TW202328141A - Quinolinofuran derivatives and use thereof - Google Patents

Abstract

The present disclosure relates to quinolinofuran derivatives and use thereof. Specifically, a compound as shown in formula I or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and the use thereof in the preparation of a medicament for preventing and/or treating MK2-mediated diseases are provided. The definition of each group in the general formula is the same as in the specification.

Description

Quinolinofuran derivatives and uses thereof

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

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 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 , such as rheumatoid arthritis and inflammatory bowel disease.

The quinothiophene structure molecules developed based on the benzothiophene structure have shown MK2 inhibitory potency 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).

The 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, the Alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^1A , each R ^1A independently selected from halogen, hydroxyl, pendant oxygen, nitro, cyano or amine;

Alternatively, any adjacent ^R1 and adjacent carbon atoms form a 3 to 6 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl, which is optionally substituted by one or more ^R1B , R ^1B is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy, the alkyl or alkyl oxygen is optionally replaced by one or a plurality of groups selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine 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;

R ⁴ are each independently selected from halogen, side oxygen (=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 ) _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 substituted by one or more R ^4A , each R ^4A is independently selected from halogen , hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 1-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 Substitution, R ^5A is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl;

R ⁵ 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^2A , each R ^2A independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine;

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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^3A , each R ^3A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine;

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

L is selected from a bond or C _1-3 (alkylene) alkylene, which is optionally substituted by one or more R ^6A , and each R ^6A is independently selected from halogen, hydroxyl, side oxygen, nitric acid Group, cyano group, amino group, 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 replaced 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, side oxygen, 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, the alkane Alkyloxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^7A , each R ^7A is independently selected from halogen, hydroxyl, pendant oxygen, 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 , and each R ^8A is independently selected from halogen, hydroxyl, pendant Oxygen, 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,

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, the Alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^1A , each R ^1A independently selected from halogen, hydroxyl, pendant oxygen, nitro, cyano or amine;

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;

R ⁴ are each independently selected from halogen, side oxygen (=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 substituted by one or more R ^4A , each R ^4A is independently selected from halogen, hydroxyl, side oxygen, 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 Substitution, R ^5A is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl;

R ⁵ 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^2A , each R ^2A independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine;

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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^3A , each R ^3A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine;

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

L is selected from a bond or C _1-3 (alkylene) alkylene, which is optionally substituted by one or more R ^6A , and each R ^6A is independently selected from halogen, hydroxyl, side oxygen, nitric acid Group, cyano group, amino group, 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, which is optionally replaced by one or more groups selected from halogen, hydroxyl, side oxygen, 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, the alkane Alkyloxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^7A , each R ^7A is independently selected from halogen, hydroxyl, pendant oxygen, 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 , and each R ^8A is independently selected from halogen, hydroxyl, pendant Oxygen, 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, 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 to 6 Member cycloalkyl, 3 to 6 member heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted by one or more R ^1A , R ^1A each 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, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted by one or more R ^1A , R ^1A each independently selected from C _1-6 alkylamino.

In some embodiments, R in the compound shown in formula I or formula IA is ^each independently selected from halogen, side oxygen (=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 ) _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 alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamino or heterocycloalkylamino Need to be replaced by one or more R ^4A , each R ^4A is independently selected from halogen, hydroxyl, side oxygen, 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.

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, side oxygen, 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 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 a C _1-3 alkylene group, the (extension group) ) alkyl 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.

或

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

or

.

或

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

or

.

或

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

or

.

或

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

or

.

或

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

or

.

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.

或

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

or

.

或

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

or

.

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

.

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

.

。 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 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 Substituted, 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, 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, and the cycloalkyl ^is optionally replaced by 1-3 R ^3A Substituted, 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 its pharmaceutically acceptable salt 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 replaced. 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, in the compound shown in formula I or formula IA or its pharmaceutically acceptable salt, R ¹ is each independently selected from 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the alkyl or alkoxy 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, each 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, 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, side oxygen (=O), hydroxyl or amine.

