CN114539225B

CN114539225B - 2-amino-pyrimidines

Info

Publication number: CN114539225B
Application number: CN202111324005.6A
Authority: CN
Inventors: 邹昊; 龚红龙; 刘浩淼; 张超; 祝伟; 李正涛
Original assignee: Shanghai Tuojie Biomedical Technology Co ltd
Current assignee: Shanghai Tuojie Biomedical Technology Co ltd
Priority date: 2020-11-11
Filing date: 2021-11-10
Publication date: 2024-02-20
Anticipated expiration: 2041-11-10
Also published as: CN114539225A

Abstract

The present disclosure relates to 2-amino-pyrimidines. In particular, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein each letter is as defined herein. The compounds of formula I are useful as cyclin-dependent kinase inhibitors for the prophylaxis and/or treatment of diseases which are associated therewith, such as cell proliferative diseases, cancer or immunological diseases.

Description

2-amino-pyrimidines

Technical Field

The disclosure belongs to the field of medicines and relates to a 2-amino-pyrimidine compound.

Background

Cyclin-dependent kinases (CDKs) are members of the serine/threonine kinase subfamily, each CDK/cyclin complex being responsible for the transition or progression at a specific stage within the cell cycle, which plays an important role in regulating eukaryotic cell division and proliferation. Cyclin-dependent kinase catalytic units are known as cyclin-mediated subunit activation. At least 16 mammalian cyclin have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B/CDK1, cyclin a/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important mediators of cell cycle progression. Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation, and apoptosis (Annu.Rev.cell.Dev.biol. (1997) 13:261-291).

In recent years, the greatest progress in the field of breast cancer treatment has undoubtedly been the use of CDK4/6 alone or in combination with endocrine therapy in the treatment of hormone receptor positive advanced breast cancers such as palbociclib, ribociclib and bomaciclib in combination with aromatase inhibitors has been approved for the treatment of Hormone Receptor (HR) -positive, human epidermal growth factor receptor 2 (HER 2) -negative advanced or metastatic breast cancer in postmenopausal women, and palbociclib and bomaciclib (abemaciclib) have been approved in combination with fulvestrant for the treatment of Hormone Receptor (HR) -positive, human epidermal growth factor receptor 2 (HER 2) -negative advanced or metastatic breast cancer (Nature Reviews 13:417-430, J Clin Oncol 2017,35,2875-2884) in postmenopausal women after disease progression following endocrine therapy. Although CDK4/6 inhibitors show significant clinical efficacy in estrogen receptor ER positive metastatic breast cancer, as with other kinases, their effect may be limited over time by the development of primary or acquired resistance.

Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. Cyclin E/CDK2 complexes play an important role in regulating G1/S conversion, histone biosynthesis and centrosome replication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and facilitates S phase entry. Activation of cyclin a/CDK2 during early S-phase promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F to complete S-phase. (Nat. Rev. Drug. Discov.2015;14 (2): 130-146).

Studies have shown that inhibition of CDK2 kinase induces tumor cell apoptosis, but causes less damage to normal cells. The monomeric form of CDK kinase is inactive, whereas cyclin A/E binds to CDK2 and promotes phosphorylated binding to activate CDK2.CDK2 may also bind cyclin a for overall progression through S phase and participate in DNA repair. In recent years, various companies respectively identify and discover a series of inhibitors for selectively inhibiting CDK2, which are used for treating diseases such as cancers, such as Seliciclib, dinaciclib, but in order to achieve better cancer treatment effect, market demands are better met, and new generation of high-efficiency low-toxicity selective CDK2 inhibitors still need to be developed.

Disclosure of Invention

The present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein X is ₁ 、X ₂ 、X ₃ 、X ₄ Each independently selected from optionally substituted or unsubstituted C, N, and not both are C; optionally substituted C, N includes substitution of at least one hydrogen on a carbon or nitrogen atom with any permissible substituents to form stable compounds. Exemplary substitutions include, but are not limited to, deuterium, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g., C) _1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C _1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C _3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-to 12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene, 5-to 6-membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO ₂ R'、SO ₂ NR '(R "), COR', COOR ', or CONR' (R"), said alkyl groupOptionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR '(R "), COR', COOR ', or CONR' (R"), optional substituents also include spiro or fused ring substitutions.

B is a 3-20 membered ring, including monocyclic, fused, bridged, spiro ring, provided that:

when B is a six-membered monocyclic ring, ring A is not optionally substituted or unsubstituted Exemplary rings include, but are not limited to, 3-to 20-membered carbocycles, heterocycles, optionally substituted with a member selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR ' (R "), COR ', COOR ', or CONR ' (R ') are substituted.

Wherein Y is selected from CR ⁵ -NR ⁶ R ⁷ 、*NR ⁷ ；

Each R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ Independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, amino, alkyl (e.g. C) _1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C _1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C _3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-to 12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene, 5-to 6-membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO ₂ R'、SO ₂ NR ' (R "), NR ' (R), COOR ' or CONR ' (R '), wherein the amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with Z, cycloalkyl optionally substituted with Z, heterocyclyl optionally substituted with Z, alkoxy optionally substituted with Z, alkenyl optionally substituted with Z, alkynyl optionally substituted with Z, aryl optionally substituted with Z, heteroaryl optionally substituted with Z, SR ', SOR ', SO ₂ R'、SO ₂ NR ' (R "), COR ', COOR ', or CONR ' (R ');

R ¹ 、R ² are not hydrogen at the same time;

each R ⁷ Are independently selected from the group consisting of-SR ', -SOR', -SO ₂ R'、-SO ₂ NR'(R”)；

Each R ', R' is independently selected from hydrogen, deuterium, hydroxy, alkyl (e.g., C) _1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C _1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), amino, imino, cycloalkyl (e.g., C _3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-to 12-membered aryl, including but not limited to phenyl, naphthyl), or heteroaryl (e.g., 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene ring, 5-to 7-membered heterocyclobenzene 5-to 6-membered heteroaryl ring, including but not limited to pyridine, piperidine), said amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally being substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with Z, alkoxy optionally substituted with Z, cycloalkyl optionally substituted with Z, heterocyclyl optionally substituted with Z, aryl optionally substituted with Z, heteroaryl optionally substituted with Z;

