TW202317564A - Cdk2 inhibitor, a preparation method and a use thereof - Google Patents

Abstract

The present disclosure relates to CDK2 inhibitor, a preparation method and a use thereof. In particular, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein each variable is as defined in the present disclosure. The compound of formula I can be used as a cyclin-dependent kinase inhibitor for the prevention and/or treatment of diseases related to cyclin-dependent kinase or cyclin, such as cell proliferative disease, cancer or immune disease.

Description

CDK2 inhibitor and its preparation method and use

The disclosure belongs to the field of medicine, and relates to a CDK2 inhibitor.

Cyclin-dependent kinases (CDKs) are members of the serine/threonine kinase subfamily, and each CDK/cyclin complex is responsible for a specific phase transition or progression within the cell cycle, which plays an important role in regulating eukaryotic cell important role in division and proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cell cycle proteins 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 regulators 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 is undoubtedly the CDK4/6 monotherapy or combined with endocrine therapy in hormone receptor positive advanced breast cancer, such as palbociclib, ribociclib and bomaciclib Abemaciclib is approved in combination with an aromatase inhibitor for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic disease in postmenopausal women breast cancer, 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 (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, like other kinases, their effects may be over time controlled by primary or acquired resistance. development restrictions.

Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. The cyclin E/CDK2 complex plays an important role in regulating the G1/S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and promotes S phase entry. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that allow DNA replication and inactivation of E2F to complete S phase (Nat.Rev.Drug.Discov.2015; 14( 2): 130-146). Cyclin E is overexpressed in various cancers, especially breast cancer, lung cancer, leukemia, and lymphoma (Guo Cuiping et al., Cyclin E regulation and malignant tumors, International Journal of Oncology, 2012,39(005): 337- 340), the amplification or overexpression of cyclin E is also associated with poor prognosis in ovarian, gastric, endometrial and other cancers.

Studies have shown that inhibition of CDK2 kinase induces tumor cell apoptosis, but causes only minor damage to normal cells. The monomeric form of the CDK kinase is inactive, whereas the binding of cyclin A/E to CDK2 and triggering phosphorylation activates CDK2. CDK2 also binds cyclin A for progression through S phase and participates in DNA repair. In recent years, major companies have identified and discovered a series of inhibitors that selectively inhibit CDK2 for the treatment of cancer and other diseases, such as Seliciclib, Dinaciclib, etc., but in order to achieve better cancer treatment effects and better meet the needs of the market However, it is still necessary to develop a new generation of selective CDK2 inhibitors with high efficiency and low toxicity.

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

Wherein, -L ₁ -is selected from a bond, C ₁ - ₆ alkylene, -O- and -NH-, and the C ₁ - ₆ alkylene is optionally selected from one or more hydroxyl groups , alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents;

，其中環A和環B各自獨立地選自芳基、雜芳基和雜環烷基，環A和環B一起形成并環結構，該A環視需要地被一個或多個Z₁取代，該B環視需要地被一個或多個Z₂取代； _R1 is

, wherein ring A and ring B are each independently selected from aryl, heteroaryl and heterocycloalkyl, ring A and ring B together form a ring structure, the A ring is optionally substituted by one or more Z ₁ , the Surround B is replaced by one or more _Z2 as needed;

R ₂ and _{R 3} are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, pendant oxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C _1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently selected from halogen _, alkyl, alkoxy, cyano, amino, Substituents of nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R ₂ and R ₃ together form a 3-8 member ring, the 3-8 member Look around is replaced by one or more Z _3's as needed;

R ₄ is -L ₂ -R ₇ ;

_R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Pendant Oxy , carboxyl and carboxylate substituent substitution;

_R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more _Z ;

-L ₂ -is selected from a bond, C ₁ - ₆ (alkylene) alkylene, -O- and -NH-, and the C ₁ - ₆ (alkylene)alkylene is optionally replaced by one or more selected from hydroxyl, alkane Substituents of radical, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;

； R ₆ is selected from H, R ₈ -(C=O)- and

;

R ₈ is an alkyl group, preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, and most preferably _a methyl group _;

R ₉ and R ₁₀ are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C _1-6 alkyl and _3-7 membered _cycloalkyl , more preferably selected from hydrogen, C _1-3 Alkyl and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;

Each X is independently selected from O, S and NH, preferably selected from O;

Z ₁ , Z ₂ , Z ₃ and Z ₄ are each independently selected from halogen, cyano, hydroxyl, nitro, side oxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, -SR', -SOR', -SO ₂ R', -SO ₂ NR'(R"), -NR'(R"), -COR', -COOR' , -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and The heteroaryl groups are each independently optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitr group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkyloxy group, cycloalkylthio group, heterocycloalkylthio group, side oxy group, carboxyl group and Carboxylate substituent substitution;

Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, the alkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxy , nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, Carboxyl and carboxylate substituents are substituted.

In some embodiments, the Z ₁ , Z ₂ , Z ₃ and Z ₄ are each independently selected from halogen, cyano, hydroxyl, nitro, pendant oxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -SR', -SOR', -SO ₂ R', -SO ₂ NR'(R"), -NR'(R"), - COR', -COOR', -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycle Alkyl, aryl and heteroaryl are each independently optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitr group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkyloxy group, cycloalkylthio group, heterocycloalkylthio group, side oxy group, carboxyl group and Carboxylate substituent substitution. In some embodiments, the -L ₁ - is selected from a bond, a C ₁ - ₆ alkylene group, -O- and -NH-, preferably selected from a bond, a C ₁ - ₃ alkylene group, -O- and -NH-, more preferably selected from the bond, C ₁ - ₂ alkylene (extended) alkylene, -O- and -NH-, particularly preferably selected from the bond, C ₁ - ₂ (extended) alkylene and -O-, the best is O.

In some embodiments, the -L ₂ - is a bond or a C ₁ - ₆ (alkylene) group, preferably a bond or a C ₁ - ₃ (alkylene) group.

、環丙基、苯基和吡啶基；該R₇視需要地被一個或多個Z₄取代。 In some embodiments, the R ₇ is selected from C _1-6 alkyl, C _3-7 cycloalkyl, _3-7 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, relatively Preferably C _1-4 alkyl, C _3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl _, ethyl, propyl, isopropyl, butyl Base, isobutyl, second butyl, third butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl , pyrazolyl, thiazolyl and oxazolyl, most preferably selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ .

_In some embodiments, the R ₅ is selected from hydrogen, C _1-6 alkyl and halogen _, preferably hydrogen or C _1-3 alkyl.

、

，其中-L₁-、R₁、R₂、R₃、R₆和Z₄如上述所定義。 In some embodiments, the compound of formula I is

,

, wherein -L ₁ -, R ₁ , R ₂ , R ₃ , R ₆ and Z ₄ are as defined above.

In some embodiments, the R ₂ and R ₃ are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro and side oxygen, preferably selected from hydrogen, _halogen and C _{1- 6} alkyl, more preferably hydrogen.

、

、

、

或

，其中-L₁-、R₁、R₆和Z₄如上述所定義。 In some embodiments, the compound of formula I is

,

,

,

or

, wherein -L ₁ -, R ₁ , R ₆ and Z ₄ are as defined above.

、

、

、

或

，其中R₁、R₆和Z₄如上述所定義。 In some embodiments, the compound of formula I is

,

,

,

or

, wherein R ₁ , R ₆ and Z ₄ are as defined above.

、

In some embodiments, the compound of formula I is

,

或

，其中R₁如上述所定義。

or

, wherein R ₁ is as defined above.

In some embodiments, the ring A and ring B are each independently selected from 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from 5-6 membered heterocyclic Alkyl, 6-10 membered aryl and 5-6 membered heteroaryl; In some embodiments, the ring A and ring B are each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl , imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolyl, tetrahydropyrrolyl, dihydropyrrolyl, triazolyl and piperidinyl, the A ring is optionally substituted by one or more _Z , The B ring is optionally replaced by one or more Z ₂ .

In some embodiments, _the Z ₁ is selected from halogen, cyano, hydroxyl, nitro, pendant oxy _{, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1} - ₆ hydroxyalkyl; in some embodiments, the _Z is selected _from halogen, cyano _, hydroxyl, nitro, pendant oxy, C _1-6 alkyl and C _1-6 alkoxy; in some embodiments, the Z _is selected from halogen, pendant oxy, and C _1-6 alkyl; in some embodiments, _Z is selected from fluorine, chlorine, bromine, pendant _oxy , methyl, ethyl, propyl, and isopropyl.

In some embodiments, the Z ₂ is selected from halogen, _cyano , hydroxyl, nitro, pendant oxy _{, C 1-6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C ₁ - ₆ hydroxyalkyl, the C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy, C ₁ - ₆ haloalkyl and C ₁ - ₆ hydroxyalkyl are optionally selected from cyano, alkyl , alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkyloxy substituents, optionally, The substituent is selected from cyano, _{C 1-6} alkyl _{, C 1-6 alkoxy, C 1-6 deuterated alkoxy ,} halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy , optionally _, the substituent is selected from cyano, C _1-3 alkyl _, C _1-3 alkoxy, C _1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, Optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, deuteromethoxy, ethoxy and tetrahydrofuranyloxy.

In some embodiments, the Z _{2 is} selected from halogen, cyano _, hydroxyl, nitro, _pendant oxy, C _1-6 alkyl and C _1-6 alkoxy, the C _1-6 alkyl and C ₁ - ₆ alkoxy groups are independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl , heterocycloalkyl _and heterocycloalkyloxy substituents, optionally, the _substituent is _{selected from cyano, C 1-6 alkyl} , C _1-6 alkoxy, C _1-6 deuterated Alkoxy, halogen, heteroaryl _, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano _, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, deuterated methoxy, ethyl Oxygen and Tetrahydrofuranyloxy.

In some embodiments, _the Z ₂ is selected from _{halogen, hydroxyl, pendant oxy, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy are} each independently Optionally, one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl and The substituent of heterocycloalkyloxy is substituted, optionally, the _substituent is selected from cyano, _{C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy , halogen} , Heteroaryl, heterocycloalkyl _{and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkoxy , C 1-3} deuterated alkyl Oxygen, heterocycloalkyl and heterocycloalkyloxy, optionally the substituent is selected from cyano, methyl, ethyl, methoxy, deuteromethoxy, ethoxy and tetrahydrofuranyloxy base.

In some embodiments, the _Z is selected from fluorine, chlorine, bromine, side oxy, hydroxyl, methyl, ethyl, propyl, isopropyl and methoxy; the methyl, ethyl, propyl, iso Propyl and methoxy are each independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, hetero Aryl, heterocycloalkyl and heterocycloalkyloxy substituents _, optionally, _{the substituent is selected from cyano, C 1-6 alkyl} , C _1-6 alkoxy, C _{1-6 Deuterated} alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, _the substituent is selected from cyano, C _1-3 alkyl, C _1-3 alkoxy , C _1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, deuterated methoxy , ethoxy and tetrahydrofuryloxy.