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, R in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salts ^{are each} 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, in the compound shown in formula I or formula IA or formula IIA or its pharmaceutically acceptable salts, any adjacent two R ⁴ and adjacent atoms form 3 to 6 membered cycloalkyl or 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 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, the alkyl Optionally substituted with 1-3 groups selected from halogen, hydroxy, pendant oxygen, nitro, cyano or amine.

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 some 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 3 to 6-membered heterocycloalkyl, the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R ^7A , R ^7A is as defined above.

In some other embodiments, R ^1a , R 1b in the compound shown in formula I or formula IA or formula IIA or a pharmaceutically acceptable salt thereof form a 5 to ⁶ -membered heterocycloalkyl with adjacent atoms, and the heterocycloalkyl depends on Need to be replaced by 1-3 R ^8A , R ^8A is as defined above.

Further, in some embodiments, in the compounds shown in formula I or formula IA or formula IIA or pharmaceutically acceptable salts thereof, 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. 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 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, side oxygen (=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 heterocycloalkane Amino group, 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, side oxygen (=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, alkylthio, cycloalkoxy, heterocycloalkoxy, cycloalkylamine, heterocycloalkylamino may be replaced by one or more R ^4A is substituted, and 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 are each independently selected from hydrogen or C _1-6 alkyl, the alkyl is optionally 1-3 groups selected from halogen, hydroxyl, side oxygen, nitro, cyano or amino are substituted.

Further, in the compound represented by formula I or formula IC or formula IIC or a pharmaceutically acceptable salt thereof, ^R9 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 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by one or more R ^1c , R ^1c is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy, the alkyl or alkyloxy is optionally replaced by one or more A group selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine is substituted;

R ¹² 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ^1d , each R ^1d independently selected from halogen, hydroxy, pendant oxygen, nitro, cyano or amine.

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.

選自

、 On the other hand, in the disclosed compound

selected from

,

選自

，例如

、

，其中R¹³、R¹⁴各自獨立地選自 鹵素(氟或氯)、羥基、硝基、氰基、胺基、C_1-6烷基、C_1-6烷氧基、3至6員環烷基、3至6員雜環烷基、C_1-6烷基硫基、3至6員環烷氧基、3至6員雜環烷氧基、3至6員環烷胺基、3至6員雜環烷胺基、芳基或雜芳基、-SR^1a、-S(O)R^1a、-S(O)₂R^1a、-(CH₂)_sCOR^1a、-(CH₂)_sNR^1aR^1b、-(CH₂)_sCONR^1aR^1b、-(CH₂)_sOCONR^1aR^1b、-(CH₂)_sNHCOR^1a、-NH(CH₂)_sCONR^1aR^1b、-NH(CH₂)_sCOR^1a，該烷基、烷氧基、環烷基、雜環烷基、烷基硫基、環烷氧基、雜環烷氧基、環烷胺基、雜環烷胺基、芳基或雜芳基視需要被 一個或多個R^9A所取代，R^9A各自獨立地選自鹵素、羥基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基；t為0至2之間整數(包括1)；R^1a、R^1b、s如前述所定義。 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 ring Alkyl, 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, heterocyclic Alkylamino, aryl or heteroaryl are optionally substituted by one or more R ^9A , each R ^9A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkane radical, 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 0 to An integer between 2 (including 1); R ^1a , R ^1b , s are as defined above.

選自

，其中R¹³選自鹵素(氟或氯)、C_1-6烷基、-S(O)R^1a和-S(O)₂R^1a， R¹⁴選自鹵素(氟或氯)、羥基、硝基、氰基、胺基、C_1-6烷基、C_1-6烷氧基、3至6員環烷基、3至6員雜環烷基、C_1-6烷基硫基、3至6員環烷氧基、3至6員雜環烷氧基、3至6員環烷胺基、3至6員雜環烷胺基、芳基或雜芳基、-SR^1a、-S(O)R^1a、-S(O)₂R^1a、-(CH₂)_sCOR^1a、-(CH₂)_sNR^1aR^1b、-(CH₂)_sCONR^1aR^1b、-(CH₂)_sOCONR^1aR^1b、-(CH₂)_sNHCOR^1a、-NH(CH₂)_sCONR^1aR^1b、-NH(CH₂)_sCOR^1a，該烷基、烷氧基、環烷基、雜環烷基、烷基硫基、環烷氧基、雜環烷氧基、環烷胺基、雜環烷胺基、芳基或雜芳基視需要被一個或多個R^9A所取代，R^9A各自獨立地選自鹵素、羥基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基；t為0至2之間整數(包括1)；R^1a、R^1b、s如前述所定義。 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, 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, aryl or heteroaryl are optionally substituted by one or more R ^9A , R ^9A are each independently selected from halogen, hydroxyl, side oxygen, 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.

