz,2H).

Step 7: preparation of Compound 19

To the reaction flask was added intermediate (R) -2-allyl-1- (7-ethyl-7-hydroxy-6, 7-dihydro-5H-cyclopentyl) -6-methylsulfanyl-1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (100 mg), m-chloroperoxybenzoic acid (134 mg), toluene (15 mL), and after 1H reaction at 25℃N, N-diisopropylethylamine (250 mg) and intermediate 19g (77 mg) were added and the reaction was carried out at room temperature for 16H. After the reaction was completed, the reaction solution was poured into a mixed solution of ethyl acetate and water, the layers were separated by extraction, the solvent was distilled off under reduced pressure from the organic phase, and the crude product was purified by column chromatography and then purified by reverse phase column to give 76mg of compound 19.

MS(ESI,[M+H]⁺)m/z:499.15

¹H NMR(500MHz,DMSO-d₆)δ10.13(s,1H),8.89(s,1H),8.84(s,1H),7.87(d,J＝8.1Hz,1H),7.70(d,J＝8.1Hz,1H),7.57(s,1H),7.38(dd,J＝8.7,2.7Hz,1H),6.83(d,J＝8.7Hz,1H),5.67(ddt,J＝16.5,10.3,6.0Hz,1H),5.05(s,1H),5.00(dd,J＝10.3,1.5Hz,1H),4.89–4.82(m,1H),4.76(d,J＝16.0Hz,1H),4.57(dd,J＝16.0,6.3Hz,1H),2.97(ddd,J＝16.8,8.7,5.6Hz,1H),2.81–2.70(m,3H),2.20(ddd,J＝13.9,8.6,5.6Hz,1H),2.02(ddd,J＝13.5,8.7,5.4Hz,1H),1.88(dq,J＝14.7,7.4,6.7Hz,1H),1.70(dq,J＝14.5,7.3Hz,1H),1.05(t,J＝7.8Hz,2H),0.87(t,J＝7.4Hz,3H).

Test example 1: in vitro kinase inhibition and selectivity

1.1 Wee1 kinase inhibitory Activity

Wee1 kinase solution (manufacturer: invitrogen, concentration 5 nM) and LANTHASCREEN ^TM Eu-anti-GST solution (manufacturer: invitrogen, concentration 2 nM) were prepared at a 1:1, adding 5 mu L of each well into a detection well, adding different compounds dissolved in DMSO into the detection well by a nanoliter sample adding instrument, and setting the final concentration of the compounds to be 1000nM-0.244nM,2 compound wells and simultaneously setting a control. Mu L KINASE TRACER (manufacturer: invitrogen, 25 nM) was added and incubated for 1 hour at room temperature; PERKINELMER ENVISION multifunctional enzyme labeling instrument is used for detection (excitation 320nm, emission 615nm/665 nm), and four-parameter fitting is adopted to calculate IC ₅₀. The test results are shown in Table 1.

1.2 Myt1 kinase inhibitory Activity

Myt1 kinase solution (manufacturer: invitrogen, concentration 5 nM) and LANTHASCREEN ^TM Eu-anti-GST solution (manufacturer: invitrogen, concentration 2 nM) were mixed at a ratio of 1:1, adding 8 mu L of each well into a detection well, adding different compounds dissolved in DMSO into the detection well by a nanoliter sample adding instrument, and setting the final concentration of the compounds to be 1000nM-0.244nM,2 compound wells and simultaneously setting a control. Mu L KINASE TRACER (manufacturer: invitrogen, concentration 2 nM) was added and incubated for 1 hour at room temperature; PERKINELMER ENVISION multifunctional enzyme labeling instrument is used for detection (excitation 320nm, emission 615nm/665 nm), and four-parameter fitting is adopted to calculate IC ₅₀. The test results are shown in Table 1.A represents IC 50.ltoreq.10 nM for Wee1 kinase activity; b represents IC 50.ltoreq.50 nM for Wee1 kinase activity; + represents IC50 > 500nM for Myt1 kinase activity.

TABLE 1 in vitro kinase inhibition Activity data

The test result shows that the compound has Wee1 kinase inhibition activity; compared with Myt1, has good selectivity to Wee1 kinase.