Z is selected from halogen (e.g. fluorine, chlorine, bromine), hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl5-12 membered heteroaryl, SR ⁸ 、SOR ⁸ 、SO ₂ R ⁸ 、SO ₂ NR ⁸ (R ⁹ )、NR ⁸ (R ⁹ )、COR ⁸ 、COOR ⁸ Or CONR ⁸ (R ⁹ ) The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ⁸ 、SOR ⁸ 、SO ₂ R ⁸ 、SO ₂ NR ⁸ (R ⁹ )、NR ⁸ (R ⁹ )、COR ⁸ 、COOR ⁸ Or CONR ⁸ (R ⁹ )；

Each R ⁸ Or R is ⁹ Independently selected from hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl.

m and n are respectively and independently selected from 0, 1, 2 and 3;

wherein represents a linking site, and the dotted line is selected from a single bond and a double bond.

In some embodiments, heterocyclyl groups in the present disclosure may be 3-12 membered heterocyclyl, 3-5 membered heterocyclyl, 5-7 membered heterocyclyl, 9-12 membered heterocyclyl, 6-10 membered heterocyclyl, and the heterocyclyl groups contain 1-4 heteroatoms independently selected from N, O or S, or contain 2-3 heteroatoms independently selected from N, O or S.

In some embodiments, cycloalkyl groups in the present disclosure may be C _3-7 Cycloalkyl, C _5-7 Cycloalkyl, C _6-7 Cycloalkyl groups.

In some embodiments, aryl groups in the present disclosure may be 5-12 membered aryl, 5-7 membered aryl, 6-10 membered aryl, 9-12 membered aryl, 6-8 membered aryl.

In some embodiments, heteroaryl groups in the present disclosure may be 3-12 membered heteroaryl, 3-5 membered heteroaryl, 5-7 membered heteroaryl, 9-12 membered heteroaryl, 6-10 membered heteroaryl, and the heteroaryl groups contain 1-4 heteroatoms independently selected from N, O or S, or contain 2-3 heteroatoms independently selected from N, O or S.

In some embodiments, the compound of formula I is a compound of formula Ia,

wherein the ring B, R ¹ 、R ² 、R ³ 、R ⁴ 、Y、X ₁ 、X ₂ 、X ₃ M and n are as defined in the compounds of formula I.

In some embodiments, X ₁ 、X ₂ 、X ₃ Independently selected from c= O, CR ¹⁰ R ¹¹ 、NR ¹² ；

The R is ¹⁰ Or R is ¹¹ Each independently selected from hydrogen, deuterium, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g., C) _1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C _1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C _3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-to 12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene, 5-to 6-membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO ₂ R'、SO ₂ NR '(R), COR', COOR 'or CONR' (R "), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR ' (R "), COR ', COOR ', or CONR ' (R ') are substituted.

Alternatively, R ¹⁰ Or R is ¹¹ Forms a 3-to 12-membered spiro ring together with the adjacent carbon atom, or CR ¹⁰ R ¹¹ Form 3-to 12-membered ring with its adjacent atoms and are attached to ring A.

The carbocycle or heterocycle may be an aromatic or non-aromatic carbocycle or heterocycle which may include one or more heteroatoms selected from O, N or S (e.g. furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine). Preferably a 3-to 12-membered carbocyclic ring, heterocyclic ring, optionally substituted with a member selected from halogen, hydroxy, oxo, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C3-7 cycloalkyl, 3-12-membered heterocyclyl, 5-12-membered aryl, 5-12-membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR ' (R "), COR ', COOR ', or CONR ' (R ');

R ¹² Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g. C) _1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C _1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups such as C _3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-to 12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl, such as 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene, 5-to 6-membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO ₂ R'、SO ₂ NR '(R), COR', COOR 'or CONR' (R "), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR ' (R), COR ', COOR ' or CONR ' (R ')Substituted.

R ', R' are as defined for the compounds of formula I.

In some embodiments, formula Ia is

In some embodiments, R ¹⁰ Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, amino, C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano.

In some embodiments, R ¹⁰ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl or isopropyl.

In some embodiments, R ¹² Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl.

In some embodiments, R ¹² Selected from hydrogen, fluorine, chlorine, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl groups.

In some embodiments, R ¹² Selected from methyl, ethyl, propyl or isopropyl.

In some embodiments, the compound is

Ring B, R ¹ 、R ² 、R ³ 、R ⁴ 、Y、X ₁ 、X ₂ 、X ₃ 、X ₄ M and n are as defined in the compounds of formula I.

In some embodiments, X ₁ 、X ₂ 、X ₃ 、X ₄ Independently selected from c= O, CR ¹⁰ R ¹¹ 、NR ¹² ；

Alternatively, R ¹⁰ Or R is ¹¹ Forms a 3-to 12-membered spiro ring together with the adjacent carbon atom, or CR ¹⁰ R ¹¹ Forms a 3-to 12-membered ring with its adjacent atom and is attached to ring A, the 3-to 12-membered ring preferably being a 3-to 12-membered carbocyclic, heterocyclic ring which may include one or more heteroatoms selected from O, N or S (e.g. furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazinePyrimidine, pyridazine), said carbocycle or heterocycle being optionally substituted with a member selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR ' (R "), COR ', COOR ', or CONR ' (R ');

R ¹² selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g. C) _1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C _1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C _3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 5-to 12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene, 5-to 6-membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO ₂ R'、SO ₂ NR '(R), COR', COOR 'or CONR' (R "), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO ₂ R'、SO ₂ NR ' (R "), COR ', COOR ', or CONR ' (R ');

r ', R' are as defined for the compounds of formula I.

In some embodiments, formula Ib is

In some embodiments of the present invention, in some embodiments,R ¹⁰ 、R ¹¹ independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, amino, C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano.

In some embodiments, R ¹⁰ 、R ¹¹ Each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl or isopropyl.

In some embodiments, R ¹² Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).