選自

，其中R¹³選自鹵素(氟或氯)和C_1-6烷基，R¹⁴選自鹵素(氟 或氯)、羥基、硝基、氰基、胺基、C_1-6烷基、C_1-6烷氧基、3至6員環烷基、3至6員雜環烷基、C_1-6烷基硫基、3至6員環烷氧基、3至6員雜環烷氧基、3至6員環烷胺基、3至6員雜環烷胺基、芳基或雜芳基、-SR^1a、 -S(O)R^1a、-S(O)₂R^1a、-(CH₂)_sCOR^1a、-(CH₂)_sNR^1aR^1b、-(CH₂)_sCONR^1aR^1b、-(CH₂)_sOCONR^1aR^1b、-(CH₂)_sNHCOR^1a、-NH(CH₂)_sCONR^1aR^1b、-NH(CH₂)_sCOR^1a，該烷基、烷氧基、環烷基、雜環烷基、烷基硫基、環烷氧基、雜環烷氧基、環烷胺基、雜環烷胺基、芳基或雜芳基視需要被一個或多個R^9A所取代，R^9A各自獨立地選自鹵素、羥基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基；t為0至2之間整數(包括1)；R^1a、R^1b、s如前述所定義。 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 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, hetero Cycloalkoxy, cycloalkylamino, heterocycloalkylamino, aryl or heteroaryl are optionally substituted by one or more R ^9A , each R ^9A independently selected from halogen, hydroxyl, side oxygen, 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 cycloalkoxy 6-membered heterocycloalkoxy; t is an integer between 0 and 2 (including 1); R ^1a , R ^1b , and s are as defined above.

選自

，例如

，其中R¹³、R¹⁴各自獨立地選自鹵素(氟或氯)、 羥基、硝基、氰基、胺基、C_1-6烷基、C_1-6烷氧基、3至6員環烷基、3至6員雜環烷基、C_1-6烷基硫基、3至6員環烷氧基、3至6員雜環烷氧基、3至6員環烷胺基、3至6員雜環烷胺基、芳基或雜芳基、-SR^1a、-S(O)R^1a、-S(O)₂R^1a、-(CH₂)_sCOR^1a、-(CH₂)_sNR^1aR^1b、-(CH₂)_sCONR^1aR^1b、-(CH₂)_sOCONR^1aR^1b、-(CH₂)_sNHCOR^1a、-NH(CH₂)_sCONR^1aR^1b、-NH(CH₂)_sCOR^1a，該烷基、烷氧基、環烷基、雜環烷基、烷基硫基、環烷氧基、雜環烷氧基、環烷胺基、雜環烷胺基、芳基或雜芳基視需要被一個或多個R^9A所取代，R^9A各自獨立地選自鹵素、羥基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基；t為0至2之間整數(包括1)；R^1a、R^1b、s如前述所定義。 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 ring Alkyl, 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, heterocyclic Alkylamino, aryl or heteroaryl are optionally substituted by one or more R ^9A , each R ^9A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkane radical, 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 0 to An integer between 2 (including 1); R ^1a , R ^1b , s are as defined above.