Test example 2: in vitro cell proliferation inhibitory Activity

2.1 A427 cell proliferation inhibition Activity assay

A427 cells in good growth state are taken, PBS is used for cleaning, pancreatin digestion, complete culture medium is stopped, the cells are collected into a centrifuge tube, the cell density is adjusted to 6 multiplied by 10 ⁴/mL, the cells are inoculated on a 96-well plate (100 mu L/well), meanwhile, a nanoliter sample adding instrument is used for compound sample adding, the final concentration of the compound is 10000nM-4.57nM,2 compound wells are arranged, and meanwhile, a control is arranged. After the cell culture is continued for 72 hours in the cell incubator, a detection reagent CCK-8 (manufacturer: beijing Tongren chemistry, 10 mu L/hole) is added, after the cell incubator is incubated for 2 hours, the absorbance of the cell incubator is detected at 450nm by a PERKINELMER ENVISION enzyme-labeled instrument, four-parameter analysis and a fit-to-effect curve are carried out, and IC ₅₀ is calculated. The test results are shown in Table 2.

2.2 LoVo cell proliferation inhibition Activity assay

LoVo cells in good growth state are taken, PBS is used for cleaning, pancreatin digestion is carried out, complete culture medium is stopped, the cells are collected into a centrifuge tube, the cell density is adjusted to 1X 10 ⁵/mL, the cells are inoculated on a 96-well plate (100 mu L/well), meanwhile, a nanoliter sample adding instrument is used for compound sample adding, the final concentration of the compound is 10000nM-4.57nM,2 compound wells are used, and meanwhile, a control is arranged. After the cell culture is continued for 72 hours in the cell incubator, a detection reagent CCK-8 (manufacturer: beijing Tongren chemistry, 10 mu L/hole) is added, after the cell incubator is incubated for 5.5 hours, the absorbance of the cell incubator is detected at 450nm by a PERKINELMER ENVISION enzyme-labeled instrument, four-parameter analysis and a fit-to-effect curve are carried out, and IC ₅₀ is calculated. The test results are shown in Table 2.

TABLE 2 data on cell proliferation inhibitory Activity

The test results show that the compound has proliferation inhibition activity (IC ₅₀ is less than 2 mu M) on A427 cells and LoVo cells.

Test example 3: in vitro cell CDK1 phosphorylation Activity

Taking U2OS cells in good growth state, washing with PBS, performing pancreatin digestion, stopping complete culture medium, collecting to a centrifuge tube, adjusting the cell density to 2×10 ⁵/mL, inoculating to 384-well plates (40 μl/well), and incubating at 37deg.C overnight; compound sample adding is carried out by using a nanoliter sample adding instrument, so that the final concentration of the compound is 10000nM-0.61nM,2 compound holes are formed, and a control is arranged at the same time; after the cells were further cultured for 2 hours, the supernatant was discarded, 40. Mu.L of paraformaldehyde (manufacturer: bio-organism) was added to each well, and incubated at room temperature for 20 minutes; after removing the supernatant and washing 2 times by adding 40. Mu.L of PBS to each well, adding 40. Mu.L of ice methanol (manufacturer: merck) to each well, and incubating for 10 minutes at room temperature; after removing the supernatant and adding 40. Mu.L TBST to each well for 2 times, adding 40. Mu.L 2% BSA-TBST blocking solution to each well, and incubating for 60 minutes at room temperature; mu.L of a mixture of GAPDH/G3PDH murine antibody and Phospho-cdc2 (Tyr 15) (10A 11) rabbit antibody (manufacturer: CST) prepared with a blocking solution was added to each well and incubated overnight at 4 ℃; after removing the supernatant and adding 40. Mu.L TBST to each well for 2 times, adding 20. Mu.L of a mixed solution (manufacturer: CST) of Anti-mouse IgG (H+L) (Dyight ^TM 680 Conjugate) antibody and Anti-rabit IgG (H+L) (Dyight ^TM, 4 XPEG Conjugate) prepared by blocking solution to each well, and incubating for 45 minutes at room temperature in a dark place; after removing the supernatant and adding 40. Mu.L TBST to each well for 2 times, the Azure Sapphire ^TM dual-mode multispectral laser imaging system was used for detection (In-Cell WB-800nm,680 nm), and IC ₅₀ was calculated by four-parameter fitting.

The test results show that the compound has in vitro cell CDK1 phosphorylation inhibition activity (IC ₅₀ is less than 5 mu M).

