OXYGEN-CONDENSED TRICYCLE DERIVATIVES, THEIR PREPARATION METHODS, AND PHARMACEUTICALS CONTAINING THEM

Abstract

The invention relates to an oxygen-containing condensed tricyclic derivative, a method for preparing it, and a pharmaceutical composition containing it. Specifically, it is proposed that the compound as shown in formulation (I) or its pharmaceutical salt be used as a cyclin-dependent kinase inhibitor for the prevention and / or treatment of diseases associated with cyclin-dependent kinases. The definition of each substituent in formulation (I) is given in the description.

Description

An oxygen-containing fused tricyclic derivative and its preparation method and use Technical Field

[0001] The present invention relates to an oxygen-containing fused tricyclic derivative and a preparation method and use thereof, and belongs to the field of medicine. Background Art

[0002] Cyclin-dependent kinases (CDKs) are an important class of kinases and play a crucial role in the division and proliferation of cancer cells and the transcriptional regulation of oncogenes. Currently, there are more than 20 subtypes of cyclin-dependent kinases (CDKs) discovered. Due to the sequence and structural similarities of the kinase domains of CDK family members, selective and precise regulation of each subtype is a major challenge.

[0003] In recent years, the greatest progress in the field of breast cancer treatment is undoubtedly the use of CDK4 / 6 alone or in combination with endocrine therapy for hormone receptor-positive advanced breast cancer. For example, palbociclib, ribociclib, and abemaciclib have been approved in combination with aromatase inhibitors for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women, and palbociclib and abemaciclib have been approved in combination with fulvestrant for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women after disease progression following endocrine therapy (Nature Reviews (2016) 13:417-430, J Clin Oncol 2017, 35, 2875-2884). Although CDK4 / 6 inhibitors have shown remarkable clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, their effects, like other kinases, may be limited over time by the development of primary or acquired resistance.

[0004] In the cell cycle pathway, the phosphorylation level of Rb protein is jointly regulated by CDK4 / 6 and CDK2. In people resistant to CDK4 / 6 inhibitors, Rb protein function loss, elevated CCNE1 expression, and increased MYC protein levels have been observed. Cyclin E is overexpressed in various cancers, particularly breast cancer, lung cancer, leukemia, and lymphoma (Guo Cuiping et al., Regulation of Cyclin E and Malignant Tumors. International Journal of Oncology, 2012, 39(005):337-340). Cyclin E amplification or overexpression is also associated with poor prognosis in ovarian cancer, gastric cancer, endometrial cancer, and other cancers.

[0005] Studies have shown that inhibiting CDK2 kinase can induce the activity of tumor cells with high CCNE1 expression, but inhibiting CDK2 activity alone is not sufficient to maintain the tumor suppression effect. Studies have found that breast cancer cells treated with CDK2 inhibitors activate cyclin A2 through the CDK4 pathway, thereby promoting the upregulation of CDK2 protein expression, thereby causing cell resistance to CDK2 inhibitors (Cell. 2023 Jun 8; 186 (12): 2628-2643.e21.). Therefore, inhibiting the activity of CDK4 and CDK2 simultaneously is of great significance for long-term tumor suppression. In addition, inhibiting CDK4 and CDK2 simultaneously may play an important role in alleviating CDK4 / 6 inhibitor resistance, and even CDK2 inhibitor resistance.

[0006] Summary of the Invention

[0007] In a first aspect, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl and 3-12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted with one or more R 21 replace;

[0010] Each R 21 Independently selected from deuterium, halogen, hydroxyl, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxy, halogen, deuterium;

[0011] R3 and R4 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl are optionally substituted by one or more R 31 replace;

[0012] Each R 31 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxyl, halogen;

[0013] Y is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogen-substituted C 1-6 alkyl;

[0014] X is selected from hydrogen, halogen, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R a replace;

[0015] Each R a Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxyl, halogen;

[0016] L1 is selected from -CO- or a bond;

[0017] R1 is selected from C 1-6 Alkyl, heterocycloalkyl, heteroaryl, -CO-NH-R 11 、-S(O)2-NH-R 12 、 The C 1-6 Alkyl, heterocycloalkyl, heteroaryl, -CO-NH-R 11 、-S(O)2-NH-R 12 、 Optionally one or more R b replace;

[0018] R 11 、R 12 、R 13 、R 14 Each independently selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0019] Each R b Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogen, hydroxy, cyano, oxo, -N(R c )2;

[0020] Each Rc are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0021] or two R c The N atom to which it is attached forms a 3-6 membered heterocycloalkyl group, wherein the 3-6 membered heterocycloalkyl group is optionally substituted with one or more halogens;

[0022] Each R5 is independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl are optionally substituted by one or more R 51 replace;

[0023] Each R 51 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxyl, halogen;

[0024] n is selected from 0, 1, 2, 3, 4.

[0025] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein L1 is a bond.

[0026] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein L1 is -CO-.

[0027] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of b Substituted 5-7 membered heterocycloalkyl; R b As defined in Formula I.

[0028] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of b Substituted 6-membered heterocycloalkyl; R b As defined in Formula I.

[0029] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of b Replaced R b As defined in Formula I.

[0030] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of b Replaced R b As defined in Formula I.

[0031] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of b Replaced R b As defined in Formula I.

[0032] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Substituted C 1-6 Alkyl, R b As defined in Formula I.

[0033] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Substituted 5-6 membered heteroaryl, R b As defined in Formula I.

[0034] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Substituted 5-membered heteroaryl, R b As defined in Formula I.

[0035] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Replaced R b As defined in Formula I.

[0036] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Substituted-CO-NH-R 11 , R 11 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; preferably R 11 C 1-6 Alkyl, 3-7 membered cycloalkyl; more preferably R 11 C 1-6 Alkyl; R b As defined in Formula I.

[0037] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Substituted-S(O)2-NH-R12 , R 12 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; preferably R 12 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl; more preferably R 12 C 1-6 Alkyl; R b As defined in Formula I.

[0038] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Replaced R 13 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; preferably R 13 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl; more preferably R 13 C 1-6 Alkyl; R b As defined in Formula I.

[0039] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1 is optionally replaced by one or more R b Replaced R 14 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; preferably R 14 Selected from C 1-6 Alkyl, 3-7 membered cycloalkyl; more preferably R 14 C 1-6 Alkyl; R b As defined in Formula I.

[0040] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b Independently selected from halogen, hydroxy, cyano, oxo.

[0041] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b are independently selected from oxo.

[0042] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0043] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b Independently selected from C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0044] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b are independently selected from halogen.

[0045] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b Independently selected from -N(R c )2, each R c are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0046] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each R b Independently selected from -N(R c 2. Two Rs c The N atom to which it is attached forms a 3-6 membered heterocycloalkyl group, which is optionally substituted by one or more halogens.

[0047] In a second aspect, the present disclosure also provides a compound as shown in Formula II or a pharmaceutically acceptable salt thereof,

[0048] wherein R2, R3, R4, R5, X, Y, L1, and n are as defined in Formula I.

[0049] In some embodiments, the compound shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl optionally substituted with one or more R 21 Replacement; R 21 As defined in Formula I.

[0050] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R2 is a 3-8 membered cycloalkyl group, and the 3-8 membered cycloalkyl group is optionally replaced by one or more R 21 Replacement; R 21 As defined in Formula I.

[0051] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R2 is a 3-6 membered cycloalkyl group, and the 3-6 membered cycloalkyl group is optionally replaced by one or more R 21 Replacement; R 21 As defined in Formula I.

[0052] In some embodiments, the compound shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, optionally replaced by one or more R 21 Substituted C 1-6 Alkyl; R 21 As defined in Formula I.

[0053] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, each R 21 Independently selected from deuterium, halogen, hydroxyl; preferably R 21 are independently selected from hydroxyl groups.

[0054] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, each R 21 Independently selected from fluorine, chlorine, and bromine.

[0055] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, each R 21 Independently selected from C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from hydroxy, halogen, deuterium.

[0056] In some embodiments, the compound shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by one or more R 31 Substitution; said R 31 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from hydroxy, halogen.

[0057] In some embodiments, the compound shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0058] In some embodiments, the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H.

[0059] In some embodiments, the compound shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0060] In some embodiments, the compound shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C 1-6 alkyl.

[0061] In some embodiments, in the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, R4 is methyl.

[0062] In some embodiments, in the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, Y is selected from halogen.

[0063] In some embodiments, in the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, Y is selected from fluorine, chlorine, and H; preferably, Y is selected from fluorine.

[0064] In some embodiments, in the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, X is selected from hydrogen, halogen, and cyano.

[0065] In some embodiments, in the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, X is selected from halogen and cyano.

[0066] In some embodiments, the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, wherein X is selected from fluorine or chlorine.

[0067] In some embodiments, in the compound represented by Formula I, Formula II, or a pharmaceutically acceptable salt thereof, each R5 is independently selected from hydroxyl, cyano, and halogen.

[0068] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, each R5 is independently selected from C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl are optionally substituted by one or more R 51 replace;

[0069] Each R 51 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 The alkoxy group, the 3-7 membered cycloalkyl group, and the 3-7 membered heterocycloalkyl group are optionally substituted by one or more substituents selected from hydroxyl group and halogen group.

[0070] In some embodiments, as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, each R5 is independently selected from halogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl, the C 1-6Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl are optionally substituted by one or more R 51 replace;

[0071] Each R 51 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 The alkoxy group, the 3-7 membered cycloalkyl group, and the 3-7 membered heterocycloalkyl group are optionally substituted by one or more substituents selected from hydroxyl group and halogen group.

[0072] In some embodiments, the compound represented by Formula II or a pharmaceutically acceptable salt thereof as shown in the second aspect, wherein:

[0073] L1 is the key;

[0074] R2 is selected from hydrogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, the C 1-6 Alkyl, 3-6 membered cycloalkyl optionally substituted with one or more R 21 Replace, each R 21 Independently selected from hydroxyl, C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from hydroxy, halogen, and deuterium;

[0075] R3 is selected from H;

[0076] R4 is selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl; preferably R4 is selected from C 1-6 alkyl;

[0077] Y is selected from hydrogen and halogen; preferably Y is selected from fluorine, chlorine and hydrogen;

[0078] X is selected from hydrogen, halogen, cyano; preferably Y is selected from fluorine, chlorine, hydrogen;

[0079] n is selected from 0 and 1;

[0080] R5 is independently selected from halogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl are optionally substituted by one or more R 51 replace;

[0081] Each R 51 Independently selected from halogen, hydroxy, and amino.

[0082] In a third aspect, the present disclosure also provides a compound or a pharmaceutically acceptable salt thereof as shown in the following formula

[0083] In a fourth aspect, the present disclosure provides an isotope substitution of the compound or a pharmaceutically acceptable salt thereof as described in the first, second, and third aspects. Preferably, the isotope substitution is a deuterium atom substitution.

[0084] The present disclosure also provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt or isotope-substituted product thereof, comprising the steps of reacting a compound of formula A with a compound of formula B.

[0085] wherein R1, R2, R3, R4, R5, X, Y, L1, and n are as defined in Formula I;

[0086] wherein LG is selected from leaving groups such as halogen, sulfonate, and borate.

[0087] Another aspect of the present disclosure provides a compound represented by formula B or a pharmaceutically acceptable salt thereof,

[0088] wherein R2, R3, R4, X, and Y are as defined in Formula I;

[0089] wherein LG is selected from leaving groups such as halogen, sulfonate, and borate.

[0090] Another aspect of the present disclosure provides a compound represented by formula A or a pharmaceutically acceptable salt thereof,

[0091] wherein R1, R5, L1, and n are as defined in Formula I.

[0092] In some embodiments, Formula A and Formula B are intermediates.

[0093] In a fifth aspect, the present disclosure provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound as described in the first aspect, the second aspect, the third aspect or a pharmaceutically acceptable salt thereof, or the isotope substitute as described in the fourth aspect and a pharmaceutically acceptable excipient.

[0094] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0095] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

[0097] The present disclosure also provides use of a compound as represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect, in the preparation of a medicament for treating or preventing a disease or condition associated with abnormal activity of serine / threonine kinase.

[0098] The present disclosure also provides use of a compound as represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect, in the preparation of a medicament for treating or preventing a disease or condition associated with abnormal activity of CDK2.

