WO2023025298A1

WO2023025298A1 - Quinolinofuran derivative and use thereof

Info

Publication number: WO2023025298A1
Application number: PCT/CN2022/115213
Authority: WO
Inventors: 王中利; 郝欣; 罗志阳; 匡亮; 柳梦林
Original assignee: 瑞石生物医药有限公司
Priority date: 2021-08-27
Filing date: 2022-08-26
Publication date: 2023-03-02
Also published as: TW202328141A

Abstract

Disclosed are a quinolinofuran derivative as shown in formula I or a pharmaceutically acceptable salt thereof, a pharmaceutically composition containing same, and a use thereof in preparing a drug for the prevention and/or treatment of MK2-mediated diseases. The definition of groups in the general formula is the same as that in the description.

Description

Quinolinofuran derivatives and uses thereof

technical field

The disclosure belongs to the field of medicine, and relates to a quinolinofuran derivative and its application.

Background technique

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2 or MK2) mediates multiple p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator of the production of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interferon gamma (IFNγ), which are involved in many acute and chronic inflammatory diseases, Examples include rheumatoid arthritis and inflammatory bowel disease.

The quinothiophene structure molecules developed based on the benzothiophene structure have shown MK2 inhibitory efficacy at the micromolar level, while showing high selectivity for other kinases, including but not limited to CDK2. For example, Bioorg.Med.Chem.Lett.19 (2009) 4882-4884 discloses:

WO2016044463 discloses another class of MK2 inhibitors, the representative molecules are as follows,

In addition, other quinothiophene skeleton structure molecules have also been reported, such as WO2014149164, WO2009010488, WO2018170204, WO2018170200, WO2018170201, etc.

However, no MK2 inhibitors are currently on the market, and the compounds of the present disclosure have not been disclosed in any literature, and such compounds exhibit specific MK2 inhibitory effects and selectivity to other kinases (including, for example, CDK2).

Contents of the invention

The present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

in,

Ring A is selected from C _6-10 aryl or 5 to 10 membered heteroaryl containing 1-3 heteroatoms;

^Each R is independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said Alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R ^1A , each R ^1A is independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

Alternatively, any adjacent ^R1 and adjacent carbon atoms form a 3 to 6 membered cycloalkyl group or a 3 to 6 membered heterocycloalkyl group, which is optionally represented by one or more ^R1B Substitution, R ^1B each independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy, the alkyl or alkyloxy is optionally replaced by One or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino are substituted;

R ² and R ³ are each independently selected from hydrogen or C _1-6 alkyl, which is optionally substituted by one or more groups selected from halogen, hydroxyl, cyano or amino;

^Each R is independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 6-membered heterocycloalkyl, C _1-6 alkylthio, 3-6 membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-6 membered cycloalkylamino, 3-6 membered heterocyclic Alkylamino, aryl or heteroaryl, -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted by one or more R ^4A , each R ^4A is independently selected from halogen, hydroxyl , oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkane Oxygen or 3 to 6 membered heterocycloalkoxy;

Alternatively, any adjacent two R ⁴ form a 3 to 6-membered cycloalkyl group or a 3 to 6-membered heterocycloalkyl group with adjacent atoms, and the cycloalkyl group or heterocycloalkyl group is optionally replaced by one or more R ^5A Substituted, each R ^5A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl;

^Each R is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R ^2A , each R ^2A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

R ⁶ are each independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R ^3A , each R ^3A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

T is selected from a bond or -L-X-;

L is selected from a bond or a C _1-3 alkylene group optionally substituted by one or more R ^6A , each R ^6A independently selected from halogen, hydroxyl, oxo, nitro, cyano, Amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl;

X is selected from -O-, -S-, -S(O)-, -SO ₂ -, -C(O)-, -OC(O)-, -C(O)O-, -N(R ⁹ )-, -C(O)N(R ⁷ )- or -N(R ⁸ )C(O)-;

Z is -CH- or N, and when Z is -CH-, Z is optionally substituted by R ⁵ ;

R ⁷ , R ⁸ , R ⁹ are each independently selected from hydrogen or C _1-6 alkyl, and the alkyl is optionally replaced by one or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino group replaced;

R ^1a or R ^1b are each independently selected from hydrogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkane Base, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^7A , each R ^7A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _{1 -6} alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl;

Alternatively, R ^1a , R ^1b and adjacent atoms form a 3- to 6-membered heterocycloalkyl group, the heterocycloalkyl group is optionally substituted by one or more R ^8A , each R ^8A independently selected from halogen, hydroxyl, Oxo, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl;

m is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;

n is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;

s is selected from an integer between 0 and 3, such as 0, 1, 2, 3;

o and p are each selected from integers between 0 and 2, such as 0, 1, and 2. Some embodiments provide the compound shown in formula I as

in,

^Each R is independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl or heteroaryl, -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , - NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted by one or more R ^4A , each R ^4A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy;

T is selected from a bond or -L-X-;

X is selected from -O-, -S-, -S(O)-, -SO ₂ -, -C(O)-, -OC(O)-, -C(O)O-, -C(O) N(R ⁷ )- or -N(R ⁸ )C(O)-;

R ⁷ and R ⁸ are each independently selected from hydrogen or C _1-6 alkyl, and the alkyl is optionally replaced by one or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino replace;

m is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;

n is selected from an integer between 0 and 4, such as 0, 1, 2, 3, 4;

s is selected from an integer between 0 and 3, such as 0, 1, 2, 3, 4;

o and p are each selected from integers between 0 and 2, such as 0, 1, and 2.

In some embodiments, in the compound shown in formula I or formula IA, ^each R is independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3-6 membered Cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted by one or more R ^1A , each R ^1A independently selected from alkyl Oxygen.

In other embodiments, in the compound shown in formula I or formula IA, ^each R is independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 Membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^1A , each R ^1A is independently selected from C _1-6 alkylamino.

In some embodiments, in the compound shown in formula I or formula IA, R ⁴ is each independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _{1 -6} alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy , 3 to 6 membered cycloalkylamino, 3 to 6 membered heterocycloalkylamino, aryl or heteroaryl, -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ₍ ^_ _{_} _{_} ^_ ^_ _{_} _{_} ^_ ^_ _{_} _{_} ^_ ^_ _{_} _{_} ^_ CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamino or heterocycloalkylamino is optionally replaced by one or A plurality of R ^4A substituted, R ^4A each independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycle Alkyl, C _1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy.

On the other hand, in some embodiments, R in the compound shown in formula I or formula IA ^is each independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy, the C _1-6 alkyl , cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy or heterocycloalkoxy are optionally replaced by one or more halogen, hydroxyl, cyano, amino or C _1-6 alkyl.

In some embodiments, in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt, T is selected from a bond or -LX-, L is selected from a bond or C _1-3 alkylene, and the alkylene is optionally Substituted by 1-3 R ^6A , X is selected from -O-, -OC(O)- or -C(O)O-, R ^6A is as defined above.

In some embodiments, in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof, T is selected from a bond.

In some embodiments, ring A in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is selected from 5-membered heterocycles containing 1-2 heteroatoms. The example structure of ring A is as follows (not limited to):

Wherein, R ⁴ and m are as defined above.

In some embodiments, Ring A in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from

On the other hand, ring A in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is selected from phenyl or a 6-membered heteroaromatic ring containing 1-2 heteroatoms. The example structure of ring A is as follows (not limited to):

Wherein, R ⁴ and m are as defined above.

On the other hand, ring A in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is selected from phenyl or a 9-10 membered heteroaromatic ring containing 1-2 heteroatoms.

In other embodiments, R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl, amino, C _1-6 ^alkyl or C _1-6 alkoxy, The alkyl or alkoxy group is optionally substituted by 1-3 R ^2A , and R ^2A is as defined above.

In other embodiments, R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is ^{independently} selected from 3 to 6 membered cycloalkyl groups, and the cycloalkyl groups are optionally replaced by 1-3 R ^2A , R ^2A is as defined above.

On the other hand, some embodiments provide a compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof, wherein o is selected from 0 or 1.

In some embodiments, ^R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl, amino, C _1-6 alkyl or C _1-6 alkoxy, so The alkyl or alkoxy group is optionally substituted by 1-3 R ^3A , and R ^3A is as defined above.

In other embodiments, R in the compound shown in formula I or formula IA or a pharmaceutically acceptable salt thereof is ^{independently} selected from 3 to 6 membered cycloalkyl groups, and the cycloalkyl groups are optionally replaced by 1-3 R ^3A , R ^3A is as defined above.

In other embodiments, p is selected from 0 or 1 in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof.

On the other hand, in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof, R ³ is selected from hydrogen.

In some embodiments, in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt, R ^is selected from C _1-6 alkyl, and the alkyl is optionally replaced by 1-3 selected from halogen, hydroxyl or amino group replaced. Further, in some other embodiments, R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt ^is selected from methyl, ethyl, hydroxymethyl, hydroxyethyl, difluoromethyl or trifluoro methyl.

In some embodiments, in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof, R ² is selected from hydrogen.

In some embodiments, in the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof, R ¹ is selected from halogen, hydroxyl, amino or cyano.

In some embodiments, ^R in the compound shown in Formula I or Formula IA or a pharmaceutically acceptable salt thereof is selected from C _1-6 alkyl or C _1-6 alkoxy, and the alkyl or alkoxy is optionally Replaced by 1-3 R ^1A . Further, in other embodiments, R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt ^is selected from methyl, ethyl, hydroxymethyl, hydroxyethyl, difluoromethyl or trifluoro methyl.

On the other hand, R in the compound shown in formula I or formula IA or its pharmaceutically acceptable salts are ^each independently selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl or alkoxy The group is optionally substituted by 1-3 R ^1A , R ^1A is as defined above.

Further, the compound represented by formula I or formula IA or a pharmaceutically acceptable salt thereof is:

Wherein, R ¹ , R ² , R ⁴ , ring A, m, and T are as defined in formula I or formula IA.

In some embodiments, R ^1A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl or amino. In some embodiments, R ^1A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from fluorine or chlorine.

In some embodiments, R ^2A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, hydroxyl or amino. In some embodiments, R ^2A in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from fluorine or chlorine.

The compound shown in formula I or formula IA or formula IIA provided by some embodiments or a pharmaceutically acceptable salt thereof is:

Wherein, R ¹ , R ² , R ⁴ , ring A, and m are as defined in formula I or formula IA.

Typical compounds shown in formula I or formula IA or pharmaceutically acceptable salts thereof include but are not limited to:

In some embodiments, each R ⁴ in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, oxo (=O), hydroxyl or amino.

In some embodiments, R ⁴ in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen or cyano.

In some embodiments, each R in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from C _1-6 alkyl, 3 to 6 ^membered cycloalkyl, 3 to 6 membered Heterocycloalkyl, the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R ^4A , R ^4A is as defined above.

In other embodiments, R ⁴ in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, C _1-6 alkyl, -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b or -(CH ₂ ) _s NHCOR ^1a , s, R ^1a , R ^1b such as as defined above.

In other embodiments, R ⁴ in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, C _1-6 alkyl or -(CH ₂ ) _s CONR ^1a R ^1b , s, R ^1a , R ^1b are as defined above.

In other embodiments, R ⁴ in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from halogen, cyano, C _1-6 alkyl or -(CH ₂ ) _s CONR ^1a R ^1b , s, R ^1a , R ^1b are as defined above.

In other embodiments, any adjacent two R in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt form a ³ to 6 membered cycloalkyl or a 3 to 6 membered hetero Cycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R ^5A , R ^5A is as defined above.

Further, in some other embodiments, R ⁷ and ^{R 8} in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof are each independently selected from hydrogen or C _1-6 alkyl, said alkyl The group is optionally substituted with 1-3 groups selected from halo, hydroxy, oxo, nitro, cyano or amino.

Further, in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R ⁷ and R ⁸ are each independently selected from hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

In certain embodiments, R ^1a or R ^1b in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, C _1-6 alkyl, 3 to 6 membered cycloalkyl Or a 3- to 6-membered heterocycloalkyl group, the alkyl group, cycloalkyl group or heterocycloalkyl group is optionally substituted by 1-3 R ^7A , R ^7A is as defined above.

In other embodiments, R ^1a , R 1b in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof form a 5 to ⁶ -membered heterocycloalkyl group with adjacent atoms, and the heterocycloalkyl group Optionally substituted by 1-3 R ^8A , R ^8A is as defined above.

Further, in some embodiments, in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R ^7A is each independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl. In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R ^7A is selected from halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6-membered cycloalkyl. In other embodiments, in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R ^7A is selected from halogen or cyano.

On the other hand, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R ^4A is each independently selected from halogen, hydroxyl, cyano, C _1-6 alkyl, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy.

In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R ^4A is selected from halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy , 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy.

In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R ^4A is selected from halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy Or 3 to 6 membered cycloalkoxy.

In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R ^8A is each independently selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _{1 -6} alkoxy or 3 to 6 membered cycloalkyl. In other embodiments, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt, R ^8A is selected from halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6-membered cycloalkyl. In other embodiments, in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R ^8A is selected from halogen, such as fluorine, chlorine, bromine or iodine. In other embodiments, in the compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof, R ^8A is selected from C _1-6 alkyl.

In some embodiments, in the compound shown in formula I or its salt, R ⁴ is each independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _{1- 6} alkoxy, C _1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 membered heterocycloalkylamino, The alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R ^4A , R ^4A is as defined in formula I.

On the other hand, some embodiments provide that in the compound shown in formula I or its pharmaceutically acceptable salt, R ⁴ is independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C _1-6 Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 Member heterocycloalkylamino, the alkyl, alkoxy, alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamino, heterocycloalkylamino are optionally represented by one or more R ^4A Substitution, R ^4A is as defined in Formula I.

In some embodiments, the compound shown in formula I is

Wherein, ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , T, o, p, m and n are as defined in formula I.

On the other hand, some embodiments provide the compound shown in formula I as

Wherein, ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , Z, o, p, m and n are as defined in formula I.

The compound shown in formula I or formula IC provided by some embodiments is

Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁹ , ring A and m are as defined in formula I.

Typical compounds represented by formula I or formula IC or pharmaceutically acceptable salts thereof include but are not limited to:

On the other hand, in some embodiments, in the compound shown in formula I or formula IC or formula IIC or its pharmaceutically acceptable salt, R ⁹ is each independently selected from hydrogen or C _1-6 alkyl, and the alkyl is optionally Substituted by 1-3 groups selected from halogen, hydroxy, oxo, nitro, cyano or amino.

Further, in the compound represented by formula I or formula IC or formula IIC or a pharmaceutically acceptable salt thereof, R ⁹ is each independently selected from hydrogen, methyl, ethyl, difluoromethyl or trifluoromethyl.

Other embodiments provide compounds shown in formula I as

Wherein, ring A, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , T, o, p and m are as defined in formula I,

R ¹⁰ , R ¹¹ and adjacent carbon atoms form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group, the cycloalkyl group or heterocycloalkyl group is optionally substituted by one or more R ^1c , Each R ^1c is independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy, and the alkyl or alkyloxy is optionally replaced by one or Substituted by multiple groups selected from halogen, hydroxy, oxo, nitro, cyano or amino;

^R is selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^1d , each R ^1d independently selected from halogen, hydroxy, oxo, nitro, cyano or amino.

In some embodiments, in the compound represented by formula ID, R ¹² is selected from C _1-6 alkyl, for example, methyl, ethyl or propyl.

On the other hand, in the compounds of the present disclosure

selected from

In some embodiments, in the compound shown in formula I

selected from

For example

Wherein R ¹³ and R ¹⁴ are each independently selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C _1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 membered Heterocycloalkylamino, aryl or heteroaryl, -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamino, heterocycloalkylamino, aromatic radical or heteroaryl is optionally substituted by one or more R ^9A , each R ^9A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered Cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy; t is an integer between 0 and 2 (including 1); R ^1a , R ^1b , s are as defined above.