選自

，例如

，其中R¹³、R¹⁴各自獨立地選自鹵素(氟或氯)、 羥基、硝基、氰基、胺基、C_1-6烷基、C_1-6烷氧基、3至6員環烷基、3至6員雜環烷基、C_1-6烷基硫基、3至6員環烷氧基、3至6員雜環烷氧基、3至6員環烷胺基、3至6員雜環烷胺基、芳基或雜芳基、-SR^1a、-S(O)R^1a、-S(O)₂R^1a、-(CH₂)_sCOR^1a、-(CH₂)_sNR^1aR^1b、-(CH₂)_sCONR^1aR^1b、-(CH₂)_sOCONR^1aR^1b、-(CH₂)_sNHCOR^1a、-NH(CH₂)_sCONR^1aR^1b、-NH(CH₂)_sCOR^1a，該烷基、烷氧基、環烷基、雜環烷基、烷基硫基、環烷氧基、雜環烷氧基、環烷胺基、雜環烷胺基、芳基或雜芳基視需要被一個或多個R^9A所取代，R^9A各自獨立地選自鹵素、羥基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基；t為0至2之間整數(包括1)，q為0至3之間整數；R^1a、R^1b、s如前述所定義。 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 ring Alkyl, 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, heterocyclic Alkylamino, aryl or heteroaryl are optionally substituted by one or more R ^9A , each R ^9A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkane radical, 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 0 to An integer between 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:

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,

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.

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 isotope substitutions of the aforementioned 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 present disclosure have an _IC50 value of 0.01 to 500 nM for the inhibition of p38a-MK2 kinase. In some embodiments, compounds of the present disclosure have an _IC50 value of 0.01 to 100 nM for inhibition of p38a-MK2 kinase. In some embodiments, compounds of the present disclosure have an _IC50 value of 0.01 to 20 nM for inhibition of p38a-MK2 kinase. In some embodiments, compounds of the present disclosure have an _IC50 value of 0.1 to 20 nM for inhibition of p38a-MK2 kinase. In some embodiments, compounds of the present disclosure have an _IC50 value of 0.1 to 30 nM for inhibition of p38a-MK2 kinase. In some embodiments, compounds of the disclosure have an _IC50 value of <50 nM for inhibition of p38a-MK2 kinase.

This 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 pharmaceutically acceptable excipients agent.

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 a pharmaceutically acceptable salt or an isotope substitute thereof. 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 certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds or their pharmaceutically acceptable salts or their isotopic 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% pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% 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 Formula I or Formula IA or Formula IIA or a pharmaceutically acceptable salt thereof Or its isotopic 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 a patient a preventive or therapeutically effective amount of the aforementioned formula I or formula IA or formula IIA The indicated compounds or their pharmaceutically acceptable salts or their isotope substitutions, or the aforementioned pharmaceutical compositions.

The present disclosure also provides the use of the compound shown in the aforementioned formula I or formula IA or formula IIA or its pharmaceutically acceptable salt 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 as shown in the aforementioned formula I or formula IA or formula IIA, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition used in 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 a disease or condition mediated by MK2.

The present disclosure also provides a compound represented by 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 this 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, diastereoisomers isomers, ( D )-isomers, ( L )-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are included in this within the scope of disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

Optically active ( R )- and ( S )-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art Methods The diastereoisomers were resolved and the pure enantiomers were recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally combined with chemical derivatization methods (e.g. amines to amines formate).

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

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

"can be"

"or"

, or both "

"and"

"Two configurations.

”並未指定構型，即可以為Z構型或E構型，或者同時包含兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

" does not specify the configuration, 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-lactimine isomerizations. An example of a lactam-lactimine equilibrium is between A and B shown below.

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

Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. The present disclosure also includes various deuterated forms of the compounds. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. The technical field has a general Those with ordinary knowledge 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 their physiologically acceptable salts or prodrugs 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 living body, facilitate the absorption of the active ingredient and thus exert the 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.

The "effective amount" or "therapeutically effective amount" mentioned in the present disclosure includes an amount sufficient to ameliorate or prevent the 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 chain 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, second-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, hydroxyl, pendant oxygen , 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, Substituted by hydroxyl, pendant oxygen, nitro, cyano or amine groups.

The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 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, hydroxyl, pendant Oxygen, 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, side oxygen, nitro, cyano or amine groups are substituted.