Test example 4: in vitro liver microsomal stability

Liver microsome body temperature incubation samples (species: human, rat, mouse) were prepared as mixed PBS buffer (ph=7.4), liver microsome solution (0.5 mg/mL), test compound and nadph+mgcl2 solution were incubated for 1 hour at 37 ℃ and 300 rpm. Samples were prepared as mixed PBS buffer (ph=7.4), liver microsome solution (0.5 mg/mL), test compound. The sample is added into acetonitrile solution containing internal standard, protein precipitation is carried out to prepare supernatant, and the supernatant is used for LC/MS/MS determination after dilution.

The test result shows that the compound of the application has stable metabolism of liver microsomes in vitro.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

Wherein,

Represents a single bond or a double bond;

X ¹、X² or X ³ are each independently selected from N or C;

p is selected from 0,1, 2 or 3;

R ³ is each independently selected from halogen, =O, -OH, -CN, -NH ₂、C_1-10 alkyl, C _1-10 alkoxy, -NHC _1-10 alkyl, -N (C _1-10 alkyl) ₂、-NHCOC_1-10 alkyl, -OCOC _1-10 alkyl, C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl, said C _1-10 alkyl, C _1-10 alkoxy, -NHC _1-10 alkyl, -N (C _1-10 alkyl) ₂、-NHCOC_1-10 alkyl, -OCOC _1-10 alkyl, C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl optionally substituted by halogen, = O, OH, CN, NH ₂、C_1-10 alkyl, C _1-6 alkoxy, -COC _1-10 alkyl, -COOC _1-10 alkyl, -CONH ₂、-CONHC_1-10 alkyl, -CON (C _1-10 alkyl) ₂、-S(O)₂C_1-8 alkyl, -S (O) ₂OC_1-8 alkyl, -S (O) ₂NHC_1-8 alkyl, C _3-10 cycloalkyl, 3-10 heterocycloalkyl, C _6-10 aryl, or 5-10 membered heteroaryl;

m is selected from 0,1, 2, 3 or 4;

n is selected from 0,1, 2, 3 or 4;

Optionally, the composition may be used in combination with,

The compound of formula I is not selected from the following compounds:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one of said X ¹、X²、X³ is selected from C; or X ³ is selected from C, X ² is selected from N, and X ¹ is selected from C or N; or X ¹ and X ² are selected from N and X ³ is selected from C; or X ¹ and X ³ are selected from C, and X ² is selected from N; optionally, a structural part Selected fromOr structural partSelected from

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said R ¹ is selected from hydrogen, halogen, -OH, -NH ₂、-CN、C_1-6 alkyl, C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, or C _3-8 cycloalkyl-C _1-6 alkyl-, said C _1-6 alkyl, C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl, or C _3-8 cycloalkyl-C _1-6 alkyl-being optionally substituted with one or more halogen, -OH, -NH ₂, or-CN;

Or R ¹ is selected from hydrogen, C _1-4 alkyl, C _3-6 alkenyl, C _3-6 cycloalkyl or C _3-4 cycloalkyl-C _1-2 alkyl-, said C _1-4 alkyl, C _3-6 alkenyl, C _3-6 cycloalkyl or C _3-4 cycloalkyl-C _1-2 alkyl-optionally substituted by one or more halogen, -OH, -NH ₂ or-CN;

Or R ¹ is selected from hydrogen, C _1-3 alkyl, C _3-4 alkenyl, C _3-4 cycloalkyl or C _3-4 cycloalkyl-C _1-2 alkyl-, said C _3-4 alkenyl being optionally substituted with one or more halogens;

Or R ¹ is selected from hydrogen, methyl, ethyl, isopropyl, Cyclopropyl or

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R ² is independently selected from halogen, -OH, -NH ₂、-CN、＝O、C_1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;

Or R ² is each independently selected from halogen, -OH, -NH ₂、-CN、＝O、C_1-4 alkyl, halo C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, or 3-6 membered heterocycloalkyl;

Or R ² is each independently selected from F, cl, br, -CN, =o, or C _1-3 alkyl;

Or R ² are each independently selected from F, =o or-CN;

And/or, optionally, p is selected from 0,1 or 2; or p is selected from 0 or 1; or p is selected from 2.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from C _5-8 cycloalkenyl or 5-8 membered heterocyclenyl;