In some embodiments, _the Z ₂ is selected from halogen, cyano, hydroxyl, nitro, pendant oxy _{, C 1-6} alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C ₁ - ₆ hydroxyalkyl; In some embodiments, the _{Z 2} is selected _{from halogen, cyano, hydroxyl, nitro, pendant oxy, C 1-6 alkyl} and C _1-6 alkoxy; In some embodiments, the _Z is selected from halogen, hydroxy, pendant oxy, C _1-6 alkyl and C _1-6 alkoxy _; in some embodiments, _Z is selected from fluorine, chlorine, bromine, _pendant oxy, hydroxy, methyl base, ethyl, propyl, isopropyl and methoxy; the alkyl, alkoxy, haloalkyl and hydroxyalkyl are optionally replaced by one or more selected from the group consisting of alkyl, alkoxy, halogen, mercapto , hydroxy, nitro, cyano, aryl, heteroaryl and heterocycloalkyl; in some embodiments, the substituent is selected from C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy, Halogen, heteroaryl and heterocycloalkyl; one is selected from C _1-3 alkyl, C _1-3 alkoxy _and heterocycloalkyl _; in some embodiments, the substituent is selected from methyl, ethyl, Methoxy, Ethoxy and Tetrahydrofuryl.

、

、

、

、

、

和

，其中Z₂如上述所定義。 In some embodiments, the R ₁ is selected from

,

,

,

,

,

and

, where _Z2 is as defined above.

、

、

、

、

、

和

，其中Z₂如上述所定義。 In some embodiments, the R ₁ is selected from

,

,

,

,

,

and

, where _Z2 is as defined above.

The present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,

Wherein, -L ₁ -is selected from a bond, C ₁ - ₆ alkylene, -O- and -NH-, and the C ₁ - ₆ alkylene is optionally selected from one or more hydroxyl groups , alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents;

R ₂ and _{R 3} are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, pendant oxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally replaced by one or more selected from halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkane Substituents of radical, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R ₂ and R ₃ together form a 3-8 membered ring, the 3-8 membered ring is optionally replaced by one or more a Z ₃ replacement;

R ₄ is -L ₂ -R ₇ ;

_R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Pendant Oxy , carboxyl and carboxylate substituent substitution;

_R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more _Z ;

-L ₂ -is selected from bond, C ₁ - ₆ (alkylene) alkylene, -O- and -NH-, the (alkylene)alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy Substituents of radical, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;

； R ₆ is selected from H, R ₈ -(C=O)- and

;

R ₈ is an alkyl group, preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, and most preferably _a methyl group _;

R ₉ and R ₁₀ are each independently selected from hydrogen, alkyl, cycloalkyl _, preferably selected from hydrogen, C _1-6 alkyl and _3-7 membered cycloalkyl, more preferably selected from hydrogen, C _1-3 Alkyl and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;

Each X is independently selected from O, S and NH, preferably O;

Z ₁ , Z ₂ , Z ₃ and Z ₄ are each independently selected from halogen, cyano, hydroxyl, nitro, side oxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, -SR', -SOR', -SO ₂ R', -SO ₂ NR'(R"), -NR'(R"), -COR', -COOR' , -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and The heteroaryl groups are each independently optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitr radical, -NR'(R"), -SOR', -SO ₂ R', -SO(NH)R', -S(NH)R', cyano, cycloalkyl, heterocycloalkyl, aryl , heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl and carboxylate substituents;

Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, the alkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto , hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, side oxygen Substituent substitution of group, carboxyl group and carboxylate group;

m and n are each independently selected from 0, 1 or 2.

In some embodiments, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, which is a compound represented by formula II, wherein, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , L ₁ and Z ₂ are as defined in the compound shown in formula I,

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein L ₁ is -O-.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein the R ₂ and R ₃ are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro and pendant Oxygen is preferably selected from hydrogen, halogen and C _1-6 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein R ₂ and R ₃ are each independently hydrogen.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from C ₁ - ₆ alkyl, C _{3 -7} cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl; _the R ₇ is optionally substituted by one or more Z ₄ selected from Fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from C ₁ - ₆ alkyl, C _{3 -7} cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl; _the R ₇ is optionally substituted by one or more Z ₄ selected from Fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from C ₁ - ₄ alkyl, C _{3 -5} cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, the R ₇ is optionally substituted by one or more Z ₄ , the Z ₄ is selected from fluorine, chlorine, bromine, methyl, Ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from C ₁ - ₄ alkyl, C _{3 -5} cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, the R ₇ is optionally substituted by one or more Z ₄ , the Z ₄ is selected from fluorine, chlorine, bromine, methyl, Ethyl, Propyl and Isopropyl.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, second butyl, third butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrimidyl Azinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, the R ₇ is optionally substituted by one or more Z ₄ selected from fluorine, chlorine, bromine, methyl, ethyl _, propyl radical, isopropyl, cyano, hydroxyl and haloalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, second butyl, third butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrimidyl Azinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, the R ₇ is optionally substituted by one or more Z ₄ selected from fluorine, chlorine, bromine, methyl, ethyl _, propyl base and isopropyl.

、環丙基、苯基和吡啶基；該R₇視需要地被一個或多個Z₄取代，該R₇視需要地被一個或多個Z₄取代，該Z₄選自氟、氯、溴、甲基、乙基、丙基、異丙基、氰基、羥基和鹵烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ , the R ₇ is optionally substituted by one or more Z ₄ , the Z ₄ is selected from fluorine, chlorine, Bromo, methyl, ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.

、環丙基、苯基和吡啶基；該R₇視需要地被一個或多個Z₄取代，該R₇視需要地被一個或多個Z₄取代，該Z₄選自氟、氯、溴、甲基、乙基、丙基和異丙基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ , the R ₇ is optionally substituted by one or more Z ₄ , the Z ₄ is selected from fluorine, chlorine, Bromo, Methyl, Ethyl, Propyl and Isopropyl.

In an optional embodiment, the present disclosure provides the compound shown in formula II, wherein, the R ₅ is selected from hydrogen, C _1-6 alkyl and halogen, and optionally, the R ₅ is hydrogen or C _1-3 alkane base.

In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein L ₁ is -O-, R ₂ and R ₃ are each independently hydrogen, and R ₅ is hydrogen.

；該X為-O-，該R₉和R₁₀各自獨立地選自氫、烷基和環烷基，可選的，R₉和R₁₀各自獨立地選自氫、 C1-6烷基和3-7員環烷基，可選的，R₉和R₁₀各自獨立地選自氫、C_1-3烷基和環丙基，可選的，R₉和R₁₀各自獨立地為氫甲基或乙基。 In an optional embodiment, the R ₆ is H or

; The X is -O-, the R ₉ and R ₁₀ are each independently selected from hydrogen, alkyl and cycloalkyl, optionally, R ₉ and R ₁₀ are each independently selected from hydrogen, C1-6 alkyl and 3-7 membered cycloalkyl, optional, R ₉ and R ₁₀ are each independently selected from hydrogen, C _1-3 alkyl and cyclopropyl, optional, R ₉ and R ₁₀ are each independently hydrogen methyl base or ethyl.

In an alternative embodiment, R ₆ is H.

。 In an optional embodiment, wherein, R ₆ is

.

、

、

和

。 In an optional embodiment, _R is selected from

,

,

and

.

In an optional embodiment, the present _disclosure provides a compound represented by formula II, wherein Z ₂ is selected from cyano, hydroxyl, nitro, _pendant oxy, C _1-6 alkyl, C _1-6 alkoxy , C ₁ - ₆ haloalkyl and C ₁ - ₆ hydroxyalkyl; the alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently selected from the group consisting of alkyl, alkoxy , deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy substituents.

In an optional embodiment, the present _disclosure provides a compound represented by formula II, wherein Z ₂ is selected from cyano, hydroxyl, nitro, _pendant oxy, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 haloalkyl and C _1-6 hydroxyalkyl; the _alkyl , alkoxy, haloalkyl and hydroxyalkyl are each independently selected from _cyano , C _1- Substituents of ₆ alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy.

In an optional embodiment, the present _disclosure provides a compound represented by formula II, wherein Z ₂ is selected from cyano, hydroxyl, nitro, _pendant oxy, C _1-6 alkyl, C _1-6 alkoxy , C _1-6 haloalkyl and C _1-6 hydroxyalkyl; _the alkyl, alkoxy, haloalkyl _and hydroxyalkyl are each independently selected from cyano, methyl, Substituents of ethyl, methoxy, monodeuteromethoxy, dideuteriomethoxy, trideuteromethoxy, 3 to 7 membered cycloalkyl and 3 to 7 membered heterocycloalkyl.

In an optional embodiment, the _{present disclosure provides a compound represented by formula II, wherein Z 2 is selected from cyano, C 1-6 alkyl , C 1-6} alkoxy, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; the alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently selected from cyano, methyl, ethyl, methoxy, _a deuterium Substituents of substituted methoxy, dideuteriomethoxy, trideuteriomethoxy, 3 to 7 membered cycloalkyl and 3 to 7 membered heterocycloalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl , -COOR' and -CONR'(R"); the alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl are optionally selected from one or more of halogen, mercapto, hydroxyl, -NR'(R") , -SOR', -SO ₂ R', -SO(NH)R' and -S(NH)R' are substituted by substituents;

Each R' or R" is independently selected from hydrogen, hydroxy and alkyl optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, The C _1-6 alkyl or 3 to 7 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, mercapto and -NR'(R"), each R' or R" such as The claim is defined in the compound shown in formula IG.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each R' or R" is independently hydrogen or C _1-6 alkyl, and the C _1-6 Alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each R' or R" is independently hydrogen or C _1-6 alkyl, and the C _1-6 Alkyl is optionally substituted with one or more deuteriums.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, The C _1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more hydroxyl groups.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, The C _1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more mercapto groups.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, The C _1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more -NR'(R"), and the R' or R" are independently hydrogen.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, The C _1-6 alkyl or 3 to 7-membered cycloalkyl is substituted by one or more -NR'(R"), the R' or R" are independently hydrogen or C _1-6 alkyl, the C _{1 -6} alkyl is optionally substituted with one or more deuteriums.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, The C _1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more -NR'(R"), the R' or R" are independently hydrogen or methyl, and the methyl is optionally replaced by a , two or three deuterium substitutions.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-6 alkyl group, and the C _1-6 alkyl group is represented by One or more halogen substitutions.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-6 alkyl group, and the C _1-6 alkyl group is represented by Substituted by one or more hydroxyl groups.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-6 alkyl group, and the C _1-6 alkyl group is represented by One or more cyano substitutions.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-6 alkyl group, and the C _1-6 alkyl group is represented by Substituted by one or more alkoxy groups.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-6 alkyl group, and the C _1-6 alkyl group is represented by One or more C _1-6 alkoxy substituted.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-6 alkyl group is represented by One or more C _1-3 alkoxy substituted.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently C _1-3 alkyl, and one or more fluorines are substituted.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-6 alkyl group, and the C _1-6 alkyl group depends on need to be substituted by one or more substituents selected from -SOR', -SO ₂ R', -SO(NH)R' and -S(NH)R';