[0099] The present disclosure also provides use of a compound as shown in Formula I, Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect, in the preparation of a medicament for treating or preventing a disease or condition associated with abnormal activity of CDK4.

[0100] The present disclosure also provides use of a compound as shown in Formula I, Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect, in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease.

[0101] The present disclosure also provides a compound as shown in Formula I, Formula II or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect for treating or preventing diseases or conditions associated with abnormal activity of serine / threonine kinases.

[0102] The present disclosure also provides a use of a compound as shown in Formula I, Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect for treating or preventing diseases or conditions associated with abnormal activity of CDK2.

[0103] The present disclosure also provides a use of a compound as shown in Formula I, Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect for treating or preventing a disease or condition associated with abnormal activity of CDK4.

[0104] The present disclosure also provides a use of a compound as shown in Formula I, Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution product described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect for treating or preventing a disease or condition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease.

[0105] The present disclosure also provides a method for treating or preventing a disease or condition associated with abnormal activity of serine / threonine kinase, comprising administering to a patient a therapeutically or preventively effective amount of a compound as shown in Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect.

[0106] The present disclosure also provides a method for treating or preventing a disease or condition associated with abnormal activity of CDK2, comprising administering to a patient a therapeutically or preventively effective amount of a compound as shown in Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect.

[0107] The present disclosure also provides a method for treating or preventing a disease or condition associated with abnormal activity of CDK4, comprising administering to a patient a therapeutically or preventively effective amount of a compound as shown in Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or the isotopic substitution described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect.

[0108] The present disclosure also provides a method for treating or preventing a disease or condition, comprising administering to a patient a therapeutically or preventively effective amount of a compound as shown in Formula I or Formula II, or a pharmaceutically acceptable salt thereof, or the isotopic substitution described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease.

[0109] In some embodiments, the disease or disorder is a proliferative disease.

[0110] In some embodiments, the proliferative disease is selected from breast cancer (e.g., triple-negative breast cancer), colon cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, liver cancer.

[0111] In some embodiments, the breast cancer is ER-negative, PR-negative, Her2-positive breast cancer.

[0112] In some embodiments, the breast cancer is CDK4 / 6 inhibitor-resistant breast cancer.

[0113] In some embodiments, the breast cancer is ER-positive breast cancer that is resistant to CDK4 / 6 inhibitors.

[0114] In some embodiments, the lung cancer is non-small cell lung cancer.

[0115] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0116] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0117] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0118] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond No configuration is specified, i.e. the bond The configuration can be E-type or Z-type, or contain both E and Z configurations.

[0119] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. 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 prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations. All tautomeric forms are within the scope of the present invention. The nomenclature of the compounds does not exclude any tautomers.

[0120] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0121] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0122] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0123] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0124] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.

[0125] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0126] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, preferably containing 1 to 6 or 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.

[0127] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 7 carbon atoms or 3-6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, paracyclic, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted.

[0128] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocycloalkyl) or polycyclic heterocycle system (i.e., polycyclic heterocycloalkyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group) or a heterocyclic group having 4 to 11 ring atoms (i.e., a 4- to 11-membered heterocyclic group); further preferably, a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group); and most preferably, a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0129] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0130] Non-limiting examples of the monocyclic heterocycloalkyl group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl.

[0131] Non-limiting examples of "polycyclic heterocycloalkyl" include:

[0132] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0133] wait.

[0134] Heterocycloalkyl groups may be optionally substituted or unsubstituted.

[0135] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups can be optionally substituted or unsubstituted.

[0136] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0137] Aryl groups can be substituted or unsubstituted.

[0138] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12 members, more preferably 6 to 10 members, more preferably 5 or 6 members. Non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0139] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0140] Heteroaryl groups can be optionally substituted or unsubstituted.

[0141] The term "hydroxy" refers to an -OH group.

[0142] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0143] The term "cyano" refers to -CN.

[0144] The term "amino" refers to -NH2.

[0145] The term "nitro" refers to -NO2.

[0146] The term "oxo" refers to a =0 substituent.

[0147] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), then two (2) hydrogen atoms on the atom are replaced. DETAILED DESCRIPTION

[0148] The present disclosure is further described below with reference to embodiments, but these embodiments do not limit the scope of the present disclosure.

[0149] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0150] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (LCMS). -6 The unit of measurement is ppm. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The spatial configuration of the compound's optical isomers (isomers) can be further confirmed by measuring single crystal parameters.

[0151] HPLC determinations were performed using Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1*50MM column, Ultimate XB-C18 3.0*150mm column, or Xtimate C18 2.1*30mm column).

[0152] MS was determined using a Waters SQD2 mass spectrometer in positive / negative ion mode with a mass scan range of 100-1200.

[0153] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0154] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0155] Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as a carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 12g, 25g, 40g, 80g or other specifications).

[0156] Reversed phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45μm, 40g, 80g, 120g, 220g or other specifications).

[0157] The high-pressure column purification system uses Waters AutoP, in conjunction with Waters XBridge BEH C18 OBD Prep Column. 5μm, 19mm X 150mm or Atlantis T3OBD Prep Column, 5μm, 19mm X 150mm.

[0158] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.

[0159] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0160] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0161] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0162] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0163] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0164] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0165] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0166] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0167] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: petroleum ether / ethyl acetate / methanol, and E: petroleum ether / tetrahydrofuran system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0168] The forward column chromatography in the purification process in the embodiment can use a silica gel column, and the eluent system includes but is not limited to: A: dichloromethane / methanol system, B: petroleum ether / ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine or acetic acid can also be added for adjustment.

[0169] The chromatographic column used in the C18 reverse phase chromatography in the purification process in the embodiment is a C18 column, and the eluent system includes but is not limited to: an acetonitrile / water system (the required solvent ratio is adjusted according to the polarity of the actual compound), and a small amount of alkaline or acidic reagents such as ammonium formate, ammonia, or formic acid can also be added for adjustment.

[0170] The solvents used in the slurrying of the purification process in the embodiment include, but are not limited to, dichloromethane, methanol, petroleum ether, ethyl acetate, ethanol, acetonitrile and water, and the slurrying is performed using a single solvent or a combination of multiple solvents.

[0171] Example 1

[0172] (S)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-3-fluorophenyl)morpholin-3-one (1)

[0173] Step 1: 4-(3-Fluoro-4-nitrophenyl)morpholin-3-one (1a)

[0174] 1bb (4-bromo-2-fluoro-1-nitrobenzene) (5 g, 22.7 mmol) was added to dioxane (40 mL). Morpholin-3-one (2.76 g, 27.3 mmol), cesium carbonate (14.8 g, 45.4 mmol), and XantPhos Pd G3 (645 mg, 0.68 mmol) were then added at room temperature. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 110°C. The reaction solution was concentrated, and the residue was separated and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 1a (1.82 g, 33.4% yield).

[0175] Step 2: 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b)

[0176] Compound 1a (1.82 g, 7.58 mmol) was added to ethanol (12 mL) and water (3 mL), followed by iron powder (1.70 g, 30.3 mmol) and ammonium chloride (1.62 g, 30.3 mmol). The mixture was reacted at 80°C and filtered while hot. The filtrate was poured into water (50 mL) and extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, filtered, and slurried (petroleum ether / ethyl acetate = 3:1) to obtain compound 1b (1.15 g, 72.3% yield).

[0177] MS (ESI) m / z = 210.2 [M+H] + .

[0178] Step 3: (S)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-naphthyridin-6-yl)pyrimidin-2-amino)-3-fluorophenyl)morpholin-3-one (1)

[0179] Compound 1b (32 mg, 0.15 mmol) was added to dioxane (4 mL). Compound A10 (50 mg, 0.12 mmol, synthesized and resolved according to the method of WO2022166799), cesium carbonate (78 g, 0.24 mmol), and XantPhos Pd G3 (9 mg, 0.01 mmol) were added at room temperature. The atmosphere was replaced with nitrogen and microwave-treated at 110°C for 1 hour. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography (acetonitrile:water = 4:1) to afford compound 1 (21.6 mg, 30.0% yield).

[0180] MS (ESI) m / z = 571.2 [M+H] + .

[0181] 1 H NMR (400MHz, DMSO-d6) δ9.57(s,1H),8.55(s,1H),7.72(t,1H),7.39(dd,1H),7.25–7.17(m,1H),6.99(d,1H),5.82(s,1H),5. 26-5.22(m,1H),4.50(d,1H),4.28–4.18(m,3H),3.97(dd,2H),3.75(dd,2H),1.67(s,3H),1.62(s,3H),1.46(d,J=6.6Hz,3H).

[0182] Example 2

[0183] (S)-4-(3-Fluoro-4-((5-fluoro-4-(8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (2)

[0184] Step 1: (S)-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (2a)

[0185] A7 (27 mg, 0.1 mmol, synthesized and resolved according to the method of patent WO2022166799) was dissolved in 1,4-dioxane (1 mL). Bis(pyrimidine)-2-(2-(2-aminobenzoyl)-1-oxaline)-2-ol (37.5 mg, 0.15 mmol), potassium acetate (20 mg, 0.2 mmol), and Pd(dppf)Cl2 (7.0 mg, 0.01 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated to 100°C and reacted for 120 minutes. The reaction mixture was cooled to room temperature, and 2,4-dichloro-5-fluoropyrimidine (16.5 mg, 0.1 mmol), sodium carbonate (21 mg, 0.2 mmol), and two drops of water were added. After nitrogen replacement three times, the temperature was raised to 110°C and the reaction was allowed to proceed for 1.5 hours. After the reaction, the reaction solution was concentrated, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried, and concentrated. The residue was separated by column chromatography to obtain compound 2a (17 mg, yield 52.6%).

[0186] MS (ESI) m / z = 323.2 [M+H] + .

[0187] Step 2: (S)-4-(3-fluoro-4-((5-fluoro-4-(8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (2)

[0188] Compound 2a (17 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (11 mg, 0.05 mmol), cesium carbonate (32 mg, 0.1 mmol), and Xantphos Pd G3 (5 mg, 0.005 mmol) were added sequentially. The mixture was reacted in a microwave oven at 110°C under a nitrogen atmosphere. The reaction solution was filtered, and the residue was separated by C18 reverse phase chromatography to obtain compound 2 (4 mg, 16.1% yield).

[0189] MS (ESI) m / z = 497.3 [M+H] + .

[0190] 1 H NMR(400MHz,DMSO)δ9.37(s,1H),8.61–8.50(m,2H),7.78(t,1H),7.38(dd,1H),7.25–7.18(m,1H),7.15(d, 1H),4.75-4.73(m,1H),4.58(dd,1H),4.20(s,2H),4.16(dd,1H),3.97(dd,,2H),3.75(dd,2H),1.56(d,3H).

[0191] Example 3

[0192] (S)-4-((5-Fluoro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-N-methylbenzamide (3)

[0193] Step 1: (S)-2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (3a)

[0194] A8 (33 mg, 0.1 mmol, synthesized and resolved according to the method of patent WO2022166799) was dissolved in 1,4-dioxane (1 mL). Under a nitrogen atmosphere, pinacol diboron (37.5 mg, 0.15 mmol), potassium acetate (20 mg, 0.2 mmol), and Pd(dppf)Cl2 (7.0 mg, 0.01 mmol) were added, and the mixture was stirred at 100°C for 120 minutes. The reaction solution was cooled to room temperature, and 2,4-dichloro-5-fluoropyrimidine (16.5 mg, 0.1 mmol), sodium carbonate (21 mg, 0.2 mmol), and two drops of water were added. The atmosphere was purged with nitrogen three times, and the reaction was continued at 110°C for 1.5 hours. After the reaction, the reaction solution was concentrated, water (5 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried, and concentrated. The residue was separated by column chromatography to obtain compound 3a (21.5 mg, yield 56.5%).

[0195] MS (ESI) m / z = 381.2 [M+H] + .

[0196] Step 2: (S)-4-((5-Fluoro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-N-methylbenzamide (3)

[0197] The target compound 3 was synthesized by replacing 4-(4-amino-3-fluorophenyl)morpholin-3-one in Example 2 with 4-amino-N-methylbenzamide.

[0198] MS (ESI) m / z = 495.3 [M+H] + .