In some embodiments, in the compound shown in formula I

selected from

Wherein R ¹³ is selected from halogen (fluorine or chlorine), C _1-6 alkyl, -S(O)R ^1a and -S(O) ₂ R ^1a , R ¹⁴ is selected from halogen (fluorine or chlorine), hydroxyl, nitric acid Group, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkylthio, 3 to 6 6-membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkylamino, aryl or heteroaryl, -SR ^1a , -S(O) R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl, heterocycle Alkyl, alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamino, heterocycloalkylamino, aryl or heteroaryl are optionally substituted by one or more R ^9A , R ^9A each independently is selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy; t is an integer between 0 and 2 (including 1); R ^1a , R ^1b , and s are as defined above.

In some embodiments, in the compound shown in formula I

selected from

Wherein R ¹³ is selected from halogen (fluorine or chlorine) and C _1-6 alkyl, R ¹⁴ is selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _{1-6 6} alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6-membered cycloalkylamino, 3 to 6-membered heterocycloalkylamino, aryl or heteroaryl, -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylthio, cycloalkoxy, heterocycloalkoxy Base, cycloalkylamino, heterocycloalkylamino, aryl or heteroaryl are optionally substituted by one or more R ^9A , each R ^9A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino , C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy base; t is an integer between 0 and 2 (including 1); R ^1a , R ^1b , and s are as defined above.

In some embodiments, in the compound shown in formula I

selected from

For example

In some embodiments, in the compound shown in formula I

selected from

For example

Wherein R ¹³ and R ¹⁴ are each independently selected from halogen (fluorine or chlorine), hydroxyl, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl , 3 to 6 membered heterocycloalkyl, C _1-6 alkylthio, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 6 membered cycloalkylamino, 3 to 6 membered Heterocycloalkylamino, aryl or heteroaryl, -SR ^1a , -S(O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamino, heterocycloalkylamino, aromatic radical or heteroaryl is optionally substituted by one or more R ^9A , each R ^9A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered Cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy; t is an integer between 0 and 2 (including 1), q is an integer between 0 and 3; R ^1a , R ^1b , s are as defined above.

Typical compounds represented by formula I or pharmaceutically acceptable salts thereof include but are not limited to:

Another aspect of the present disclosure provides a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, the method comprising a step of a coupling reaction between a compound of formula A and a compound of formula B under metal catalysis,

Wherein, X ¹ is hydrogen or a leaving group, selected from but not limited to halogen such as chlorine, bromine; X ² is hydrogen or a borate ester group.

On the other hand, the present disclosure also provides a method for preparing the compound represented by formula IA or a pharmaceutically acceptable salt thereof, the method comprising the step of coupling reaction between the compound of formula A and the compound of formula B-1 under metal catalysis,

In some embodiments, the metal catalyst in the aforementioned reaction is selected from but not limited to metal palladium, such as divalent palladium catalyst (not limited to palladium acetate). On the other hand, an appropriate base can also be added to the aforementioned coupling reaction to ensure that the reaction proceeds more smoothly. In some embodiments, the base is selected from, but not limited to, organic or inorganic bases, such as sodium tert-butoxide.

This aspect also provides a compound represented by formula B or a pharmaceutically acceptable salt thereof,

Wherein ^X is hydrogen or a leaving group, selected from but not limited to halogen such as chlorine, bromine;

R ¹ , R ² , R ³ , R ⁵ , R ⁶ , Z, o, p, n are as defined in formula I.

On the other hand, the present disclosure also provides a compound represented by formula B-1 or a pharmaceutically acceptable salt thereof,

Wherein ^X is hydrogen or a leaving group, selected from but not limited to halogen, such as chlorine, bromine;

R ¹ , R ² , R ³ , R ⁵ , R ⁶ , o, p, n are as defined in Formula IA.

The present disclosure also provides isotopic substitutions of the foregoing compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopic substitution is deuterated.

The disclosed compound has good inhibitory effect on p38a-MK2 kinase. In some embodiments, compounds of the disclosure have an _IC50 value for inhibition of p38a-MK2 kinase in the range of 0.01 to 500 nM. In some embodiments, compounds of the disclosure have an _IC50 value for inhibition of p38a-MK2 kinase in the range of 0.01 to 100 nM. In some embodiments, compounds of the disclosure have an _IC50 value for inhibition of p38a-MK2 kinase in the range of 0.01 to 20 nM. In some embodiments, compounds of the disclosure have an _IC50 value for inhibition of p38a-MK2 kinase in the range of 0.1 to 20 nM. In some embodiments, compounds of the disclosure have an _IC50 value for inhibition of p38a-MK2 kinase in the range of 0.1 to 30 nM. In some embodiments, compounds of the disclosure have an _IC50 value of <50 nM for inhibition of p38a-MK2 kinase.

The present disclosure also provides a pharmaceutical composition, comprising at least one therapeutically effective amount of the aforementioned compound represented by Formula I or Formula IA or Formula IIA or a pharmaceutically acceptable salt thereof, or an isotope substitution thereof and a pharmaceutically acceptable excipient.

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

In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotope substitutions. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic substitutions.

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% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.

The present disclosure also provides a method for preventing and/or treating MK2-mediated diseases or disorders, which includes administering to patients a preventive or therapeutically effective amount of the compound shown in the aforementioned formula I or formula IA or formula IIA or its pharmaceutically acceptable Salt or its isotope substitution, or the aforementioned pharmaceutical composition.

In some embodiments, the MK2-mediated disease or disorder is selected from an autoimmune disease, an inflammatory disease, cancer, a fibrotic disease, or a metabolic disease.

The present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cancer, fibrotic diseases or metabolic diseases, which comprises administering to patients a preventive or therapeutic effective amount of the aforementioned formula I or formula IA or formula The compound shown in IIA or its pharmaceutically acceptable salt or its isotope substitution, or the aforementioned pharmaceutical composition.

The present disclosure also provides the use of the compound shown in the aforementioned formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of medicines for preventing and/or treating MK2-mediated diseases or disorders . In some embodiments, the MK2-mediated disease or disorder is preferably an autoimmune disease, an inflammatory disease, cancer, a fibrotic disease, or a metabolic disease.

The present disclosure also provides a compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition as shown in the aforementioned formula I or formula IA or formula IIA for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cancer, fibrosis Use in medicine for disease or metabolic disease.

The present disclosure also provides a compound represented by formula I or formula IA or formula IIA or a pharmaceutically acceptable salt or its isotope substitution or the aforementioned pharmaceutical composition, which is used for preventing and/or treating MK2-mediated diseases or conditions.

The present disclosure also provides a compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salt or its isotope substitution or the aforementioned pharmaceutical composition, which is used for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, Cancer, fibrotic disease, or metabolic disease.

Pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic or organic salts.

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 subject to the present within the scope of the 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 this disclosure. 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 amino 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 a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).

In the chemical structures of the compounds described in this disclosure, the bond

Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond

can be

or both

Two configurations.

If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine, lactam-lactim isomerization . An example of a lactam-lactim equilibrium is between A and B as shown below.

All compounds in this disclosure can be drawn as Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.

The present disclosure also includes certain 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 the compounds. 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. Commercially available deuterated starting materials can be used when preparing deuterated forms of compounds, or conventional techniques can be used to synthesize deuterated reagents, including but not limited to deuterated borane, trideuterioborane 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.

Explanation of terms:

"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 physiologically acceptable carriers and excipients. agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.

"Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives that have been approved by the U.S. Food and Drug Administration to be acceptable for human or livestock use , dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.

"Effective amount" or "therapeutically effective amount" in the present disclosure includes an amount sufficient to ameliorate or prevent symptoms or conditions of a medical disease. 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, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-dimethylpropyl, 2,2-dimethylpropyl and its various branched isomers, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, Nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 To 6-membered heterocycloalkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally selected from one or more halogen, hydroxyl , Oxo, nitro, cyano or amino groups are substituted.

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 3 to 6 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 halogen, hydroxy, oxo , nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, Hydroxy, oxo, nitro, cyano or amino groups are substituted.

The term "heterocycloalkyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms, non-limiting examples of "heterocycloalkyl" include:

etc. 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 halogen, hydroxy, oxo, nitro, cyano, Amino, C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C _1-6 alkoxy, 3-6 membered cycloalkoxy or 3-6 membered heterocycloalkane Oxygen, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, hydroxyl, oxo, nitro , cyano or amino groups are substituted.

Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C1- 6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 3 heteroatoms, 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5- or 6-membered. For example, non-limiting examples thereof include:

etc. Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, oxo (=O), hydroxyl, nitro, Cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, aryl or heteroaryl, -SR ^1a , -S (O)R ^1a , -S(O) ₂ R ^1a , -(CH ₂ ) _s COR ^1a , -(CH ₂ ) _s NR ^1a R ^1b , -(CH ₂ ) _s CONR ^1a R ^1b , -(CH ₂ ) _s OCONR ^1a R ^1b , -(CH ₂ ) _s NHCOR ^1a , -NH(CH ₂ ) _s CONR ^1a R ^1b , -NH(CH ₂ ) _s COR ^1a , the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl or heteroaryl is optionally replaced by one or more of halogen, hydroxyl, oxo, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6-membered heterocycloalkyl, C _1-6 alkoxy, 3-6 membered cycloalkoxy or 3-6 membered heterocycloalkoxy, wherein 3-6 membered cycloalkyl or 3-6 membered Heterocycloalkyl is optionally substituted, with any substituent selected from halogen, hydroxy, oxo, nitro, cyano or amino.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino , C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 membered cycloalkoxy or 3 to 6 membered heterocycloalkoxy group, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally selected from one or more halogen, hydroxyl, oxo, nitro, cyano or amino substituted.

Similarly, "cycloalkoxy or -O-(cycloalkyl)" and "heterocycloalkoxy or -O-(heterocycloalkyl)" are as defined for alkoxy.

The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio. Alkylthio may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, Amino, C _1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C _1-6 alkoxy, 3-6 membered cycloalkoxy or 3-6 membered heterocycloalkane Oxygen, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, hydroxyl, oxo, nitro , cyano or amino.

The term "cycloalkylamino", wherein alkyl is as defined above. Non-limiting examples of cycloalkylamino include: methylamino, ethylamino or dimethylamino. Cycloalkylamino may be optionally substituted or unsubstituted, and when substituted, the substituents are as defined for "alkylthio".

The term "cycloalkylamino" or "cycloalkylamino" refers to -N-(cycloalkyl), wherein cycloalkyl is as defined above.

The term "heterocycloalkylamino" or "heterocycloalkylamino" refers to -N-(heterocycloalkyl), wherein heterocycloalkyl is as defined above.

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

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

The term "cyano" refers to -CN.

The term "amino" refers to _-NH2 .

The term "nitro" refers to _-NO2 .

The term "oxo" refers to a =O substituent.

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the 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 can determine (by experiment or theory) possible or impossible substitutions without undue effort.

Detailed ways

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 to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (Methanol-d ₄ ), internal standard is Tetramethylsilane (TMS).

The determination of HPLC uses Agilent1100 high pressure liquid chromatography, GAS15B DAD ultraviolet detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.

Preparative HPLC conditions: Waters; Column: Sunfire (Prep C18 OBD 19*250mm 10μm).

Chiral resolution conditions (HPLC): Waters; Chiralpak AD-H [amylose-tris(3,5-dimethylphenylcarbamate) coated chiral stationary phase] chromatographic column 25*250mm.

MS was determined with Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, Waters Xbridge C18 4.6*50mm, 5um chromatographic column, scanning in positive/negative ion mode, and the mass scanning range was 80-1200.

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate, the specification of the thin-layer chromatography (TLC) silica gel plate is 0.2mm±0.03mm, and the specification of the thin-layer chromatography separation and purification product is 0.4mm-0.5mm. The flash column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage). Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or Changzhou Santai pre-packed pre-packed ultra-pure normal-phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

The known starting materials in this disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Beide Pharmaceutical and other companies.

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

The nitrogen atmosphere means that the reaction bottle is connected to a 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.

Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.

Nitrogen atmosphere or hydrogenation atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated 3 times.

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

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

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

Example 1

(R)-3-((2-chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[ 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one(1)

Step 1: Preparation of 5-bromoquinolin-6-ol (1b)

At room temperature, add quinolin-6-ol 1a (80.0 g, 0.551 mol) and glacial acetic acid (700 mL) into a 2 L three-necked flask. Control: Add liquid bromine (92.5g, 0.578mol) dropwise under the condition that the temperature is not higher than 25°C. React at 20°C for 3 hours. The reaction was quenched by adding excess saturated sodium sulfite solution. A saturated solution of sodium carbonate was added to the mixture to adjust pH=7. Extracted with ethyl acetate (400mL X 4), washed with water (500mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 1b.

LCMS: m/z = 223.8 (M+H) ⁺ .

Step 2: Preparation of ethyl 2-((5-bromoquinolin-6-yl)oxy)acetate (1c)

At 0°C, compound 1b (50.0 g, 223 mmol) and N,N-dimethylformamide (500 mL) were added into a 2 L three-necked flask. Sodium hydrogen (60%, 22.3g, 557mmol) was added slowly, stirred for 0.5 hours, and ethyl bromoacetate (67.1g, 401mmol) was added. React at room temperature for 1.5 hours. Add water (500mL) to quench, extract with ethyl acetate (500mL×3), wash with water (500mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 1c. The crude product was used directly in the next step without purification.

LCMS: m/z = 310.0 (M+H) ⁺ .

Step 3: Preparation of ethyl 2-((5-cyanoquinolin-6-yl)oxy)acetate (1d)

Add compound 1c (50.0g, 161mmol), zinc acetate (5.92g, 32.2 mmol), zinc cyanide (56.8g, 484mmol), 1,1'-bis(diphenylphosphine) into a 1L three-neck flask at room temperature Ferrocene (9.10 g, 16.1 mmol), tris(dibenzylideneacetone)dipalladium (7.38 g, 8.06 mmol) and N,N-dimethylformamide (500 mL). React at 150°C for 2 hours. Slowly add water (200mL) to quench, ethyl acetate extraction (500mL × 3), wash with water (500mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the residue is subjected to column chromatography (petroleum ether/ethyl acetate ) was purified to obtain compound 1d.

LCMS: m/z = 256.9 (M+H) ⁺ .

Step 4: Preparation of ethyl 1-aminofuro[3,2-f]quinoline-2-carboxylate (1e)

At room temperature, compound 1d (15.1 g, 58.9 mmol) and tetrahydrofuran (200 mL) were added into a 1 L three-neck flask. Potassium tert-butoxide (6.61 g, 58.9 mmol) was added at 0° C. and stirred at room temperature for 1 hour. Slowly add water (200mL) to quench, dichloromethane extraction (300mL X 3), wash with water (500mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the residue is subjected to column chromatography (dichloromethane/methanol) Purification afforded compound 1e.

LCMS: m/z = 256.9 (M+H) ⁺ .

Step 5: Preparation of (R)-1-((2-((tert-butoxycarbonyl)amino)propyl)amino)furo[3,2-f]quinoline-2-carboxylic acid ethyl ester (1f)

At 0°C, compound 1e (1.50 g, 5.85 mmol), sodium hydrogen (60%, 0.28 g, 7.024 mmol) and N-methylpyrrolidone (60 mL) were sequentially added into a 100 mL three-neck flask. After stirring at 0°C for 1 hour, (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide (1.42 g, 5.97 mmol) was added. Stir at 0°C for 1 hour, slowly add to 1N hydrochloric acid (15mL), adjust pH=8 with sodium carbonate, extract with ethyl acetate (40mL X 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and pass through the column Purification by chromatography (petroleum ether/ethyl acetate) gave compound 1f.