Each R' or R" is independently C _1-6 alkyl optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on need to be replaced by one or more SOR';

R' is selected from C _1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on Need to be substituted by one or more SOR', R' is C _1-3 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on need to be replaced by one or more SO ₂ R';

R' is selected from C _1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on Need to be substituted by one or more -SO ₂ R';R' is C _1-3 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on need to be replaced by one or more -SO(NH)R';

R' is selected from C _1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on Need to be substituted by one or more -SO(NH)R';R' is C _1-3 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on need to be replaced by one or more -S(NH)R';

R' is selected from C _1-6 alkyl, which is optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl, and cyano.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently a C _1-3 alkyl group, and the C _1-3 alkyl group depends on need to be replaced by one or more -S(NH)R';

R' is C _1-3 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently -COOR', and the R' is independently selected from hydrogen, hydroxyl and C _1-6 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z ₂ is independently -COOR', and the R' is hydrogen.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently -CONR'(R"), and the R' or R" are independently _{is selected from hydrogen or C 1-6 alkyl} optionally substituted with one or more deuteriums.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z ₂ are each independently -CONR'(R"), and the R' or R" are independently is hydrogen or methyl optionally substituted with one, two or three deuteriums.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein L ₁ is -O-.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein the R ₂ and R ₃ are each independently selected from hydrogen, halogen, C _1-6 alkyl , cyano, hydroxyl, nitro and side oxygen, preferably selected from hydrogen, halogen and C _1-6 alkyl, more preferably hydrogen.

、環丙基、苯基和吡啶基；該R₇視需要地被一個或多個Z₄取代，該Z4如式I-G所示化合物中定義。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from From C ₁ - ₆ alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C ₁ - ₄ alkyl , C _3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second Butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and Oxazolyl, preferably selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ , and the Z 4 is as defined in the compound shown in formula IG.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein the _Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, iso Propyl, cyano, hydroxy and haloalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein the _Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and iso Propyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein the R ₅ is selected from hydrogen, C _1-6 alkyl and halogen.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein, wherein, the R ₅ is hydrogen or C _1-3 alkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein L ₁ is -O-, R ₂ and R ₃ are each independently hydrogen, and R ₅ is hydrogen.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein R ₆ is H.

In an optional embodiment, the present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,

Z _is selected from halogen, cyano, hydroxy, nitro, pendant oxy, alkyl, alkoxy, haloalkyl and hydroxyalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,

Z ₁ is selected from halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 hydroxyalkyl.

In an optional embodiment, the present disclosure provides a compound represented by formula IG or a pharmaceutically acceptable salt thereof, wherein Z ₁ is halogen.

In an optional embodiment, the present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein n is 0.

In an optional embodiment, the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula III or a compound represented by formula IV or a pharmaceutically acceptable salt thereof,

Wherein, R ₄ , R ₅ , X, R ₉ , R ₁₀ and Z ₂ are as defined in the compound shown in formula I or the compound shown in formula II.

In an optional embodiment, the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula V or a compound represented by formula VI or a pharmaceutically acceptable salt thereof,

Wherein, R ₄ , R ₅ , X, R ₉ , R ₁₀ and Z ₂ are respectively as defined in the compound shown in formula I or the compound shown in formula II.

、

、

、

或

。 In some embodiments, the R ₁ is selected from

,

,

,

or

.

、

、

、

In some embodiments, the R ₁ is

,

,

,

In some embodiments, the _Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl , ethyl, propyl and isopropyl.

In some embodiments, the _Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl , ethyl, propyl and isopropyl.

In some embodiments, the R' or R" are independently hydrogen or hydroxyl.

In the second aspect, the present disclosure also provides a series of compounds selected from:

、

、

和

或其可藥用的鹽。

,

,

and

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides a series of compounds selected from:

、

、

、

、

和

。 Compounds provided by this disclosure are not:

,

,

,

,

and

.

The present disclosure also provides isotope substitutions of the above-mentioned compounds, and in some embodiments, the isotope substitutions are deuterium atom substitutions.

In an alternative embodiment, the disclosure provides a deuterated version of the following compound,

In the third aspect, the present disclosure also provides a preparation method of the compound described in the first or second aspect or a pharmaceutically acceptable salt thereof.

In some embodiments, the following steps are included:

；其中，

;in,

The compound shown in formula I-5 and the compound shown in formula I-6 are subjected to substitution reaction under basic conditions to obtain the compound shown in formula I;

The reagent for alkaline conditions is an organic base or an inorganic base, and the organic base is selected from triethylamine, N , N -diisopropylethylamine, n-butyllithium, diisopropylamide lithium, bistrimethylsilane Lithium base amide, potassium acetate, sodium tertiary butoxide and potassium tertiary butoxide; the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium tertiary butoxide, acetic acid Potassium, Cesium Carbonate, Sodium Hydroxide and Lithium Hydroxide;

LG ₃ is phenoxy or 4-nitrophenoxy.

In some embodiments, the following steps are included: the step of removing the protecting group PG from the compound represented by formula X under acidic conditions,

Among them, R ₂ , R ₃ , R ₄ , R ₅ , L ₁ and Z ₂ are as defined in claim 1, R ₆ is hydrogen, PG is an amino protecting group, which can be selected from tertiary butyl, acetyl , trifluoroacetyl, trityl, benzyl and formyl.

The present disclosure also provides a compound represented by formula X,

Wherein, R ₂ , R ₃ , R ₄ , R ₅ , L ₁ and Z ₂ are as defined in the compound shown in formula I, II, III, IV, V or IV, and PG is an amino protecting group, which can be selected from the Tributyl, acetyl, trifluoroacetyl, trityl, benzyl and formyl.

The present disclosure also provides a compound represented by formula XI,

Wherein, X is selected from halogen, and R is selected from alkyl, deuterated alkyl, heterocycloalkyl and cycloalkyl.

In the fourth aspect, the present disclosure also provides a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt thereof as described in the first or second aspect, and at least one pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

In certain 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 compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% pharmaceutically acceptable excipients.

In the fifth aspect, the present disclosure also provides a method for preventing and/or treating a patient suffering from a disease related to cyclin-dependent kinase, by administering to the patient a therapeutically effective amount of the compound disclosed herein or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition.

In another aspect, the present disclosure also provides a method for preventing and/or treating a patient suffering from a cell cycle protein-related disease, by administering to the patient a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof or The aforementioned pharmaceutical composition.

In some embodiments, the cyclin-dependent kinase-associated disease or cyclin-associated disease is preferably a cell proliferative disease, cancer or immune disease.

In some embodiments, the cyclin-dependent kinase-associated disease or cyclin-associated disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, Colorectal, lung, kidney, skin, glioblastoma, neuroblastoma, and sarcoma.

In some specific embodiments, the cancer is selected from cyclin E1 and/or cyclin E2 amplified cancers.

The present disclosure also provides a method for preventing and/or treating a patient suffering from cancer, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, the cancer Breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, and sarcoma .

The present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases related to cyclin-dependent kinases.

In some specific embodiments, the cyclin-dependent kinase is CDK2, and the disease associated with the cyclin-dependent kinase is selected from cell proliferative diseases, cancer or immune diseases.

In another aspect, the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases related to cell cyclins .

In some specific embodiments, the cyclin is selected from cyclin E, such as cyclin E1, cyclin E2. The cyclin-associated disease is selected from cell proliferative disease, cancer or immune disease.

In some embodiments, the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for treating cancer.

In some specific embodiments, the cancer is 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, adult Glioma, neuroblastoma, and sarcoma.

In some specific embodiments, the cancer is selected from cyclin E1 and/or cyclin E2 amplified cancers. The pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic salts or organic salts, and the compounds described in this disclosure can react with acidic or basic substances to form corresponding salts. The disclosed compounds have a good inhibitory effect on cyclin-dependent kinases, and the IC ₅₀ value of the inhibitory activity on CDK2/cyclin E is 0.01 to 1000nM, and the inhibitory activity of some compounds on CDK2/cyclin E The IC ₅₀ value of the inhibitory activity of some compounds on CDK2/cyclin E is in the _{range of 0.01 to 300nM, and the IC 50 value} of the inhibitory activity of some compounds on CDK2/cyclin E is in the range of 0.01 The inhibitory activity of some compounds on CDK2/cyclin E has _IC50 values from 0.01 to 100nM up to 200nM, and the inhibitory activity of some compounds on CDK2/cyclin E has IC50 values <100nM.

Some embodiments provide compounds that achieve <50 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <20 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve <10 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds with CDK2/cyclin E inhibitory activity to <5nM. Other embodiments provide compounds that achieve <1 nM inhibitory activity against CDK2/cyclin E.

On the other hand, the disclosed compounds also have a good inhibitory effect on CDK2/cyclin A. Some embodiments provide compounds that achieve <500 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <200 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <150 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve <100 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <50 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <20 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve <10 nM inhibitory activity against CDK2/cyclin E.

In other embodiments, the compounds disclosed herein have weak inhibitory activity on other kinases such as CDK4, CDK5, CDK7, CDK9 or GSK3β, and have CDK2-specific selection.

On the other hand, compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as 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 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 interconversion Isomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine, lactam-lactimine, pyrazolyl isomerizations.

An example of a pyrazolyl equilibrium is between E and F as shown below:

Specific to this disclosure:

All tautomeric forms are within the scope of the invention. The naming of compounds does not exclude any tautomers.

Compounds of the present disclosure may be asymmetric, eg, possess one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

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 chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art diastereoisometry Constituents were resolved and then recovered to obtain the pure enantiomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally combined with chemical derivatization methods (e.g. amines to amines formate).

The disclosure also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally 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 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, etc.

Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. The present disclosure also includes various deuterated forms of compounds of formula I. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound of formula I. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula I, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optionally" or "optionally" means that the subsequently described event or circumstance can 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 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. And the case of cyano substitution.

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。雖然為簡便起見將全部上述結構式畫成某些異構體形式，但是本發明可以包括所有的異構體，如互變異構體、旋轉異構體、幾何異構體、非對映異構體、外消旋體和對映異構體。本揭露所述化合物的化學結構中，鍵“

”並未指定構型，即鍵“

”的構型可以為E型或Z型，或者同時包含E和Z兩種構型。 In the chemical structure of the compound described in the present invention, the bond "

"indicates that no configuration is specified, i.e. if chiral isomers exist in the chemical structure, the bond"

"can be"

"or"

, or both "

"and"

"Two configurations. Although all of the above structural formulas are drawn as certain isomer forms for simplicity, the present invention may include all isomers, such as tautomers, rotamers, geometric isomers Body, diastereoisomer, racemate and enantiomer. In the chemical structure of the compound described in this disclosure, the bond "

"No configuration specified, i.e. key"

The configuration of " can be E-type or Z-type, or contain both E-type and Z-type configurations.