[0199] 1H NMR (400MHz, DMSO) δ10.08(s,1H),8.66(d,1H),8.24-8.22(m,1H),7.90–7.84(m,2H),7.81–7.73(m,2H),7.19(d,1H) ,5.85(s,1H),5.27-5.25(m,1H),4.55(d,1H),4.33–4.25(m,1H),2.76(d,3H),1.69(s,3H),1.63(s,3H),1.50(d,3H).

[0200] Example 4

[0201] (S)-4-(3-Fluoro-4-((5-fluoro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (4)

[0202] According to the similar synthesis method of Example 3, 4-amino-N-methylbenzamide was replaced with 4-(4-amino-3-fluorophenyl)morpholin-3-one to obtain the target compound 4.

[0203] MS (ESI) m / z = 555.3 [M+H] + .

[0204] 1 H NMR (400MHz, DMSO) δ9.36(s,1H),8.55(d,1H),7.79(t,1H),7.38(dd,1H),7.21-7.17(m,1H),7.11(d,1H),5.83(s,1H),5.28–5. 20(m,1H),4.57–4.49(m,1H),4.24(d,1H),4.21(s,2H),3.97(dd,2H),3.78–3.71(m,2H),1.67(s,3H),1.62(s,3H),1.47(d,3H).

[0205] Example 5

[0206] (S)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-N-methylbenzenesulfonamide (5)

[0207] 4-Amino-N-methylbenzenesulfonamide (28.6 mg, 0.15 mmol) was added to dioxane (4 mL). A10 (50 mg, 0.13 mmol), cesium carbonate (82 g, 0.25 mmol), and XantPhos Pd G3 (7 mg, 0.007 mmol) were added at room temperature. The atmosphere was replaced with nitrogen and microwaved at 100°C for 1 hour. The reaction solution was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to provide compound 5 (24 mg, 34.9% yield).

[0208] MS (ESI) m / z = 547.2 [M+H] + .

[0209] 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.71(s,1H),8.01–7.92(m,2H),7.72–7.64(m,2H),7.24(q,1H),7.09(d,1H ),5.83(s,1H),5.27(q,1H),4.56–4.48(m,1H),4.28(dd,1H),2.38(d,3H),1.69(s,3H),1.63(s,3H),1.48(d,3H).

[0210] Example 6

[0211] (S)-4-(3-Fluoro-4-((5-fluoro-4-(8-fluoro-2,3-dimethyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (6)

[0212] Step 1: (S)-6-Bromo-8-fluoro-2,3-dimethyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (6a)

[0213] Compound A7 (110 mg, 0.41 mmol) was added to tetrahydrofuran (8 mL), and the atmosphere was replaced with nitrogen three times. LDA (0.35 mL, 0.61 mmol, 2.0 M THF solution) was added at -78°C and stirred for 1 hour. Iodomethane (115 mg, 0.81 mmol) was then added at the same temperature. After reacting at -78°C for 1 hour, saturated ammonium chloride (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated, and the residue was isolated by column chromatography to obtain compound 6a (104 mg, 81.0% yield).

[0214] MS (ESI) m / z = 285.2 [M+H] + .

[0215] Step 2: (S)-8-Fluoro-2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (6b)

[0216] Compound 6a (100 mg, 0.35 mmol) was dissolved in 1,4-dioxane (3 mL). Bis(pyraclostrobin) (134 mg, 0.54 mmol), potassium acetate (103 mg, 1.05 mmol), and Pd(dppf)Cl2 (14.5 mg, 0.02 mmol) were added sequentially. The mixture was microwaved at 110°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered and concentrated, and the residue was separated by column chromatography to afford compound 6b (50 mg, 15.5% yield).

[0217] MS (ESI) m / z = 333.3 [M+H] + .

[0218] Step 3: (S)-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2,3-dimethyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (6c)

[0219] Compound 6b (50.0 mg, 0.15 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.05 mL). 2,4-Dichloro-5-fluoropyrimidine (25.0 mg, 0.15 mmol), sodium carbonate (32.0 mg, 0.30 mmol), and Pd(dppf)Cl2 (2.00 mg, 0.003 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was continued at 110°C for 18 hours. The reaction solution was filtered and concentrated, and the residue was isolated and purified by column chromatography to obtain compound 6c (50 mg, 35.0% yield).

[0220] MS (ESI) m / z = 337.1 [M+H] + .

[0221] Step 4: (S)-4-(3-fluoro-4-((5-fluoro-4-(8-fluoro-2,3-dimethyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (6)

[0222] Compound 6c (50.0 mg, 0.15 mmol) was dissolved in 1,4-dioxane (3 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (37.0 mg, 0.18 mmol), cesium carbonate (96.0 mg, 0.30 mmol), and XantPhos Pd G3 (3.00 mg, 0.003 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to obtain compound 6 (3.60 mg, 4.8% yield).

[0223] MS (ESI) m / z = 511.1 [M+H] + .

[0224] Example 7

[0225] (S)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluoro-N-methylbenzenesulfonamide (7)

[0226] Step 1: 3-Fluoro-N-methyl-4-nitrobenzenesulfonamide (7a)

[0227] 3-Fluoro-4-nitrobenzenesulfonyl chloride (300 mg, 1.25 mmol) was added to dichloromethane (10 mL) and water (3 mL). Methylamine hydrochloride (127 mg, 1.88 mmol) and potassium carbonate (173 g, 1.25 mmol) were added under ice-cooling and allowed to react for 1 hour. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (15 mL × 3). The organic phases were combined and concentrated, and the residue was separated by column chromatography to obtain compound 7a (234 mg, 80.1% yield).

[0228] Step 2: 4-Amino-3-fluoro-N-methylbenzenesulfonamide (7b)

[0229] Compound 7a (234 mg, 1.00 mmol) was added to ethanol (12 mL) and water (3 mL), followed by iron powder (224 mg, 4.00 mmol) and ammonium chloride (218 mg, 4.00 mmol). The mixture was reacted at 80°C for 2 hours and then filtered while hot. The filtrate was poured into water (50 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried, filtered, concentrated, and slurried to afford compound 7b (163 mg, 80.2% yield).

[0230] MS (ESI) m / z = 205.2 [M+H] + .

[0231] Step 3: (S)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluoro-N-methylbenzenesulfonamide (7)

[0232] Compound 7b (25.7 mg, 0.13 mmol) was added to dioxane (4 mL). A10 (50 mg, 0.13 mmol), cesium carbonate (85 mg, 0.26 mmol), and XantPhos Pd G3 (6 mg, 0.006 mmol) were added at room temperature. The mixture was microwaved at 100°C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to afford compound 7 (30 mg, 42.2% yield).

[0233] MS (ESI) m / z = 565.2 [M+H] + .

[0234] 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H),8.67(s,1H),8.18(t,1H),7.63–7.53(m,2H),7.45(s,1H),7.04(d,1H),5 .82(s,1H),5.26(q,1H),4.56–4.48(m,1H),4.26(dd,1H),2.43(s,3H),1.68(s,3H),1.62(s,3H),1.47(d,3H).

[0235] Example 8

[0236] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)(cyclopropyl)sulfonimide (8)

[0237] Step 1: tert-Butyl (2-fluoro-4-mercaptophenyl)carbamate (8a)

[0238] 4-Amino-3-fluorobenzene-1-thiophenol (143 mg, 1.0 mmol) was dissolved in ethanol (5 mL), and DMAP (12.2 mg, 0.10 mmol) and di-tert-butyl dicarbonate (310 mg, 1.5 mmol) were added. The mixture was allowed to react at room temperature for 60 minutes. After completion of the reaction, the mixture was concentrated, and water (5 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by column chromatography to obtain compound 8a (200 mg, 82.3% yield).

[0239] Step 2: 4-(Cyclopropylthio)-2-fluoroaniline (8b)

[0240] Compound 8a (120 mg, 0.5 mmol) was dissolved in tert-butanol (2.5 mL), and potassium tert-butoxide (112 mg, 1.0 mmol) was added. Cyclopropane bromide (120 mg, 1.0 mmol) was slowly added with stirring. The mixture was microwaved at 120°C for 2 hours under a nitrogen atmosphere. The reaction solution was filtered, and water (5 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried, concentrated, and used directly in the next reaction.

[0241] MS (ESI) m / z = 184.3 [M+H] + .

[0242] Step 3: (S)-2-(6-(5-chloro-2-((4-(cyclopropylthio)-2-fluorophenyl)amino)pyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (8c)

[0243] According to the similar synthetic method of Example 1, 8c was synthesized by replacing 4-(4-amino-3-fluorophenyl)morpholin-3-one with compound 8b.

[0244] MS (ESI) m / z = 544.2 [M+H] + .

[0245] Step 4: (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)(cyclopropyl)sulfonimide (8)

[0246] Compound 8c (27 mg, 0.05 mmol) was dissolved in ethanol (1 mL), and iodobenzene acetate (80 mg, 0.25 mmol) and ammonium acetate (38 mg, 0.5 mmol) were added. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was purified by C18 reverse-phase chromatography to obtain the target compound 8 (10 mg, 34.8% yield).

[0247] MS (ESI) m / z = 575.2 [M+H] + .

[0248] 1 H NMR(400MHz,DMSO)δ9.89(s,1H),8.66(s,1H),8.13(t,1H),7.72–7.63(m,2H),7.04(d,1H),5.83(s,1H),5.26(d,1H),4.52(d,1H),4 .30-4.26(m,1H),2.70-2.66(m,1H),1.68(s,3H),1.62(s,3H),1.47(d,3H),1.11-1.07(m,1H),1.01–0.90(m,2H),0.89-0.79(m,2H).

[0249] Example 9

[0250] 4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluoro-N-methylbenzenesulfonimide (9)

[0251] Attached is the synthesis steps of intermediate A10-NH2

[0252] Step 1: 4-Bromo-3-fluorobenzene-1-sulfonamide (9b)

[0253] 4-Bromo-3-fluorobenzenesulfonyl chloride (9a) (1.0 g, 3.65 mmol) was added to acetonitrile (10 mL), cooled to 0°C, and aqueous ammonia (1.42 mL, 10.97 mmol) was added, followed by stirring at 0°C for 30 minutes. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried, filtered, and the filtrate was concentrated. The residue was separated by column chromatography to obtain compound 9b (0.9 g, 96.8% yield).

[0254] Step 2: 4-Bromo-N-(tert-butyldimethylsilyl)-3-fluorobenzenesulfonamide (9c)

[0255] Compound 9b (500 mg, 1.96 mmol) was added to anhydrous tetrahydrofuran (10 mL). Under a nitrogen atmosphere, the temperature was lowered to 0°C, and 60% sodium hydride (197.1 mg, 4.92 mmol) was added portionwise. After reacting for 30 minutes, tert-butyldimethylsilyl chloride (357.5 mg, 2.36 mmol) was added, and the mixture was warmed to room temperature and stirred for 3 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried. The filtrate was concentrated, and the residue was separated by column chromatography to obtain compound 9c (600 mg, 82.8% yield).

[0256] MS (ESI) m / z = 368.1 [M+H] + .

[0257] Step 3: 4-Bromo-N-(tert-butyldimethylsilyl)-3-fluoro-N'-methylbenzenesulfonimide (9d)

[0258] Compound 9c (150 mg, 0.41 mmol) was dissolved in chloroform (10 mL). Under a nitrogen atmosphere, triethylamine (0.23 mL, 1.63 mmol) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. Triphenylphosphine dichloride (272.1 mg, 0.81 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. A 30% ethanolic methylamine solution (462.8 mg, 4.48 mmol) was added, and the mixture was reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), and dried. The filtrate was concentrated, and the residue was separated by column chromatography to obtain compound 9d (80 mg, 51.5% yield).

[0259] MS (ESI) m / z = 381.0 [M+H] + .

[0260] Step 4: (S)-2-(6-(2-amino-5-chloropyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (A10-NH2)

[0261] A10 was dissolved in 7 mol ammonia methanol solution (2 mL) and reacted at 70° C. for 3 hours. After the reaction solution was concentrated, the residue was separated by column chromatography to obtain A10-NH 2 (30 mg, yield 63.1%).

[0262] MS (ESI) m / z = 378.1 [M+H] + .