In some embodiments, R ¹² Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

In some embodiments, formula Ib isWherein,

ring C is selected from C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl);

R ¹³ Selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).

o is selected from 0, 1, 2;

in some embodiments, R ¹³ Selected from the group consisting of preferably hydrogen, fluorine, chlorine, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

In some embodiments, R ¹² Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

In some embodiments, ring C is selected from

In some embodiments, formula Ib is

The method comprises the steps of carrying out a first treatment on the surface of the Wherein,

ring D is selected from C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl).

R ¹³ Independently selected from hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine), hydroxy, nitro, cyano, C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl),C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine).

o is selected from 0, 1, 2.

In some embodiments, R ¹³ Each independently selected from the group consisting of preferably hydrogen, fluorine, chlorine, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

In some embodiments, ring D is selected from

In some embodiments of the present invention, in some embodiments,selected from->Wherein p and q are independently selected from 0, 1, 2 and 3 respectively, and p and q are not 0 at the same time.

In some embodiments of the present invention, in some embodiments,selected from->

In some embodiments, when Y is selected from CR ⁵ -NR ⁶ R ⁷ When R is ⁵ 、R ⁶ Independently selected from hydrogen.

In some embodiments of the present invention, in some embodiments,selected from the group consisting of

In some embodiments, R in Y ⁷ Selected from-SO ₂ R'、-SO ₂ NR'(R”)。

In some embodiments of the present invention, in some embodiments,the-SO ₂ R'、-SO ₂ In NR ' (R '), R ' is selected from C _1-6 Alkyl (e.g. methyl, ethyl, propyl or isopropyl), C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl), 5-12 membered aryl (e.g., phenyl, naphthyl), or 5-12 membered heteroaryl (e.g., pyridine, piperidine), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano.

In some embodiments, the-SO ₂ R'、-SO ₂ In NR ' (R '), R ' is selected from methyl, ethyl, propyl, 5-12 membered heteroaryl (e.g., pyridine, piperidine), and,C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), -or-and-optionally>

In some embodiments, the-SO ₂ R ' in NR ' (R ') is selected from hydrogen, C _1-6 Alkyl (e.g., methyl, ethyl, propyl, or isopropyl).

In some embodiments, the-SO ₂ R ' in NR ' (R ') is selected from hydrogen, methyl, ethyl, propyl.

In some embodiments, R ¹ Selected from halogen (e.g., fluorine, chlorine, bromine), preferably fluorine, chlorine.

In some embodiments, R ² Selected from hydrogen, deuterium.

In some embodiments, R ³ Selected from hydrogen, deuterium, halogen, preferably hydrogen, fluorine, chlorine.

In some embodiments, n is selected from 1.

In some embodiments, R ⁴ Selected from hydrogen, deuterium, halogen, preferably hydrogen.

In some embodiments, m is selected from 0, 1, preferably 0.

In some embodiments, the compound isPreferablyRing C is selected from C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl).

R ¹³ Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl.

R ¹⁴ Selected from methyl, ethyl, propyl, 5-12 membered heteroaryl, and, C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), -or-and-optionally>

o is selected from 0, 1, 2.

In some embodiments, ring C is selected from />

In some embodiments, the compound is

Preferably->

Wherein,

ring D is selected from C _3-7 Cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), 3-7 membered heterocyclyl (e.g., pyrrolyl);

R ¹³ selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl;

R ¹⁴ selected from methyl, ethyl, propyl, 5-12 membered heteroaryl (e.g., pyridine, piperidine), and,C _1-6 Alkoxy (e.g. methoxy, ethoxy, propoxy or isopropoxy), -or-and-optionally>

o is selected from 0, 1, 2.

In some embodiments, ring D is selected from/>

In some embodiments, ring B is selected fromWherein p and q are independently selected from 0, 1, 2 and 3 respectively, and p and q are not 0 at the same time.

In some embodiments, the compound isPreferably

Wherein,

ring D is selected from/>

In some embodiments, the compound is selected from:

/>

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a process for preparing a compound of formula I,

when Y is selected from CR ⁵ -NR ⁶ R ⁷ When it comprises

/>

When Y is selected from the group consisting of NR ⁷ When it comprises

Wherein LG is ¹ Or LG (light emitting diode) ² Selected from leaving groups, ra is selected from protecting groups.

In some embodiments, the leaving group comprises a halogen, sulfonate, boronic acid, boronate.

In some embodiments, the protecting group comprises t-butoxycarbonyl, benzyloxycarbonyl.

Also provided in the present disclosure is a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the foregoing compound or a pharmaceutically acceptable salt thereof.

In certain 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. The present disclosure also provides a method of preventing and/or treating a patient suffering from a protein-dependent kinase related disease by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

In some embodiments, the protein-dependent kinase related disease is selected from a cell proliferative disease, a cancer, or an immune disease.

In some embodiments, the protein-dependent kinase related disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), renal cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondrioma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gall bladder cancer, bile duct cancer, chorionic epithelial cancer or pediatric tumor.

The present disclosure also provides a method of preventing and/or treating a patient suffering from cancer selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), kidney cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gall bladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the foregoing.

The present disclosure provides the use of a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the manufacture of a medicament for the prevention and/or treatment of a protein dependent kinase, preferably CDK2, associated with a protein dependent kinase, preferably a cell proliferative disorder, cancer or immune disorder.

In some embodiments, the present disclosure provides the use of a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the foregoing in the manufacture of a medicament for treating a cancer, preferably, a cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer (including HCC), pancreatic cancer, colorectal cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), renal cancer (including RCC), skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondrioma, bone tumor, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorioallantoic carcinoma, or pediatric tumor.

In another aspect, pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic salts or organic salts.

In another aspect, the compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of 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 disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure.

In addition, 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 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 proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are between a and B as shown below.

All compounds of the invention can be drawn as form a or form B. All tautomeric forms are within the scope of the invention. The naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

Optically active (R) -and (S) -isomers and 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 may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

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

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. The present disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

"optionally" or "optionally" is intended to mean 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. For example, "optionally halogen-or cyano-substituted C1-6 alkyl" means that halogen or cyano may be, but need not be, present, and that the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

In the chemical structure of the compounds of the invention, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations. Although all of the above structural formulae are drawn as certain isomeric forms for simplicity, the present invention may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.