LCMS: m/z = 414.1 (M+H) ⁺ .

Step 6: Preparation of ethyl (R)-1-((2-aminopropyl)amino)furo[3,2-f]quinoline-2-carboxylate (1 g)

Under ice cooling, compound 1f (1.00 g, 2.42 mmol), dichloromethane (60 mL) and trifluoroacetic acid (4.14 g, 36.3 mmol) were sequentially added into a 100 mL three-neck flask. Stir at room temperature for 4 hours and at 45°C for 8 hours. Under an ice bath, add water (20 mL), adjust the pH to 8 with sodium bicarbonate, extract with dichloromethane (60 mL X 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1 g. The crude product was used directly in the next step without purification.

LCMS: m/z = 314.1 (M+H) ⁺ .

Step 7: (R)-10-Methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3, Preparation of 2-f] quinolin-8-one (1h)

Under ice-cooling, compound 1g (3.10 g, 9.89 mmol) and methanol (80 mL) were sequentially added into a 250 mL three-neck flask. After stirring to dissolve, sodium methoxide (0.530 g, 9.89 mmol) was added. Stir at 70°C for 15 hours under nitrogen protection. Cool to room temperature and concentrate. Add ice water (30mL), extract with dichloromethane (50mL X 2), and dry over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (dichloromethane/methanol) to obtain compound 1h.

LCMS: m/z = 268.0 (M+H) ⁺ .

Step 8: (R)-10-Methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5',6':4,5]furo[3 ,2-f] Preparation of di-tert-butyl quinoline-9,12-dicarboxylate (1i)

At room temperature, compound 1h (250 mg, 0.935 mmol), 4-dimethylaminopyridine (286 mg, 2.34 mmol) and 1,4-dioxane (20 mL) were sequentially added into a 100 mL three-neck flask. Stir for 10 minutes and add di-tert-butyl dicarbonate (1.18 mL, 5.14 mmol). Stir overnight at 100°C. Concentrate under reduced pressure, add water (30mL), extract with dichloromethane (70mL X 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain the compound 1i.

LCMS: m/z = 468.4 (M+H) ⁺ .

Step 9: (R)-9,12-Bis(tert-butoxycarbonyl)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine Preparation of a[5',6':4,5]furo[3,2-f]quinoline 4-oxide (1j)

At room temperature, compound 1i (2.15 g, 4.60 mmol) and dichloromethane (100 mL) were sequentially added into a 250 mL three-neck flask. After stirring and dissolving, m-chloroperoxybenzoic acid (85%, 1.40 g, 6.90 mmol) was added and reacted at 35° C. for 8 hours. Add water (30mL), extract with dichloromethane (50mL X 2), wash with saturated sodium bicarbonate (30mL X 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and beat with diethyl ether (30mL) to obtain compound 1j.

LCMS: m/z = 484.1 (M+H) ⁺ .

Step 10: (R)-3-Chloro-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5',6':4,5] Preparation of di-tert-butyl furo[3,2-f]quinoline-9,12-dicarboxylate (1k)

At room temperature, compound 1j (2.08 g, 4.30 mmol) and N,N-dimethylformamide (80 mL) were sequentially added into a 250 mL three-neck flask. After stirring to dissolve, oxalyl chloride (5.0 mL, 59.1 mmol) was added dropwise. Stir at room temperature for 8 hours. Add water (50mL), extract with dichloromethane (100mL X 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1k.

LCMS: m/z = 502.1 (M+H) ⁺ .

Step 11: (R)-3-Chloro-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furan Preparation of [3,2-f]quinolin-8-one (1l)

Under ice cooling, compound 1k (1.65 g, 3.29 mmol) and dichloromethane (50 mL) were sequentially added into a 100 mL three-neck flask. After stirring and dissolving, trifluoroacetic acid (5.62 g, 49.3 mmol) was slowly added dropwise. The reaction was carried out at room temperature for 0.5 hours and at 45°C for 9 hours. Under ice bath, adjust the pH to 8 with saturated sodium bicarbonate, extract with dichloromethane (70 mL X 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 11.

LCMS: m/z = 302.1 (M+H) ⁺ .

Step 12: (R)-3-Hydroxy-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furan Preparation of [3,2-f]quinolin-8-one (1m)

At room temperature, compound 11 (220 mg, 0.729 mmol), acetic acid (10 mL) and water (3.5 mL) were sequentially added into a 25 mL microwave tube. React overnight at 140°C. Cool to room temperature, concentrate under reduced pressure, and slurry with diethyl ether (3 mL) to obtain compound 1m.

LCMS: m/z = 284.0 (M+H) ⁺ .

Step 13: (R)-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- Preparation of 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (1)

Under ice cooling, compound 1m (155mg, 0.547mmol), N,N-dimethylformamide (8mL) and potassium tert-butoxide (112mg, 1.10mmol) were sequentially added into a 25mL three-neck flask. After stirring at 0°C for 15 minutes, compound 2,4-dichloro-5-(ethoxymethyl)pyrimidine (170 mg, 0.821 mmol) was added. The reaction was carried out at room temperature for 4 hours, and compound 1 was obtained after purification by preparative liquid chromatography (ammonia bicarbonate/acetonitrile/water system).

LCMS: m/z = 454.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.08(d, J=8.8Hz, 1H), 8.66(s, 1H), 7.94(s, 2H), 7.55(d, J=8.8Hz, 1H), 4.71 (s, 2H), 3.72-3.67 (m, 3H), 3.52-3.50 (m, 2H), 1.34-1.26 (m, 6H).

Example 2

(R)-3-((6-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5 ',6':4,5]furo[3,2-f]quinolin-8-one (2)

According to the preparation method of Example 1, 4,6-dichloropyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 2.

LCMS: m/z = 395.9 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.05(d, J=8.8Hz, 1H), 8.63(s, 1H), 7.93(s, 2H), 7.52(d, J=9.2Hz, 1H), 7.46 (s, 1H), 3.75-3.68 (m, 1H), 3.55-3.46 (m, 2H), 1.33 (d, J=7.2Hz, 3H).

Example 3

(R)-3-((2-Chloro-6-methylpyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]di Azepine[5',6':4,5]furo[3,2-f]quinolin-8-one(3)

According to the preparation method of Example 1, 2,4-dichloro-6-methylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 3.

LCMS: m/z = 410.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.05(d, J=8.8Hz, 1H), 7.96-7.91(m, 2H), 7.51(d, J=8.8Hz, 1H), 7.15(s, 1H ), 3.76-3.67 (m, 1H), 3.52-3.46 (m, 2H), 2.53 (s, 3H), 1.33 (d, J=6.8Hz, 3H).

Example 4

(R)-3-((6-chloro-2-methylpyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]di Azepine[5',6':4,5]furo[3,2-f]quinolin-8-one (4)

According to the preparation method of Example 1, 4,6-dichloro-2-methylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 4.

LCMS: m/z = 410.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.05(d, J=8.8Hz, 1H), 7.93(s, 2H), 7.51(d, J=8.8Hz, 1H), 7.24(s, 1H), 3.74-3.69 (m, 1H), 3.56-3.46 (m, 2H), 2.50 (s, 3H), 1.33 (d, J=6.8Hz, 3H).

Example 5

(R)-6-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6' :4,5]furo[3,2-f]quinolin-3-yl)oxy)pyridinecarbonitrile (5)

According to the preparation method of Example 1, 4,6-dichloro-2-cyanopyridine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 5.

LCMS: m/z = 420.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.16(d, J=8.8Hz, 1H), 8.21(s, 1H), 7.99-7.95(m, 2H), 7.86-7.84(m, 2H), 7.61 (d, J = 8.8Hz, 1H), 6.93 (s, 1H), 3.84 (br s, 1H), 3.58 (br s, 2H), 1.19 (d, J = 6.8Hz, 3H).

Example 6

(R)-2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6' :4,5]furo[3,2-f]quinolin-3-yl)oxy)nicotinonitrile (6)

According to the preparation method of Example 1, 2,6-dichloro-nicotinonitrile was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 6.

LCMS: m/z = 420.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.06(d, J=9.2Hz, 1H), 8.32(d, J=8.4Hz, 1H), 7.92(s, 2H), 7.53(d, J=8.8 Hz, 1H), 7.38 (d, J = 8.8Hz, 1H), 3.72 (br s, 1H), 3.53-3.51 (m, 2H), 1.33 (d, J = 6.8Hz, 3H).

Example 7

(R)-3-((6-Chloro-2-methoxypyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4] Diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (7)

According to the preparation method of Example 1, 2,4-dichloro-6-methoxypyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 7.

LCMS: m/z = 426.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14(d, J=9.0Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.83 (d,J=4.7Hz,1H),7.66(d,J=8.9Hz,1H),7.19(s,1H),6.93(t,J=4.7Hz,1H),3.80(s,3H),3.61 -3.55 (m, 1H), 3.37 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 8

(R)-2-chloro-N-methyl-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[ 5',6':4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidine-4-carboxamide (8)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 2,6-dichloropyrimidine-4-carboxamide to obtain compound 8 .

LCMS: m/z = 453.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17(s, 1H), 8.94(s, 1H), 8.07-7.99(m, 1H), 7.94(d, J=9.3Hz, 1H), 7.84( d,J=5.2Hz,1H),7.71(d,J=7.8Hz,2H),6.94(s,1H),5.74(d,J=12.0Hz,1H),4.10(m,1H),3.18- 3.15 (m, 2H), 2.83 (d, J=6.0Hz, 3H), 1.19 (m, 3H).

Example 9

(R)-3-((6-fluoropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5 ',6':4,5]furo[3,2-f]quinolin-8-one (9)

According to the preparation method of Example 1, 4,6-difluoro-pyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 9.

LCMS: m/z = 380.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.07(d, J=8.8Hz, 1H), 8.57(m, 1H), 7.94(s, 2H), 7.54(d, J=8.8Hz, 1H), 7.04 (s, 1H), 3.73-3.72 (m, 1H), 3.53-3.52 (m, 2H), 1.34 (d, J=8.8Hz, 3H).

Example 10

(R)-3-((6-chloro-2-(methylthio)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1, 4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (10)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced by 4,6-dichloro-2-methylthiopyrimidine to prepare compound 10.

LCMS: m/z = 442.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.10(d, J=8.9Hz, 1H), 7.96(s, 2H), 7.88(s, 1H), 7.57(d, J=8.9Hz, 1H), 3.72 (m, 1H), 3.51 (d, J=8.6Hz, 2H), 1.33 (d, J=6.9Hz, 3H).

Example 11

(R)-3-((6-chloropyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5' ,6':4,5]furo[3,2-f]quinolin-8-one (11)

At room temperature, sequentially add compound 1l (100mg, 0.33mmol) and N,N-dimethylformamide (4mL) into a 25mL single-necked bottle, stir well, add compound 4-amino-6-chloro-pyrimidine (42mg, 0.33 mmol), cesium carbonate (189mg, 0.58mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (38mg, 0.066mmol) and tris(dibenzylideneacetone)dipalladium ( 15mg, 0.017mmol), the reaction system was replaced with nitrogen three times, and stirred at 100°C for 16 hours. Cool to room temperature, and purify by preparative liquid chromatography (acetonitrile/water/ammonium bicarbonate system) to obtain compound 11.

LCMS: m/z = 395.1 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ10.86(s,1H),8.91(d,J＝9.0Hz,1H),8.65(s,1H),8.48(s,1H),7.90(s, 2H), 7.77 (t, J = 7.4Hz, 2H), 6.78 (s, 1H), 3.57 (m, 1H), 3.35 (m, 2H), 1.19 (d, J = 6.8Hz, 3H).

Example 12

(R)-4-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6' :4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidine-2-carboxylic acid methyl ester (12)

According to the preparation method of Example 1, the 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-pyrimidine-2-carboxylic acid methyl ester to obtain the compound 12.

LCMS: m/z = 454.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.16(d, J=8.9Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.91(d, J=9.7Hz, 2H), 7.83 (d,J=4.9Hz,1H),7.68(d,J=8.9Hz,1H),6.94(s,1H),3.83(s,3H),3.58(m,1H),3.37(m,2H) , 1.19 (d, J=6.8Hz, 3H).

Example 13

(R)-N-(tert-butyl)-2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine Epo[5',6':4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidine-4-carboxamide (13)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 2,6-dichloro-pyrimidine-4-carboxylic acid tert-butyramide to obtain Compound 13.

LCMS: m/z = 495.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(d, J=8.9Hz, 1H), 8.27(s, 1H), 8.05-7.90(m, 3H), 7.83(d, J=4.8Hz, 1H), 7.70(d, J=10.5Hz, 1H), 6.94(s, 1H), 3.58(m, 1H), 3.37(m, 2H), 1.41(s, 9H), 1.19(d, J=6.8 Hz, 3H).

Example 14

(R)-2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6' :4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidine-4-carbonitrile (14)

According to the preparation method of Example 1, 2,6-dichloro-4-cyanopyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 14.

LCMS: m/z = 421.1 (M+H) ⁺ .

Example 15

(R)-3-((6-Chloro-2-(morpholinomethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (15)

Step 1: Preparation of 4-(4,6-dichloro-pyrimidine-2-methyl)-morpholine (15b)

Add compound 15a (400mg, 2.20mmol), sodium triacetoxyborohydride (953mg, 4.50mmol), morpholine (196mg, 2.20mmol), 1,2-dichloroethane into a 50mL single-necked bottle at room temperature (20mL). Stir at room temperature for 3 hours under nitrogen atmosphere. Add water (20mL), and extract with ethyl acetate (20mL X 3). Concentrate under reduced pressure, and the residue is purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate) to obtain compound 15b.

LCMS: m/z = 248.0 (M+H) ⁺ .

Step 2: (R)-3-((6-Chloro-2-(morpholinylmethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H Preparation of -[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (15)

At room temperature, compound 1m (100mg, 0.35mmol), compound 15b (131.30mg, 0.52mmol), potassium carbonate (487.80mg, 3.53mmol) and N,N-dimethylformamide (5mL ). Under nitrogen atmosphere, stir at 90°C for 3 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 15.

LCMS: m/z = 495.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.05(d, J=8.9Hz, 1H), 8.27(s, 1H), 7.91(d, J=3.2Hz, 2H), 7.52(d, J=8.9 Hz,1H),7.34(s,1H),3.75–3.70(m,1H),3.67(s,2H),3.58-3.49(m,6H),2.60-2.50(m,4H),1.33(d, J=6.9Hz, 3H).

Example 16

(R)-3-((2-((tert-butylamino)methyl)-6-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (16)

According to the preparation method of Example 1, replace 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 with (4,6-dichloro-pyrimidine-2-methyl)-tert-butylamine to prepare Compound 16 was obtained.

LCMS: m/z = 481.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.06(d, J=8.9Hz, 1H), 7.93(s, 2H), 7.53(d, J=8.9Hz, 1H), 7.31(s, 1H), 3.82 (s, 2H), 3.76-3.66 (m, 1H), 3.51 (m, 2H), 1.33 (d, J=6.9Hz, 3H), 1.07 (s, 9H).

Example 17

(R)-3-((6-Chloro-2-(dimethylamino)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (17)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-2-N,N dimethylpyrimidinamine to prepare Compound 17 was obtained.

LCMS: m/z = 439.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.10(d, J=9.1Hz, 1H), 7.98(d, J=9.2Hz, 1H), 7.91(d, J=9.2Hz, 1H), 7.80( d,J=5.0Hz,1H),7.61(d,J=8.9Hz,1H),6.90(t,J=5.0Hz,1H),6.49(s,1H),3.58(m,1H),3.36( m, 2H), 3.04 (s, 3H), 2.82 (s, 3H), 1.19 (d, J=6.8Hz, 3H).