[0263] Step 5: N'-(tert-Butyldimethylsilyl)-4-((5-chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluoro-N-methylbenzenesulfonimide (9e)

[0264] Compound 9d (10 mg, 0.03 mmol) was dissolved in 1,4-dioxane (1.5 mL), and A10-NH2 (9.9 mg, 0.03 mmol), cesium carbonate (17.1 mg, 0.05 mmol), and Brettphos Pd G3 (4.8 mg, 0.005 mmol) were added sequentially. The mixture was microwaved at 100°C under a nitrogen atmosphere for 1 hour. The reaction solution was concentrated, and the residue was separated by column chromatography to obtain compound 9e (10 mg, 56.2% yield).

[0265] MS (ESI) m / z = 678.2 [M+H] + .

[0266] Step 6: 4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluoro-N-methylbenzenesulfonimide (9)

[0267] Compound 9e (25 mg, 0.03 mmol) was dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (0.18 mL, 0.18 mmol) was added at room temperature. The mixture was allowed to react for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried. The filtrate was concentrated, and the residue was purified by C18 reverse-phase chromatography to obtain compound 9 (7.1 mg, 34.1% yield).

[0268] MS (ESI) m / z = 564.2 [M+H] + .

[0269] Example 10

[0270] (S)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (10)

[0271] Using 4-(4-aminophenyl)morpholin-3-one (commercially available, CAS: 438056-69-0) and A10 as starting materials, the target compound 10 was obtained according to a synthetic method similar to that of Example 1.

[0272] MS (ESI) m / z = 553.4 [M+H] + .

[0273] 1 H NMR(400MHz,DMSO)δ9.96(s,1H),8.55(s,1H),7.73–7.66(m,2H),7.25–7.17(m,2H),6.99(d,1H),5.76(s,1H),5.21-5.19(m,1 H),4.44(d,1H),4.20-4.16(m,1H),4.11(s,2H),3.89(dd,2H),3.62(dd,2H),1.61(s,3H),1.56(s,3H),1.41(d,J=6.6Hz,3H).

[0274] Example 11

[0275] (S)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-N-methylbenzamide (11)

[0276] Using 4-amino-N-methylbenzamide and A10 as raw materials, the target compound 11 was obtained according to a synthetic method similar to that in Example 1.

[0277] MS (ESI) m / z = 511.4 [M+H] + .

[0278] 1 H NMR (400MHz, DMSO) δ10.22(s,1H),8.67(s,1H),8.28-8.25(m,1H),7.84(d,2H),7.76(d,2H),7.08(d,1H),5. 84(s,1H),5.35–5.23(m,1H),4.52(d,1H),4.27(dd,1H),2.76(d,3H),1.69(s,3H),1.63(s,3H),1.48(d,3H).

[0279] Example 12

[0280] 1-(4-((5-chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)-4-(dimethylamino)piperidin-2-one (12)

[0281] Referring to the synthesis method of Example 1, 4-(4-amino-3-fluorophenyl)morpholin-3-one was replaced with 1-(4-amino-3-fluorophenyl)-4-(dimethylamino)-2-piperidinone (synthesized by a similar method to patent CN114364675A) to obtain the target compound 12.

[0282] MS (ESI) m / z = 612.2 [M+H] + .

[0283] Example 13

[0284] (S)-4-(8-Fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)-2-((2-fluoro-4-(3-oxomorpholino)phenyl)amino)pyrimidine-5-carbonitrile (13)

[0285] Step 1: 4-Chloro-2-((2-fluoro-4-(3-oxomorpholino)phenyl)amino)pyrimidine-5-carbonitrile (13a)

[0286] 2,4-Dichloropyrimidine-5-carbonitrile (250 mg, 1.44 mmol) was added to tert-butanol (5 mL) and 1,2-dichloroethane (5 mL). Zinc dichloride (207 mg, 1.52 mmol) and triethylamine (58.6 mg, 0.52 mmol) were added under ice-cooling. The atmosphere was replaced with nitrogen three times and stirred on ice-cooling for 1 hour. 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (101 mg, 0.48 mmol) was added and the mixture was reacted at 80°C for 18 hours. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated, and the residue was separated by column chromatography to obtain compound 13a (119 mg, 71.1% yield).

[0287] MS (ESI) m / z = 348.1 [M+H] + .

[0288] Step 2: (S)-4-(8-Fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)-2-((2-fluoro-4-(3-oxoformyl)phenyl)amino)pyrimidine-5-carbonitrile (13)

[0289] Compound 13a (33.0 mg, 0.10 mmol) was dissolved in 1,4-dioxane (3 mL) and water (3 drops). A8 (75.0 mg, 0.20 mmol), sodium carbonate (21.2 mg, 0.2 mmol), and Pd(dppf)Cl2 (4.00 mg, 0.005 mmol) were added sequentially. The mixture was microwaved at 100°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to afford compound 13 (14.2 mg, 26.7% yield).

[0290] MS (ESI) m / z = 562.3 [M+H] + .

[0291] 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.88(s,1H),7.65(s,1H),7.46(dd,1H) ,7.30-7.26(m,1H),7.09(d,1H),5.83(s,1H),5.28(d,1H),4.55(d,1H),4.29 (d,1H),4.22(s,2H),3.98(dd,2H),3.81–3.73(m,2H),1.65(d,6H),1.48(d,J=6.6Hz,3H).

[0292] Example 14

[0293] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)(methyl)sulfonimide (14)

[0294] Step 1: (S)-2-(6-(5-chloro-2-((2-fluoro-4-(methylthio)phenyl)amino)pyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-2-yl)propan-2-ol (14a)

[0295] Compound A10 (55 mg, 0.14 mmol) was dissolved in 1,4-dioxane (1 mL), and 2-fluoro-4-methylthioaniline (23.9 mg, 0.15 mmol), cesium carbonate (90 mg, 0.28 mmol), and XantPhos Pd G3 (13.1 mg, 0.014 mmol) were added sequentially. The mixture was microwaved at 110°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, and the residue was separated by column chromatography to obtain compound 14a (65 mg, 90.6% yield).

[0296] Step 2: (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)(methyl)sulfonimide (14)

[0297] Compound 14a (60 mg, 0.12 mmol) was dissolved in ethanol (1 mL), and iodophenyl diacetic acid (111.9 mg, 0.35 mmol) and ammonium acetate (44.6 mg, 0.58 mmol) were added sequentially. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was separated by C18 reverse-phase chromatography to obtain compound 14 (11 mg, 17.3% yield).

[0298] MS (ESI) m / z = 549.27 [M+H] + .

[0299] 1 H NMR(400MHz,DMSOd6)δ9.91(s,1H),8.66(s,1H),8.14(t,1H),7.76–7.69(m,2H),7.04(d,1H),5.83( s,1H),5.285.24(m,1H),4.52(d,J=11.4Hz,1H),4.26(d,2H),3.08(d,3H),1.65(d,6H),1.47(d,3H).

[0300] Example 15

[0301] (3-Fluoro-4-((5-fluoro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)(methyl)sulfonimide (15)

[0302] According to the similar synthesis method of Example 14, compound 3a was used instead of compound A10 to obtain the target compound 15.

[0303] MS (ESI) m / z = 533.22 [M+H] + .

[0304] 1 H NMR(400MHz,DMSOd6)δ9.71(s,1H),8.66(d,1H),8.29–8.24(m,1H),7.76–7.68(m,2H),7.16(d,1H),5.85(s, 1H),5.27(q,1H),4.58–4.52(m,1H),4.31–4.21(m,2H),3.09(s,3H),1.68(s,3H),1.62(s,3H),1.48(d,3H).

[0305] Example 16

[0306] (S)-3-Fluoro-4-((5-fluoro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide (16)

[0307] According to the similar synthesis method of Example 7, compound 3a was used instead of compound A10 to obtain the target compound 16.

[0308] MS (ESI) m / z = 549.21 [M+H] + .

[0309] 1 H NMR(400MHz,DMSO DMSO-d6)δ9.73(s,1H),8.67(d,1H),8.35–8.27(m,1H),7.60-7.56(m,2H),7.44(d,1H),7.16(d,1H),5.84 (s,1H),5.27(q,1H),4.59–4.52(m,1H),4.27(dd,1H),2.43(d,3H),1.68(s,3H),1.62(s,3H),1.48(d,3H).

[0310] Example 17

[0311] (4-((5-Fluoro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)(methyl)sulfonimide (17)

[0312] According to the similar synthesis method of Example 14, compound 3a was used instead of compound A10, and 4-methylthioaniline was used instead of 2-fluoro-4-methylthioaniline to obtain the target compound 17.

[0313] MS (ESI) m / z = 515.22 [M+H] + .

[0314] 1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.67(d,1H),8.35–8.27(m,1H),7.62-7.56(m,2H),7.44(d,1H),7.16(d,1H) ,5.84(s,1H),5.27(q,1H),4.59–4.52(m,1H),4.27(dd,1H),2.43(d,3H),1.68(s,3H),1.62(s,3H),1.48(d,3H).

[0315] Example 18

[0316] (S)-4-(4-((5-fluoro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (18)

[0317] According to the similar synthetic method of Example 1, compound 3a was used instead of compound A10, and 4-(4-aminophenyl)morpholin-3-one was used instead of compound 1b to obtain the target compound 18.

[0318] MS (ESI) m / z = 537.22 [M+H] + .

[0319] 1 H NMR(400MHz, DMSO-d6)δ9.89(s,1H),8.61(d,1H),7.84–7.76(m,2H),7.32–7.25(m,2H),7.17(d,1H),5.84(s,1H),5.26(q, 1H),4.57–4.52(m,1H),4.27(dd,1H),4.18(s,2H),3.96(dd,2H),3.73–3.66(m,2H),1.68(s,3H),1.63(s,3H),1.49(d,3H).

[0320] Example 19

[0321] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)(methyl)sulfenamide (19)

[0322] According to the similar synthesis method of Example 14, using 4-methylthioaniline instead of 2-fluoro-4-methylthioaniline, the target compound 19 was obtained.

[0323] MS (ESI) m / z = 531.17 [M+H] + .

[0324] 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.71(s,1H),8.01–7.93(m,2H),7.85–7.77(m,2H),7.08(d,1H),5.83(s,1H),5 .30–5.23(m,1H),4.55–4.49(m,1H),4.28(dd,1H),4.01(s,1H),3.02(s,3H),1.68(s,3H),1.63(s,3H),1.48(d,3H).

[0325] Example 20

[0326] (R)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-3-fluorophenyl)morpholin-3-one (20)

[0327] Step 1: (R)-2-(6-bromo-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (20a)

[0328] Compound A11 (the A7 enantiomer was synthesized and separated according to a similar method to patent WO2022166799) was added to tetrahydrofuran (25 mL), replaced with nitrogen three times, and LDA (5.55 mL, 11.1 mmol, 2.0 M THF solution) was added at -78 ° C. and stirred for 1 hour. Acetone (1.24 g, 22.1 mmol) was added and reacted for 1 hour. Saturated ammonium chloride (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated, and the residue was separated by column chromatography to obtain compound 20a (2.17 g, yield 90.1%).

[0329] MS (ESI) m / z = 329.2 [M+H] + .

[0330] Step 2: (R)-2-(8-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (20b)

[0331] Compound 20a (2.17 g, 6.59 mmol) was dissolved in 1,4-dioxane (20 mL). Bis(pinacol)diboronate (5.02 g, 19.8 mmol), potassium acetate (1.94 g, 19.8 mmol), and PdCl2(PPh3)2 (232 mg, 0.33 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was continued at 110°C for 18 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography to obtain compound 20b (1.96 g, 79.2% yield).

[0332] MS (ESI) m / z = 377.3 [M+H] + .

[0333] Step 3: (R)-2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (20c)

[0334] Compound 20b (1.45 g, 3.85 mmol) was dissolved in 1,4-dioxane (8 mL) and water (0.05 mL). 2,4,5-trichloropyrimidine (0.71 g, 3.85 mmol), sodium carbonate (0.82 mg, 7.71 mmol), and PdCl2(dppf) (138 mg, 0.19 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was continued at 80°C for 18 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography to obtain compound 20c (1.60 g, 104.0% yield).

[0335] MS (ESI) m / z = 397.2 [M+H] + .

[0336] Step 4: (R)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-3-fluorophenyl)morpholin-3-one (20)

[0337] Compound 20c (83.0 mg, 0.21 mmol) was dissolved in 1,4-dioxane (4 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (44.0 mg, 0.21 mmol), cesium carbonate (137 mg, 0.42 mmol), and XantPhos Pd G3 (10.0 mg, 0.01 mmol) were added sequentially. The mixture was microwaved at 100°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to obtain compound 20 (38.0 mg, 31.8% yield).