Term interpretation:

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary agent, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

The term "effective amount" or "therapeutically effective amount" as used in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.

"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 CycloalkoxyRadicals, 3-to 6-membered heterocycloalkoxy radicals, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example "C _2-6 Alkenyl "means alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if specified, means that particular number of carbon atoms. Such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more of the following groups, independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heteroCycloalkoxy radicals C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following, independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "cycloalkenyl" refers to partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Examples include, but are not limited to, cyclopentenyl, cyclohexenyl, or cyclohexadienyl. The cycloalkenyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolylPiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:

Etc.

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

etc.

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

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 pi-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 an aryl ring, non-limiting examples of which include:

Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples of which include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,etc.

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:

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groupsIndependently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano. Similarly, "alkynyloxy", "alkenyloxy", "cycloalkoxy", "heterocycloalkoxy", "cycloalkenyloxy" are defined as above for "alkoxy".

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

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

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to an =o substituent.

"monovalent group" means a compound that "formally" eliminates a monovalent atom or group. "subunit" means a compound that "formally" eliminates two atoms or groups of atoms that are monovalent or bivalent to form. The example "alkyl" refers to the portion of the alkane molecule remaining after removal of 1 hydrogen atom, including straight and branched chain monovalent radicals of 1 to 20 carbon atoms. "alkylene (-CH) ₂ (-) "means the remainder of the alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subunits of 1 to 20 carbon atoms. Alkylene groups containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH) ₂ (-), ethylene (e.g. -CH) ₂ CH ₂ -or-CH (CH) ₃ ) (-), propylene (e.g. -CH) ₂ CH ₂ CH ₂ -or-CH (CH) ₂ CH ₃ ) -) butylene (e.g. -CH ₂ CH ₂ CH ₂ CH ₂ -). The alkylene groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 Cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl, said C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyloxy, C _2-6 Alkynyloxy, C _3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C _3-8 The cycloalkenyloxy, 5-to 6-membered aryl or heteroaryl group is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.

Similarly, "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene", "heterocycloalkylene" are defined as "alkylene".

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds. Optional substituents also include spiro or fused ring substitutions.

Detailed Description

The present disclosure is further described below in connection with the examples, which are not intended to limit the scope of the present disclosure.

Experimental methods for which specific conditions are not noted in the examples of the present disclosure are generally performed according to conventional conditions or according to conditions suggested by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using Shimadzu 2010Mass Spectrometer or Agilent 6110A MSD mass spectrometer.

HPLC was performed using a Shimadzu LC-20A systems, shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatograph (Ultimate XB-C18.0 x 150mm column or Xtime C18.1 x 30mm column).

Chiral HPLC analysis was performed using a chiral HPLC analysis of 3um, chiral pak AD-3X 4.6mm I.D.,3um, chiral pak AS-3 150X 4.6mm I.D.,3um, chiral pak AS-3X 4.6mm I.D.,3um, chiral pak OD-3X 4.6mm I.D.,3um, chiral Cel OJ-H150X 4.6mm I.D.,5um, chiral Cel OJ-3X 4.6mm I.D.,3um column;

the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh of yellow sea silica gel as a carrier.

Chiral preparative columns used DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 um) or Phenomnex-Amylose-1 (250 mm. Times.30 mm,5 um).

The CombiFlash flash rapid prep instrument used CombiFlash Rf150 (teldyne ISCO).

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: the volume ratio of petroleum ether/ethyl acetate/methanol is regulated according to the polarity of the compound, and can be regulated by adding a small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like.

Example 1

N- (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclobutyl) methanesulfonamide

First step

Tert-butyl (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclobutyl) carbamate 1c

Compound 1a (170 mg,0.53mmol, prepared as disclosed in patent application WO 201075074) and compound 1b (98 mg,0.53 mmol) were dissolved in 4mL of N, N-dimethylformamide, cesium carbonate (430 mg,1.32 mmol) was added, and the mixture was reacted at 100℃for 12 hours. After completion of the reaction, 10mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography eluting with petroleum ether and ethyl acetate to give the title compound 1b (190 mg, yield: 76%) to give the title compound 1b (105 mg, yield: 95%).

¹ H NMR(400MHz,CDCl ₃ ):δppm 8.25-8.17(m,1H),8.07(s,1H),7.73(d,J＝11.6Hz,1H),5.40-5.24(m,1H),4.71(td,J＝7.2,13.6Hz,2H),4.16-4.08(m,2H),2.67(s,3H),2.38(br t,J＝6.4Hz,2H),1.68(d,J＝7.2Hz,6H),1.45(s,9H).(ESI).

Second step

N1- (5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) cyclobutane-1, 3-diamine 1d

Compound 1c (190 mg,0.40 mmol) was dissolved in 4mL of methanol, and 4mL of hydrogen chloride methanol solution (4M) was added and reacted at 25℃for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give the title compound 1d (150 mg, crude product).

¹ H NMR(400MHz,CDCl ₃ ):δppm 8.62-8.47(m,2H),8.16(br d,J＝11.2Hz,1H),5.16(br d,J＝7.2Hz,1H),4.08-3.80(m,1H),3.71-3.56(m,1H),2.94(br s,1H),2.72(s,3H),2.67(br s,2H),2.50-2.22(m,1H),1.82(d,J＝6.8Hz,6H).

Third step

N- (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclobutyl) methanesulfonamide 1

Compound 1d (150 mg,0.40 mmol) and triethylamine (0.14 mL,1.0 mmol) were dissolved in 4mL of dichloromethane, and methanesulfonyl chloride (0.040 mL,0.52 mmol) was added at 0deg.C and reacted at 20deg.C for 2 hours. After completion of the reaction, 10mL of water was added thereto, followed by extraction with ethyl acetate (15 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography eluting with 0.225% aqueous formic acid, acetonitrile to give the title compound 1 (23 mg, yield: 13%).