Explanation of terms:

The term "pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically acceptable salt or prodrug thereof and other chemical components, as well as other components such as a physiologically acceptable carrier and excipient. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration for use in humans or livestock animals. excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifier.

The term "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred is an alkyl group containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second Butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-di Methylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Pentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably the substituents are one or more of the following groups independently selected from alkyl group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "alkylene" means what remains of an alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms. An alkylene group containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH ₂ -), ethylidene (such as -CH ₂ CH ₂ - or -CH(CH ₃ )-), propylidene (such as -CH ₂ CH ₂ CH ₂ - or -CH(CH ₂ CH ₃ )-), butylene (such as -CH ₂ CH ₂ CH ₂ CH ₂ -). Unless otherwise specified, an alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings. 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 groups, independently selected from alkyl, alkenyl , alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The cycloalkyl ring may be fused to an aryl or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl Alkyl etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more The following groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkane radical, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen or A heteroatom of S(O) _m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperrolyl, Pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls. Non-limiting examples of "heterocycloalkyl" include:

和

，等等。

and

,etc.

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

和

等。

and

wait.

Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, Cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate substituted.

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 members, e.g. phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded 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 of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio , Heterocycloalkylthio, pendant oxygen, carboxyl or carboxylate substituted.

，

、

等。 The term "heteroaryl" refers to a heteroaromatic system comprising 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 5 or 6 members. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl,

,

,

wait.

The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring where the ring bonded 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 groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cyclo Substituted by alkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "spiro" refers to a compound in which two rings share one atom.

The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is divided into single spirocycloalkyl, double spirocycloalkyl or multi-spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl . More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spirocycloalkyl group. "Spirocarbocycle" refers to the ring system in a spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group that shares one atom (called spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) heteroatoms of _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Spiroheterocycloalkyl is divided into single spiroheterocycloalkyl, double spiroheterocycloalkyl or polyspiroheterocycloalkyl according to the number of spiro atoms shared between the ring and the ring, preferably single spiroheterocycloalkyl and Double spiroheterocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocycloalkyl group. "Spiroheterocycle" refers to the ring system in a spiroheterocycloalkyl. Non-limiting examples of spiroheterocycloalkyl include:

The terms "fused ring" and "joined ring" are used interchangeably, and refer to a compound in which two or more rings are fused by sharing two adjacent atoms.

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring of which shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. "Fused carbocycle" refers to the ring system in a fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group of 5 to 20 members in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), The remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic condensed heterocyclic ring alkyl. "Fused heterocycle" refers to the ring system in a fused heterocycloalkyl group. Non-limiting examples of fused heterocycloalkyl include:

The term "fused heteroaryl" may contain 5-14 ring atoms (including at least one heteroatom), which is formed by connecting two or more ring structures with two adjacent atoms. Aromatic fused ring structure, including carbon atoms, nitrogen atoms and sulfur atoms can be oxidized, preferably "5-12 member fused heteroaryl", "7-12 member fused heteroaryl", "9-12 member Fused heteroaryl" etc., such as benzofuryl, benzoisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazole, indazolyl, benzotri Azolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, Acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, etc. . "Fused heteroaryl ring" refers to a ring system in a fused heteroaryl group.

Fused heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carboxyl or carboxylate. The term "bridged ring" refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.

The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The term "bridged heterocycloalkyl" refers to a 5 to 14 membered, polycyclic heterocycloalkyl group of 5 to 14 members, any two rings sharing two atoms not directly attached, which may contain one or more double bonds, but none of the rings has A fully conjugated π-electron system wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocycloalkyl groups include:

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxo group, carboxyl group or carboxylate group substituted.

The term "hydroxyl" refers to a -OH group.

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

The term "haloalkyl" refers to an alkyl group substituted by halogen, wherein alkyl is as defined above.

The term "heterocycloalkyloxy" refers to heterocycloalkyl-O-, wherein heterocycloalkyl is as defined above.

The term "heterocycloalkylthio" refers to heterocycloalkyl-S-, wherein heterocycloalkyl is as defined above.

The term "side oxygen" refers to the =0 group. For example, a carbon atom is connected to an oxygen atom by a double bond, where a ketone or aldehyde group is formed.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "carboxy" refers to -C(O)OH.

The term "substituted" refers to one or more hydrogen atoms in a group, preferably at most 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort.

"Substituted by one or more" means that it can be substituted by single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or one or a combination of a plurality of different substituents.

The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

The experimental methods in the examples of the present disclosure that do not indicate specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased in the market.

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is carried out with Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is tetramethyl silane (TMS).

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

The determination of HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatography (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column).

Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um column;

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 of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.

The chiral preparation column used DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

The CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).

The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

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

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

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

Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the eluting agent system and the developing agent system of the column chromatography that the purified compound adopts and the thin-layer chromatography, the solvent The volume ratio is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

cis 3-(5-((3-(methoxymethyl)-1-methyl- 1H -pyrazolo[ 3,4-c ]pyridin-7-yl)amino) -1H -pyrazole -3-yl) cyclopentyl isopropyl carbamate 1

first step

N -2-Dimethoxy- N -methylacetamide 1B

At room temperature, sequentially dissolve compound 1A (13.5g, 0.12mol), methoxylamine hydrochloride (13.4g, 0.14mol) in 100mL of anhydrous dichloromethane, and add triethylamine dropwise at 0-5°C (37.8 g, 0.37 mol). After dripping, it was slowly raised to room temperature and reacted overnight. After the reaction was complete, 150 mL of water was added to quench the reaction, extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), and anhydrous Dry over sodium sulfate, filter, collect the filtrate, concentrate under reduced pressure and column chromatography to obtain the title compound 1B (12 g, yield: 72%).

second step

1-(2-Chloro-3-fluoropyridin-4-yl)-2-methoxyethan-1-one 1C

-65°C, dissolve 2-chloro-3-fluoropyridine (12.6g, 75.7mmol) in 40mL of anhydrous tetrahydrofuran, slowly add n-butyl lithium (35.8mL, 2.5N solution in tetrahydrofuran) dropwise, and maintain the internal temperature at - Stirring was continued for 1 hour at 55°C, then Compound 1B (8.5g, 63.8mmol) was dissolved in 40mL of anhydrous THF and slowly added dropwise to the reaction solution, and stirring was continued at -65°C for 1 hour after the addition was complete. Quenched with 100 mL of saturated ammonium chloride solution, extracted with ethyl acetate (50 mL×3), combined the organic phases, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, collected the filtrate, and concentrated under reduced pressure Column chromatography gave the title compound 1C (6.0 g, yield: 46%). LCMS (ESI) m/z 204.1 [M+H] ⁺ .

third step

7-Chloro-3-(methoxymethyl) -1H -pyrazolo[ 3,4-c ]pyridine 1D

At room temperature, sequentially dissolve compound 1C (3.0g, 14.7mmol), sodium bicarbonate (1.24g, 14.7mmol), hydrazine hydrate (0.79mL, 16.2mmol) in 18mL of dioxane and 3mL of ethanol, seal the tube The temperature was raised to 70°C and stirring was continued for 15 hours. After the reaction was complete, filter and spin the filtrate to column chromatography to obtain the title compound 1D (2 g, yield: 68%). LCMS (ESI) m/z 198.1 [M+H] ⁺ .

the fourth step

7-Chloro-3-(methoxymethyl)-1-methyl- 1H -pyrazolo[ 3,4-c ]pyridine 1E

At room temperature, compound 1D (0.9g, 4.6mmol) was dissolved in 5mL of N,N -dimethylformamide, the temperature was cooled to 0-5°C in an ice bath, cesium carbonate (4.45g, 13.6mmol) was added, and the temperature was After stirring for 20 minutes, methyl iodide (0.71 g, 5 mmol) was added dropwise, and after the addition was completed, it was slowly raised to room temperature and reacted for 2 hours. After the reaction was complete, it was quenched with 50 mL of water, followed by extraction with ethyl acetate (30 mL×3), The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and concentrated under reduced pressure. Column chromatography gave the title compound 1E (0.30 g, yield: 31%). LCMS (ESI) m/z 212.1 [M+H] ⁺ .

the fifth step

cis 3-(1-(tert-butyl)-5-((3-(methoxymethyl)-1-methyl- 1H -pyrazolo[ 3,4-c ]pyridin-7-yl )amino) -1H -pyrazol-3-yl)cyclopentylisopropylcarbamate 1F

Under nitrogen atmosphere, compound 1E (100mg, 0.47mmol), cis 3-(5-amino-1-(tertiary butyl) -1H -pyrazol-3-yl)cyclopentylisopropylaminomethyl Ester 1-INT (0.15g, 0.47mmol, prepared by the method disclosed in the patent application "WO 2020/157652 A2"), sodium tert-butoxide (0.9g, 0.94mmol), XPhos (9mg, 0.02mmol, A mixture of 4 mol%), Pd(dba) ₂ (5.4 mg, 0.01 mmol, 2 mol%) and toluene (2 mL) was maintained at 100°C for 19 hours. The reaction solution was concentrated and purified by silica gel chromatography to obtain the title compound 1F (130 mg, yield: 56%).

MS (ESI) m/z 484.6 [M+H] ⁺ .

step six

cis 3-(5-((3-(methoxymethyl)-1-methyl- 1H -pyrazolo[ 3,4-c ]pyridin-7-yl)amino) -1H -pyrazole -3-yl) cyclopentyl isopropyl carbamate 1

Under a nitrogen atmosphere, compound 1F (60mg, 0.12mmol) was dissolved in 2mL formic acid, heated at 75°C for 20 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was adjusted to pH with saturated sodium bicarbonate solution =7, extracted with ethyl acetate (15mL×3), combined the organic phases, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, collected the filtrate, concentrated under reduced pressure, and the residue was used as a silica gel tube column layer Analysis gave the title compound 1 (2 mg) as a pair of enantiomers.

MS (ESI) m/z 428.5 [M+H] ⁺ .