[0338] MS (ESI) m / z = 571.2 [M+H] + .

[0339] 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.55(s,1H),7.72(t,1H),7.39(dd,1H),7.21(dd,1H),6.99(d,1H),5.82(s,1H),5 .24(q,1H),4.50(d,1H),4.24(dd,1H),4.20(s,2H),3.97(dd,2H),3.74(dd,2H),1.67(s,3H),1.62(s,3H),1.46(d,3H).

[0340] Example 21

[0341] 4-(3-Fluoro-4-((5-fluoro-4-((3S)-8-fluoro-2-(1-hydroxyethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (21)

[0342] Step 1: 1-((S)-6-Bromo-8-fluoro-3-methyl-3,4-dihydro-5-oxo-1,2a-diazaacenaphthylene-2-yl)ethan-1-ol (21a)

[0343] Compound A7 (270 mg, 1.0 mmol) was added to anhydrous THF (10 mL). Under a nitrogen atmosphere, the temperature was lowered to -78°C, and LDA (0.6 mL, 2N THF solution) was slowly added. After reacting for 60 minutes, acetaldehyde (66 mg, 1.5 mmol) was added, and stirring was continued at the same temperature for another 60 minutes. After completion of the reaction, saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried, and concentrated, and the residue was isolated by column chromatography to obtain compound 21a (250 mg, 79.6% yield).

[0344] MS (ESI) m / z = 315.1 [M+H] + .

[0345] Step 2: 1-((S)-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxo-1,2a-diazaacenaphthylene-2-yl)ethan-1-ol (21b)

[0346] Compound 21a (31 mg, 0.1 mmol) was dissolved in 1,4-dioxane (2 mL). Under a nitrogen atmosphere, pinacol diboronate (37.5 mg, 0.15 mmol), potassium acetate (20 mg, 0.2 mmol), and Pd(dppf)Cl2 (7.0 mg, 0.01 mmol) were added, and the mixture was stirred at 100°C for 120 minutes. The reaction solution was then cooled to room temperature, and 2,4-dichloro-5-fluoropyrimidine (16.5 mg, 0.1 mmol) and sodium carbonate (21 mg, 0.2 mmol) were added. A small amount of Pd(dppf)Cl2 and two drops of water were added, and the atmosphere was replaced with nitrogen three times. The reaction was continued at 110°C for 1.5 hours. After completion of the reaction, the mixture was concentrated, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried, and concentrated. The residue was separated by column chromatography to afford compound 21b (18 mg, 49.2% yield).

[0347] MS (ESI) m / z = 367.2 [M+H] + .

[0348] Step 3: 4-(3-Fluoro-4-((5-fluoro-4-((3S)-8-fluoro-2-(1-hydroxyethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (21)

[0349] Compound 21b (18 mg, 0.05 mmol) was dissolved in 1,4-dioxane (1 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (11 mg, 0.05 mmol), cesium carbonate (32 mg, 0.1 mmol), and Xantphos Pd G3 (5 mg, 0.005 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered, and the residue was separated by C18 reverse-phase chromatography to obtain compound 21 (7 mg, 25.9% yield).

[0350] MS (ESI) m / z = 541.3 [M+H] + .

[0351] 1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.55(d,1H),7.79(t,1H),7.38(dd,1H),7.25(dd,1H),7.14(dd,1H),5.94-5.86(m,1H), 5.17–5.05(m,2H),4.60–4.48(m,1H),4.33–4.17(m,1H),4.21(s,2H),3.97(dd,2H),3.75(dd,2H),1.61(t,3H),1.46(dd,3H).

[0352] Example 22

[0353] 4-(3-Fluoro-4-((5-fluoro-4-((3S)-8-fluoro-2-(1-methoxyethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)morpholin-3-one (22)

[0354] Step 1: (3S)-6-Bromo-8-fluoro-2-(1-methoxyethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (22a)

[0355] Compound 21a (314 mg, 1.0 mmol) was added to anhydrous THF (10 mL). Under a nitrogen atmosphere, the temperature was lowered to 0°C, and 60% sodium hydride (60 mg, 1.5 mmol) was added portionwise. After reacting for 30 minutes, iodomethane (170 mg, 1.2 mmol) was added, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 2). The organic phases were combined and dried, and the reaction solution was concentrated. The residue was separated by column chromatography to obtain compound 22a (250 mg, 76.2% yield).

[0356] MS (ESI) m / z = 329.2 [M+H] + .

[0357] The remaining steps were carried out according to a similar synthetic method as in Example 21, using compound 22a instead of compound 21a to obtain the target compound 22.

[0358] MS (ESI) m / z = 555.3 [M+H] + .

[0359] 1H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.56(d,1H),7.80(t,1H),7.38(dd,1H),7.21(dd,1H),7.14(d,1H),5.09–4.94(m,1H),4.92-4.88 (m,1H),4.58-4.55(m,1H),4.32-4.29(m,1H),4.21(s,2H),3.97(dd,2H),3.79–3.71(m,2H),3.30(s,3H),1.61(dd,3H),1.44(dd,3H).

[0360] Example 23

[0361] (S)-1-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)3-fluorophenyl)piperazin-2-one (23)

[0362] Step 1: tert-Butyl 4-(3-fluoro-4-nitrophenyl)-3-oxopiperazine-1-carboxylate (23a)

[0363] Under a nitrogen atmosphere, tert-butyl 3-oxopiperazine-1-carboxylate (200 mg, 1.0 mmol) was dissolved in 1,4-dioxane (10 mL). 4-Bromo-2-fluoro-1-nitrobenzene (220 mg, 1.0 mmol), cesium carbonate (650 mg, 2 mmol), and Xantphos Pd G3 (45 mg, 0.05 mmol) were added sequentially. The mixture was microwaved at 110°C for 1.5 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was separated by column chromatography to obtain compound 23a (180 mg, 53.1% yield).

[0364] MS (ESI) m / z = 240.2 [M-100 + H] + .

[0365] Step 2: tert-Butyl 4-(4-amino-3-fluorophenyl)-3-oxopiperazine-1-carboxylate (23b)

[0366] Compound 23a (170 mg, 0.5 mmol) was dissolved in ethanol:water (4 mL:1 mL) at room temperature, and ammonium chloride (53 mg, 1.0 mmol) was added. The temperature was raised to 60°C, and iron powder (280 mg, 5 mmol) was added and allowed to react for 2 hours. After completion of the reaction, the mixture was filtered through hot celite, and the filtrate was concentrated under reduced pressure. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined and concentrated to afford compound 23b (140 mg, 93.3% yield).

[0367] MS (ESI) m / z = 310.2 [M-100 + H] + .

[0368] Step 3: (S)-1-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)3-fluorophenyl)piperazin-2-one (23)

[0369] Compound 23b (60 mg, 0.2 mmol) was dissolved in 1,4-dioxane (3 mL), and compound A10 (80 mg, 0.2 mmol), cesium carbonate (130 mg, 0.4 mmol), and Xantphos Pd G3 (18 mg, 0.02 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated, and hydrochloric acid (2N EA solution, 1 mL) was added. The mixture was stirred at room temperature for 1 hour. After concentration, the residue was separated by C18 reverse-phase chromatography to obtain the desired product 23 (20 mg, 17.5% yield).

[0370] MS (ESI) m / z = 570.3 [M+H] + .

[0371] 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.54(d,1H),7.70(t,1H),7.33-7.31(m,1H),7.19–7.10(m,1H),6.99(d,1H),5.83(s,1H),5.24-5 .22(m,1H),4.50(d,1H),4.24(d,1H),3.84–3.67(m,2H),3.60-3.58(m,2H),3.00-2.98(m,2H),1.65(d,6H),1.46(d,3H),1.24(s,1H).

[0372] Example 24

[0373] (S)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)2-fluorophenyl)morpholin-3-one (24)

[0374] Step 1: 4-(4-amino-2-fluorophenyl)morpholin-3-one (24a)

[0375] 3-Fluoro-4-iodoaniline (237 mg, 1.0 mmol) was dissolved in NMP (10 mL), and 1,4-oxazacyclohexan-3-one (101 mg, 1.0 mmol), cuprous iodide (38 mg, 0.2 mmol), potassium phosphate (454 mg, 2 mmol), and DMEDA (35 mg, 0.4 mmol) were added sequentially. The mixture was microwaved at 130°C under a nitrogen atmosphere for 2 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was separated by column chromatography to obtain compound 24a (200 mg, 95.2% yield).

[0376] MS (ESI) m / z = 211.1 [M+H] + .

[0377] Step 2: (S)-4-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)2-fluorophenyl)morpholin-3-one (24)

[0378] Compound 24a (21 mg, 0.1 mmol) was dissolved in 1,4-dioxane (1 mL), and compound A10 (40 mg, 0.1 mmol), cesium carbonate (65 mg, 0.2 mmol), and Xantphos Pd G3 (9 mg, 0.01 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered, and the residue was separated by C18 reverse-phase chromatography to obtain the desired product 24 (10 mg, 17.5% yield).

[0379] MS (ESI) m / z = 571.3 [M+H] + .

[0380] 1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.68(s,1H),7.92(dd,1H),7.49(dd,1H),7.35-7.33(m,1H),7.08(d,1H),5.8 3(s,1H),5.26(d,1H),4.51(d,1H),4.27(d,1H),4.21(s,2H),3.97(dd,2H),3.63(dd,2H),1.65(d,6H),1.48(d,3H).

[0381] Example 25

[0382] (S)-4-(2-chloro-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (25)

[0383] Using 3-chloro-4-iodoaniline as starting material, the target compound 25 was obtained according to a synthetic method similar to that of Example 24.

[0384] MS (ESI) m / z = 587.2 [M+H] + .

[0385] 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.69(s,1H),8.10(d,1H),7.71(dd,1H),7.36(d,1H),7.08(d,1H),5.83(s,1H),5 .26(d,1H),4.51(d,1H),4.27(d,1H),4.20(s,2H),3.97(dd,2H),3.60(dd,2H),1.68(s,3H),1.63(s,3H),1.48(d,3H).

[0386] Example 26

[0387] (S)-4-(3-Fluoro-4-((5-fluoro-4-(8-fluoro-2-(methoxymethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (26)

[0388] Step 1: (S)-6-Bromo-8-fluoro-2-(methoxymethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (26a)

[0389] Compound A7 (160 mg, 0.59 mmol) was added to tetrahydrofuran (5 mL). Under a nitrogen atmosphere, LDA (0.33 mL, 0.66 mmol, 2.0 M THF solution) was added at -78°C, stirred for 1 hour, and bromomethyl methyl ether (89 mg, 0.71 mmol) was added, and the reaction was allowed to proceed for 1 hour. Saturated ammonium chloride (50 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated, and the residue was isolated by column chromatography to obtain product 26a (100 mg, 53.7% yield).

[0390] MS (ESI) m / z = 315.2 [M+H] + .

[0391] Step 2: (S)-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-(methoxymethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (26b)

[0392] Compound 26a (117 mg, 0.37 mmol) was dissolved in 1,4-dioxane (3 mL). Diboronic acid pinacol ester (283 mg, 1.11 mmol), potassium acetate (109 mg, 1.11 mmol), and Pd(dppf)Cl2 (26 mg, 0.1 mmol) were added sequentially. The mixture was reacted at 110°C for 2 hours under a nitrogen atmosphere. 2,4-Dichloro-5-fluoropyrimidine (87 mg, 0.52 mmol), sodium carbonate (76.0 mg, 0.72 mmol), and Pd(dppf)Cl2 (26 mg, 0.1 mmol) were then added sequentially. The mixture was reacted at 110°C for 2 hours under a nitrogen atmosphere. The reaction solution was filtered and concentrated, and the residue was isolated by column chromatography to obtain product 26b (100 mg, 55.0% yield).

[0393] MS (ESI) m / z = 367.1 [M+H] + .

[0394] Step 3: (S)-4-(3-fluoro-4-((5-fluoro-4-(8-fluoro-2-(methoxymethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)morpholin-3-one (26)

[0395] Compound 26b (50.0 mg, 0.14 mmol) was dissolved in 1,4-dioxane (2 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (29.0 mg, 0.14 mmol), cesium carbonate (96.0 mg, 0.30 mmol), and XantPhos Pd G3 (5.0 mg, 0.005 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to obtain the product (20 mg, 27.1% yield).