MS(ESI)m/z 451.2[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ ):δppm 8.30(d,J＝2.4Hz,1H),8.29(d,J＝2.4Hz,1H),8.27(s,1H),8.24(s,1H),7.77(s,1H),7.76-7.73(m,1H),4.97-4.91(m,2H),4.41(quin,J＝6.0Hz,1H),4.15(quin,J＝7.2Hz,2H),3.77-3.66(m,1H),2.94(s,3H),2.93(s,3H),2.93-2.88(m,2H),2.70(s,6H),2.50(t,J＝6.8Hz,4H),2.07-1.93(m,2H),1.72(d,J＝1.6Hz,6H),1.71(d,J＝1.2Hz,6H).

Example 2

trans-N- (3- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) cyclopentyl) methanesulfonamide

The synthetic procedure of example 2 is described in example 1, wherein compound 1b is replaced with the compound trans-tert-butyl- (3-aminocyclopentyl) carbamate.

MS(ESI)m/z 465.2[M+H] ⁺

¹ H NMR(400MHz,CDCl ₃ ):δ8.23(d,J＝3.6Hz,1H),8.07(s,1H),7.73(d,J＝12.0Hz,1H),5.08(br d,J＝6.4Hz,1H),4.72(td,J＝6.8,14.0Hz,1H),4.48-4.38(m,1H),4.27(br d,J＝6.4Hz,1H),4.09-3.95(m,1H),3.00(s,3H),2.68(s,3H),2.40-2.26(m,2H),2.09(t,J＝7.2Hz,2H),1.69(d,J＝6.8Hz,6H),1.64-1.59(m,2H).

Example 3

5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- ((1- (methylsulfonyl) azetidin-3-yl) methyl) pyrimidin-2-amine

The synthetic procedure of example 3 is described in example 1, wherein compound 1b is replaced with the compound tert-butyl-3- (aminomethyl) azetidine-1-carboxylate.

MS(ESI)m/z 451.2[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ＝8.44(d,J＝3.8Hz,1H),8.10(br s,1H),7.60(br d,J＝11.9Hz,1H),7.53(br t,J＝5.6Hz,1H),4.90-4.76(m,1H),3.92(t,J＝8.3Hz,2H),3.71-3.63(m,2H),3.55(br s,2H),2.97(s,3H),2.87(br s,1H),2.63(s,3H),1.59(d,J＝6.8Hz,6H).

Example 4

6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one

First step

4c

Compound 4a (30 mg,0.12 mmol), pinacol biborate (45 mg,0.18 mmol), potassium acetate (23 mg,0.24 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (18 mg,0.02 mmol) were dissolved in 2mL of 1, 4-dioxane in this order under nitrogen. The reaction was carried out at 100℃for 1 hour. The reaction solution was cooled to room temperature, and 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (14 mg,0.05 mmol), potassium carbonate (33 mg,0.24 mmol), 4b (30 mg,0.18 mmol), tris (dibenzylideneacetone) dipalladium (22 mg,0.02 mmol) and 0.5mL of water were added to react at 80℃for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, and the residue was purified by C-18 reverse phase chromatography to give the title compound 4C (25 mg, yield: 69%).

MS(ESI)m/z 306.4[M+H] ⁺ .

Second step

6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 4

Compounds 4c (25 mg,0.08 mmol), 4d (16 mg,0.09 mmol), cesium carbonate (53 mg,0.16 mmol), tris (dibenzylideneacetone) dipalladium (15 mg,0.02 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (19 mg,0.03 mmol) were dissolved in 2mL of N, N-dimethylformamide in this order under nitrogen. The reaction was carried out at 100℃for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, and the residue was purified by C-18 reverse phase chromatography to give the title compound 2 (0.3 mg, yield: 1%).

MS(ESI)m/z 448.5[M+H] ⁺ .

Example 5

6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one

First step

7-bromo-2, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 5a

4a (100 mg,0.393 mmol) was dissolved in 2mL of N, N-dimethylformamide at 0deg.C, sodium hydride (100 mg,0.393 mmol) was added, and the reaction was stirred at 25deg.C under argon for 0.5 hours. Methyl iodide (112 mg,0.787 mmol) was then added to the reaction mixture at 0℃and the mixture was heated to 25℃under argon and stirred for 0.5 hours. After the completion of the reaction, the reaction mixture was poured into 20mL of an ice-water mixture, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to give the title compound 5a (105 mg, yield: 95%).

MS(ESI)m/z 268.3,270.3[M+H] ⁺ .

Second step

2, 4-trimethyl-7- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one 5b

Compound 5a (105 mg, 0.399mmol), pinacol diboronate (129 mg,0.509 mmol), and potassium acetate (77 mg,0.783 mmol) were dissolved in 2mL dioxane, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (29 mg,0.039 mmol) was added and the reaction stirred at 95℃under argon for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added, extraction (10 mL. Times.3) was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to give the title compound 5b (120 mg, yield: 97%).

MS(ESI)m/z 316.5[M+H] ⁺ .

Third step

6- (2-chloro-5-fluoropyrimidin-4-yl) -2, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 5c

Compound 5b (120 mg,0.381 mmol), compound 4b (64 mg,0.381 mmol) and potassium carbonate (105 mg,0.761 mmol) were dissolved in 2mL dioxane and 0.5mL water, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (28 mg,0.038 mmol) was added thereto, and the mixture was stirred at a temperature of 95℃under argon to react for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with petroleum ether and ethyl acetate to give the title compound 5c (80 mg, yield: 65%).

MS(ESI)m/z 320.4[M+H] ⁺ .

Fourth step

6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2, 4-trimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 5

Compound 5c (80 mg,0.250 mmol), compound 4d (67 mg,0.375 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (23 mg,0.038 mmol) and cesium carbonate (244 mg,0.751 mmol) were dissolved in 2mL tetrahydrofuran, palladium acetate (8 mg,0.038 mmol) was added, and the mixture was heated to 80℃under argon with stirring for reaction under microwave for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography using water and acetonitrile to give the title compound 5 (45.5 mg, yield: 39%).

MS(ESI)m/z 462.5[M+H] ⁺ .

Example 6

2-cyclopropyl-6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one

The synthetic procedure of example 6 is described in example 5, wherein the compound iodocyclopropane is substituted for the compound iodomethane.

MS(ESI)m/z 488.5[M+H] ⁺ .