Example 2

(1R,3S)-3-(3-(Pyrazolo[1,5-a]pyrazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentylisopropylaminomethyl Ester 2

first step

N-(2,2-Dimethoxyethyl)-1H-pyrazole-5-carboxamide 2C

Under nitrogen atmosphere, compound 1H-pyrazole-3-carboxylic acid 2A (3.0g, 26.8mmol), O-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexa Fluorophosphate (12.2g, 32.1mmol), N,N-diisopropylethylamine (6.9g, 53.6mmol) and 2,2-dimethoxyethane-1-amine 2B (3.4g, 32.1mmol ) was dissolved in N,N-dimethylformamide (20 mL). The reaction was carried out at room temperature for 12 hours. Add 100ml of water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash the organic phases, dry, and concentrate under reduced pressure. The residue is purified by silica gel normal phase chromatography to obtain the title compound 2C (2.6 g, yield 48.8%).

second step

7-Hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 2D

Compound 2C (2.6 g, 13.1 mmol) was added to 4 mL of dichloromethane, and trifluoroacetic acid (4 mL) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure to obtain the title compound 2D (2.0 g, yield 100%).

third step

Pyrazolo[1,5-a]pyrazin-4(5H)-one 2E

Under nitrogen atmosphere, polyphosphoric acid (10 mL) was added to compound 2D (2.0 g, 13.1 mmol), and reacted at 140° C. for 3 hours. Add water (50ml), adjust the pH to 10 with ammonia water, extract with dichloromethane, combine the organic phases, wash the organic phases, dry, and concentrate under reduced pressure. The ester (3:1) solution was beaten, filtered, and the filter cake was dried to obtain the title compound 2E (1.1 g, yield 56.8%).

the fourth step

4-Chloropyrazolo[1,5-a]pyrazine 2F

Compound 2E (700mg, 5.2mmol) and N,N-diisopropylethylamine (669mg, 5.2mmol) were added to the reaction flask, phosphorus oxychloride (5mL) was added, and the reaction was carried out at 100°C for 2 hours. The reaction solution was lowered to room temperature, the reaction solution was poured into ice water (25ml), extracted with dichloromethane, the organic phases were combined, the organic phase was washed, dried, concentrated under reduced pressure, and the residue was purified by silica gel normal phase chromatography to obtain Title compound 2F (260 mg, 32.7% yield).

MS (ESI) m/z 154.4 [M+H] ⁺ .

the fifth step

(1R,3S)-3-(1-(tertiary-butyl)-5-(pyrazolo[1,5-a]pyrazin-4-ylamino)-1H-pyrazol-3-yl ) cyclopentyl isopropyl carbamate 2H

Under nitrogen atmosphere, compound 2F (40mg, 0.26mmol), (1R,3S)-3-(5-amino-1-(tertiary-butyl)-1H-pyrazol-3-yl)cyclopentyl Isopropyl carbamate 2G (80.3 mg, 0.26 mmol, prepared by the method disclosed in the patent application "WO 2020/157652 A2"), tris(dibenzylideneacetone) dipalladium (23.8 mg, 0.03 mmol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34.7 mg, 0.06 mmol) were dissolved in 1,4-dioxane (3 mL). Potassium carbonate (71.9mg, 0.52mmol) was added and reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to obtain the title compound 2H (53 mg, yield 47.7%).

MS (ESI) m/z 426.4 [M+H] ⁺ .

step six

(1R,3S)-3-(3-(Pyrazolo[1,5-a]pyrazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentylisopropylaminomethyl Ester 2

Compound 2H (53mg, 0.12mmol) was dissolved in 3mL formic acid and reacted at 80°C for 18 hours. After cooling to room temperature, the reaction solution was directly purified by C-18 reverse phase chromatography to obtain the title compound 2 (10 mg, yield 21.7%).

MS (ESI) m/z 370.4 [M+H] ⁺ .

Example 3

(1R,3S)-3-(3-((2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl isopropyl carbamate 3

first step

Ethyl-5-methoxy-2,4-dicarbonylpentanoate 3C

1-Methoxypropan-2- one 3A (2.5 g, 28.4 mmol) was dissolved in ethanol (20 mL) under nitrogen atmosphere. Cool down to 0°C, add potassium tert-butoxide (3.2g, 28.4mmol) in batches at 0°C, stir at 0°C for half an hour, add diethyl oxalate 3B (4.2g, 28.4mmol), and React for 18 hours. The pH was adjusted to 4 with dilute hydrochloric acid (1 mol/l), extracted with dichloromethane, the organic phases were combined, washed, dried, and concentrated under reduced pressure to obtain the title compound 3C (2.1 g, yield 39.6%).

second step

Ethyl-3-(methoxymethyl)-1H-pyrazole-5-carboxylate 3D

Compound 3C (2.1 g, 11.2 mmol) was added into 15 mL of ethanol, and hydrazine hydrate (50%wt, 0.7 g, 11.2 mmol) was added. React at 70°C for 1 hour, cool to room temperature, add water (50ml), extract with ethyl acetate, combine the organic phases, wash the organic phases, dry, and concentrate under reduced pressure to obtain the title compound 3D (1.2g, yield 58.4%).

MS (ESI) m/z 185.5 [M+H] ⁺ .

third step

3-(Methoxymethyl)-1H-pyrazole-5-carboxylic acid 3E

Dissolve compound 3D (1.2g, 7.7mmol) in 10mL of methanol, add 2mL of water, add lithium hydroxide (368mg, 15.4mmol), react at room temperature for 5 hours, adjust the pH with dilute hydrochloric acid (1mol/L) to 1, extracted with ethyl acetate, combined the organic phases, washed the organic phases, dried, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to obtain the title compound 3E (850 mg, yield 83.6%).

MS (ESI) m/z 157.1 [M+H] ⁺ .

the fourth step

N-(2,2-dimethoxyethyl)-3-(methoxymethyl)-1H-pyrazole-5-carboxamide 3F

Compound 3E (750mg, 4.8mmol), 1-propylphosphoric anhydride (50%wt, 3.4g, 5.3mmol), N,N-diisopropylethylamine (1.2g, 9.6mmol), 2,2- Dimethoxyethane-1-amine 2B (555 mg, 5.3 mmol) was dissolved in N,N-dimethylformamide (15 mL). The reaction was carried out at room temperature for 12 hours. 100ml of water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed, dried, and concentrated under reduced pressure to obtain the title compound 3F (1.1 g, yield 100%).

MS (ESI) m/z 242.2 [MH] ^- .

the fifth step

7-Hydroxy-2-(methoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 3G

Compound 3F (1.1 g, 5.6 mmol) was added to 4 mL of dichloromethane, and trifluoroacetic acid (4 mL) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure to obtain the title compound 3G (1.2 g, yield 100%).

step six

2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4(5H)-one 3H

Methanesulfonic acid (8 mL) was added to compound 3G (1.2 g, 6.1 mmol) and reacted at room temperature for 3 days. The reaction solution was directly purified by C-18 reverse phase chromatography to obtain the title compound 3H (430 mg, yield 39.4%).

MS (ESI) m/z 180.2 [M+H] ⁺ .

step seven

4-Chloro-2-(methoxymethyl)pyrazolo[1,5-a]pyrazine 3I

Compound 3H (110mg, 0.6mmol) and N,N-diisopropylethylamine (72mg, 0.6mmol) were added to the reaction flask, phosphorus oxychloride (3mL) was added, and the reaction was carried out at 100°C for 2 hours. The reaction solution was lowered to room temperature, the reaction solution was poured into ice water (20ml), extracted with dichloromethane, the organic phases were combined, the organic phase was washed, dried, concentrated under reduced pressure, and the residue was purified by silica gel normal phase chromatography to obtain Title compound 3I (86 mg, 71.1% yield).

MS (ESI) m/z 198.1 [M+H] ⁺ .

eighth step

(1R,3S)-3-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amine Base)-1H-pyrazol-3-yl)cyclopentyl isopropyl carbamate 3J

Under a nitrogen atmosphere, compound 3I (60 mg, 0.3 mmol), compound 2G (93.8 mg, 0.3 mmol, prepared by the method disclosed in the patent application "WO 2020/157652 A2"), tris(dibenzylideneacetone) Dipalladium (27.5 mg, 0.03 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34.7 mg, 0.06 mmol) in 1,4-dioxane (3 mL) . Potassium carbonate (82.9mg, 0.6mmol) was added and reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product of the title compound 3J (52mg, yield 36.4%)

MS (ESI) m/z 470.5 [M+H] ⁺ .

Ninth step

(1R,3S)-3-(3-((2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl isopropyl carbamate 3

Compound 3J (52mg, 0.11mmol) was dissolved in 3mL formic acid and reacted at 80°C for 18 hours. After cooling to room temperature, the reaction solution was directly purified by C-18 reverse phase chromatography to obtain the title compound 3 (12.6 mg, yield 27.5%).

MS (ESI) m/z 414.4 [M+H] ⁺ .

1H NMR: (400MHz,DMSO- d ₆ ) δ =ppm 10.02(s,1H),8.02-8.00(d, J =4.8Hz,1H),7.38-7.37(d, J =4.8Hz,1H),7.28 (s,1H),6.96-6.94(d, J =7.2,Hz,1H),6.58(s,1H),5.01(s,1H),4.55(s,2H),3.60-3.54(m,1H) ,3.32(s,3H),3.10-3.06(m,1H),2.05-2.03(m,1H),1.91-1.90(m,1H),1.75-1.50(m,3H),1.50-1.45(m, 1H), 1.03-1.02(d, J =6.0Hz, 6H).

Example 4

(1R,3S)-3-(3-((2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl (1-methylcyclopropyl) carbamate 4

first step

(1R,3S)-3-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino )-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate

Under nitrogen, (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopenta(1-methylcyclopropyl)aminomethyl Ester 4A (81.1 mg, 0.253 mmol, prepared by the method disclosed in patent application "WO 2020/157652 A2") was dissolved in tetrahydrofuran (2 mL). NaHMDS (0.278 mL, 0.557 mmol, 2M) was added under ice-cooling, and stirred at room temperature for 0.5 hours. Compound 3I (50 mg, 0.253 mmol) was added to the reaction solution, and the reaction solution was stirred at 60°C under nitrogen for 1 hour. The reaction solution was quenched with saturated ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product of the title compound 4B (35 mg).

MS (ESI) m/z 482.4 [M+H] ⁺ .

second step

(1R,3S)-3-(3-((2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl (1-methylcyclopropyl) carbamate

Compound 4B (35mg, 0.073mmol) was dissolved in 2mL of formic acid and reacted at 80°C for 2 hours. After cooling to room temperature, the reaction solution was concentrated and purified by reverse phase C-18 column chromatography to obtain the title compound 4 (15 mg, yield 48.5%).

MS (ESI) m/z 426.3 [M+H] ⁺ .

Example 5

(1R,3S)-3-(5-((2-((methoxy-d3)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyridine Azol-3-yl) cyclopentyl isopropyl carbamate 5

first step

(1R,3S)-3-(5-((2-(Bromomethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl) Cyclopentylisopropyl carbamate 5A

Under nitrogen, compound 3 (100mg, 0.242mmol) was dissolved in dichloromethane (0.2mL), boron tribromide (0.73mL, 0.726mmol, 1M) was added, and reacted overnight at room temperature. The reaction solution was quenched with methanol, concentrated under reduced pressure, and the crude product was subjected to reverse-phase column chromatography to obtain the title compound 5A (85 mg, yield 87.9%).