[0396] MS (ESI) m / z = 541.3 [M+H] + .

[0397] 1 H NMR(400MHz,DMSO)δ9.36(s,1H),8.57(d,1H),7.80(t,1H),7.39(dd,1H),7.25–7.18(m,1H),7.15(d,1H),4.98-4.92(m, 1H),4.85–4.71(m,2H),4.52(dd,1H),4.31(dd,1H),4.21(s,2H),3.97(dd,2H),3.75(dd,2H),3.38(s,3H),1.46(d,3H).

[0398] Example 27

[0399] (S)-4-(3-Fluoro-4-((5-fluoro-4-(8-fluoro-2-isopropyl-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)morpholin-3-one (27)

[0400] Step 1: (S)-2-(8-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propan-2-ol (A9)

[0401] Compound A8 (328 mg, 1.0 mmol) was dissolved in dioxane (10 mL). Bis(pyraclostrobin) (635 mg, 2.50 mmol), potassium acetate (250 mg, 2.5 mmol), and Pd(dppf)Cl2 (65 mg, 0.05 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1 hour. The reaction mixture was used directly in the next step.

[0402] MS (ESI) m / z = 377.4 [M+H] + .

[0403] Step 2: (S)-8-Fluoro-3-methyl-2-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (27a)

[0404] Compound A9 (200 mg, 0.53 mmol) was added to tetrahydrofuran (5 mL), and Burgess reagent (138 mg, 0.58 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated, and the residue was separated by column chromatography to obtain compound 27a (248 mg, 130.0% yield).

[0405] MS (ESI) m / z = 359.2 [M+H] + .

[0406] Step 3: (S)-8-Fluoro-2-isopropyl-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (27b)

[0407] Compound 27a (248 mg, 0.69 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (24 mg) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography to obtain compound 27b (226 mg, 91.0% yield).

[0408] MS (ESI) m / z = 361.3 [M+H] + .

[0409] Step 4: (S)-6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-isopropyl-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (27c)

[0410] Compound 27b (226 mg, 0.63 mmol) was dissolved in 1,4-dioxane (8 mL) and water (0.05 mL). 2,4-Dichloro-5-fluoropyrimidine (110 mg, 0.66 mmol), sodium carbonate (134 mg, 1.26 mmol), and PdCl2(dppf) (21.0 mg, 0.03 mmol) were added sequentially. The mixture was reacted at 100°C under a nitrogen atmosphere for 5 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography to obtain compound 27c (120 mg, 52.4% yield).

[0411] MS (ESI) m / z = 365.2 [M+H] + .

[0412] Step 5: (S)-4-(3-fluoro-4-((5-fluoro-4-(8-fluoro-2-isopropyl-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)morpholin-3-one (27)

[0413] Compound 27c (120 mg, 0.33 mmol) was dissolved in 1,4-dioxane (4 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (69.0 mg, 0.33 mmol), cesium carbonate (214 mg, 0.66 mmol), and XantPhos Pd G3 (19.0 mg, 0.02 mmol) were added sequentially. The mixture was microwaved at 100°C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to afford compound 27 (70.0 mg, 39.5% yield).

[0414] MS (ESI) m / z = 539.3 [M+H] + .

[0415] 1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.54(d,1H),7.79(t,1H),7.38(dd,1H),7.23-7.21(m,1H),7.10(d,1H),5.00–4.90(m ,1H),4.55(dd,1H),4.28(dd,1H),4.21(s,2H),4.01–3.93(m,2H),3.78–3.71(m,2H),3.27-3.25(m,1H)1.44–1.33(m,9H).

[0416] Example 28

[0417] (S)-4-(3-Fluoro-4-((5-fluoro-4-(8-fluoro-2-(1-hydroxycyclobutyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)morpholin-3-one (28)

[0418] Step 1: (S)-1-(6-Bromo-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)cyclobutan-1-ol (28a)

[0419] Compound A7 (150 mg, 0.55 mmol) was added to tetrahydrofuran (6 mL). Under a nitrogen atmosphere, LDA (0.33 mL, 0.66 mmol, 2.0 M THF solution) was added at -78°C. After stirring for 1 hour, cyclobutanone (155 mg, 2.21 mmol) was added and the reaction was allowed to proceed for 1 hour. Saturated ammonium chloride (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated, and the residue was separated and purified by column chromatography to obtain compound 28a (135 mg, 71.1% yield).

[0420] MS (ESI) m / z = 341.1 [M+H] + .

[0421] Step 2: (S)-1-(8-Fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)cyclobutan-1-ol (28b)

[0422] Compound 28a (135 mg, 0.40 mmol) was dissolved in 1,4-dioxane (4 mL). Diboronic acid pinacol ester (305 mg, 1.20 mmol), potassium acetate (118 mg, 1.20 mmol), and PdCl2(dppf) (14.5 mg, 0.02 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1 hour. The reaction mixture was used directly in the next step.

[0423] MS (ESI) m / z = 389.3 [M+H] + .

[0424] Step 3: (S)-1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)cyclobutan-1-ol (28c)

[0425] The reaction mixture from step 2 was added sequentially with water (0.05 mL), 2,4-dichloro-5-fluoropyrimidine (67.0 mg, 0.40 mmol), sodium carbonate (42.0 mg, 0.40 mmol), and PdCl(dppf) (14.5 mg, 0.02 mmol). The mixture was reacted at 90°C under a nitrogen atmosphere for 18 hours. The reaction mixture was filtered and concentrated, and the residue was separated by column chromatography to obtain compound 28c (172 mg, 109.2% yield over two steps).

[0426] MS (ESI) m / z = 393.2 [M+H] + .

[0427] Step 4: (S)-4-(3-fluoro-4-((5-fluoro-4-(8-fluoro-2-(1-hydroxycyclobutyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)morpholin-3-one (28)

[0428] Compound 28c (66.0 mg, 0.17 mmol) was dissolved in 1,4-dioxane (3 mL), and 4-(4-amino-3-fluorophenyl)morpholin-3-one (1b) (37.0 mg, 0.18 mmol), cesium carbonate (110 mg, 0.34 mmol), and XantPhos Pd G3 (3.00 mg, 0.003 mmol) were added sequentially. The mixture was microwaved at 100°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to obtain compound 28 (22.0 mg, 23.3% yield).

[0429] MS (ESI) m / z = 567.2 [M+H] + .

[0430] 1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.55(d,1H),7.80(t,1H),7.38(dd,1H),7.23-7.19(m,1H),7.12(d,1H),6.39(s,1H),5.03(q,1H),4. 50(dd,1H),4.30–4.18(m,3H),4.01–3.90(m,2H),3.79–3.71(m,2H),2.78-2.74(m,2H),2.42-2.38(m,2H),1.8-1.84(m,2H),1.43(d,3H).

[0431] Example 29

[0432] (S)-2-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenylacetonitrile (29)

[0433] Using p-aminophenylacetonitrile as the starting material, the target compound 29 was synthesized in a similar manner to Example 1. MS (ESI) m / z = 511.2 [M+H] + .

[0434] Example 30

[0435] (S)-3-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)3-fluorophenyl)oxazolidin-2-one (30)

[0436] Step 1: 2-Chloroethyl (3-fluoro-4-nitrophenyl) carbamate (30a)

[0437] Add 3-fluoro-4-nitroaniline (1 g, 6.4 mmol) to anhydrous THF (10 mL). Add 2-chloroethyl methane (1 g, 7.6 mmol) and pyridine (0.6 mL, 7.6 mmol) under ice-cooling. React on ice-cooling for 1 hour. Pour the reaction mixture into water (50 mL), extract with dichloromethane (15 mL x 3), concentrate, and use directly in the next step.

[0438] Step 2: 3-(3-Fluoro-4-nitrophenyl)oxazolidin-2-one (30b)

[0439] Compound 30a (1.68 g, 6.4 mmol) was added to acetonitrile (20 mL), followed by potassium carbonate (1.3 g, 9.6 mmol) and reacted at 80°C for 2 hours. The mixture was filtered, concentrated, and poured into water (5 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried, filtered, slurried, and filtered to afford compound 30b (1.1 g, 87.6% yield).

[0440] The remaining steps were carried out according to a similar synthetic method as in Example 7, using compound 30b instead of compound 7b to obtain the target compound 30.

[0441] MS (ESI) m / z = 557.2 [M+H] + .

[0442] Example 31

[0443] (S)-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropyl-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)(4-ethylpiperazin-1-yl)methanone (31)

[0444] Step 1: (4-Bromo-3-fluorophenyl)(4-ethylpiperazin-1-yl)methanone (31a)

[0445] 4-Bromo-3-fluorobenzoic acid (220 mg, 1.0 mmol) was added to DMF (10 mL), followed by the addition of 1-ethylpiperazine (115 mg, 1.0 mmol), TBTU (321 mg, 1.0 mmol), and DIEA (258 mg, 2.0 mmol) at room temperature. The mixture was reacted under a nitrogen atmosphere at room temperature for 2 hours. The reaction solution was poured into water (5 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and concentrated, and the residue was separated by column chromatography to obtain the product, Compound 31a (250 mg, 79.3% yield).

[0446] MS (ESI) m / z = 315.3 [M+H] + .

[0447] Step 2: (S)-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)(4-ethylpiperazin-1-yl)methanone (31)

[0448] Using compound 31a as raw material, the target compound 31 was obtained according to the synthesis method of Example 9.

[0449] MS (ESI) m / z = 612.4 [M+H] + .

[0450] Example 32

[0451] (S)-(4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)(4-ethylpiperazin-1-yl)methanone (32)

[0452] According to the similar synthesis method of Example 31, 4-bromo-2-fluorobenzoic acid was used instead of 4-bromo-3-fluorobenzoic acid to obtain the target compound 32.

[0453] MS (ESI) m / z = 612.4 [M+H] + .

[0454] Example 33

[0455] 4-(4-((5-chloro-4-((3S)-8-fluoro-2-(1-methoxyethyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-3-fluorophenyl)morpholin-3-one (33)

[0456] According to the similar synthesis method of Example 22, 2,4,5-trichloropyrimidine was used instead of 2,4-dichloro-5-fluoropyrimidine to obtain the target compound 33.

[0457] MS (ESI) m / z = 571.3 [M+H] + .

[0458] Example 34

[0459] 1-(4-((5-chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)-3-(dimethylamino)pyrrolidin-2-one (34)

[0460] Step 1: tert-Butyl (1-((4-bromo-3-fluorophenyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (34b)

[0461] Compound 34a (500 mg, 2.005 mmol), 4-bromo-3-fluoroaniline (381.04 mg, 2.005 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1143.76 mg, 3.008 mmol), and N,N-diisopropylethylamine (0.994 mL, 6.016 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was poured into saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 34b (400 mg, 29.8% yield) as a brown oil.

[0462] MS (ESI) m / z = 421.2 [M+H] + .

[0463] Step 2: tert-Butyl (1-(4-bromo-3-fluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (34c)

[0464] Compound 34b (100 mg, 0.237 mmol) was dissolved in iodomethane (5 mL) at room temperature and allowed to react overnight under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (10 mL). The system was cooled to 0°C under a nitrogen atmosphere, and lithium bistrimethylsilylamide (0.237 mL, 0.237 mmol) was slowly added dropwise to the reaction system. The mixture was allowed to return to room temperature until the reaction was complete. The reaction solution was poured into saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 34c (50 mg, 56.4% yield).

[0465] MS (ESI) m / z = 373.1 [M+H] + .

[0466] Step 3: 3-Amino-1-(4-bromo-3-fluorophenyl)pyrrolidin-2-one (34d)

[0467] Compound 34c (50 mg, 0.134 mmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4N THF, 5 mL) at room temperature for 2 hours. The reaction solution was then concentrated under reduced pressure to afford crude product 34d (50 mg, 120.56% yield).

[0468] MS (ESI) m / z = 273.1 [M+H] + .

[0469] Step 4: 1-(4-Bromo-3-fluorophenyl)-3-(dimethylamino)pyrrolidin-2-one (34e)

[0470] Compound 34d (50 mg, 0.183 mmol), formaldehyde (16.49 mg, 0.549 mmol), and acetic acid (0.052 mL, 0.915 mmol) were dissolved in methanol (5 mL) at room temperature and stirred for 30 minutes. Sodium cyanoborohydride (23.01 mg, 0.366 mmol) was then added and stirred for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 34e (25 mg, 45.3% yield).