Examples 7 and 8

Trans N- (3- ((4- (4, 4-dimethyl-1-carbonyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5-fluoropyrimidin-2-yl) amino) cyclopentyl) methanesulfonamide isomer 1 and isomer 2

First step

Trans-tert-butyl (3- ((4- (4, 4-dimethyl-1-carbonyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -5-fluoropyrimidin-2-yl) amino) cyclopentyl) carbamate 7b

Compound 4c (520 mg,1.7 mmol), 7a (409 mg,2.0 mmol) and N, N-diisopropylethylamine (440 mg,3.4 mmol) were dissolved in 12mL of N, N-dimethylacetamide in this order under a nitrogen atmosphere. The reaction was carried out at 125℃for 5 hours. The reaction solution was cooled to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected, and the residue after concentration under reduced pressure was purified by C-18 reverse phase chromatography to give the title compound 7b (680 mg, yield: 85%).

MS(ESI)m/z 470.5[M+H] ⁺ 。

Second step

Trans-6- (2- ((3-aminocyclopentyl) amino) -5-fluoropyrimidin-4-yl) -4, 4-dimethyl-3, 4-dihydroisoquinolin-1 (2H) -one 7c

Compound 7a (400 mg,0.85 mmol) was dissolved in 16mL of methanol at room temperature. 2mL of trifluoroacetic acid was added and the reaction was carried out at room temperature for 3 hours. Concentrated under reduced pressure, 100mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to give the title compound 7c (310 mg, yield: 99%).

MS(ESI)m/z 370.5[M+H] ⁺

Third step

Compound 7c (100 mg,0.27 mmol) was dissolved in 10mL of dichloromethane at room temperature. Cooled to 0 ℃, methanesulfonyl chloride (34 mg,0.3 mmol) was added and reacted at 0 ℃ for 1 hour. Concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give crude product, which was resolved by chiral column supercritical fluid chromatography to give Compound 7 (39.6 mg, yield: 33%) and 8 (38.4 mg, yield: 32%). The chiral analysis method is Chiralpak IG-3, mobile phase A-supercritical carbon dioxide, B-methanol and 0.05% diethylamine, the flow rate is 4ml/min, and the isocratic is 40% B. The resulting isomers were separated according to isomer retention time:

compound 7:

MS(ESI)m/z 448.5[M+H] ⁺

chiral analysis Retention Time (RT) 2.576min

Compound 8:

MS(ESI)m/z 448.5[M+H] ⁺

chiral analysis Retention Time (RT) 3.385min.

Example 9

6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutaneo

-1,4 '-isoquinolin-1' -one

First step

4-bromo-2- (cyanomethyl) benzoic acid methyl ester 9b

Compound 9a (2.6 g,8.4 mmol) was dissolved in 20mL of acetonitrile, and potassium carbonate (2.3 g,16.9 mmol) and trimethylsilane nitrile (1.0 g,10.1 mmol) were added and stirred at room temperature for 14 hours. The reaction was quenched by addition of 100mL of saturated sodium hydroxide solution. Extraction with ethyl acetate (100 mL. Times.3), washing with saturated sodium chloride solution (100 mL), drying over anhydrous sodium sulfate, filtering, collecting filtrate, concentrating the filtrate under reduced pressure, and eluting the residue with petroleum ether and ethyl acetate by silica gel column chromatography to give the title compound 9b (1.15 g, yield: 54%). MS (ESI) m/z 254.3,256.3[ M+H ] ] ⁺

Second step

4-bromo-2- (1-cyanocyclobutyl) benzoic acid methyl ester 9d

Compound 9b (300 mg,1.2 mmol) was dissolved in 8mL of N, N-dimethylformamide under nitrogen. Cooled to 0 ℃, sodium hydride (132 mg,3.3 mmol) was added in portions and stirred at 0 ℃ for half an hour. 9c (284 mg,1.4 mmol) was added and stirred at 0deg.C for half an hour. Heat to 10 ℃ and stir for half an hour. The reaction was quenched with 80mL of saturated ammonium chloride solution, extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether, ethyl acetate to give the title compound 9d (60 mg, yield: 17%).

MS(ESI)m/z 294.3,296.3[M+H] ⁺

Third step

6 '-bromo-2', 3 '-dihydro-1' H-spiro [ cyclobutano-1, 4 '-isoquinolin-1' -one 9e

Compound 9d (60 mg,0.2 mmol) was dissolved in 4mL methanol under nitrogen. Cobalt chloride hexahydrate (145 mg,0.6 mmol) was added, sodium borohydride (41 mg,1.2 mmol) was added in portions and stirred at 0℃for 1 hour. The reaction was quenched with 30mL of saturated ammonium chloride solution, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with petroleum ether, ethyl acetate to give the title compound 9e (20 mg, yield: 37%).

MS(ESI)m/z 266.3,268.3[M+H] ⁺

Fourth step

6'- (2-chloro-5-fluoropyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutano-1, 4 '-isoquinolin ] -1' -one 9f

Compound 9e (120 mg,0.45 mmol), pinacol biborate (172 mg,0.68 mmol), potassium acetate (89 mg,0.9 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (67 mg,0.1 mmol) were dissolved in 2mL of 1, 4-dioxane in this order under nitrogen. The reaction was carried out at 100℃for 1 hour. The reaction solution was cooled to room temperature, and 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphamantane (40 mg,0.14 mmol), potassium carbonate (125 mg,0.9 mmol), 4b (113 mg,0.68 mmol), tris (dibenzylideneacetone) dipalladium (83 mg,0.09 mmol) and 0.5mL of water were added to react at 80℃for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, and the residue was purified by C-18 reverse phase chromatography to give the title compound 9f (75 mg, yield: 52%).

MS(ESI)m/z 318.4[M+H] ⁺

Fifth step

6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutano-1, 4 '-isoquinolin ] -1' -one 9

Compounds 9f (35 mg,0.11 mmol), 4d (29 mg,0.17 mmol), cesium carbonate (72 mg,0.2 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (20 mg,0.02 mmol) were dissolved in 2mL of N, N-dimethylformamide in this order under nitrogen. The reaction was carried out at 100℃for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, and the residue was purified by C-18 reverse phase chromatography to give the title compound 9 (0.6 mg, yield: 1%).