、

或

，等等。雜環烷基可以是視需要取代的或非取代的， 當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、羥 基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基，該烷基、環烷基、雜環烷基、烷氧基、環烷氧基、雜環烷氧基進一步視需要被一個或多個選自鹵素、羥基、側氧、硝基、氰基或胺基的基團所取代。 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:

,

or

,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, hydroxyl, pendant oxygen, 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 heterocycloalkyl Cycloalkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally selected from one or more halogen, hydroxyl, side oxygen, nitr group, cyano group or amino group substituted.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxyl, pendant oxygen, nitro, cyano, amine, 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.

或

，等等。雜芳基可以是視需要取代的或 非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自鹵素、側氧(=O)、羥基、硝基、氰基、胺基、C_1-6烷基、C_1-6烷氧基、3至6員環烷基、3至6員雜環烷基、芳基或雜芳基、-SR^1a、-S(O)R^1a、-S(O)₂R^1a、-(CH₂)_sCOR^1a、-(CH₂)_sNR^1aR^1b、-(CH₂)_sCONR^1aR^1b、-(CH₂)_sOCONR^1aR^1b、-(CH₂)_sNHCOR^1a、-NH(CH₂)_sCONR^1aR^1b、-NH(CH₂)_sCOR^1a，該烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基視需要被一個或多個鹵素、羥基、側氧、硝基、氰基、胺基、C_1-6烷基、3至6員環烷基、3至6員雜環烷基、C_1-6烷氧基、3至6員環烷氧基或3至6員雜環烷氧基所取代，其中3至6員環烷基或3至6員雜環烷基為任意取代的，任意取代基選自鹵素、羥基、側氧、硝基、氰基或胺基。 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:

or

,etc. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, pendant oxygen (=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, cycloalkane radical, heterocycloalkyl, aryl or heteroaryl optionally replaced by one or more halogen, hydroxyl, pendant oxygen, 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 substituted, wherein 3 to 6 membered cycloalkyl or 3 to The 6-membered heterocycloalkyl group is optionally substituted, and any substituent is selected from halogen, hydroxyl, pendant oxygen, 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, hydroxyl, pendant oxygen, 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 heterocycle Alkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally replaced by one or more selected from halogen, hydroxyl, side oxygen, nitro , cyano or amine 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 can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxyl, pendant oxygen, 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 heterocycloalkyl Cycloalkoxy, the alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy are further optionally selected from one or more halogen, hydroxyl, side oxygen, nitr Substituted by group, cyano group or amino group.

The term "cycloalkylamino", wherein alkyl is as defined above. Non-limiting examples of cycloalkylamino include: methylamino, ethylamino or dimethylamino. Cycloalkylamino groups 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 "side oxygen" refers to a =O substituent.

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

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 the measuring solvent is deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (Methanol- d ₄ ), and the 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 separation conditions (HPLC): Waters; Chiralpak AD-H [amylose-tris(3,5-dimethylphenylcarbamate) coated chiral stationary phase] chromatographic column 25* 250mm.

The determination of MS uses 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 is 80~1200.

The thin-layer chromatography silica gel plate uses Hydrocarbon Tai 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 fast 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 prepacked prepacked ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

The known starting materials in this disclosure can be used 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), Bi De 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.

The nitrogen atmosphere or hydrogenation atmosphere is usually evacuated, 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 temperature of the reaction is room temperature, which is 20° C. to 30° C.

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

Example 1

( R )-3-((2-Chloro-5-(ethoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H - [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-neck flask. Sodium hydrogen (60%, 22.3g, 557mmol) was slowly added, stirred for 0.5 hours, and ethyl bromoacetate (67.1g, 401mmol) was added. React at room temperature for 1.5 hours. Add water (500 mL) to quench, ethyl acetate extraction (500 mL X 3), wash with water (500 mL), 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 )

At room temperature, add compound 1c (50.0g, 161mmol), zinc acetate (5.92g, 32.2mmol), zinc cyanide (56.8g, 484mmol), 1,1'-bis(diphenylphosphine ) 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, extract with ethyl acetate (500mL X 3), wash with water (500mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is subjected to column chromatography (petroleum ether/ethyl acetate) Purification afforded 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, extract with dichloromethane (300mL X 3), wash with water (500mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is purified by column chromatography (dichloromethane/methanol) Compound 1e is obtained.