MS(ESI)m/z 462.3,464.3[M+H] ⁺

second step

(1R,3S)-3-(5-((2-((methoxy-d3)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyridine Azol-3-yl) cyclopentyl isopropyl carbamate 5

Compound 5A (40 mg, 0.087 mmol) was added to 2 mL of deuterated methanol, and potassium carbonate (18 mg, 0.131 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated. The crude product was subjected to reverse phase column chromatography to obtain the title compound 5 (20 mg, yield 55%).

MS (ESI) m/z 417.4 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ ) δ =12.12(s,1H),9.98(s,1H),8.01(d, J =4.7Hz,1H),7.37(d, J =4.7Hz,1H) ,7.27(s,1H),6.96(d, J =7.8Hz,1H),6.58(s,1H),5.01(s,1H),4.55(s,2H),3.58(h, J =6.7Hz, 1H), 3.08(t, J =9.0Hz, 1H), 2.11-1.54(m, 6H), 1.03(d, J =4.0Hz, 6H).

Example 6

(1R,3S)-3-(5-((2-(morpholinomethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl ) cyclopentyl isopropyl carbamate 6

Compound 5A (10 mg, 0.022 mmol) was added to 1 mL of dimethylsulfoxide, and morpholine (18 mg, 0.043 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated. The crude product was subjected to reverse-phase column chromatography to obtain the title compound 6 (3 mg, yield 30%).

MS (ESI) m/z 469.6 [M+H] ⁺ .

Example 7

(1R,3S)-3-(5-((2-(cyanomethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl) Cyclopentyl isopropyl carbamate 7

Compound 5A (10 mg, 0.022 mmol) was added to 1 mL of tetrahydrofuran, trimethylsilyl cyanide (6 mg, 0.066 mmol) and tetrabutylammonium fluoride (0.066 mL, 0.066 mmol, 1 M) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated. The crude product was subjected to reverse phase column chromatography to obtain the title compound 7 (2 mg, yield 22%).

MS (ESI) m/z 409.8 [M+H] ⁺ .

Example 8

(1R,3S)-3-(5-((2-(Hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl) Cyclopentyl isopropyl carbamate 8

To the cloudy solution of compound 3 (400 mg, 0.968 mmol) in dichloromethane (8 mL) was added dropwise a solution of boron trichloride in dichloromethane (1 mol/L, 6 mL). The reaction was carried out at room temperature for 3 hours. The reaction solution was poured into 50 mL of ice water, and a white solid was obtained by suction filtration. The white solid was purified by C-18 reverse phase chromatography to obtain the title compound 8 (200 mg, yield: 52%).

MS (ESI) m/z 400.4 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ ) δ =10.18(bs,1H),8.42(s,2H),7.98(d, J =4.0Hz,1H),7.35(d, J =4.0Hz,1H) ,7.27(s,1H),7.69(d, J =8.0Hz,1H),6.57(s,1H),5.04-5.02(m,1H),4.62(s,2H),3.63-3.54(m,1H ), 3.15-3.06 (m, 1H), 2.07-1.62 (m, 6H), 1.05-1.02 (m, 6H).

Example 9

(1R,3S)-3-(3-((2-((methylsulfonyl)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -5-yl) cyclopentyl isopropyl carbamate 9

first step

(1R,3S)-3-(3-((2-((methylthio)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole- 5-yl) cyclopentyl isopropyl carbamate 9A

Compound 5A (780 mg, 1.866 mmol) was dissolved in 6 mL of dimethylsulfoxide. Sodium methylthiolate (261 mg, 3.733 mmol) was added. React at room temperature for 1 hour. The reaction solution was poured into 50 mL of water, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phase was separated, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 9A (650 mg, Yield: 81%).

MS (ESI) m/z 430.20 [M+H] ⁺ .

second step

(1R,3S)-3-(3-((2-((methylsulfonyl)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -5-yl) cyclopentyl isopropyl carbamate 9

Compound 9A (540 mg, 1.257 mmol) was dissolved in 5 mL of dichloromethane. Add m-chloroperoxybenzoic acid (433.8 mg, 2.514 mmol) and react at room temperature for 16 hours. Add water (40mL) to the reaction solution, then extract with dichloromethane (50mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, collect the filtrate, concentrate the filtrate under reduced pressure, prepare and purify the crude product by HPLC, freeze-dry The title compound 9 (120 mg, yield: 19.03%) was obtained.

MS (ESI) m/z = 462.3 [M+H] ⁺ .

Example 10

(1R,3S)-3-(3-((2-(1-Hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl isopropyl carbamate 10

first step

Diethyl 1-(2,2-dimethoxyethyl)-1H-pyrazole-3,5-dicarboxylate 10B

Dissolve 1H-pyrazole-3,5-diethyl 10A (8 g, 37.699 mmol) in N,N-dimethylformamide (100 mL), add 2-bromo-1,1-dimethyl Oxyethane 10A-1 (7.65g, 45.238mmol), cesium carbonate (24.57g, 75.397mmol), react at 100°C for 16 hours. After the reaction, dilute the reaction solution with 300 mL of ethyl acetate, wash with 300 mL of water, separate the organic phase, and wash twice with 300 mL of saturated aqueous sodium chloride solution, collect the organic phase, dry over anhydrous sodium sulfate, filter, collect the filtrate, and concentrate the filtrate The crude product of the title compound was obtained, and the crude product was separated and purified by silica gel chromatography using petroleum ether/ethyl acetate as the eluent to obtain the title compound 10B (6.1 g, yield: 54%).

MS (ESI) m/z 269.1 [M-31] ⁺ .

second step

4-Hydroxypyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester 10C

Compound 10B (2g, 6.66mmol), ammonium acetate (10.27g, 133.196mmol), and acetic acid (6mL) were placed in a 25mL microwave tube and irradiated with microwaves at 150°C for 2 hours. Separation and purification by chromatography, and lyophilization gave the title compound 10C (320 mg, yield: 23%).

MS (ESI) m/z 208.1 [M+H] ⁺ .

third step

Ethyl 4-chloropyrazolo[1,5-a]pyrazine-2-carboxylate 10D

Compound 10C (800mg, 3.861mmol) was placed in a 100mL round bottom flask, phosphorus oxychloride (6mL) was added, and reacted at 100°C for 1 hour. After the reaction, concentrated under reduced pressure to obtain the crude product of the title compound, which was isolated by silica gel chromatography using petroleum ether/ethyl acetate as the eluent to obtain the title compound 10D (450 mg, yield: 52%).

MS (ESI) m/z 226.1 [M+H] ⁺ .

the fourth step

4-Chloropyrazolo[1,5-a]pyrazin-2-ethan-1-one 10E

At -60°C, under a nitrogen atmosphere, methylmagnesium bromide (0.9 mL, 1.773 mmol, 3M) was added dropwise to a solution of compound 10D (0.2 g, 0.886 mmol) in tetrahydrofuran (10 mL), slowly returned to room temperature, and the reaction 2 hours. After the reaction, add saturated ammonium chloride aqueous solution (10mL) to the reaction solution, extract with ethyl acetate (50mL), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product of the title compound, which is subjected to silica gel chromatography Using petroleum ether/ethyl acetate as the eluent, the title compound 10E (60 mg, yield: 35%) was obtained.

MS (ESI) m/z 196.1 [M+H] ⁺ .

the fifth step

(1R,3S)-3-(5-((2-Acetylpyrazolo[1,5-a]pyrazin-4-yl)amino)-1-(tert-butyl)-1H- Pyrazol-3-yl) cyclopentyl isopropyl carbamate 10F

At -60°C, under a nitrogen atmosphere, sodium bis(trimethylsilyl)amide (1.22mL, 1.227mmol) was added dropwise to a solution of compound 2G (95mg, 0.307mmol) in tetrahydrofuran (10mL). Stir for 0.5 hour, add compound 10E (60 mg, 0.307 mmol) dropwise at the same temperature, slowly return to room temperature, and stir for 1 hour. After the reaction, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of the title compound 10F (90 mg, yield: 63%).

MS (ESI) m/z 468.1 [M+H] ⁺ .

step six

(1R,3S)-3-(1-(tert-butyl)-5-((2-(1-hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino )-1H-pyrazol-3-yl)cyclopentyl isopropyl carbamate 10G

Sodium borohydride (7 mg, 0.215 mmol) was slowly added to a solution of compound 10F (20 mg, 0.043 mmol) in methanol (3 mL) at 0°C, and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, diluted with ethyl acetate (15mL), washed with water (10mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 10G crude product (11mg, product rate: 54%).

MS (ESI) m/z 470.1 [M+H] ⁺ .

step seven

(1R,3S)-3-(3-((2-(1-Hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl isopropyl carbamate 10

A solution of compound 10G (11 mg, 0.023 mmol) in formic acid (2 mL) was heated to 100° C. and stirred for 1 hour. After the reaction was completed, it was cooled to room temperature. Tetrahydrofuran (5 mL) and water (1 mL) were added to the reaction liquid, and then lithium hydroxide (10 mg, 0.227 mmol) was added, and the reaction liquid was heated to 75° C. and stirred for 16 hours. After the reaction, HPLC was used for separation and purification, and lyophilized to obtain the title compound 10 (3.9 mg, yield: 40%, the compound was a pair of isomers).

MS (ESI) m/z 414.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO- d ₆ ) δ =9.89(s,1H),7.95(d, J =4.8Hz,1H),7.30(d, J =4.8Hz,1H),7.21(s,1H) ,6.93(d, J =7.8Hz,1H),6.52(s,1H),5.30(s,1H),4.98(s,1H),4.85(d, J =6.7Hz,1H),3.54(q, J =6.7Hz, 1H), 3.06(d, J =9.8Hz, 1H), 1.98(d, J =20.8Hz, 1H), 1.86(d, J =13.8Hz, 1H), 1.80-1.53(m, 4H), 1.41(d, J =6.5Hz, 3H), 0.99(d, J =6.6Hz, 6H).

Compound 10 was resolved by the following method to obtain a pair of isomers (retention time 1.776min and 2.073min).

Methods as below:

Column: CHIRALPAK IG-3 (50*4.6mm I.D., 3μm);

Conditions: B is 40% EtOH (0.1% IPAm) under CO ₂ conditions; in 0.2-1.2min, the gradient rises from 5% B to 50% B and holds for one minute.

Flow rate: 3.4mL/min;

ABPR: 1800psi;

Temperature: 35°C.

Example 11

(1R,3S)-3-(3-((2-(2-Hydroxypropan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -5-yl) cyclopentyl isopropyl carbamate 11

first step

(1R,3S)-3-(3-((2-Acetylpyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopenta isopropyl carbamate 11A

Compound 10F (20mg, 0.043mmol) was placed in a 25mL round bottom flask, formic acid (2mL) was added, the temperature was raised to 100°C, and stirred at 100°C for 1 hour. After the reaction, the reaction solution was separated and purified by reverse phase chromatography (acetonitrile/water as the eluent), and lyophilized to obtain the title compound 11A (12 mg, yield: 68%).