MS(ESI)m/z 460.5[M+H] ⁺

Example 10

6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclopropaneo-1, 4 '-isoquinolin ] -1' -one

The synthetic procedure of example 10 is described in example 9, wherein compound 9c is replaced with compound 1, 2-dibromoethane.

MS(ESI)m/z 446.5[M+H] ⁺

Example 11

6- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2,2', 3',5',6' -hexahydro-1H-spiro [ isoquinolin-4, 4' -pyran ] -1-one

/>

The synthetic procedure of example 11 is described in example 9, wherein compound 9c is replaced with compound 1-bromo-2- (2-bromoethoxy) ethane.

MS(ESI)m/z 490.5[M+H] ⁺

Example 12

6'- (5-fluoro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclopenta-1, 4 '-isoquinolin ] -1' -one

The synthetic procedure of example 12 is described in example 9, wherein compound 9c is replaced with compound 1, 4-dibromobutane.

MS(ESI)m/z 474.5[M+H] ⁺

Example 13

6'- (5-fluoro-2- (((1- (methylsulfonyl) azetidin-3-yl) methyl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutaneo-1, 4 '-isoquinolin-1' -one

The synthetic procedure of example 13 is described in example 9, wherein compound 4d is replaced with the compound (1- (methylsulfonyl) azetidin-3-yl) methylamine.

MS(ESI)m/z 446.4[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)δ8.50(d,J＝3.5Hz,1H),8.16(s,2H),7.99(d,J＝8.1Hz,1H),7.93(d,J＝8.0Hz,1H),7.62(s,1H),3.93(t,J＝8.3Hz,2H),3.67(dd,J＝8.2,5.7Hz,2H),3.55(t,J＝6.6Hz,2H),3.47(d,J＝2.9Hz,2H),2.97(s,3H),2.87(s,1H),2.26(d,J＝6.0Hz,2H),2.12(d,J＝10.1Hz,4H).

Example 14

6'- (5-chloro-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutaneo

-1,4 '-isoquinolin-1' -one

The synthetic procedure of example 14 is described in example 9, wherein compound 4b is replaced with compound 2,4, 5-trichloropyrimidine.

MS(ESI)m/z 446.4[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.13(br s,1H),7.99-7.85(m,2H),7.69(br s,2H),3.86(br s,1H),3.53(br d,J＝11.8Hz,2H),3.46(br d,J＝2.4Hz,2H),2.92-2.80(m,5H),2.30-2.18(m,2H),2.16-2.05(m,3H),1.98(br s,2H),2.03-1.92(m,1H),1.64-1.49(m,2H).

Example 15

6'- (2- ((1- (methylsulfonyl) piperidin-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -2',3 '-dihydro-1' H-spiro [ cyclobutaneo-1, 4 '-isoquinolin-1' -one)

The synthetic procedure of example 15 is described in example 9, wherein compound 4b is replaced with compound 2, 4-dichloro-5- (trifluoromethyl) pyrimidine.

MS(ESI)m/z 510.5[M+H] ⁺

Example 16

6- (5-fluoro-2- (((1- (methylsulfonyl) azetidin-3-yl) methyl) amino) pyrimidin-4-yl) -4, 4-dimethyl-3, 4-)

Dihydro isoquinolin-1 (2H) -ones

The synthetic procedure of example 16 is described in example 4, wherein compound 4d is replaced with the compound (1- (methylsulfonyl) azetidin-3-yl) methylamine.

MS(ESI)m/z 434.4[M+H] ⁺

¹ H NMR(400MHz,DMSO-d6)δ8.12(s,1H),8.03–7.94(m,2H),7.91(d,J＝8.1Hz,1H),7.60(s,1H),3.92(t,J＝8.2Hz,2H),3.67(dd,J＝8.1,5.7Hz,2H),3.53(d,J＝6.6Hz,2H),3.23(d,J＝3.1Hz,2H),2.97(s,3H),2.86(s,1H),1.32(s,6H).

Example 17

6'- (5-chloro-2- (((1- (methylsulfonyl) azetidin-3-yl) methyl) amino) pyrimidin-4-yl) -2',3 '-dihydro-1' H-

Spiro [ cyclobutaneo-1, 4 '-isoquinolin ] -1' -one

/>

The synthetic procedure of example 17 is described in example 9, wherein compound 4b is replaced with compound 2,4, 5-trichloropyrimidine and compound 4d is replaced with compound (1- (methylsulfonyl) azetidin-3-yl) methylamine.

MS(ESI)m/z 462.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ8.40(s,1H),8.07(s,1H),7.89(d,J＝7.9Hz,1H),7.81(s,1H),7.62(s,1H),3.84(t,J＝8.3Hz,2H),3.59(dd,J＝8.2,5.7Hz,2H),3.46(t,J＝6.5Hz,2H),3.40(d,J＝2.9Hz,2H),2.90(s,3H),2.25–2.15(m,3H),2.11–1.88(m,4H).

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1, compounds of the present disclosure for cyclin-dependent kinase activity assays

1. Experimental material and instrument

2. Experimental procedure

Compound dilutions were transferred into each well of the assay plate using Echo 550 (784075, greiner). Sealing the measuring plate, centrifuging the measuring plate at 1000g for 1 minute; 2 Xenzyme was prepared in 1 Xkinase buffer (prepared from 1 volume of 5 Xkinase buffer and 4 volumes of distilled water and 50uM DTT), 2.5. Mu.l of 2 Xenzyme was added to 384 well assay plates, and the plates were centrifuged at 1000g for 30s and left at room temperature for 10 min. A2 x substrate and ATP mixture was prepared in 1x kinase buffer and the reaction was started by adding 2.5. Mu.l of the 2x substrate and ATP mixture. The plates were centrifuged at 1000g for 30 seconds, the assay plates were sealed and reacted at room temperature for 1 hour. Add 4. Mu.l ADP-Glo reagent, incubate at room temperature for 40 minutes, add 8. Mu.l kinase detection reagent, incubate at room temperature for 40 minutes.

Each well was read on an Envision 2104 plate reader.