Or ring E is selected from C _5-6 cycloalkenyl or 5-6 membered heterocycloalkenyl;

Or ring E is selected from cyclopentenyl, cyclohexenyl or oxacyclopentenyl;

Or ring E is selected from cyclopentenyl or cyclohexenyl;

Optionally, a structural part Selected from

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the ring Cy is selected from C _6-8 aryl, C _3-8 cycloalkyl, or 6-17 membered heterocyclyl;

or ring Cy is selected from phenyl or 9-17 membered heterocyclyl;

or the ring Cy is selected from phenyl or 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-or 17-membered heterocyclyl;

Or ring Cy is selected from phenyl or a 5-17 membered partially saturated heterocyclic group;

or the ring Cy is selected from phenyl or a 9-10 membered partially saturated heterocyclic group;

Or the ring Cy is selected from phenyl or benzo 5-13 membered heterocyclenyl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein each R ³ is independently selected from halo, =o, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, -OCOC _1-6 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl, the C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, -OCOC _1-6 alkyl, C _3-8 cycloalkyl or 3-8 membered heterocycloalkyl optionally substituted with halogen, =o, -OH, -CN, -NH ₂、C_1-6 alkyl, C _1-6 alkoxy, -COC _1-6 alkyl, -COOC _1-6 alkyl, -CONH ₂、-CONHC_1-6 alkyl, -CON (C _1-6 alkyl) ₂、-S(O)₂C_1-6 alkyl, -S (O) ₂OC_1-6 alkyl, -S (O) ₂NHC_1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C ₆ aryl or 5-6 membered heteroaryl substitution;

Or R ³ is each independently selected from halogen (F, cl, br, I), -OH, C _1-6 alkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂、-NHCOC_1-6 alkyl, or 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted by = O, C _1-6 alkyl, -COC _1-6 alkyl, or-S (O) ₂C_1-6 alkyl; or R ³ is each independently selected from halogen (F, cl, br, I), -OH, -C _1-6 alkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) ₂, or-NHCOC _1-6 alkyl;

Or R ³ is each independently selected from halogen (F, cl, br, I), -OH, C _1-3 alkyl, -NHC _1-3 alkyl, -N (C _1-3 alkyl) ₂、-NHCOC_1-3 alkyl, or 6 membered heterocycloalkyl, said 6 membered heterocycloalkyl optionally substituted with =o, methyl, -COCH ₃, or-S (O) ₂CH₃;

and/or, optionally, the m is selected from 0,1, 2 or 3; or m is selected from 1,2 or 3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ is independently selected from halogen, -OH, -NH ₂、-CN、C_1-6 alkyl, C _1-6 alkoxy, or C _3-6 cycloalkyl, the C _1-6 alkyl, C _1-6 alkoxy, or C _3-6 cycloalkyl being optionally substituted with halogen, -OH, -NH ₂, or-CN;

Or R ⁴ is each independently selected from halogen, -OH, -NH ₂、-CN、C_1-4 alkyl, C _1-4 alkoxy, or C _3-4 cycloalkyl, said C _1-4 alkyl, C _1-4 alkoxy, or C _3-4 cycloalkyl being optionally substituted with halogen, -OH, -NH ₂, or-CN;

Or R ⁴ is each independently selected from halogen, -OH, -NH ₂、-CN、C_1-4 alkyl, or C _3-4 cycloalkyl, said C _1-4 alkyl optionally substituted with one or more of fluoro, chloro, bromo, iodo, -OH, -NH ₂, or-CN;

or R ⁴ is independently selected from-OH, -NH ₂、-CH₃, ethyl, -CF ₃、-CHF₂, or cyclopropyl;

And/or, optionally, said n is selected from 1,2, 3 or 4; or n is selected from 1,2 or 3.

9. The compound of any one of claim 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula I-1, formula I-2, formula IA, formula IB, formula IA-1, formula IB-1, formula IC-1, formula ID-1, formula IE, formula IF, formula IG, or formula IH, or a pharmaceutically acceptable salt thereof,

10. The following compounds or pharmaceutically acceptable salts thereof,

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof.

12. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the prevention or treatment of a related disorder treated by degradation or inhibition of a protein; optionally, the disease is selected from Wee 1-related diseases; optionally, the disease is selected from cancer.