[0471] MS (ESI) m / z = 301.1 [M+H] + .

[0472] Step 5: 1-(4-((5-chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)-3-(dimethylamino)pyrrolidin-2-one (34)

[0473] Compound 34e (25 mg, 0.066 mmol), A10 (20 mg, 0.066 mmol), cesium carbonate (54.09 mg, 0.166 mmol), and Brettphos Pd G3 (1.50 mg, 0.002 mmol) were dissolved in 1,4-dioxane (3 mL) at room temperature and reacted in a microwave oven at 100°C for 1 hour under a nitrogen atmosphere. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography to afford the target compound 34 (2.38 mg, 6.0% yield).

[0474] MS (ESI) m / z = 598.3 [M+H] + .

[0475] Example 35

[0476] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)2-fluorophenyl)((S)-3-(dimethylamino)pyrrolidin-1-yl)methanone (35)

[0477] Step 1: (S)-(4-amino-2-fluorophenyl)(3-(dimethylamino)pyrrolidin-1-yl)methanone (35a)

[0478] 4-Bromo-2-fluorobenzoic acid (100 mg, 0.46 mmol) was added to DMF (4 mL), followed by the addition of (3S)-3-(dimethylamino)tetrahydropyrrole (63.0 mg, 0.55 mmol), TBTU (220 mg, 0.68 mmol), and DIEA (118 mg, 0.91 mmol) at room temperature. The mixture was reacted under a nitrogen atmosphere at room temperature for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (10 mL x 2), and concentrated. The residue was isolated by column chromatography to afford product 35a (91 mg, 63.0% yield).

[0479] MS (ESI) m / z = 252.2 [M+H] + .

[0480] Step 2: (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)2-fluorophenyl)((S)-3-(dimethylamino)pyrrolidin-1-yl)methanone (35)

[0481] Compound 35a (45 mg, 0.14 mmol) was added to dioxane (2.5 mL). Compound A10 (53 mg, 0.14 mmol), cesium carbonate (91 g, 0.28 mmol), and XantPhos Pd G3 (9 mg, 0.01 mmol) were added at room temperature. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated, and the residue was purified by C18 reverse-phase chromatography to afford compound 35 (38.0 mg, 44.1% yield).

[0482] MS (ESI) m / z = 612.2 [M+H] + .

[0483] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.71(d,1H),7.94-7.90(m,1H),7.53- 7.51(m,1H),7.36-7.34(m,1H),7.09(dd,1H),5.83(s,1H),5.26(q,1H),4.5 1(d,1H),4.28(dd,1H),3.74–3.55(m,2H),3.43-3.41(m,2H),3.21–3.06(m, 1H),2.77–2.59(m,2H),2.17(s,3H),2.07(s,3H),1.66(d,6H),1.48(d,3H).

[0484] According to the method of Example 35, the following compounds of Examples 36-42 were synthesized.

[0485] Example 36

[0486] (2-Chloro-4-((5-chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)((S)-3-(dimethylamino)pyrrolidin-1-yl)methanone (36)

[0487] MS (ESI) m / z = 628.3 [M+H] + .

[0488] 1 H NMR(400MHz,DMSO)δ10.31(s,1H),8.70(d,1H),8.06(dd,1H),7.74-7.70(m,1H) ,7.30(dd,1H),7.08(dd,1H),5.83(s,1H),5.26(q,1H),4.55–4.48(m,1H),4.27( dd,1H),3.78–3.58(m,2H),3.32–3.10(m,2H),2.99(dd,1H),2.72(dd,1H),2.17 (s,3H),2.07(s,3H),1.80–1.65(m,1H),1.68(s,3H),1.63(s,3H),1.48(d,,3H).

[0489] Example 37

[0490] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-6-yl)pyrimidin-2-yl)amino)-2-fluorophenyl)((R)-3-(dimethylamino)pyrrolidin-1-yl)methanone (37)

[0491] MS (ESI) m / z = 612.4 [M+H] + .

[0492] 1 H NMR(400MHz,DMSO)δ10.38(s,1H),8.71(d,1H),7.94-7.90(m,1H),7.53-7.49(m,1H),7 .36-7.32(m,1H),7.09(dd,1H),5.80(s,1H),5.28-5.24(m,1H),4.55–4.47(m,1H),4.32 –4.24(m,1H),3.74–3.55(m,2H),3.46–3.27(m,2H),3.21–3.06(m,1H),2.77–2.60(m,1 H),2.17(s,3H),2.07(s,3H),1.80–1.64(m,1H),1.68(s,3H),1.63(s,3H),1.48(d,3H).

[0493] Example 38

[0494] (2-Chloro-4-((5-chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)phenyl)((R)-3-(dimethylamino)pyrrolidin-1-yl)methanone (38)

[0495] MS (ESI) m / z = 628.3 [M+H] + .

[0496] 1 H NMR(400MHz,DMSO)δ10.31(s,1H),8.70(d,1H),8.06(dd,,1H),7.74-7.70(m, 1H),7.30(dd,1H),7.08(dd,1H),5.83(s,1H),5.26(q,1H),4.52(d,1H),4.27 (d,1H),3.73-3.63(m,2H),3.32–3.10(m,2H),2.99(dd,1H),2.72(dd,1H),2.17(s,3 H), 2.07 (s, 3H), 1.78–1.65 (m, 1H), 1.68 (s, 3H), 1.63 (s, 3H), 1.48 (d, J = 6.6Hz, 3H).

[0497] Example 39

[0498] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)((S)-3-(dimethylamino)pyrrolidin-1-yl)methanone (39)

[0499] MS (ESI) m / z = 612.4 [M+H] + .

[0500] Example 40

[0501] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)((S)-3-(dimethylamino)pyrrolidin-1-yl)methanone (40)

[0502] MS (ESI) m / z = 594.4 [M+H] + .

[0503] Example 41

[0504] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)-3-fluorophenyl)((R)-3-(dimethylamino)pyrrolidin-1-yl)methanone (41)

[0505] MS (ESI) m / z = 612.4 [M+H] + .

[0506] Example 42

[0507] (4-((5-Chloro-4-((S)-8-fluoro-2-(2-hydroxypropan-2-yl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-yl)amino)phenyl)((R)-3-(dimethylamino)pyrrolidin-1-yl)methanone (42)

[0508] MS (ESI) m / z = 594.4 [M+H] + .

[0509] Example 43

[0510] (S)-2-(6-(5-chloro-2-((2-fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)pyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthen-2-yl)propanol (43)

[0511] Step 1: 1-((3-Fluoro-4-nitrophenyl)sulfonyl)-4-methylpiperazine (43a)

[0512] Under a nitrogen atmosphere, 3-fluoro-4-nitrobenzenesulfonyl chloride (230 mg, 1.0 mmol) was dissolved in anhydrous dichloromethane (10 mL), and 4-methylpiperazine (150 mg, 1.5 mmol) was added. The mixture was allowed to react at room temperature for 1.5 hours. The reaction solution was concentrated, and the residue was separated by column chromatography to obtain compound 43a (130 mg, 42.8% yield).

[0513] MS (ESI) m / z = 304.2 [M+H] + .

[0514] Step 2: 2-Fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)aniline (43b)

[0515] Compound 43a (150 mg, 0.5 mmol) was dissolved in ethanol:water (4 mL:1 mL) at room temperature, and ammonium chloride (53 mg, 1.0 mmol) was added. The temperature was raised to 60°C, and iron powder (280 mg, 5 mmol) was added and allowed to react for 2 hours. After completion of the reaction, the mixture was filtered through celite while hot, and the filtrate was concentrated. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined and concentrated to afford compound 43b (70 mg, 51.1% yield).

[0516] MS (ESI) m / z = 274.2 [M+H] + .

[0517] Step 3: (S)-2-(6-(5-chloro-2-((2-fluoro-4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)pyrimidin-4-yl)-8-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)propanol (43)

[0518] Compound 43b (55 mg, 0.2 mmol) was dissolved in 1,4-dioxane (3 mL), and compound A10 (80 mg, 0.2 mmol), cesium carbonate (130 mg, 0.4 mmol), and Xantphos Pd G3 (18 mg, 0.02 mmol) were added sequentially. The mixture was microwaved at 110°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered and concentrated under reduced pressure. Hydrochloric acid (2N EA solution) was added directly, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was isolated by C18 reverse-phase chromatography to afford the desired product 43 (20 mg, 15.9% yield).

[0519] MS (ESI) m / z = 634.3 [M+H] + .

[0520] Example 44

[0521] (S)-4-(4-((5-chloro-4-(8-fluoro-2-(1-hydroxycyclopentyl)-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-6-yl)pyrimidin-2-amino)-3-fluorophenyl)morpholin-3-one (44)

[0522] Referring to Example 28, the target compound 44 was obtained using A7 and cyclopentanone as raw materials.

[0523] MS (ESI) m / z = 597.3 [M+H] + .

[0524] Biological tests

[0525] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0526] Test Example 1: Inhibitory activity test of the disclosed compounds on ovarian cancer cells (OVCAR3)

[0527] Table 1. Experimental materials and instruments

[0528] 1) Experimental steps

[0529] Ovarian cancer cells OVCAR3 were cultured in RPMI 1640 medium with 10% FBS in a cell culture incubator at 37% and 5% CO2. On the first day, cells were plated in 384-well plates at a cell density of 800 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10 μM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.1%. After the cells were cultured in the incubator for 7 days, cell viability was tested using CTG Cell Viability Detection Reagent (MCE). The test method was consistent with the operating method provided by the kit. GraphPad Prism 8 was used to process the data and calculate the IC 50 .

[0530] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0531] X: logarithmic value of compound concentration; Y: inhibition %.

[0532] Table 2. IC of the compounds disclosed herein against OVCAR3 50 (nM)

[0533] Test Example 2: Inhibitory activity test of the disclosed compounds on triple-negative breast cancer cells (HCC1806)

[0534] 1) Experimental materials and instruments

[0535] Table 3. Experimental materials and instruments

[0536] 2) Experimental steps

[0537] Triple-negative breast cancer cells HCC1806 (Nanjing Kebai Biotechnology Co., Ltd.) were cultured in a cell culture incubator at 37°C and 5% CO2 using RPMI 1640 medium with 10% FBS. On the first day, cells were plated in 384-well plates at a cell density of 200 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10 μM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.2%. After the cells were cultured in the incubator for 7 days, CTG Cell Viability Detection Reagent (MCE) was used to test cell viability. The test method was consistent with the operating method provided by the kit. XLfit was used to process the data and calculate the IC 50 .

[0538] Calculation formula Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0539] X: logarithmic value of compound concentration; Y: inhibition %.

[0540] Table 4. IC values ​​of the disclosed compounds against HCC1806 50 (nM)

[0541] Note: PF-07220060 (WO2019207463AExample A94) and PF-07104091 (WO2020157652AExample 13) are Pfizer's clinically selective CDK4 inhibitor and CDK2 inhibitor, respectively.

[0542] In the experiment of this cell line, Example 1 has better inhibitory activity than the clinical molecular CDK4 inhibitor PF-07220060 and the CDK2 inhibitor PF-07104091.

[0543] Test Example 3: Activity Detection of the Disclosed Compounds on Cyclin-Dependent Kinases (CDK2 / CycE1, CDK4 / CycD1)

[0544] 1) Experimental materials and instruments

[0545] Table 5. Experimental materials and instruments

[0546] 2) Experimental steps

[0547] Using an Echo 650, add the test compound to a maximum concentration of 1 μM and perform a three-fold serial dilution for a total of nine concentration points. Seal the assay plate and centrifuge it at 1000 g for 1 minute. Prepare 2.5× enzyme in 1× kinase buffer (50 mM HEPES, pH 7.5, 0.0015% Brij-35, 1 M DTT). Add 10 μl of 2.5× enzyme to a 384-well assay plate. Centrifuge the plate at 1000 g for 30 seconds and let it sit at room temperature for 10 minutes. Prepare a 2.5× substrate and ATP mix in 1× kinase buffer and initiate the reaction by adding 10 μl of the 2.5× substrate and ATP mix. Centrifuge the plate at 1000 g for 30 seconds, seal the plate, and let it react at room temperature for 1 hour. Add 25 μl of stop solution reagent (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA).