MS (ESI) m/z 412.1 [M+H] ⁺ .

second step

(1R,3S)-3-(3-((2-(2-Hydroxypropan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -5-yl) cyclopentyl isopropyl carbamate 11

At -60 degrees Celsius, under a nitrogen atmosphere, to a solution of compound 11A (12 mg, 0.029 mmol) in tetrahydrofuran (3 mL), methylmagnesium bromide (0.1 mL, 0.292 mmol, 3M) was added dropwise, and slowly returned to room temperature and stirred for 2 Hour. After the reaction, it was purified by HPLC and lyophilized to obtain the title compound 11 (1.2 mg, yield: 8.5%). MS (ESI) m/z 428.1 [M+H] ⁺ .

Example 12

(1R,3S)-3-(3-((2-(Hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl) Cyclopentyl ((S)-second-butyl) carbamate 12

first step

(1R,3S)-3-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino )-1H-pyrazol-3-yl)cyclopentyl ((S)-second butyl)carbamate 12B

(1R,3S)-3-(5-Amino-1-(tertiary butyl)-1H-pyrazol-3-yl)cyclopentyl ((S)-second butyl)carbamic acid Ester 12A (20.0 mg, 0.10 mmol, synthesized according to the method reported in WO2020157652) was dissolved in tetrahydrofuran (1 mL), and sodium bis(trimethylsilyl)amide (0.20 mL) was added dropwise at -60 ° C under a nitrogen atmosphere , 0.40mmol, 4eq, 2N), reacted at -60°C for 30 minutes. A solution of compound 3I (32.6 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added at -60°C, and the reaction was slowly returned to room temperature for 1 hour. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate (20 mL), the combined organic phase was washed once with saturated brine (20 mL), dried over magnesium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated to obtain the title compound 12B (30 mg, crude product) .

MS (ESI) m/z 484.5 [M+H] ⁺ .

second step

(1R,3S)-3-(3-((2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl ((S)-second butyl) carbamate 12 C

Compound 12B (30mg, 0.06mmol) was added into formic acid (1mL) and reacted at 100°C for 3h. After the reaction, it was separated and purified by reverse phase chromatography (using acetonitrile/water as eluent) to obtain the title compound 12C (18 mg, yield: 67.87%).

MS (ESI) m/z 428.4 [M+H] ⁺ .

third step

(1R,3S)-3-(3-((2-(Hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl) Cyclopentyl ((S)-second-butyl) carbamate 12

Compound 12C (16mg, 0.037mmol) was added to boron trichloride in dichloromethane (0.4mL) at 0°C, and reacted at 20°C for 2h. After the reaction was completed, it was quenched with water, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed once with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by HPLC. Lyophilization afforded the title compound 12 (1.5 mg, yield: 9.69%).

MS (ESI) m/z 414.4 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ ) δ =12.09(s,1H),9.92(s,1H),7.98(d, J =4.8Hz,1H),7.34(d, J =4.8Hz,1H) ,7.24(s,1H),6.89(d, J =8.0Hz,1H),6.63(s,1H),5.33-5.29(m,1H),5.01(s,1H),4.61(d, J =5.6 Hz,2H),3.11-3.09(m,1H),2.08-1.96(m,2H),1.92-1.88(m,1H),1.77-1.65(m,3H),1.37-1.24(m,3H), 1.01(d, J =6.4Hz, 3H), 0.86(t, J =7.2, 7.6Hz, 3H).

Example 13

(1R,3S)-3-(3-((2-(1-Hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5- base) cyclopentyl ((S)-second butyl) carbamate 13

Starting from compound 12A , compound 13 was synthesized according to the similar synthesis steps of Example 10.

MS (ESI) m/z 428.2 [M+H] ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ ) δ =12.10(s,1H),9.91(s,1H),7.98(d, J =4.8Hz,1H),7.33(d, J =4.8Hz,1H) ,7.24(s,1H),6.89(d, J =8.4Hz,1H),6.56(s,1H),5.31(d, J =4.8Hz,1H),5.03-4.98(m,1H),4.90- 4.86(m,1H),3.42-3.35(m,1H),3.10-3.06(m,1H),2.07-2.01(m,1H),1.93-1.87(m,1H),1.80-1.61(m,4H ), 1.44(d, J =6.4Hz, 3H), 1.37-1.31(m, 2H), 1.01(d, J =6.4Hz, 3H), 0.79(t, J =7.2, 7.6Hz, 3H).

Example 14

(1R,3S)-3-(3-((2-(2-Hydroxypropan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -5-yl)cyclopentyl ((S)-second butyl)carbamate 14

Starting from compound 12A , compound 14 was synthesized according to the similar synthesis steps of Example 11.

MS (ESI) m/z 442.2 [M+H] ⁺ .

biological evaluation

The following further describes and explains the present disclosure in combination with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test Example 1. Detection of cyclin-dependent kinase activity of the disclosed compounds.

1. Experimental materials and instruments

2. Experimental steps

Compound dilutions were transferred to each well of the assay plate using an Echo 550 (784075, Greiner). Seal the assay plate and centrifuge the assay plate at 1000g for 1 min; prepare 2x enzyme in 1x kinase buffer (40mM Tris-HCl, pH 7.4, 20mM MgCl2, 0.1mg/ml BSA, 50uM DTT), add 2.5μl of 2x enzyme For a 384-well assay plate, centrifuge the plate at 1000g for 30s and let it stand at room temperature for 10 minutes. Prepare 2x substrate and ATP mix in 1x kinase buffer and start the reaction by adding 2.5 μl of 2x substrate and ATP mix. The plate was centrifuged at 1000g for 30 seconds, the assay plate was sealed, and reacted at room temperature for 1 hour. Add 4 μl ADP-Glo reagent and incubate at room temperature for 40 minutes, then add 8 μl kinase detection reagent and incubate at room temperature for 40 minutes.

The luminescent signal of 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) x 100. cmpd signal: compound signal; Ave_PC signal: average signal of positive control; Ave_VC signal: average signal of vehicle group.

_IC50s were calculated using GraphPad 8.0 by fitting the percent inhibition values and the logarithm of the compound concentration to a non-linear regression (dose response - variable slope). Y=bottom+(top-bottom)/(1+10^((LogIC50-X)*slope)), where X: logarithm of inhibitor concentration; Y: % inhibition.

See Table 1 for the measured _IC50 values.

According to Example 192 of WO20200157652A, compounds EX192-P1 and EX192-P2 were synthesized.

Test Example 2. Test of the Inhibitory Activity of the Compounds Disclosed on Ovarian Cancer Cells (OVCAR3)

Experimental Materials and Instruments

Experimental procedure

Ovarian cancer cells OVCAR3 (derived from ATCC) were cultured in RPMI 1640 medium with 10% FBS in a 37%, 5% CO ₂ cell culture incubator. On the first day, cells were plated in 96-well plates at a concentration of 2500 cells/well and incubated 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 continued to be cultured in the incubator for 7 days, the cell viability was tested using the Celltiter Glo detection kit (Promega), and the test method was consistent with the operation method provided by the kit. Data were processed and _IC50 calculated using GraphPad Prism 8.

Calculation formula Y=bottom+(top-bottom)/(1+10^((LogIC50-X)*slope)).

X: log value of compound concentration; Y: % inhibition.

Table 2. The IC ₅₀ (nM) of the disclosed compounds to OVCAR3

Claims (35)

A compound represented by formula I or a pharmaceutically acceptable salt thereof,

Wherein, -L ₁ -is selected from a bond, C ₁ - ₆ alkylene, -O- and -NH-, and the C ₁ - ₆ alkylene is optionally selected from one or more hydroxyl groups , alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents; _R1 is

, wherein ring A and ring B are each independently selected from aryl, heteroaryl and heterocycloalkyl, ring A and ring B together form a ring structure, the A ring is optionally substituted by one or more Z ₁ , the Surround B is replaced by one or more _Z2 as needed; R ₂ and _{R 3} are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, pendant oxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C _1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently selected from halogen _, alkyl, alkoxy, cyano, amino, Substituents of nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R ₂ and R ₃ together form a 3-8 member ring, the 3-8 member Look around is replaced by one or more Z _3's as needed; R ₄ is -L ₂ -R ₇ ; _R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Pendant Oxy , carboxyl and carboxylate substituent substitution; _R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more _Z ; -L ₂ -is selected from a bond, C ₁ - ₆ (alkylene) alkylene, -O- and -NH-, and the C ₁ - ₆ (alkylene)alkylene is optionally replaced by one or more selected from hydroxyl, alkane Substituents of radical, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro; R ₆ is selected from H, R ₈ -(C=O)- and

; R ₈ is an alkyl group, preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, and most preferably _a methyl group _; R ₉ and R ₁₀ are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C _1-6 alkyl and _3-7 membered _cycloalkyl , more preferably selected from hydrogen, C _1-3 Alkyl and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl; Each X is independently selected from O, S and NH, preferably O; Z ₁ , Z ₂ , Z ₃ and Z ₄ are each independently selected from halogen, cyano, hydroxyl, nitro, side oxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, -SR', -SOR', -SO ₂ R', -SO ₂ NR'(R"), -NR'(R"), -COR', -COOR' , -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and The heteroaryl groups are each independently optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitr group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkyloxy group, cycloalkylthio group, heterocycloalkylthio group, side oxy group, carboxyl group and Carboxylate substituent substitution; Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, the alkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxy , nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, Carboxyl and carboxylate substituents are substituted. The compound or pharmaceutically acceptable salt thereof as claimed in item 1, wherein, the -L ₁ - is selected from a bond, C ₁ - ₆ alkylene, -O- and -NH-, preferably selected from Bond, C ₁ - ₃ alkylene, -O- and -NH-, more preferably selected from bond, C ₁ - ₂ alkylene, -O- and -NH-, particularly preferably selected from Bond, C ₁ - ₂ (alkylene) and -O-, most preferably -O-. The compound or pharmaceutically acceptable salt thereof as claimed in item 1 or 2, wherein -L ₂ - is a bond or a C ₁ - ₆ (alkylene) group, preferably a bond or a C ₁ - ₃ ( Extended) alkyl. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein R ₇ is selected from C _1-6 alkyl, C _3-7 cycloalkyl, 3-7 _membered heterocycle Alkyl, 6-12 membered aryl and _{5-12 membered heteroaryl, preferably selected from C 1-4 alkyl} , C _3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl Base, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl , naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, most preferably selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ . The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, wherein, the _{R 5} is selected from hydrogen, C _{1-6 alkyl} and halogen, preferably hydrogen or C _1-3 alkane base. A compound or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 5, which is a compound shown in formula I-1, I-2, I-3, I-4 or I-5 or a compound thereof medicinal salt,