Percent inhibition was calculated as follows:

percent inhibition = 100- (cmpd signal-ave_pc signal)/(ave_vc signal-ave_pc signal) ×100.

IC50 was calculated using GraphPad 8.0 by fitting the percent inhibition values and the logarithm of the compound concentration to a nonlinear regression (dose response-variable slope).

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

X: logarithm of inhibitor concentration; y: % inhibition.

Measured IC ₅₀ The values are shown in Table 1.

TABLE 1 CDK2/Cyclin E IC for compounds of the present disclosure ₅₀

Examples numbering	CDK2(nM)
		PHA-793887	8.1
1	44.7
		2	12.0
3	16.4
		4	2.4
5	3.5
		6	9.0
7	17.7
		8	1.8
9	0.9
		10	1.1
11	0.9
		12	0.5
13	37.9
		14	4.2
15	63.1
		16	11.4
17	123

Claims

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

wherein formula I is selected from the group consisting of compounds of formula II-a, III-b, III-d, or III-e

Selected from->

Y is selected from CR ⁵ -NR ⁶ R ⁷ 、*NR ⁷ ；R ⁵ 、R ⁶ Each independently selected from hydrogen; each R ⁷ Are independently selected from-SO ₂ R'; r' is selected from C _1-6 Alkyl, said C _1-6 Alkyl is optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano;

the conditions are as follows:

when B is a six-membered monocyclic ring,ring A is not optionally substituted or unsubstituted

Each R ¹ 、R ² 、R ³ 、R ⁴ Are independently selected from hydrogen, deuterium, halogen and C _1-6 Alkyl, said C _1-6 Alkyl is optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano;

and R is ¹ 、R ² Are not hydrogen at the same time;

the R is ¹⁰ Or R is ¹¹ Each independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, said C _1-6 Alkyl is optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano;

R ¹² selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _3-7 Cycloalkyl group, the C _1-6 Alkyl, C _3-7 Cycloalkyl is optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano;

R ¹³ Are independently selected from hydrogen, deuterium, halogen and C _1-6 Alkyl, C _3-7 Cycloalkyl;

ring D is selected from C _3-7 Cycloalkyl, 3-7 membered heterocyclyl;

m and n are respectively and independently selected from 0, 1, 2 and 3;

o is selected from 0, 1, 2;

wherein, represent the connection site, the dotted line is selected from single bond, double bond.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,

when formula I is selected from formula II-a, R ¹⁰ Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl or isopropyl.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein,

when formula I is selected from formula II-a, R ¹² Selected from hydrogen, fluorine, chlorine, C _1-6 Alkyl, C _3-7 Cycloalkyl groups.

4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, R ¹² Selected from methyl, ethyl, propyl or isopropyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, when formula I is selected from formula III-a or III-b, R ¹⁰ 、R ¹¹ Each independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl or isopropyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, when formula I is selected from formula III-a or III-b, R ¹² Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, when formula I is selected from formulas III-d or III-e, R ¹³ Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, when formula I is selected from formulas III-d or III-e, R ¹² Selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring D is selected from

10. The method of any one of claims 1-9A compound of formula (I) or a pharmaceutically acceptable salt thereof,selected from the group consisting of

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R' is selected from methyl, ethyl, propyl.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from fluorine and chlorine.

14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen, deuterium.

15. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen, deuterium, halogen.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen, fluorine, chlorine.

17. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein n is selected from 1.

18. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Selected from hydrogen, deuterium, halogen.

19. A compound or a pharmaceutically acceptable salt thereof as claimed in claim 18Pharmaceutically acceptable salts, wherein R ⁴ Selected from hydrogen.

20. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein m is selected from 0 or 1.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein m is 0.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which isWherein,

ring D is selected from C _3-7 Cycloalkyl, 3-7 membered heterocyclyl;

R ¹⁴ selected from methyl, ethyl, propyl;

R ¹ as defined in claim 1;

o is selected from 0, 1, 2.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein,

ring D is selected from

24. The compound or pharmaceutically acceptable salt thereof according to claim 22 or 23, wherein,selected from the group consisting of

25. A compound according to claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen.

26. A compound according to claim 25 or a pharmaceutically acceptable salt thereof, R ¹ Selected from fluorine and chlorine.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is

Wherein ring D is selected from

R ¹⁴ Selected from methyl, ethyl, propyl;

R ¹ selected from halogen.

28. A compound according to claim 27 or a pharmaceutically acceptable salt thereof, R ¹ Selected from fluorine and chlorine.

29. The compound of claim 1, selected from the group consisting of:

，

or a pharmaceutically acceptable salt thereof.

30. An isotopic substitution of a compound according to any one of claims 1 to 29.

31. The isotopic substitution of the compound as recited in claim 30 wherein said isotopic substitution is deuterium atom substitution.

32. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

33. Use of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32, in the manufacture of a medicament for the prevention and/or treatment of a disease associated with a protein dependent kinase selected from CDK2.

34. The use according to claim 33, wherein the protein dependent kinase related disease is selected from the group consisting of a cell proliferative disease, a cancer or an immune disease.

35. Use of a compound according to any one of claims 1-31 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 32 for the manufacture of a medicament for the prevention and/or treatment of a cancer selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid cancer, ureteral tumor, bladder tumor, gall bladder cancer, cholangiocarcinoma, chorioallantoic epithelial cancer or pediatric tumor.

36. The use of claim 35, wherein liver cancer is selected from HCC.

37. The use of claim 35, wherein the lung cancer is selected from NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma.

38. The use of claim 35, wherein the renal cancer is selected from RCC.

39. A process for the preparation of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof,

when Y is selected from CR ⁵ -NR ⁶ R ⁷ When it comprises

When Y is selected from the group consisting of NR ⁷ When it comprises

Therein, B, R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、X ₁ 、X ₂ 、X ₃ 、X ₄ M, n are as defined in claim 1;

LG ¹ or LG (light emitting diode) ² A leaving group selected from halogen, benzenesulfonyl, methanesulfonyl or p-toluenesulfonyl;

ra is selected from protecting groups selected from t-butoxycarbonyl, benzyloxycarbonyl.