Example 18

(R)-3-((6-chloro-2-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (18)

According to the preparation method of Example 1, replace 2,4-dichloro-5-(ethoxymethyl) in step 13 with 4,6-dichloro-2-(2-methoxyethoxy)-pyrimidine ) pyrimidine to obtain compound 18.

LCMS: m/z = 470.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14(d, J=8.9Hz, 1H), 8.00(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.82 (d, J=4.5Hz, 1H), 7.65(d, J=8.9Hz, 1H), 7.19(s, 1H), 6.92(t, J=4.4Hz, 1H), 4.26(t, J=4.4Hz ,2H),3.62-3.56(m,1H),3.54(t,J=4.8Hz,2H),3.37(m,2H),3.20(s,3H),1.19(d,J=6.8Hz,3H) .

Example 19

(R)-3-((6-chloro-2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (19)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-2-pyrimidine-isopropanol to obtain compound 19 .

LCMS: m/z = 454.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.13(d, J=9.5Hz, 1H), 7.99(d, J=8.5Hz, 1H), 7.92-7.84(m, 1H), 7.79(d, J＝11.5Hz, 1H), 7.65(d, J＝8.4Hz, 1H), 7.43(d, J＝16.4Hz, 1H), 6.92(s, 1H), 5.11(s, 1H), 3.57-3.52( m, 1H), 3.36-3.35 (m, 2H), 1.36 (s, 6H), 1.19 (d, J=6.3Hz, 3H).

Example 20

(R)-3-((6-chloro-2-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[ 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (20)

According to the preparation method of Example 1, 4,6-dichloro-methoxymethylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 20.

LCMS: m/z = 440.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.15(d, J=8.9Hz, 1H), 8.00(d, J=9.2Hz, 1H), 7.91(d, J=9.2Hz, 1H), 7.85 (d,J=4.5Hz,1H),7.65(d,J=8.9Hz,1H),7.54(s,1H),6.95(m,1H),4.42(s,2H),3.63–3.57(m, 1H), 3.39 (m, 2H), 3.27 (s, 3H), 1.20 (d, J=6.8Hz, 3H).

Example 21

(10R)-3-((6-chloro-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro -8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (21)

(R)-3-((6-chloro-2-(((R)-tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11, 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one and (R)-3-( (6-Chloro-2-(((S)-tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one

Compounds 21-1 and 21-2

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-2-(3-tetrahydrofuran-oxy)pyrimidine to prepare Compound 21 was obtained.

LCMS: m/z = 482.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=9.0Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.93(d, J=9.2Hz, 1H), 7.82 (d, J=4.7Hz, 1H), 7.66(d, J=8.9Hz, 1H), 7.21(s, 1H), 6.93(t, J=4.9Hz, 1H), 5.21(t, J=5.5Hz ,1H),3.77(d,J=8.1Hz,1H),3.73(d,J=4.8Hz,2H),3.65(d,J=6.0Hz,2H),3.59–3.56(m,2H),2.09 -1.94 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Compounds 21-1 and 21-2 were obtained after chiral column resolution

Compound 21-1:

Retention time: 3.042 minutes.

LCMS: m/z = 482.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=8.8Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.93(d, J=9.2Hz, 1H), 7.83 (d, J=4.8Hz, 1H), 7.66(d, J=8.8Hz, 1H), 7.21(s, 1H), 6.92(t, J=4.0Hz, 1H), 5.21(dd, J=6.0, 4.4Hz, 1H), 3.79-3.71(m, 2H), 3.70-3.62(m, 2H), 3.58(dt, J=10.4, 5.6Hz, 1H), 3.37(s, 2H), 2.12-1.92(m , 2H), 1.19 (d, J=6.8Hz, 3H).

Compound 21-2:

Retention time: 1.833 minutes.

LCMS: m/z = 482.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=9.2Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.93(d, J=9.2Hz, 1H), 7.82 (d, J=4.8Hz, 1H), 7.66(d, J=8.8Hz, 1H), 7.21(s, 1H), 6.92(t, J=4.8Hz, 1H), 5.25-5.16(m, 1H) ,3.74(dd,J＝9.6,5.6Hz,2H),3.68-3.63(m,2H),3.60-3.55(m,1H),3.37(s,2H),2.09-1.93(m,2H),1.19 (d, J=6.8Hz, 3H).

Example 22

(R)-10-methyl-3-((2-(methylsulfonyl)pyrimidin-4-yl)oxy)-9,10,11,12-tetrahydro-8H-[1,4]diazepine Epo[5',6':4,5]furo[3,2-f]quinolin-8-one(22)

According to the preparation method of Example 1, 4-chloro-2-methanesulfonylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 22.

LCMS: m/z = 440.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.18(d, J=9.1Hz, 1H), 9.04(d, J=5.7Hz, 1H), 8.02(d, J=9.1Hz, 1H), 7.92 (d, J=9.2Hz, 1H), 7.84(d, J=4.4Hz, 1H), 7.70-7.60(m, 2H), 6.95(t, J=4.8Hz, 1H), 3.59-3.57(m, 1H), 3.39–3.36(m, 2H), 3.30(s, 3H), 1.19(d, J=6.8Hz, 3H).

Example 23

(10R)-3-((6-chloro-2-((3,5-dimethylpiperazin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl-9, 10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (23)

Step 1: Preparation of tert-butyl 4-((4,6-dichloropyrimidin-2-yl)methyl)-2,6-dimethylpiperazine-1-carboxylate (23b)

2,6-Dimethylpiperazine-1-carboxylate tert-butyl ester 23a (250 mg, 1.17 mmol) was dissolved in dichloromethane (5 mL), and 4,6-dichloropyrimidine-2 was added to the mixture -Formaldehyde (206mg, 1.17mmol), sodium triacetoxyborohydride (492mg, 2.33mmol), the mixture was reacted at 15°C for 8 hours. Concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 23b.

LCMS: m/z = 375.2 (M+H) ⁺ .

Step 2: 4-((4-chloro-6-(((R)-10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine And[5',6':4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidin-2-yl)methyl)-2,6-dimethylpiperazine - Preparation of tert-butyl 1-carboxylate (23c)

Compound 23b (180mg, 0.48mmol) was dissolved in N,N-dimethylformamide (2mL), compound 1m (136mg, 0.48mmol) and potassium carbonate (530mg, 3.84mmol) were added, and reacted at 90°C for 3 hours. Cool to room temperature, add water (50mL), extract with dichloromethane (50mL×3), dry the organic phase, filter, concentrate, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 23c.

LCMS: m/z = 622.0 (M+H) ⁺ .

Step 3: (10R)-3-((6-Chloro-2-((3,5-dimethylpiperazin-1-yl)methyl)pyrimidin-4-yl)oxy)-10-methyl -9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 23) Preparation

Compound 23c (40mg, 0.064mmol) was mixed with hydrochloric acid in dioxane (5mL, 4M), the reaction solution was stirred at 15°C for 0.5 hours, concentrated under reduced pressure, and the residue was analyzed by preparative liquid chromatography (C18, acetonitrile /water (ammonia bicarbonate)) to obtain compound 23.

LCMS: m/z = 522.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.15(d, J=8.8Hz, 1H), 7.99(d, J=9.1Hz, 1H), 7.90(d, J=9.2Hz, 1H), 7.83 (d,J=4.8Hz,1H),7.64(d,J=8.9Hz,1H),7.52(s,1H),6.97(s,1H),3.60–3.55(m,1H),3.54(s, 2H), 3.39(m, 2H), 2.69(m, 3H), 2.66(m, 2H), 1.71(t, J=10.0Hz, 2H), 1.18(d, J=6.8Hz, 3H), 0.83( s,3H), 0.82(s,3H).

Example 24

(R)-3-((6-chloro-2-isopropoxypyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4 ]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one(24)

Step 1: Preparation of 4,6-dichloro-2-isopropoxypyrimidine (24b)

Isopropanol (370 mg, 6.16 mmol) was dissolved in tetrahydrofuran (20 mL) at 15°C, and sodium hydride (193 mg, 4.84 mmol, 60%) was added to the mixture. The mixture was added dropwise to a solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine 24a (1.00 g, 4.40 mmol) in tetrahydrofuran (10 mL) at 0°C, and reacted at 0°C for 2 hours. Add water to quench (50mL), and extract with ethyl acetate (100mL X 2). The organic phase was dried, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 24b.

LCMS: m/z = 207.0 (M+H)+.

Step 2: (R)-3-((6-Chloro-2-isopropoxypyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[ Preparation of 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (24)

Compound 24b (240mg, 1.09mmol) was dissolved in N,N-dimethylformamide (10mL), compound 1m (100mg, 0.353mmol) and potassium carbonate (500mg, 3.68mmol) were added thereto, and reaction 5 at 100°C Hour. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 24.

LCMS: m/z = 454.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.13(d, J=9.2Hz, 1H), 8.00(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.80 (d,J=4.8Hz,1H),7.65(d,J=8.8Hz,1H),7.14(s,1H),6.91(t,J=5.2Hz,1H),4.92(dt,J=12.4, 6.4Hz, 1H), 3.64–3.53(m, 1H), 3.39–3.35(m, 2H), 1.22–1.17(m, 9H).

Example 25

(R)-3-((6-chloro-2-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9,10, 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (25)

Step 1: Preparation of 4,6-dichloro-2-((2,2,2-trifluoroethoxy)methyl)pyrimidine (25b)

Sodium hydride (33mg, 0.86mmol, 60%) was dissolved in tetrahydrofuran (5mL), and 2,2,2-trifluoroethanol (99mg, 0.99mmol) was added to the mixture, and the mixture was reacted at 15°C for 0.5 Hour. A solution of 4,6-dichloro-2-(chloromethyl)pyrimidine 25a (150mg, 0.76mmol) in tetrahydrofuran (5mL) was added, and the mixture was reacted at 60°C for 0.5 hours. Cool to room temperature, add acetic acid to adjust the pH to 8, add water (30 mL), and extract with ethyl acetate (40 mL). The organic phase was dried, filtered, concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to give compound 25b.

LCMS: m/z = 261.0 (M+H) ⁺ .

Step 2: (R)-3-((6-Chloro-2-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)oxy)-10-methyl-9 ,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (25)

Dissolve compound 25b (190mg, 0.73mmol) in N,N-dimethylformamide (5mL), add compound 1m (100mg, 0.35mmol) and potassium carbonate (804mg, 5.82mmol) to it, and react at 100°C for 3 hours . After filtration and concentration under reduced pressure, the residue was purified by preparative liquid phase (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 25.

LCMS: m/z = 508.3 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.93(d, J=8.8Hz, 1H), 7.82(d, J=9.2Hz, 1H), 7.76(d, J=5.2Hz, 1H), 7.66 (d,J=9.2Hz,1H),7.35(d,J=9.2Hz,1H),7.32(s,1H),6.85–6.78(m,1H),5.62(s,2H),5.04(q, J=9.2Hz, 2H), 3.57–3.53(m, 1H), 3.47–3.42(m, 2H), 1.17(d, J=6.8Hz, 3H).

Example 26

(R)-3-((6-chloro-2-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (26)

Step 1: Preparation of 1-((4,6-dichloropyrimidin-2-yl)oxy)-2-methylpropan-2-ol (26a)

At room temperature, sequentially add 2-methyl-1,2-propanediol (1.50g, 16.64mmol), tetrahydrofuran (7mL) and potassium tert-butoxide (1.87g, 16.64mmol) into a 25mL three-neck flask, replace with nitrogen three times, and cool down To -78°C, compound 24a (4.16g, 18.31mmol) was added, and reacted at this temperature for 3 hours. Add water (50mL) to quench, and extract with ethyl acetate (50mL×3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 26a.

LCMS: m/z = 237.0 (M+H) ⁺ .

Step 2: (R)-3-((6-Chloro-2-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (26)

At room temperature, compound 1m (80mg, 0.28mmol), potassium carbonate (390mg, 2.82mmol) and N,N-dimethylformamide (5mL) were added to a 25mL three-necked flask, replaced with nitrogen three times, and stirred at 90°C for 10 minutes. After cooling to room temperature, compound 26a (134mg, 0.57mmol) was slowly added, stirred for 10 minutes, and heated to 90°C for 3 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 26.

LCMS: m/z = 484.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14(d, J=9.0Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.83 (d,J=4.7Hz,1H),7.66(d,J=8.9Hz,1H),7.18(s,1H),6.93(t,J=4.8Hz,1H),4.65(s,1H),3.95 (s, 2H), 3.58 (m, 1H), 3.37 (m, 2H), 1.19 (d, J=6.8Hz, 3H), 1.09 (s, 6H).

Example 27

(R)-3-((2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (27)

According to the preparation method of Example 1, 2,4-dichloro-6-trifluoromethylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to obtain compound 27 .

LCMS: m/z = 464.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(d, J=8.9Hz, 1H), 8.08(s, 1H), 8.04(d, J=9.2Hz, 1H), 7.94(d, J= 9.2Hz, 1H), 7.83(d, J=4.7Hz, 1H), 7.74(d, J=8.9Hz, 1H), 6.93(m, 1H), 3.58(m, 1H), 3.37(m, 2H) , 1.19 (d, J=6.8Hz, 3H).

Example 28

(R)-6-((10-Methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5 ]furo[3,2-f]quinolin-3-yl)oxy)pyrimidine-4-carbonitrile (28)

According to the preparation method of Example 1, 4-cyano-6-chloropyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 28.

LCMS: m/z = 387.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(d, J=8.9Hz, 1H), 9.00(d, J=0.9Hz, 1H), 8.19(d, J=1.0Hz, 1H), 8.04 (d, J=9.2Hz, 1H), 7.94(d, J=9.2Hz, 1H), 7.83(d, J=4.7Hz, 1H), 7.68(d, J=8.9Hz, 1H), 6.93(m , 1H), 3.58 (m, 1H), 3.37 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 29

(R)-3-((6-chloro-2-(trifluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (29)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-2-trifluoromethylpyrimidine to obtain compound 29 .

LCMS: m/z = 464.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(d, J=8.9Hz, 1H), 8.07–7.98(m, 2H), 7.94(d, J=9.2Hz, 1H), 7.84(d, J＝4.7Hz, 1H), 7.71(d, J＝8.9Hz, 1H), 6.94(t, J＝4.7Hz, 1H), 3.63–3.57(m, 1H), 3.53–3.46(m, 2H), 1.20 (d, J=6.8Hz, 3H).

Example 30

(R)-3-((2-chloro-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (30)

Step 1: Preparation of 2,4-dichloro-6-(2-methoxyethoxy)pyrimidine (30b)

At room temperature, sodium hydride (710mg, 17.74mmol, 60%) and tetrahydrofuran (10mL) were added to a 50mL three-necked flask, and after cooling down to 0°C, ethylene glycol monomethyl ether (0.52mL, 6.57mmol) was added in tetrahydrofuran (3mL ) solution, stirred at this temperature for 0.5 hours. The temperature was lowered to -65°C, and a solution of compound 2,4,6-trichloropyrimidine 30a (1.57 g, 8.54 mmol) in tetrahydrofuran (10 mL) was added dropwise, and reacted at this temperature for 3 hours. Pour into ice water (200mL) slowly, and extract with ethyl acetate (50mL×3). The organic phase was dried, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 30b.

LCMS: m/z = 223.0 (M+H) ⁺ .

Step 2: (R)-3-((2-Chloro-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Preparation of tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (30)

At room temperature, compound 1m (100mg, 0.35mmol), compound 30b (87mg, 0.39mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (10mL) were added to a 25mL single-necked bottle to replace Nitrogen was blown three times, the temperature was raised to 80°C, and the mixture was stirred for 16 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 30.