,

, wherein -L ₁ -, R ₁ , R ₂ , R ₃ , R ₆ and Z ₄ are as defined in any one of claims 1 to 5. _The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein, the R ₂ and R ₃ are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl , nitro and side oxygen, preferably selected from hydrogen, halogen and C ₁ - ₆ alkyl, more preferably hydrogen. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein the ring A and ring B are each independently selected from 3-7 membered heterocycloalkyl, 6-12 membered aryl And 5-12 membered heteroaryl, preferably selected from 5-6 membered heterocycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from phenyl, pyridyl, pyrimidinyl, Pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolyl, tetrahydropyrrolyl, dihydropyrrolyl, triazolyl and piperidinyl, the A ring is optionally replaced by a Or a plurality of Z ₁ substitutions, the B ring is optionally substituted by one or more Z ₂ ; the Z ₁ is selected from halogen, cyano, hydroxyl, nitro, side oxygen, C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy, C _1-6 haloalkyl and C _1-6 hydroxyalkyl, preferably selected _from halogen, cyano, hydroxyl _, nitro, pendant oxy _, C _{1-6 alkyl} and C _1-6 Alkoxy, more preferably selected from halogen, pendant oxy and C _1-6 alkyl, most preferably selected from fluorine, chlorine, bromine, pendant oxy, methyl, ethyl, propyl and isopropyl; _the Z ₂ selected from halogen, _{cyano, hydroxyl, nitro, pendant oxy, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl} , preferably selected from halogen, _{cyano, hydroxyl, nitro, pendant oxy, C 1-6 alkyl and C 1-6 alkoxy , more} preferably selected from halogen, hydroxy, pendant oxy, C _1-6 alkyl and C _1-6 alkoxy group, best _selected from fluorine, chlorine, bromine, pendant _oxy , hydroxyl, methyl, ethyl, propyl, isopropyl and methoxy; the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 hydroxyalkyl _{are each} independently selected from cyano, alkyl, alkoxy, _deuterated alkoxy, _Halogen , mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy are substituted by substituents, the substituents are preferably selected from cyano, C _1-6 alkane radical, C _1-6 alkoxy _, C _1-6 deuterated alkoxy _{, halogen} , heteroaryl, heterocycloalkyl and heterocycloalkyloxy, more preferably selected from cyano, C _1-3 alkane C _1-3 alkoxy, C _1-3 deuterated alkoxy _, heterocycloalkyl and heterocycloalkyloxy, most preferably selected from cyano, methyl, ethyl, methoxy, deuterium Substituted methoxy, ethoxy and tetrahydrofuryloxy. The compound or pharmaceutically acceptable salt thereof as claimed in any one of items 1 to 8, wherein _Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano , hydroxy and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl. A compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,

-L ₁ -is selected from bond, C ₁ - ₆ (alkylene) alkylene, -O- and -NH-, the C ₁ - ₆ (alkylene)alkylene is optionally replaced by one or more selected from hydroxyl, alkane Substituents of radical, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro; R ₂ and _{R 3} are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl, nitro, pendant oxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C _1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently selected from halogen _, alkyl, alkoxy, cyano, amino, Substituents of nitro, hydroxy, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R ₂ and R ₃ together form a 3-8 member ring, the 3-8 member Look around is replaced by one or more Z _3's as needed; R ₄ is -L ₂ -R ₇ ; _R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Pendant Oxy , carboxyl and carboxylate substituent substitution; _R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more _Z ; -L ₂ -is selected from a bond, C ₁ - ₆ (alkylene) alkylene, -O- and -NH-, and the C ₁ - ₆ (alkylene)alkylene is optionally replaced by one or more selected from hydroxyl, alkane Substituents of radical, alkoxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro; R ₆ is selected from H, R ₈ -(C=O)- and

; R ₈ is an alkyl group, preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, and most preferably _a methyl group _; R ₉ and R ₁₀ are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C _1-6 alkyl and _3-7 membered _cycloalkyl , more preferably selected from hydrogen, C _1-3 Alkyl and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl; Each X is independently selected from O, S and NH, preferably O; Z ₁ , Z ₂ , Z ₃ and Z ₄ are each independently selected from halogen, cyano, hydroxyl, nitro, side oxy, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, -SR', -SOR', -SO ₂ R', -SO ₂ NR'(R"), -NR'(R"), -COR', -COOR' , -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and The heteroaryl groups are each independently optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitr radical, -NR'(R"), -SOR', -SO ₂ R', -SO(NH)R', -S(NH)R', cyano, cycloalkyl, heterocycloalkyl, aryl , heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl and carboxylate substituents; Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, the alkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto , hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, side oxygen Substituent substitution of group, carboxyl group and carboxylate group; m and n are each independently selected from 0, 1 and 2. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 10, which is a compound represented by formula II or a pharmaceutically acceptable salt thereof,

Wherein, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , L ₁ and Z ₂ are as defined in claim 1 or 9. The compound or a pharmaceutically acceptable salt thereof as claimed in claim 10 or 11, wherein L ₁ is -O-. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 10 to 12, wherein, the R ₂ and R ₃ are each independently selected from hydrogen, halogen, C _1-6 alkyl, cyano, hydroxyl , nitro and side oxygen, preferably selected from hydrogen, halogen and C _1-6 alkyl, more preferably hydrogen. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 10 to 13, wherein R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from C ₁ - ₆ Alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C ₁ - ₄ alkyl, C _3-5 Cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third Butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, most Preferably selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ , and the Z ₄ is as defined in Claim 1. The compound or pharmaceutically acceptable salt thereof as claimed in item 14, wherein, the Z is selected from fluorine, chlorine, bromine, methyl _, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl , preferably selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 10 to 15, wherein, the R ₅ is selected from hydrogen, C _1-6 alkyl and halogen, preferably hydrogen, C _1-3 alkane base. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10 to 16, wherein L ₁ is -O-, R ₂ and R ₃ are each independently hydrogen, and R ₅ is hydrogen. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 10 to 17, wherein R ₆ is H. _{The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 10 to 18, wherein Z is selected from cyano, hydroxyl, nitro, side oxygen, C 1-6 alkyl ,} C ₁ - ₆ alkoxy, C ₁ - ₆ haloalkyl and C ₁ - ₆ hydroxyalkyl; the C ₁ - ₆ alkyl, C ₁ - ₆ alkoxy, C ₁ - ₆ haloalkyl and C ₁ - ₆ The hydroxyalkyl groups are independently optionally replaced by one or more selected from the group consisting of alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkane Substituent group and heterocycloalkyloxy group, _the substituent is preferably selected from cyano group, C _1-6 alkyl _{group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group} , heterocycle Alkyl and heterocycloalkyloxy, more preferably selected from cyano, methyl, ethyl, methoxy, a deuteriomethoxy, diduteriomethoxy, trideuteromethoxy, 3 to 7-membered cycloalkyl and 3 to 7-membered heterocycloalkyl. The compound or pharmaceutically acceptable salt thereof as claimed in item 10 or 11, wherein Z ₂ are each independently selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -COOR' and -CONR'( R"); the alkyl, haloalkyl, hydroxyalkyl and cycloalkyl are each independently optionally selected from one or more of halogen, mercapto, hydroxyl, -NR'(R"), -SOR', - Substituent substitution of SO ₂ R', -SO(NH)R' and -S(NH)R'; Each R' or R" is independently selected from hydrogen, hydroxy and alkyl optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano; Preferably, the Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, and the C _1-6 alkyl or 3 to 7 membered cycloalkyl is optionally selected from one or more Substituents of halogen, hydroxyl, mercapto and -NR'(R"), each R' or R" is independently hydrogen or C _1-6 alkyl, and the C _1-6 alkyl is optionally replaced by one or A plurality of substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano are substituted, preferably, the C _1-6 alkyl is optionally substituted by one or more deuteriums. The compound or pharmaceutically acceptable salt thereof as claimed in item 20, wherein, Z ₂ are each independently C _1-6 alkyl or 3 to 7 membered cycloalkyl, the C _1-6 alkyl and 3 to 7 A cycloalkyl group is substituted with one or more hydroxyl groups. The compound represented by formula IG or a pharmaceutically acceptable salt thereof as described in any one of claims 10 to 11 and 20, wherein L ₁ is -O-. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 10 to 11 and 20 to 22, wherein, the R ₂ and R ₃ are each independently selected from hydrogen, halogen, C _1-6 alkyl, The cyano group, hydroxyl group, nitro group and pendant oxygen group are preferably selected from hydrogen, halogen and C _1-6 alkyl, more preferably hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 10 to 11 and 20 to 23, wherein R ₄ is -L ₂ -R ₇ ; -L ₂ - is a bond; the R ₇ is selected from C ₁ - ₆ alkyl, C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C ₁ - ₄ alkyl, C _3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxa Azolyl, preferably selected from isopropyl,

, cyclopropyl, phenyl and pyridyl; the R ₇ is optionally substituted by one or more Z ₄ , and the Z ₄ is as defined in Claim 9. The compound or pharmaceutically acceptable salt thereof as claimed in item 24, wherein, the Z is selected from fluorine, chlorine, bromine, methyl _, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl , preferably selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 10 to 11 and 20 to 25, wherein, the R ₅ is selected from hydrogen, C _1-6 alkyl and halogen, preferably hydrogen, C _1-3 alkyl. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 10 to 11 and 20 to 26, wherein L ₁ is -O-, R ₂ and R ₃ are each independently hydrogen, and R ₅ is hydrogen . The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 27, wherein the compound is selected from:

An isotopic substitution of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, preferably, the isotopic substitution is a deuterium atom substitution. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 28 or the isotope substitution as described in claim item 29 and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 28 or the isotope substitution as described in claim item 29 and a pharmaceutically acceptable Excipients, based on the total weight of the composition, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients. A compound as described in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, an isotope substitution as described in claim 29, or a pharmaceutical composition as described in claim 30 or 31 is used in the preparation Use in drugs for preventing and/or treating diseases related to cyclin-dependent kinases, the cyclin-dependent kinase is preferably CDK2, and the diseases related to cyclin-dependent kinases are preferably cell proliferation diseases, cancer or immune disease. A compound as described in any one of Claims 1 to 28 or a pharmaceutically acceptable salt thereof, an isotope substitution as described in Claim 29, or a pharmaceutical composition as described in Claim 30 or 31 in the preparation Use in medicines for preventing and/or treating diseases related to cell cyclin, the cell cycle protein is preferably cell cycle protein E, more preferably cell cycle protein E1 or cell cycle protein E2, which is cell cycle protein related The disease is preferably a cell proliferative disease, cancer or an immune disease. A compound as described in any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, an isotope substitution as described in claim 29, or a pharmaceutical composition as described in claim 30 or 31 is used in the preparation Use in a medicament for the prevention and/or treatment of 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, and sarcoma. A preparation method of a compound represented by formula II or a pharmaceutically acceptable salt thereof, which comprises the step of removing the protecting group PG from the compound represented by formula III under acidic conditions,

Among them, R ₂ , R ₃ , R ₄ , R ₅ , L ₁ and Z ₂ are as defined in claims 10 to 28, R ₆ is hydrogen, PG is an amino protecting group, preferably selected from tertiary butyl, Acetyl, trifluoroacetyl, trityl, benzyl and formyl, most preferably tert-butyl.