[0548] Read the conversion rate data on the CaliperEZ Reader. Copy the conversion rate data from the CaliperEZ Reader. Convert the conversion rate to inhibition rate data.

[0549] Inhibition % = (max-conversion) / (max-min)*100, where “min” refers to the reading of the control wells in which no enzyme was added for reaction; and “max” refers to the reading of the control wells in which DMSO was added.

[0550] IC fitting using XLFit Excel add-in version 5.4.0.8 50 value,

[0551] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope).

[0552] Table 6. IC values ​​of the compounds disclosed herein for CDK2 / CycE1 and CDK4 / CycD1 50 value

[0553] Note: Example 1 of the patent was synthesized according to CN116217588A as Comparative Example 1 of this application.

[0554] Compound 1 exhibits good inhibitory activity against CDK4 / CycD1 and CDK2 / CycE1. Compared with Comparative Example 1, Example 1 has stronger inhibitory activity against CDK2 / CycE1, thus potentially alleviating the problem of drug resistance to some CDK4 / 6 inhibitors. Example 1 may also have a wider range of indications.

[0555] Test Example 4. Inhibitory activity test of the disclosed compounds on human breast cancer cells (MDA-MB-231)

[0556] Table 7. Experimental materials and instruments

[0557] Experimental procedures

[0558] Human breast cancer cells MDA-MB-231 were cultured in a cell culture incubator at 37°C and 5% CO2 using DMEM medium containing 10% FBS. On the first day, cells were plated in 384-well plates at a cell density of 600 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10uM, with 3-fold dilution and 9 concentrations, and the final concentration of DMSO was 0.2%. After the cells were cultured in the incubator for 7 days, cell viability was tested using CTG Cell Viability Detection Reagent. The test method was consistent with the operating method provided by the kit. XLFit was used to process the data and calculate the IC 50 .

[0559] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0560] X: logarithmic value of compound concentration; Y: % inhibition.

[0561] Table 8. IC values ​​of compounds of the present disclosure against MDA-MB-231 50 (nM)

[0562] In the experiment of this cell line, Example 1 has better inhibitory activity than the clinical molecular CDK4 inhibitor PF-07220060 and the CDK2 inhibitor PF-07104091.

[0563] Test Example 5. Inhibitory activity test of the disclosed compounds on human non-small cell lung cancer cells (A549)

[0564] Table 9. Experimental materials and instruments

[0565] Experimental procedures

[0566] Human non-small cell lung cancer cells A549 were cultured in a cell culture incubator at 37°C and 5% CO2 using F12K medium containing 10% FBS. On the first day, cells were plated in 384-well plates at a cell density of 300 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10uM, with 3-fold dilution and 9 concentrations, and the final concentration of DMSO was 0.2%. After the cells were cultured in the incubator for 5 days, cell viability was tested using CTG Cell Viability Detection Reagent. The test method was consistent with the operating method provided by the kit. XLFit was used to process the data and calculate the IC 50 .

[0567] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0568] X: logarithmic value of compound concentration; Y: % inhibition.

[0569] Table 10. IC values ​​of compounds of the present disclosure against A549 50 (nM)

[0570] In the experiment of this cell line, Example 1 has better inhibitory activity than the clinical molecular CDK4 inhibitor PF-07220060 and the CDK2 inhibitor PF-07104091.

[0571] Test Example 6. Inhibitory activity test of the disclosed compounds on human prostate cancer cells (22RV1)

[0572] Table 11. Experimental materials and instruments

[0573] Experimental procedures

[0574] Human prostate cancer cells 22RV1 were cultured in RPMI 1640 medium with 10% FBS at 37°C in a cell culture incubator with 5% CO2. On the first day, cells were plated in 384-well plates at a density of 500 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10uM, with 3-fold dilution and 9 concentrations. The final concentration of DMSO was 0.2%. After the cells were cultured in the incubator for 5 days, cell viability was tested using CTG Cell Viability Detection Reagent. The test method was consistent with the operating method provided by the kit. XLFit was used to process the data and calculate the IC 50 .

[0575] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0576] X: logarithmic value of compound concentration; Y: % inhibition.

[0577] Table 12. IC values ​​of compounds of the present disclosure against 22RV1 50 (nM)

[0578] In the experiment of this cell line, Example 1 has better inhibitory activity than the clinical molecular CDK2 inhibitor PF-07104091.

[0579] Test Example 7. Inhibitory activity test of the disclosed compounds on human breast cancer cells (SUM-149PT)

[0580] Table 13. Experimental materials and instruments

[0581] Experimental procedures

[0582] Human breast cancer cells SUM-149PT were cultured in a cell culture incubator at 37°C and 5% CO2 using DMEM medium containing 10% FBS. On the first day, cells were plated in 384-well plates at a cell density of 800 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10uM, with 3-fold dilution and 9 concentrations, and the final concentration of DMSO was 0.2%. After the cells were cultured in the incubator for 5 days, cell viability was tested using CTG Cell Viability Detection Reagent. The test method was consistent with the operating method provided by the kit. XLFit was used to process the data and calculate the IC 50 .

[0583] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0584] X: logarithmic value of compound concentration; Y: % inhibition.

[0585] Table 14. IC values ​​of compounds of the present disclosure against SUM-149PT 50 (nM)

[0586] In the experiment of this cell line, Example 1 has better inhibitory activity than the clinical molecular CDK2 inhibitor PF-07104091.

[0587] Test Example 8. Inhibitory activity test of the disclosed compounds on CDK4 / 6 inhibitor-resistant human breast cancer cells (MCF-7-palbociclib-resistant cell line)

[0588] 1) Experimental materials and instruments

[0589] Table 15. Experimental materials and instruments

[0590] 2) Experimental steps

[0591] MCF-7 / Palbo-R cell source: MCF7 cells (Nanjing Kebai Biotechnology Co., Ltd.) were treated with 1 μM palbociclib for a long time and induced to resist drug.

[0592] Palbociclib-resistant breast cancer cell line MCF-7 / Palbo-R was cultured in DMEM with 10% FBS in a 37% CO2 cell culture incubator. On the first day, cells were plated in 384-well plates at a cell density of 800 cells / well and cultured overnight in the incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10uM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.2%. After the cells were cultured in the incubator for 5 days, the cell viability was tested using the CellTiter-Glo luminescent cell activity detection kit. The test method was consistent with the operating method provided by the kit. XLfit was used to process the data and calculate the IC 50 .

[0593] The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 - (RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control)) * 100%.

[0594] Table 16. IC values ​​of the compounds of the present disclosure against MCF-7 / Palbo-R 50 (nM)

[0595] In the experiment of this cell line, the molecule of Example 1 has better inhibitory activity than the clinical molecule CDK4 inhibitor PF-07220060 and the CDK2 inhibitor PF-07104091.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, in, R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl and 3-12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3-8 membered cycloalkyl and 3-12 membered heterocycloalkyl are optionally substituted with one or more R 21 replace; Each R 21 are independently selected from deuterium, halogen, hydroxyl, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxy, halogen, deuterium; R3 and R4 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl are optionally substituted with one or more R 31 replace; Each R 31 are independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxyl and halogen; Y is selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogen substituted C 1-6 alkyl; X is selected from hydrogen, halogen, cyano, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R a replace; Each R a are independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxyl and halogen; L1 is selected from -CO- or a bond; R1 is selected from C 1-6 Alkyl, heterocycloalkyl, heteroaryl, -CO-NH-R 11 、-S(O)2-NH-R 12 , The C 1-6 Alkyl, heterocycloalkyl, heteroaryl, -CO-NH-R 11 、-S(O)2-NH-R 12 , Optionally one or more R b replace; R 11 , R 12 , R 13 , R 14 Each independently selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkane base; Each R b Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogen, hydroxy, cyano, oxo, -N(R c )2; Each R c are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; or two R c The N atom to which it is attached forms a 3-6 membered heterocycloalkyl group, wherein the 3-6 membered heterocycloalkyl group is optionally substituted by one or more halogens; Each R5 is independently selected from hydroxy, cyano, halogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-12 membered heterocycloalkyl are optionally substituted with one or more R 51 replace; Each R 51 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 Alkoxy, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl are optionally substituted by one or more substituents selected from hydroxyl and halogen; n is selected from 0, 1, 2, 3, 4.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein L1 is a bond.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein L1 is -CO-.

4. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R1 is selected from b substituted 5-7 membered heterocycloalkyl; preferably R1 is selected from optionally substituted with one or more R b substituted 6-membered heterocycloalkyl; more preferably R1 is selected from b Replaced Where R b As defined in claim 1.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R1 is selected from C 1-6 Alkyl, 5-6 membered heteroaryl, -CO-NH-R 11 、-S(O)2-NH-R 12 , The C 1-6 Alkyl, 5-6 membered heteroaryl, -CO-NH-R 11 、-S(O)2-NH-R 12 , Optionally one or more R b replace; R 11 , R 12 , R 13 , R 14 Each independently selected from C 1-6 Alkyl, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; preferably R 11 , R 12 , R 13 , R 14 Each independently selected from C 1-6 alkyl; Where R b As defined in claim 1.

6. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R b Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogen, hydroxy, cyano, oxo.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula II or a pharmaceutically acceptable salt thereof, in, R2, R3, R4, R5, X, Y, L1, and n are as defined in claim 1.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R2 is selected from hydrogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl optionally with one or more R 21 replace; Each R 21 are each independently selected from deuterium, halogen, hydroxyl, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 The alkoxy group, the 3-7 membered cycloalkyl group, and the 3-7 membered heterocycloalkyl group are optionally substituted by one or more substituents selected from hydroxy, halogen, and deuterium.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R3 and R4 are each independently selected from hydrogen, cyano, halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R 31 replace; Each R 31 Each independently selected from halogen, hydroxyl, amino, C 1-3 Alkoxy, the C 1-3 The alkoxy group is optionally substituted with one or more substituents selected from hydroxy, halogen.

10. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein Y is selected from halogen; preferably Y is selected from fluorine.

11. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein X is selected from hydrogen, halogen, cyano; preferably X is selected from fluorine or chlorine.

12. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein each R5 is independently selected from hydroxyl, cyano, halogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, 3-8 membered cycloalkyl, C 1-6 Alkoxy and 3-6 membered heterocycloalkyl are optionally substituted with one or more R 51 replace; Each R 51 Independently selected from halogen, hydroxy, amino, C 1-3 Alkoxy, 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, the C 1-3 The alkoxy group, the 3-7 membered cycloalkyl group, and the 3-7 membered heterocycloalkyl group are optionally substituted by one or more substituents selected from hydroxyl group and halogen group.

13. A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

14. An isotope substitution of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, preferably, the isotope substitution is a deuterium atom substitution.

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or an isotope-substituted compound according to claim 14, and a pharmaceutically acceptable excipient.

16. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 14, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating or preventing a disease or condition associated with abnormal activity of serine / threonine kinase.

17. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 14, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating or preventing a disease or condition associated with abnormal activity of CDK2.

18. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 14, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating or preventing a disease or disorder associated with abnormal activity of CDK4.

19. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to claim 14, or a pharmaceutical composition according to claim 15 in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease; preferably, the disease or condition is a proliferative disease; most preferably, the proliferative disease is selected from breast cancer (e.g., triple-negative breast cancer or ER-negative, PR-negative and Her2-positive breast cancer or CDK4 / 6 inhibitor-resistant breast cancer), colon cancer, lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer, liver cancer.

20. A method for preparing a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or an isotope-substituted product according to claim 14, comprising the step of reacting a compound represented by formula A with a compound represented by formula B, in, R1, R2, R3, R4, R5, X, Y, L1, n are as defined in claims 1-13; wherein LG is selected from a leaving group; preferably, the LG is selected from a halogen, a sulfonate, and a borate.

21. A compound represented by formula B or a pharmaceutically acceptable salt thereof, Wherein R2, R3, R4, X, and Y are as defined in claims 1-13; Wherein LG is selected from a leaving group, preferably, the LG is selected from a halogen, a sulfonate and a borate.

22. A compound represented by formula A or a pharmaceutically acceptable salt thereof, Wherein R1, R5, L1 and n are as defined in claims 1-13.