LCMS: m/z = 470.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.13(d, J=8.9Hz, 1H), 8.00(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.83 (d,J=4.1Hz,1H),7.67(d,J=8.9Hz,1H),7.03(s,1H),6.94(m,1H),4.37–4.31(m,2H),3.61–3.55( m, 3H), 3.51–3.43 (m, 2H), 3.23 (s, 3H), 1.20 (d, J=6.7Hz, 3H).

Example 31

(R)-3-((2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12 -Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (31)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxy methyl) pyrimidine to obtain compound 31.

LCMS: m/z = 436.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=9.0Hz, 1H), 8.00(d, J=9.2Hz, 1H), 7.89(d, J=9.2Hz, 1H), 7.82 (d, J=5.0Hz, 1H), 7.64(d, J=8.9Hz, 1H), 6.92(t, J=4.8Hz, 1H), 3.58(m, 1H), 3.42–3.35(m, 2H) , 3.01 (t, J = 7.8Hz, 2H), 2.86 (t, J = 7.5Hz, 2H), 2.20–2.09 (m, 2H), 1.19 (d, J = 6.8Hz, 3H).

Example 32

(R)-3-((2-chloro-6-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (32)

Step 1: Preparation of 1-((2,6-dichloropyrimidin-4-yl)oxy)-2-methylpropan-2-ol (32a)

2-Methyl-1,2-propanediol (800mg, 8.87mmol) was dissolved in N,N-dimethylformamide (50mL), and cesium carbonate (8.68g, 26.6mmol), compound 30a (1.95g, 10.60mmol) in tetrahydrofuran (10mL) was reacted at 15°C for 1 hour. Add water (150mL), and extract with ethyl acetate (150mL X 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 32a.

LCMS: m/z = 237.3 (M+H) ⁺ .

Step 2: (R)-3-((2-Chloro-6-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (32)

Compound 32a (300mg, 1.26mmol) was dissolved in N,N-dimethylformamide (5mL), compound 1m (143mg, 0.506mmol) and potassium carbonate (699mg, 5.06mmol) were added thereto, and reaction 3 at 90°C Hour. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 32.

LCMS: m/z = 484.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.05(d, J=9.2Hz, 1H), 7.98–7.90(m, 2H), 7.53(d, J=8.8Hz, 1H), 6.82(s, 1H ), 4.06 (s, 2H), 3.76–3.67 (m, 1H), 3.54–3.45 (m, 2H), 1.33 (d, J=6.8Hz, 3H), 1.19 (s, 6H).

Example 33

(R)-3-((6-Chloro-2-(isopropoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H- [1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (33)

Step 1: Preparation of 4,6-dichloro-2-(isopropoxymethyl)pyrimidine (33a)

At room temperature, sequentially add compound 25a (150mg, 0.76mmol), isopropanol (0.058mL, 0.76mmol), tetrahydrofuran (2mL) and sodium hydride (18mg, 0.76mmol, 60%) into a 20mL single-necked bottle, nitrogen replacement Three times, stirring at room temperature for 3 hours. Add water (10mL), and extract with ethyl acetate (10mL X 3). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 33a.

LCMS: m/z = 221.0 (M+H) ⁺ .

Step 2: (R)-3-((6-Chloro-2-(isopropoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro Preparation of -8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (33)

At room temperature, compound 1m (100mg, 0.35mmol), compound 33a (100mg, 0.45mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (2mL) were sequentially added into a 20mL single-necked bottle. Nitrogen was replaced three times, and stirred at 90°C for 3 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 33.

LCMS: m/z = 468.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.78(d, J=9.0Hz, 1H), 7.74(s, 2H), 7.27(d, J=9.0Hz, 1H), 6.71(s, 1H), 5.59(s,2H),5.28–5.08(m,1H),3.75–3.62(m,1H),3.55–3.43(m,2H),1.31(d,J＝6.9Hz,3H),1.15(dd, J=6.2, 1.2Hz, 6H).

Example 34

(R)-3-((6-chloro-2-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[ 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one(34)

The preparation method was the same as in Example 33, except that sodium ethoxide was used instead of isopropanol to obtain compound 34.

LCMS: m/z = 454.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.78(d, J=9.0Hz, 1H), 7.74(d, J=1.2Hz, 2H), 7.26(d, J=9.0Hz, 1H), 6.77( s,1H),5.58(s,2H),4.33(q,J＝7.1Hz,2H),3.75–3.62(m,1H),3.55–3.38(m,2H),1.31(d,J＝6.9Hz , 3H), 1.22 (t, J = 7.1 Hz, 3H).

Example 35

(R)-3-((2-Chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[ 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (35)

Step 1: Preparation of 6-(methoxymethyl)pyrimidine-2,4-diol (35b)

At room temperature, 6-(chloromethyl)pyrimidine-2,4-diol 35a (1.00 g, 6.15 mmol) and methanol solution of sodium methoxide (10 mL, 30%) were sequentially added to a 50 ml single-necked bottle, and replaced with nitrogen three times, Stir at 70°C for 3 hours. Concentrate under reduced pressure, dissolve the residue in water (50 mL), adjust the pH of the solution to ~7 with 2N hydrochloric acid, and extract with ethyl acetate (50 mL X 3). The organic phase was dried, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 35b.

LCMS: m/z = 157.1 (M+H) ⁺ .

Step 2: Preparation of 2,4-dichloro-6-(methoxymethyl)pyrimidine (35c)

At room temperature, compound 35b (200mg, 1.27mmol) and phosphorus oxychloride (4mL) were sequentially added into a 50ml single-necked bottle, replaced with nitrogen three times, and heated to 120°C for 5 hours. Concentrate under reduced pressure, add water (40mL), and extract with dichloromethane (40mL X 3). The organic phase was dried, filtered, concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to give compound 35c

LCMS: m/z = 193.0 (M+H) ⁺ .

Step 3: (R)-3-((2-Chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- Preparation of 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (35)

At room temperature, sequentially add compound 1m (100mg, 0.35mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (3mL) into a 25ml single-necked bottle, replace with nitrogen three times, and stir at 90°C for 10 minutes . Cool to room temperature, add compound 35c (105 mg, 0.53 mmol), and stir at 90°C for 3 hours under nitrogen atmosphere. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 35.

LCMS: m/z = 440.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17(d, J=8.9Hz, 1H), 8.02(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.84 (d,J=4.7Hz,1H),7.68(d,J=8.9Hz,1H),7.25(s,1H),6.94(t,J=4.9Hz,1H),4.55(s,2H),3.61 -3.56 (m, 1H), 3.42 (s, 3H), 3.38 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 36

(R)-3-((2-Chloro-6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one(36)

Step 1: Preparation of 2,4-dichloro-6-(oxetan-3-yloxy)pyrimidine (36a)

At room temperature, dissolve oxetan-3-ol (0.97g, 13.08mmol) in tetrahydrofuran (20mL), add sodium hydride (0.65g, 16.36mmol, 60%) under nitrogen atmosphere, stir for 20 minutes, add compound 30a (2.00g, 10.90mmol), stirred at room temperature for 16 hours. Add water (40mL) to quench, extract with ethyl acetate (50mL X 3), wash with saturated brine (50mL X 3). The organic phase was dried, filtered and concentrated to give crude compound 36a. The crude product was used directly in the next step without purification.

LCMS: m/z = 220.9 (M+H) ⁺ .

Step 2: (R)-3-((2-Chloro-6-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (36)

At room temperature, compound 1m (100mg, 0.35mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (3mL) were sequentially added to a 25ml single-necked bottle, replaced with nitrogen three times, and stirred at 90°C for 10 minute. Cool to room temperature, add compound 36a (117mg, 0.53mmol), and stir at 90°C for 3 hours under nitrogen atmosphere. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 36.

LCMS: m/z = 467.9 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14(d, J=8.4Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.81 (s,1H),7.64(d,J=8.8Hz,1H),7.10(s,1H),6.92(t,J=5.2Hz,1H),5.35(t,J=6.0Hz,1H),4.58 –4.49 (m, 4H), 3.61 – 3.56 (m, 1H), 3.39 – 3.35 (m, 2H), 1.20 (d, J=6.8Hz, 3H).

Example 37, 38

(R)-2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6' :4,5]furo[3,2-f]quinolin-3-yl)oxy)-4-(trifluoromethyl)nicotinonitrile and (R)-6-chloro-2-((10 -Methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f ]quinolin-3-yl)oxy)-4-(trifluoromethyl)nicotinonitrile

According to the preparation method of Example 1, replace 2,4-dichloro-5-(ethoxymethyl) in step 13 with 3-cyano-2,6-dichloro-4-(trifluoromethyl)pyridine ) pyrimidine to obtain compound 37 and compound 38.

Compound 37:

LCMS: m/z = 487.9 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(d, J=8.8Hz, 1H), 8.09(s, 1H), 8.03(d, J=9.2Hz, 1H), 7.91(d, J= 9.2Hz, 1H), 7.85(d, J=4.4Hz, 1H), 7.68(d, J=8.8Hz, 1H), 6.95(t, J=8.8Hz, 1H), 3.62–3.56(m, 1H) , 3.46–3.38 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Compound 38:

LCMS: m/z = 487.9 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.06 (d, J = 8.8Hz, 1H), 7.88 (d, J = 7.6Hz, 3H), 7.59 (d, J = 8.8Hz, 1H), 3.76– 3.68 (m, 1H), 3.57–3.46 (m, 2H), 1.33 (d, J=6.4Hz, 3H).

Examples 39, 40

(R)-3-((2-Chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one and (R)-3-((4-chloro-5-(tri Fluoromethyl)pyrimidin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4, 5] Furo[3,2-f]quinolin-8-one

According to the preparation method of Example 1, 2,4-dichloro-5-trifluoromethylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to obtain compound 39 and compound 40.

Compound 39:

LCMS: m/z = 464.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(d, J=10.8Hz, 2H), 8.05(d, J=9.2Hz, 1H), 7.98(d, J=9.2Hz, 1H), 7.84 (d,J=4.8Hz,1H),7.77(d,J=8.8Hz,1H),6.94(t,J=3.6Hz,1H),3.63–3.55(m,1H),3.42–3.34(m, 2H), 1.20 (d, J=6.8Hz, 3H).

Compound 40:

LCMS: m/z = 463.9 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.06(d, J=8.8Hz, 1H), 8.95(s, 1H), 7.92(s, 2H), 7.57(d, J=8.8Hz, 1H), 3.76–3.68 (m, 1H), 3.57–3.49 (m, 2H), 1.33 (d, J=6.4Hz, 3H).

Example 41

(R)-3-((6-chloro-2-(difluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (41)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-2-(difluoromethyl)pyrimidine to obtain Compound 41.

LCMS: m/z = 446.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17(d, J=8.9Hz, 1H), 8.02(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.88 –7.78(m,2H),7.69(d,J＝8.9Hz,1H),6.99–6.66(m,2H),3.63–3.55(m,1H),3.41–3.34(m,2H),1.19(d , J=6.8Hz, 3H).

Example 42

(R)-3-((2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9,10, 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (42)

Step 1: (R)-2-chloro-4-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5' ,6':4,5]furo[3,2-f]quinolin-3-yl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- Preparation of tert-butyl carboxylate (42b)

Compound 1m (80mg, 0.28mmol) was dissolved in N,N-dimethylformamide (5mL) at room temperature, potassium carbonate (390mg, 2.82mmol) was added, nitrogen was replaced three times, and stirred at 90°C for 10 minutes. Cool to room temperature, slowly add 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-tert-butyl carboxylate 42a (172mg, 0.57mmol), and heat up to React at 90°C for 3 hours. Filter, add water (20mL), extract with ethyl acetate (20mL X 3), dry the organic phase, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (dichloromethane/methanol) to obtain compound 42b.

LCMS: m/z = 551.2 (M+H) ⁺ .

Step 2: (R)-3-((2-Chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9 ,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (42)

Compound 42b (100mg, 0.18mmol) was dissolved in dichloromethane (5mL) at room temperature, trifluoroacetic acid (103mg, 0.91mmol) was added, nitrogen was replaced three times, and the temperature was raised to 50°C for 1 hour. Concentrate under reduced pressure, adjust the pH to 7-8 with saturated sodium bicarbonate solution, add water (20mL), extract with ethyl acetate (20mL X 3), dry the organic phase, filter, concentrate under reduced pressure, and the residue is subjected to preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 42.

LCMS: m/z = 451.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.03(d, J=8.8Hz, 1H), 7.92(s, 2H), 7.53(d, J=8.8Hz, 1H), 4.03(s, 2H), 3.75–3.67(m,1H),3.57–3.46(m,2H),3.20(t,J=5.2Hz,2H),2.93–2.86(m,2H),1.33(d,J=6.8Hz,3H) .

Example 43

(R)-3-((4-chloropyrimidin-2-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5 ',6':4,5]furo[3,2-f]quinolin-8-one (43)

According to the preparation method of Example 1, 4-chloro-2-fluoropyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 43.

LCMS: m/z = 396.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=8.8Hz, 1H), 8.69(d, J=5.2Hz, 1H), 7.99(d, J=9.2Hz, 1H), 7.89 (d,J=9.2Hz,1H),7.84(d,J=4.4Hz,1H),7.66(d,J=8.8Hz,1H),7.58(d,J=5.2Hz,1H),6.99–6.88 (m, 1H), 3.63–3.55 (m, 1H), 3.51–3.41 (m, 2H), 1.20 (d, J=6.8Hz, 3H).

Example 44

(R)-3-((5-((tert-butylamino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (44)

Step 1: Preparation of 2,4-dichloro-5-(chloromethyl)pyrimidine (44b)

At room temperature, 5-(hydroxymethyl)pyrimidine-2,4-diol 44a (10.00g, 70.37mmol) was dissolved in toluene (25mL), and phosphorus oxychloride (13.08mL, 140.74mmol) and N , N-diisopropylethylamine (34.89mL, 211.10mmol), replaced with nitrogen three times, heated to 120°C and stirred for 16 hours. Quenched by saturated sodium bicarbonate solution, extracted with ethyl acetate (100mL × 2), the organic phase was washed with saturated brine (80mL), the organic phase was dried, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether). /ethyl acetate) to obtain compound 44b.

LCMS: m/z = 197.0 (M+H) ⁺ .

Step 2: Preparation of 2,4-dichloro-5-(iodomethyl)pyrimidine (44c)

Compound 44b (500mg, 2.53mmol) was dissolved in acetone (10mL) at room temperature, sodium iodide (385mg, 2.57mmol) was added, nitrogen was replaced three times, stirred at room temperature for 20 minutes, then heated to 65°C and stirred for 15 minutes. Cool to room temperature, filter, wash the filter cake with acetone (5mL×2), and concentrate the filtrate under reduced pressure to obtain crude compound 44c. The crude product was used directly in the next step without purification.

LCMS: m/z = 288.9 (M+H) ⁺ .

Step 3: Preparation of N-((2,4-dichloropyrimidin-5-yl)methyl)-2-methylpropan-2-amine (44d)

Compound 44c (0.70 g, 2.42 mmol) was dissolved in acetonitrile (10 mL) at room temperature, potassium carbonate (1.10 g, 7.96 mmol) and tert-butylamine (0.22 g, 3.01 mmol) were added, and stirred at room temperature for 3 hours. Concentrate under reduced pressure, add water (80mL) to the residue, extract with ethyl acetate (100mL × 2), wash the organic phase with saturated brine (80mL), dry, filter, concentrate under reduced pressure, the residue is subjected to column chromatography (petroleum ether/ethyl acetate) to afford compound 44d.

LCMS: m/z = 234.1 (M+H) ⁺ .

Step 4: (R)-3-((5-((tert-butylamino)methyl)-2-chloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Preparation of Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (44)

Compound 1m (100mg, 0.35mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (3mL) were mixed at room temperature, replaced with nitrogen three times, and stirred at 90°C for 10 minutes. Cool to room temperature, add compound 44d (165 mg, 0.71 mmol), and stir at 90°C for 3 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 44.

LCMS: m/z = 481.1 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ9.15(d,J=9.2Hz,1H),8.76(s,1H),8.20(s,1H),8.01(d,J=9.2Hz,1H) ,7.92(d,J=9.2Hz,1H),7.84(s,1H),7.67(d,J=8.8Hz,1H),6.93(t,J=5.2Hz,1H),3.86–3.78(m, 2H), 3.62–3.54 (m, 1H), 3.51–3.43 (m, 2H), 1.19 (d, J=6.8Hz, 3H), 1.11 (s, 9H).

Example 45

(R)-3-((5,6-dichloropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine And[5',6':4,5]furo[3,2-f]quinolin-8-one (45)

According to the preparation method of Example 1, 4,5,6-trichloropyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 45.

LCMS: m/z = 429.9 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17(d, J=8.9Hz, 1H), 8.61(s, 1H), 8.02(d, J=9.2Hz, 1H), 7.92(d, J= 9.2Hz, 1H), 7.83(d, J=4.7Hz, 1H), 7.72(d, J=8.9Hz, 1H), 6.92(t, J=4.7Hz, 1H), 3.62–3.54(m, 1H) , 3.42–3.32 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 46

(R)-3-((2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1, 4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one(46)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 2-chloro-6-(trifluoromethyl)-4-aminopyrimidine to prepare Compound 46 was obtained.

LCMS: m/z = 463.1 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO-d ₆ )δ11.54(br,1H),8.99(d,J=9.2Hz,1H),8.42(s,1H),7.96(d,J=9.2Hz,1H) ,7.88(d,J=9.2Hz,1H),7.77(d,J=4.8Hz,2H),6.82(t,J=4.8Hz,1H),3.89–3.45(m,3H),1.19(d, J=6.8Hz, 3H).

Example 47

(R)-3-((2-chloro-6-(difluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (47)

Step 1: Preparation of 6-(difluoromethyl)pyrimidine-2,4-diol (47b)

Dissolve ethyl 4,4-difluoro-3-oxobutanoate 47a (5.00 g, 30.12 mmol) in toluene (150 mL) at room temperature, add urea (3.62 g, 60.24 mmol) and ethanol solution of sodium ethoxide (20% mass fraction, 20.48g, 60.24mmol), replaced with nitrogen three times, heated to 130°C and stirred for two days. Concentrated and slurried with ethyl acetate (30 mL) to afford compound 47b.

LCMS: m/z = 163.1 (M+H) ⁺ .

Step 2: Preparation of 2,4-dichloro-6-(difluoromethyl)pyrimidine (47c)

Compound 47b (4.00g, 24.68mmol) and N,N-diisopropylethylamine (2.72g, 21.08mmol) were dissolved in acetonitrile (40mL), cooled to 0°C, and phosphorus oxychloride (10mL ), replaced with nitrogen three times, heated to 95°C and stirred for 16 hours. Cool to room temperature, quench with ice water (100mL), extract with ethyl acetate (70mL X 2), wash with saturated brine (50mL). The organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate) to give compound 47c

LCMS: m/z = 199.0 (M+H) ⁺ .

Step 3: (R)-3-((2-Chloro-6-(difluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H Preparation of -[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (47)

Compound 1m (80mg, 0.28mmol) was dissolved in N,N-dimethylformamide (5mL) at room temperature, potassium carbonate (390mg, 2.82mmol) was added, nitrogen was replaced three times, and stirred at 90°C for 10 minutes. After cooling to room temperature, compound 47c (112 mg, 0.57 mmol) was added slowly, and reacted at room temperature for 16 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 47.

LCMS: m/z = 446.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(d, J=8.8Hz, 1H), 8.04(d, J=9.2Hz, 1H), 7.94(d, J=9.2Hz, 1H), 7.84 (s,1H),7.73(d,J=6.0Hz,2H),7.03(dd,J=74.0,33.6Hz,2H),3.65–3.57(m,1H),3.43–3.35(m,2H), 1.20 (d, J=6.4Hz, 3H).

Example 48

(S)-3-((6-chloropyrimidin-4-yl)amino)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine [5',6':4,5]furo[3,2-f]quinolin-8-one (48)

Step 1: Preparation of (S)-tert-butyl 4-((benzylamino)methyl)-2,2-dimethyloxazolidine-3-carboxylate (48b)

At room temperature, (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 48a (1.00 g, 4.36 mmol), benzylamine (0.47 g, 4.36mmol) and methanol (10mL), stirred at 60°C for 16 hours under nitrogen atmosphere. Cool to room temperature, add sodium borohydride (0.25 g, 6.54 mmol), and react at room temperature for 4 hours. Add saturated sodium bicarbonate solution to adjust the pH of the system to neutral, extract with dichloromethane (50mL X 3), wash with saturated sodium chloride solution (50mL X 3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure , the residue was purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 48b.

LCMS: m/z = 321.1 (M+H) ⁺ .

Step 2: Preparation of (S)-tert-butyl 4-(aminomethyl)-2,2-dimethyloxazolidine-3-carboxylate (48c)

At room temperature, compound 48b (700 mg, 2.19 mmol), 10% palladium on carbon (70 mg) and methanol (10 mL) were sequentially added into a 25 ml single-necked bottle, and stirred at room temperature for 16 hours under a hydrogen atmosphere. Filtration and concentration under reduced pressure afforded crude compound 48c. The crude product was used directly in the next step without purification.

LCMS: m/z = 231.3 (M+H) ⁺ .

Step 3: Preparation of ethyl 1-bromofuro[3,2-f]quinoline-2-carboxylate (48d)

At room temperature, copper bromide (10.51g, 46.83mmol) and tert-butyl nitrite (6.04g, 58.53mmol) were added to dry acetonitrile (300mL), the temperature was raised to 65°C, stirred for 10 minutes, and 1-amino Ethyl furo[3,2-f]quinoline-2-carboxylate 1e (10.0g, 39.02mmol) was reacted at 65°C for 10 hours. After the reaction, it was cooled to room temperature, filtered, and slurried with ether to obtain compound 48d.

LCMS: m/z = 320.0 (M+H) ⁺ .

Step 4: (S)-1-(((3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)methyl)amino)furo[3,2-f] Preparation of ethyl quinoline-2-carboxylate (48e)

At room temperature, compound 48c (1.34g, 5.81mmol), cesium carbonate (2.52g, 7.75mmol), 1,1-binaphthalene-2, 2'-bisdiphenylphosphine (241mg, 0.39mmol) and tris(dibenzylideneacetone)dipalladium (355mg, 0.39mmol) were replaced with nitrogen three times, and reacted overnight at 110°C. Cool to room temperature, add water (20mL), extract with dichloromethane (30mL × 3), dry the organic phase, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 48e .

LCMS: m/z = 470.3 (M+H) ⁺ .

Step 5: Preparation of (S)-1-((2-amino-3-hydroxypropyl)amino)furo[3,2-f]quinoline-2-carboxylic acid ethyl ester (48f)

To a solution of compound 48e (700mg, 1.49mmol) in methanol (15mL) was added methanolic hydrogen chloride (4mL, 4.0M) at room temperature, and reacted overnight at 55°C. The reaction solution was concentrated, added with ice water (20 mL), saturated sodium bicarbonate solution, dichloromethane (30 mL X 3) for extraction, the organic phase was dried, filtered, concentrated under reduced pressure, and beaten with ether to obtain compound 48f.

LCMS: m/z = 330.1 (M+H) ⁺ .

Step 6: (S)-10-(Hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo Preparation of [3,2-f]quinolin-8-one (48g)

To a solution of compound 48f (320 mg, 0.97 mmol) in methanol (25 mL) was added sodium methoxide (131 mg, 2.43 mmol) at room temperature, and reacted overnight at 70°C. Concentrate, add ice water (1.5 mL), adjust pH to 5 with 1N hydrochloric acid, and purify by prep-HPLC (C18, acetonitrile/water (formic acid)) to obtain compound 48 g.

LCMS: m/z = 284.1 (M+H) ⁺ .

Step 7: (S)-10-(((tert-butoxycarbonyl)oxy)methyl)-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5' Preparation of ,6':4,5]furo[3,2-f]quinoline-9,12-dicarboxylic acid di-tert-butyl ester (48h)

At room temperature, 4-dimethylaminopyridine (259 mg, 2.12 mmol) was added to a solution of compound 48 g (150 mg, 0.53 mmol) in dioxane (120 mL), stirred for 10 minutes, and di-tert-butyl dicarbonate (2 mL, 8.71 mmol), reacted at 100°C for 60 hours. Concentrate, add water (20mL), extract with ethyl acetate (40mL X 3), dry the organic phase, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 48h.

LCMS: m/z = 584.3 (M+H) ⁺ .

Step 8: (S)-9,12-Bis(tert-butoxycarbonyl)-10-(((tert-butoxycarbonyl)oxy)methyl)-8-oxo-9,10,11,12-tetra Preparation of Hydrogen-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinoline 4-oxide (48i)

At room temperature, m-chloroperoxybenzoic acid (89 mg, 0.51 mmol) was added to a solution of compound 48h (150 mg, 0.26 mmol) in dichloromethane (20 mL), and reacted overnight at 35°C. Quenched with saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (20 mL X 3), dried the organic phase, concentrated under reduced pressure, and beat with ether to obtain compound 48i.

LCMS: m/z = 600.3 (M+H) ⁺ .

Step 9: (S)-10-(((tert-butoxycarbonyl)oxy)methyl)-3-chloro-8-oxo-10,11-dihydro-8H-[1,4]diazepine Preparation of di-tert-butyl a[5',6':4,5]furo[3,2-f]quinoline-9,12-dicarboxylate (48j)

At room temperature, oxalyl chloride (0.2 mL, 0.23 mmol) was added to a solution of compound 48i (135 mg, 0.23 mmol) in N,N-dimethylformamide (5 mL), and reacted overnight at room temperature. Concentrate under reduced pressure, add ice water (10mL), extract with dichloromethane (10mL × 3), dry the organic phase, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain Compound 48j.

LCMS: m/z = 618.2 (M+H) ⁺ .

Step 10: (S)-3-Chloro-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4, 5] Preparation of Furo[3,2-f]quinolin-8-one (48k)

At room temperature, to a solution of compound 48j (120 mg, 0.19 mmol) in ethyl acetate (10 mL) was added hydrogen chloride in ethyl acetate (5 mL, 3.0 M), and reacted at 45°C for 18 hours. Concentrate under reduced pressure and beat with ether to obtain compound 48k.

LCMS: m/z = 318.3 (M+H) ⁺ .

Step 11: (S)-3-((6-Chloropyrimidin-4-yl)amino)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]di Preparation of azepine[5',6':4,5]furo[3,2-f]quinolin-8-one (48)

At room temperature, compound 48k (20mg, 0.063mmol), 4-amino-6-chloropyrimidine (16.32mg, 0.13mmol), cesium carbonate (677mg, 2.08mmol) were added to dioxane (5mL), nitrogen replacement 5 times, stirred for 10 minutes, then added 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (3.65mg, 0.006mmol) and tris(dibenzylideneacetone)dipalladium (5.77mg , 0.006mmol), and replaced with nitrogen 5 times, and reacted overnight at 100°C. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonia bicarbonate)) to obtain compound 48.

LCMS: m/z = 411.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ10.87(s, 1H), 8.92(d, J=9.2Hz, 1H), 8.65(d, J=0.8Hz, 1H), 8.48(s, 1H) ,7.90(s,2H),7.78(d,J=9.2Hz,1H),7.57(s,1H),6.78-6.76(m,1H),5.02-4.99(m,1H),3.58-3.51(m ,2H), 3.44-3.37(m,2H), 3.33-3.25(m,1H).

Example 49

(S)-3-((6-chloropyrimidin-4-yl)oxy)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine And[5',6':4,5]furo[3,2-f]quinolin-8-one (49)

Step 1: (S)-3-Hydroxy-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4, 5] Preparation of Furo[3,2-f]quinolin-8-one (49a)

At room temperature, water (1 mL) was added to a solution of compound 48J (60 mg, 0.19 mmol) in acetic acid (3 mL), and the reaction was carried out at 135° C. for 30 hours. Concentrate under reduced pressure and beat with ether to obtain compound 49a.

LCMS: m/z = 300.0 (M+H) ⁺ .

Step 2: (S)-3-((6-chloropyrimidin-4-yl)oxy)-10-(hydroxymethyl)-9,10,11,12-tetrahydro-8H-[1,4] Preparation of diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (49)

Add 4,6-dichloropyrimidine (26mg, 0.17mmol) and potassium carbonate (240mg, 1.74mmol) to a solution of compound 49a (52mg, 0.17mmol) in N,N-dimethylformamide (3mL) at room temperature, React at 30°C for 10 hours. Filter, concentrate under reduced pressure, add a small amount of water, extract with ethyl acetate (10mL × 3), dry, filter, concentrate under reduced pressure, and the residue is purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain the compound 49.

LCMS: m/z = 412.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.06(d, J=8.8Hz, 1H), 8.63(s, 1H), 7.94(s, 2H), 7.54(d, J=8.8Hz, 1H), 7.46 (s, 1H), 3.69-3.64 (m, 2H), 3.64-3.62 (m, 3H).

Example 50

(R)-3-((6-chloro-5-fluoropyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Epo[5',6':4,5]furo[3,2-f]quinolin-8-one(50)

According to the preparation method of Example 1, 4,6-dichloro-5-fluoropyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 50.

LCMS: m/z = 414.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17(d, J=9.2Hz, 1H), 8.56(s, 1H), 8.01(d, J=9.2Hz, 1H), 7.89(d, J= 9.2Hz, 1H), 7.82(d, J=4.8Hz, 1H), 7.71(d, J=8.8Hz, 1H), 6.91(t, J=4.8Hz, 1H), 3.62-3.54(m, 1H) , 3.41-3.33 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 51

(R)-3-((2-chloro-6-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)oxy)-10-methyl-9,10,11, 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (51)

Step 1: Preparation of 1-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-2-ol (51a)

Under ice-cooling, 1-amino-2-methyl-2-propanol (389mg, 4.36mmol) was dissolved in acetonitrile (40mL), N,N-diisopropylethylamine (1.97g, 15.30mmol) and Compound 30a (800 mg, 4.36 mmol) was replaced with nitrogen three times, and stirred at room temperature for 3 hours. Add water (5 mL), extract with dichloromethane (40 mL X 2), dry the organic phase, filter, and concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 51a.

LCMS: m/z = 236.2 (M+H) ⁺ .

Step 2: (R)-3-((2-Chloro-6-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)oxy)-10-methyl-9,10 , Preparation of 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (51)

At room temperature, compound 1m (100mg, 0.35mmol) and compound 51a (83mg, 0.35mmol) were dissolved in N,N-dimethylformamide (3mL), potassium carbonate (147mg, 1.06mmol) was added, and nitrogen replacement was performed three times , 130°C for 6 hours. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 51.

LCMS: m/z = 483.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.03(d, J=8.8Hz, 1H), 7.96-7.92(m, 2H), 7.48(d, J=8.8Hz, 1H), 6.41(s, 1H ), 3.72-3.69 (m, 1H), 3.52-3.48 (m, 2H), 3.16 (s, 2H), 1.34 (d, J=7.2Hz, 1H), 0.99 (s, 6H).

Example 52

(R)-3-((6-chloro-2-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (52)

Step 1: Preparation of 4,6-dichloro-2-(oxetan-3-yloxy)pyrimidine (52a)

At room temperature, oxetan-3-ol (300 mg, 4.05 mmol) was dissolved in tetrahydrofuran (3 mL) and potassium tert-butoxide (454 mg, 4.05 mmol), replaced with nitrogen three times, and stirred at -78°C for 20 minutes. Compound 24a (1.01 g, 4.45 mmol) was added and reacted at -78°C for 3 hours. Add water (50mL), extract with ethyl acetate (20mL×3), dry the organic phase, filter and concentrate, and the residue is purified by column chromatography (ethyl acetate/petroleum ether) to obtain compound 52a.

LCMS: m/z = 220.8 (M+H) ⁺ .

Step 2: (R)-3-((6-Chloro-2-(oxetan-3-yloxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11 , Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (52)

At room temperature, compound 1m (100mg, 0.35mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (3mL) were added, replaced with nitrogen three times, and stirred at 90°C for 10 minutes. Cool to room temperature, add compound 52a (234mg, 1.06mmol), and stir at 90°C for 3 hours under nitrogen atmosphere. Filtration and concentration under reduced pressure, the residue was filtered and concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 52.

LCMS: m/z = 468.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.15(d, J=8.8Hz, 1H), 8.02(d, J=9.2Hz, 1H), 7.93(d, J=9.2Hz, 1H), 7.83 (d,J=4.4Hz,1H),7.64(d,J=8.8Hz,1H),7.26(s,1H),6.94(s,1H),5.33-5.26(m,1H),4.57(t, J=6.8Hz, 2H), 4.51-4.45(m, 2H), 3.63-3.54(m, 1H), 3.41-3.33(m, 2H), 1.19(d, J=6.8Hz, 3H).

Example 53

(R)-3-((6-chloro-2-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)oxy)-10-methyl-9,10,11, 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (53)

Step 1: Preparation of 1-((4,6-dichloropyrimidin-2-yl)amino)-2-methylpropan-2-ol (53a)

At room temperature, 1-amino-2-methyl-2-propanol (1.00g, 4.40mmol), compound 24a (0.39g, 4.40mmol), N,N-diisopropylethylamine (0.73mL, 4.40 mmol) and dimethyl sulfoxide (10 mL), replaced with nitrogen three times, and stirred at 90°C for 6 hours. Cool to room temperature, add water (100mL), extract with ethyl acetate (50mL×4), dry the organic phase, filter and concentrate, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain compound 53a.

LCMS: m/z = 236.1 (M+H) ⁺ .

Step 2: (R)-3-((6-Chloro-2-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)oxy)-10-methyl-9,10 , Preparation of 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (53)

At room temperature, compound 1m (100mg, 0.35mmol), potassium carbonate (488mg, 3.53mmol) and N,N-dimethylformamide (3mL) were added, replaced with nitrogen three times, and stirred at 90°C for 10 minutes. Cool to room temperature, add compound 53a (125mg, 0.53mmol), and stir at 90°C for 3 hours under nitrogen atmosphere. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 53.

LCMS: m/z = 483.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.11(d, J=8.8Hz, 1H), 7.98(d, J=9.2Hz, 1H), 7.90(t, J=8.8Hz, 1H), 7.82 (s,1H),7.58(d,J=8.8Hz,1H),7.26(t,J=5.6Hz,1H),6.92(s,1H),6.47(d,J=18.8Hz,1H),4.36 (d,J=63.6Hz,1H),3.62-3.54(m,1H),3.41-3.35(m,2H),3.21(d,J=6.0Hz,1H),2.93(d,J=5.6Hz, 1H), 1.19(d, J=6.8Hz, 3H), 1.05(s, 3H), 0.86(s, 3H).

Example 54

(R)-3-((4-chloropyrimidin-2-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5' ,6':4,5]furo[3,2-f]quinolin-8-one (54)

According to the preparation method of Example 1, 2-amino-4-chloropyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 54.

LCMS: m/z = 395.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.84(d, J=9.2Hz, 1H), 8.62(d, J=9.2Hz, 1H), 8.46(d, J=5.2Hz, 1H), 8.04( d,J=9.2Hz,1H),7.90(d,J=9.2Hz,1H),7.80(d,J=9.2Hz,1H),7.01(d,J=5.2Hz,1H),3.75-3.67( m, 1H), 3.52-3.47 (m, 2H), 1.32 (d, J=6.8Hz, 3H).

Example 55

(R)-3-((2-Chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9,10, 11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (55)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxy (methyl) pyrimidine to obtain compound 55.

LCMS: m/z = 452.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.14 (d, J=9.2Hz, 1H), 7.97 (dd, J=36.0, 9.2Hz, 2H), 7.83 (d, J=4.8Hz, 1H) ,7.67(d,J=8.8Hz,1H),6.93(s,1H),4.81(s,2H),4.04(t,J=5.6Hz,2H),3.62-3.54(m,1H),3.41- 3.33 (m, 2H), 2.92 (t, J=5.6Hz, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 56

(R)-3-((6-Chloro-2-methylpyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Epo[5',6':4,5]furo[3,2-f]quinolin-8-one(56)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 2-methyl-4-amino-6-chloropyrimidine to prepare compound 56.

LCMS: m/z = 409.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ10.80(s,1H),8.90(d,J＝9.2Hz,1H),8.30(s,1H),7.89(s,2H),7.78(t, J＝8.4Hz, 2H), 6.78(t, J＝4.8Hz, 1H), 3.60-3.52(m, 1H), 3.40-3.30(m, 2H), 2.52(s, 3H), 1.19(d, J =6.8Hz, 3H).

Example 57

(R)-3-((2-Chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12- Tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (57)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 2,4-dichloro-5,7-dihydrofuropyrimidine to obtain Compound 57.

LCMS: m/z = 438.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17(d, J=8.8Hz, 1H), 7.98(dd, J=40.0,9.2Hz, 2H), 7.84(d, J=5.0Hz, 1H) ,7.69(d,J＝8.9Hz,1H),6.94(s,1H),5.04(s,4H),3.62-3.54(m,1H),3.41-3.33(m,2H),1.19(d,J =6.8Hz, 3H).

Example 58

(R)-3-((2-chloro-5-(2-methoxyethoxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro- 8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (58)

According to the preparation method of Example 1, replace 2,4-dichloro-5-(ethoxymethyl) in step 13 with 2,4-dichloro-5-(2-methoxyethoxy)-pyrimidine ) pyrimidine to obtain compound 58.

LCMS: m/z = 470.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=9.2Hz, 1H), 8.57(s, 1H), 7.99(d, J=9.2Hz, 1H), 7.87(d, J= 9.2Hz, 1H), 7.83(d, J=4.8Hz, 1H), 7.68(d, J=8.8Hz, 1H), 6.93(t, J=4.8Hz, 1H), 4.33(dd, J=5.2, 3.6Hz, 2H), 3.61(dd, J=5.2, 3.6Hz, 2H), 3.62-3.54(m, 1H), 3.41-3.33(m, 2H), 3.21(s, 3H), 1.19(d, J =6.8Hz, 3H).

Example 59

(R)-3-((2-Chloro-6-hydroxypyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Epo[5',6':4,5]furo[3,2-f]quinolin-8-one(59)

According to the preparation method of Example 1, replace 2,4-dichloro-5-(ethoxymethyl) in step 13 with 2,4-dichloro-5-(2-methoxyethoxy)-pyrimidine ) pyrimidine to obtain compound 59.

LCMS: m/z = 412.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.09(d, J=9.0Hz, 1H), 7.97(d, J=9.2Hz, 1H), 7.88(d, J=9.2Hz, 1H), 7.81 (d, J=4.4Hz, 1H), 7.53(d, J=8.8Hz, 1H), 6.91(t, J=4.8Hz, 1H), 6.15(s, 1H), 3.62-3.51(m, 2H) , 3.51-3.42 (m, 2H), 1.18 (d, J=6.8Hz, 3H).

Example 60

(R)-3-((2-Chloro-7,7-dimethyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)-10-methyl- 9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (60 )

According to the preparation method of Example 1, 2,4-dihydrofuro[3,4-d]pyrimidine in step 13 was replaced Chloro-5-(ethoxymethyl)pyrimidine to obtain compound 60.

LCMS: m/z = 466.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.19 (dd, J=29.2, 8.8Hz, 1H), 8.11-7.68 (m, 4H), 6.96 (d, J=23.6Hz, 1H), 5.00( d, J = 28.8Hz, 2H), 3.69-3.58 (m, 3H), 1.50 (d, J = 29.2Hz, 6H), 1.22 (d, J = 22.4Hz, 3H).

Example 61

(R)-3-((2-Chloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)-10-methyl-9, 10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (61)

According to the preparation method of Example 1, 2,4-dihydrofuro[3,4-d]pyrimidine in step 13 was replaced Chloro-5-(ethoxymethyl)pyrimidine to obtain compound 61.

LCMS: m/z = 468.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=8.8Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.82 (s,1H),7.67(d,J=8.8Hz,1H),6.94(d,J=13.2Hz,1H),3.91(s,2H),3.66(brs,1H),3.37(brs,2H) , 3.07 (dd, J=21.6, 11.2Hz, 4H), 1.19 (d, J=5.6Hz, 3H).

Example 62

(R)-3-((2-Chloro-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-10-methyl -9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 62)

At room temperature, compound 42 (8.3mg, 0.018mmol), paraformaldehyde (3.64mg, 0.040mmol), sodium cyanoborohydride (3.47mg, 0.055mmol) and methanol (1.5ml) were added sequentially, and stirred at room temperature for 40 minutes. After filtration, the filtrate was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 62.

LCMS: m/z = 465.3 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.14(d, J=8.8Hz, 1H), 8.01(d, J=9.2Hz, 1H), 7.92(d, J=9.2Hz, 1H), 7.83 (d,J=4.0Hz,1H),7.67(d,J=8.8Hz,1H),6.92(s,1H),3.62(d,J=26.8Hz,3H),3.37(s,3H),2.94 (s, 2H), 2.82 (s, 2H), 2.46 (s, 2H), 1.17 (dd, J=6.8Hz, 3H).

Example 63

(R)-3-((2-chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H-[1, 4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one(63)

Step 1: (R)-3-Bromo-10-methyl-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5',6':4,5] Preparation of di-tert-butyl furo[3,2-f]quinoline-9,12-dicarboxylate (63a)

At room temperature, compound 1j (1.70g, 3.52mmol) was dissolved in N,N-dimethylformamide (20mL), replaced with nitrogen three times, cooled to 0°C, and phosphorus oxybromide (0.89g, 3.10mmol) was added dropwise ), stirred at room temperature for 2 hours. It was quenched by adding methanol (5 mL), extracted with dichloromethane (50 mL), washed with water (50 mL X 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed with ether to obtain compound 63a.

LCMS: m/z = 546.1 (M+H) ⁺ .

Step 2: (R)-3-Bromo-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furan Preparation of [3,2-f]quinolin-8-one (63b)

At room temperature, compound 63a (1.40 g, 2.75 mmol), dichloromethane (20 mL), and trifluoroacetic acid (2 mL) were sequentially added, replaced with nitrogen three times, and reacted at 45° C. for 16 hours. Concentrated under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 63b.

LCMS: m/z = 346.1 (M+H) ⁺ .

Step 3: Preparation of 2-chloro-6-(difluoromethyl)pyrimidin-4-amine (63c)

Compound 47c (200 mg, 1.01 mmol) was dissolved in 1,4-dioxane (1 mL) at room temperature, ammonia water (1 mL) was added, and stirred at room temperature for 2 hours. Concentrated under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 63c.

LCMS: m/z = 180.1 (M+H) ⁺ .

Step 4: (R)-3-((2-Chloro-6-(difluoromethyl)pyrimidin-4-yl)amino)-10-methyl-9,10,11,12-tetrahydro-8H- Preparation of [1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (63)

At room temperature, compound 63c (61.14 mg, 0.34 mmol) was dissolved in 1,4-dioxane (1.5 mL), compound 63b (60 mg, 0.17 mmol), cesium carbonate (337.02 mg, 1.03 mmol), three (Dibenzylideneacetone)dipalladium (31.80mg, 0.035mmol), 1,1-binaphthyl-2,2'-bisdiphenylphosphine (43.26mg, 0.069mmol), nitrogen replacement three times, react at 100°C for 0.5 hours . After filtration and concentration under reduced pressure, the residue was purified by column chromatography (dichloromethane/methanol) and preparative liquid chromatography (C18, acetonitrile/water (formic acid)) to obtain compound 63.

LCMS: m/z = 445.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ11.36(s, 1H), 8.96(d, J=9.2Hz, 1H), 7.93(dd, J=20.0, 9.2Hz, 2H), 7.78(d, J＝4.4Hz, 2H), 7.13(s, 1H), 7.00(s, 1H), 6.86(s, 1H), 6.81(t, J＝4.8Hz, 1H), 3.57(d, J＝4.8Hz, 1H), 3.38 (m, 2H), 1.19 (d, J=6.8Hz, 3H).

Example 64

(R)-3-((6-fluoro-2-hydroxypyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1,4]diazepine Epo[5',6':4,5]furo[3,2-f]quinolin-8-one(64)

According to the preparation method of Example 1, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced by 2,4,6-trifluoropyrimidine to prepare compound 64.

LCMS: m/z = 396.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ9.00(d, J=8.8Hz, 1H), 8.38(s, 2H), 7.88(dd, J=30.4, 9.2Hz, 2H), 7.78(d, J＝4.4Hz, 1H), 7.35(d, J＝9.2Hz, 1H), 6.87(s, 1H), 5.28(s, 1H), 3.58(s, 1H), 3.55-3.53(m, 2H), 1.18 (d, J=6.8Hz, 3H).

Example 65

(R)-3-((2-chloro-5-(difluoromethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8H-[1 ,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one (65)

According to the preparation method of Example 1, 2,4-dichloro-5-difluoromethylpyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to obtain compound 65 .

LCMS: m/z = 446.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.19(d, J=9.0Hz, 1H), 9.01(s, 1H), 8.05(d, J=9.2Hz, 1H), 7.96(d, J= 9.2Hz, 1H), 7.85(d, J=4.7Hz, 1H), 7.74(d, J=8.9Hz, 1H), 7.40(t, J=53.4Hz, 1H), 6.95(t, J=4.8Hz , 1H), 3.59 (s, 1H), 3.38 (s, 2H), 1.19 (d, J=6.8Hz, 3H).

biological evaluation

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

The structure of reference compound A:

Compound A was prepared by the method disclosed in the patent application "Example 11 on page 99 of the specification in WO2018170203".

Test Example 1: In vitro MK2 Enzyme Activity Detection Test

1. Experimental materials

名称name	品牌brand	货号/型号Item No./Model
MAPKAPK2MAPKAPK2	CarnaCarna	02-14202-142
P11(FAM标记的多肽)P11 (FAM-tagged polypeptide)	GLGL	117885117885
ATPATP	SigmaSigma	A7699A7699
DMSODMSO	SigmaSigma	D2650D2650
EDTAEDTA	SigmaSigma	E5134E5134
96-孔板96-well plates	CorningCorning	33653365
384-孔板384-well plate	CorningCorning	35733573

2. Experimental steps

In vitro MK2 kinase activity was tested by the method of Mobility Shift Assay. In the experiment, the initial concentration of the test compound for the inhibition of MK2 activity was 10000 nM, diluted 3 times, and a total of 10 concentrations were tested in duplicate wells. Compound PF-3644022 was used as a standard control.

Prepare 1X kinase buffer (50mM HEPES, pH 7.5, 0.0015% Brij-35) and stop solution (100mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent#3, 50mM EDTA). Add appropriate amount of kinase to 1-fold kinase buffer to prepare 2.5-fold enzyme solution; prepare compound test concentration 5-fold compound dilution (1-fold kinase buffer, 10% DMSO), initial stock solution 50 μM, 1:5 use; appropriate amount Add FAM-labeled polypeptide (P11) and ATP to 1-fold kinase buffer to prepare 2.5-fold substrate solution. Add 5 μl 5-fold compound dilution and 10 μl 2.5-fold enzyme solution to the reaction wells of the 384-well reaction plate, mix well and incubate at room temperature for 10 minutes; then add 10 μl 2.5-fold substrate solution to the 384-well plate, and centrifuge at 1000 rpm for 1 minute; The reaction plate was incubated at 28°C for 60 minutes; 25 μl of stop solution was added to the 384-well reaction plate to terminate the reaction, and centrifuged at 1000 rpm for 1 minute; finally, the conversion rate data was read on Caliper EZ Reader II.

The _IC50 values of the compounds were fitted with XLFit excel add-in version 5.4.0.8.

Fitting formula:

Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)

Among them, Y is the conversion signal value, X is the concentration of the test compound, Top is the highest position of the dose-response curve, Bottom is the baseline position of the dose-response curve, and HillSlope is the slope coefficient.

The MK2 kinase biochemical inhibitory activity of the disclosed compounds was determined by the above tests, and the measured IC ₅₀ values are shown in Table 1.

Table 1

编号serial number	MK2IC ₅₀(nM) MK2IC ₅₀ (nM)	编号serial number	MK2IC ₅₀(nM) MK2IC ₅₀ (nM)
化合物ACompound A	316 ^a 316 ^a	化合物1Compound 1	909909
化合物2Compound 2	9898	化合物3Compound 3	210210
化合物4Compound 4	182182	化合物5Compound 5	232232
化合物6Compound 6	267267	化合物7Compound 7	8080
化合物8Compound 8	82.682.6	化合物9Compound 9	8181
化合物10Compound 10	140.8140.8	化合物11Compound 11	54.554.5
化合物12Compound 12	4.34.3	化合物13Compound 13	347.1347.1
化合物14Compound 14	5.25.2	化合物15Compound 15	767767
化合物16Compound 16	6262	化合物17Compound 17	363363
化合物18Compound 18	3434	化合物19Compound 19	191191
化合物20Compound 20	3333	化合物21Compound 21	9797
化合物21-1Compound 21-1	112112	化合物21-2Compound 21-2	9494
化合物22Compound 22	143143	化合物23Compound 23	232232
化合物24Compound 24	7474	化合物25Compound 25	>1000>1000
化合物26Compound 26	4444	化合物27Compound 27	2.82.8
化合物28Compound 28	270270	化合物29Compound 29	1.41.4
化合物30Compound 30	666666	化合物31Compound 31	360360
化合物32Compound 32	462462	化合物33Compound 33	>1000>1000
化合物34Compound 34	>1000>1000	化合物35Compound 35	500500
化合物36Compound 36	115115	化合物37Compound 37	2525
化合物38Compound 38	4.14.1	化合物39Compound 39	6.26.2
化合物40Compound 40	23twenty three	化合物41Compound 41	6.86.8
化合物42Compound 42	107107	化合物43Compound 43	162162
化合物44Compound 44	105105	化合物45Compound 45	529529
化合物46Compound 46	>1000>1000	化合物47Compound 47	7575
化合物48Compound 48	4242	化合物49Compound 49	825825
化合物50Compound 50	196196	化合物51Compound 51	422422

化合物52Compound 52	115115	化合物53Compound 53	252252
化合物54Compound 54	23twenty three	化合物55Compound 55	702702
化合物56Compound 56	147147	化合物57Compound 57	280280
化合物58Compound 58	279279	化合物59Compound 59	9797
化合物60Compound 60	580580	化合物61Compound 61	950950
化合物62Compound 62	347347	化合物63Compound 63	22twenty two
化合物64Compound 64	6262	化合物65Compound 65	1111

Note: a The average value of multiple measurements.

Conclusion: The disclosed compound has strong inhibitory activity on MK2 kinase.

Test Example 2: In Vitro PBMC Cell Detection Cytokine Test

1. Experimental materials

2. Experimental steps

The in vitro PBMC cell cytokine assay was tested by the method of LPS-induced cell production of cytokine TNF-α. In the experiment, the initial test concentration of the test compound was 10000 nM, diluted 3 times, and a total of 9 concentrations were tested in duplicate wells.

PBMC cells were collected for cell counting and viability calculation. Seed 2× ¹⁰ cells/0.1 mL/well into a 96-well plate. Compounds (initial stock solution 40 μM dissolved in DMSO, used 1:4) and LPS dilutions (0.4 ng/mL dissolved in PBS, used 1:4) were prepared. Add 50 μl compound diluent and 50 μl LPS diluent (final concentration 0.1 ng/ml) to each well, and incubate at 37° C. 5% CO ₂ for 24 hours. The normal control group used DMSO instead of the compound dilution, and the test control group used medium instead of the LPS dilution.

Collect 120 μl of supernatant. The concentration of TNF-α in the sample was tested using an ELISA kit.

Add 80 μL to each well

Reagent, to detect cell viability.

The compounds of the present disclosure can inhibit the release of PBMC pro-inflammatory cytokines in vitro through the above tests, and the measured IC ₅₀ values are shown in Table 2.

Table 2

Conclusion: The disclosed compound has strong inhibitory effect on the release of PBMC pro-inflammatory cytokines.

Test Example 3: Pharmacokinetic Evaluation in Rats

After the compound was formulated into a clear solution of appropriate concentration with 5% DMSO, 5% Solutol and 90% water, male SD rats (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) (n=3, a total of 6 rats/compound) were respectively Give intravenous injection and gavage. Plasma samples were collected within 5 minutes, 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, and the plasma drug concentrations were determined using LC-MS/MS, and non-atrial Compartmental analysis was used to estimate pharmacokinetic parameters.

Table 3, the pharmacokinetic parameters of the disclosed compound in SD rats

Note: i.g. intragastric administration; i.v. intravenous administration.

Conclusion: The disclosed compound has good pharmacokinetic absorption activity in SD rats, and has pharmacokinetic advantages.

Claims

Compound shown in formula I or its pharmaceutically acceptable salt

Wherein, ring A is selected from C 6-10 aryl or 5 to 10 membered heteroaryl containing 1-3 heteroatoms;

Each R is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said Alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 1A , each R 1A is independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

Alternatively, any adjacent R1 and adjacent carbon atoms form a 3 to 6 membered cycloalkyl group or a 3 to 6 membered heterocycloalkyl group, which is optionally represented by one or more R1B Substitution, R 1B each independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy, the alkyl or alkyloxy is optionally replaced by One or more substitutions selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

R 2 and R 3 are independently selected from hydrogen or C 1-6 alkyl, which is optionally replaced by one or more selected from halogen, hydroxyl, cyano or amino;

Each R is independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 6-membered heterocycloalkyl, C 1-6 alkylthio, 3-6 membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-6 membered cycloalkylamino, 3-6 membered hetero Cycloalkylamino, aryl or heteroaryl, -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 ) s OCONR 1a R 1b , -(CH 2 ) s NHCOR 1a , -NH(CH 2 ) s CONR 1a R 1b , -NH(CH 2 ) s COR 1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted by one or more R 4A , each R 4A is independently selected from halogen , hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6 membered Cycloalkoxy or 3 to 6 membered heterocycloalkoxy;

Alternatively, any adjacent two R 4 form a 3 to 6-membered cycloalkyl group or a 3 to 6-membered heterocycloalkyl group with adjacent atoms, and the cycloalkyl group or heterocycloalkyl group is optionally replaced by one or more R 5A Substituted, each R 5A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

Each R is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 2A , each R 2A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

R 6 are each independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 3A , each R 3A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

T is selected from a bond or -L-X-;

L is selected from a bond or a C 1-3 alkylene group optionally substituted by one or more R 6A , each R 6A independently selected from halogen, hydroxyl, oxo, nitro, cyano, Amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

X is selected from -O-, -S-, -S(O)-, -SO 2 -, -C(O)-, -OC(O)-, -C(O)O-, -N(R 9 )-, -C(O)N(R 7 )- or -N(R 8 )C(O)-;

Z is -CH- or N, and when Z is -CH-, Z is optionally substituted by R 5 ;

R 7 , R 8 , R 9 are each independently selected from hydrogen or C 1-6 alkyl, and the alkyl is optionally replaced by one or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino group replaced;

R 1a or R 1b are each independently selected from hydrogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkane Base, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 7A , each R 7A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1 -6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

Alternatively, R 1a , R 1b and adjacent atoms form a 3- to 6-membered heterocycloalkyl group, the heterocycloalkyl group is optionally substituted by one or more R 8A , each R 8A independently selected from halogen, hydroxyl, Oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

m is selected from an integer between 0 and 4;

n is selected from an integer between 0 and 4;

s is selected from an integer between 0 and 3;

o and p are each selected from an integer between 0 and 2.
The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound shown in formula I is

in,

Ring A is selected from C 6-10 aryl or 5 to 10 membered heteroaryl containing 1-3 heteroatoms;

Each R is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said Alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 1A , each R 1A is independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R 2 and R 3 are each independently selected from hydrogen or C 1-6 alkyl, which is optionally substituted by one or more groups selected from halogen, hydroxyl, cyano or amino;

Each R is independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl or heteroaryl, -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 ) s OCONR 1a R 1b , -(CH 2 ) s NHCOR 1a , -NH(CH 2 ) s CONR 1a R 1b , - NH(CH 2 ) s COR 1a , the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted by one or more R 4A , each R 4A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy;

Alternatively, any adjacent two R 4 form a 3 to 6-membered cycloalkyl group or a 3 to 6-membered heterocycloalkyl group with adjacent atoms, and the cycloalkyl group or heterocycloalkyl group is optionally replaced by one or more R 5A Substituted, each R 5A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

Each R is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 2A , each R 2A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

R 6 are each independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 3A , each R 3A is independently selected from halogen, hydroxyl, oxo, nitro, cyano or amino;

T is selected from a bond or -L-X-;

L is selected from a bond or a C 1-3 alkylene group optionally substituted by one or more R 6A , each R 6A independently selected from halogen, hydroxyl, oxo, nitro, cyano, Amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

X is selected from -O-, -S-, -S(O)-, -SO 2 -, -C(O)-, -OC(O)-, -C(O)O-, -C(O) N(R 7 )- or -N(R 8 )C(O)-;

R 7 and R 8 are each independently selected from hydrogen or C 1-6 alkyl, and the alkyl is optionally replaced by one or more groups selected from halogen, hydroxyl, oxo, nitro, cyano or amino replace;

R 1a or R 1b are each independently selected from hydrogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, said alkane Base, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R 7A , each R 7A is independently selected from halogen, hydroxyl, oxo, nitro, cyano, amino, C 1 -6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

Alternatively, R 1a , R 1b and adjacent atoms form a 3- to 6-membered heterocycloalkyl group, the heterocycloalkyl group is optionally substituted by one or more R 8A , each R 8A independently selected from halogen, hydroxyl, Oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl;

m is selected from an integer between 0 and 4;

n is selected from an integer between 0 and 4;

s is selected from an integer between 0 and 3;

o and p are each selected from an integer between 0 and 2.
The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein T is selected from a bond or -LX-, L is selected from a bond or a C 1-3 alkylene group, and the alkylene group is optionally replaced by 1- Replaced by 3 R 6A , X is selected from -O-, -OC(O)- or -C(O)O-, R 6A is as defined in claim 1.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein ring A is selected from phenyl or a 5- or 6-membered heteroaromatic ring containing 1-2 heteroatoms, preferably:

Wherein, R 4 and m are as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein each R is independently selected from halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the The alkyl or alkoxy group is optionally substituted by 1-3 R 2A , and R 2A is as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R 6 are each independently selected from halogen, hydroxyl, amino, C 1-6 alkyl or C 1-6 alkoxy, the The alkyl or alkoxy group is optionally substituted by 1-3 R3A , and R3A is as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein R is selected from C 1-6 alkyl, and the alkyl is optionally replaced by 1-3 selected from halogen, hydroxyl or amino The group is substituted; further, R 2 is preferably methyl, ethyl, hydroxyethyl, difluoromethyl or trifluoromethyl.
The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R is selected from C 1-6 alkyl or C 1-6 alkoxy, and the alkyl or alkoxy is optionally Substituted by 1-3 R 1A , R 1A is as defined in claim 1 or 2; further, R 1 is preferably methyl, ethyl, hydroxymethyl, difluoromethyl or trifluoromethyl.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the compound of formula I is

Wherein, R 1 , R 2 , R 4 , ring A, m, T are as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to claim 1, 2 or 10, wherein each R 1A is independently selected from halogen, hydroxyl or amino, preferably fluorine or chlorine.
The compound or pharmaceutically acceptable salt thereof according to claim 1, 2 or 10, wherein the compound of formula I is selected from:

Wherein, R 1 , R 2 , R 4 , ring A, m are as defined in claim 1 or 2.
The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from halogen, hydroxyl or amino.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein R 4 are each independently selected from C 1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkane The alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R 4A , R 4A is as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein each R 4 is independently selected from halogen, C 1-6 alkyl, -(CH 2 ) s COR 1a , -(CH 2 ) s NR 1a R 1b , -(CH 2 ) s CONR 1a R 1b , -(CH 2 ) s OCONR 1a R 1b or -(CH 2 ) s NHCOR 1a , s, R 1a , R 1b as claimed in claim 1 or 2 defined.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein any adjacent two R 4 form 3 to 6-membered cycloalkyl or 3 to 6-membered heterocycloalkyl with adjacent atoms, The cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R 5A , R 5A as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R 1a or R 1b are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6 Membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R 7A , R 7A is as defined in claim 1 or 2 .
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R 1a , R 1b and adjacent atoms form a 5- to 6-membered heterocycloalkyl group, and the heterocycloalkyl group is optionally replaced by 1 -3 R 8A substituted, R 8A as defined in claim 1 or 2.
The compound or pharmaceutically acceptable salt thereof according to claim 1, 2 or 17, wherein R 7A are each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy Or 3 to 6 membered cycloalkyl, preferably halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl, more preferably halogen, cyano or cyclopropyl.
The compound or pharmaceutically acceptable salt thereof according to claim 1, 2 or 14, wherein each R 4A is independently selected from halogen, hydroxyl, cyano, C 1-6 alkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy, preferably halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, 3 to 6-membered cycloalkoxy or 3 to 6-membered heterocycloalkoxy, more preferably halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy Or 3 to 6 membered cycloalkoxy.
The compound or pharmaceutically acceptable salt thereof according to claim 1, 2 or 18, wherein R 8A are each independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy Or 3 to 6 membered cycloalkyl, preferably halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or 3 to 6 membered cycloalkyl, more preferably C 1-6 alkyl.
The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 are each independently selected from halogen, oxo (=O), hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, 3-6 membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-6 membered cycloalkylamino, 3-6 membered heterocycloalkane Amino, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by one or more R 4A , R 4A is as defined in claim 1.
The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound shown in formula I is

Wherein, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T, o, p, m and n are as defined in claim 1.
The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound shown in formula I is

Wherein, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , Z, o, p, m and n are as defined in claim 1.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-24, wherein the compound shown in formula I is selected from:
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-25, wherein the compound shown in formula I is selected from:
According to the isotopic substitution of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-26, preferably, the isotopic substitution is deuterated.
A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26, or an isotope substitution according to claim 27, and pharmaceutically acceptable excipients.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-26, or the isotope substitution according to claim 27, or the pharmaceutical composition according to claim 28 is used for preventing and/or Or use in medicines for the treatment of MK2-mediated diseases.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-26, or the isotope substitution according to claim 27, or the pharmaceutical composition according to claim 28 is used for preventing and/or Or use in a medicament for the treatment of autoimmune diseases, inflammatory diseases, fibrotic diseases or metabolic diseases.