LCMS: m/z = 256.9 (M+H) ⁺ .

Step 5: ( R )-ethyl 1-((2-((tertiary butoxycarbonyl)amino)propyl)amino)furo[3,2-f]quinoline-2-carboxylate ( 1f ) preparation

At 0°C, compound 1e (1.50g, 5.85mmol), sodium hydrogen (60%, 0.28g, 7.024mmol) and N-methylpyrrolidone (60mL) were sequentially added into a 100mL three-neck flask. After stirring at 0°C for 1 hour, (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 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 the residue through column layer Compound 1f was obtained by purification by chromatography (petroleum ether/ethyl acetate).

LCMS: m/z = 414.1 (M+H) ⁺ .

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

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 ice bath, add water (20mL), adjust pH=8 with sodium bicarbonate, extract with dichloromethane (60mL X 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1g . 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 (3.10g, 9.89mmol) and methanol (80mL) were sequentially added into a 250mL 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 (30 mL), extract with dichloromethane (50 mL 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. After stirring for 10 minutes, di-tert-butyl dicarbonate (1.18 mL, 5.14 mmol) was added. 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 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 azeo[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 (30 mL), extract with dichloromethane (50 mL X 2), wash with saturated sodium bicarbonate (30 mL X 2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and beat with ether (30 mL) 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 (50 mL), extract with dichloromethane (100 mL 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 pH=8 with saturated sodium bicarbonate, extract with dichloromethane (70mL X 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 1l .

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 )

Compound 11 (220 mg, 0.729 mmol), acetic acid (10 mL) and water (3.5 mL) were sequentially added to a 25 mL microwave tube at room temperature. 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 (ammonium bicarbonate/acetonitrile/water system).

LCMS: m/z = 454.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.08(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-8 H- [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) δ 9.05(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-8 H- [1,4] Diazepine[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) δ 9.05(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-8 H- [1,4] Diazepine[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) δ 9.05(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-8 H -[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, 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 was replaced with 4,6-dichloro-2-cyanopyridine to prepare compound 5 .

LCMS: m/z = 420.0 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 9.16(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-8 H- [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) δ 9.06(d, J =9.2Hz, 1H), 8.32(d, J =8.4Hz, 1H), 7.92( s , 2H), 7.53(d, J =8.8Hz ,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-8 H- [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 )δ 9.14(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-8 H- [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-carboxylic acid formamide to obtain the compound 8 .

LCMS: m/z = 453.1 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 9.17(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-8 H- [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) δ 9.07(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, 4,6-dichloro-2-methylthiopyrimidine was used instead of 2,4-dichloro-5-(ethoxymethyl)pyrimidine in step 13 to prepare compound 10 .

LCMS: m/z = 442.1 (M+H) ⁺ .

¹ H NMR(400MHz,CD ₃ OD)δ 9.10(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-8 H- [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), N,N-dimethylformamide (4mL) into a 25mL single-necked bottle, stir well, add compound 4-amino-6-chloro-pyrimidine ( 42 mg, 0.33 mmol), cesium carbonate (189 mg, 0.58 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (38 mg, 0.066 mmol), 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 )δ 10.86(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-8 H- [1,4]diazepine[5',6 ': methyl 4,5]furo[3,2-f]quinolin-3-yl)oxy)pyrimidine-2-carboxylate ( 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 )δ 9.16(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-(tertiary butyl)-2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8 H -[1,4] Diazazo[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 tertiary butyramide, Compound 13 was obtained.

LCMS: m/z = 495.2 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 9.18(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 =6.8Hz ,3H).

Example 14

( R )-2-chloro-6-((10-methyl-8-oxo-9,10,11,12-tetrahydro-8 H- [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) ⁺ .

¹ H NMR(400MHz,CD ₃ OD)δ 9.10(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 15

( R )-3-((6-Chloro-2-(morpholinylmethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H- [ 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 )

At room temperature, compound 15a (400mg, 2.20mmol), sodium triacetyloxyborohydride (953mg, 4.50mmol), morpholine (196mg, 2.20mmol), 1,2-dichloro Ethane (20 mL). Stir at room temperature for 3 hours under nitrogen atmosphere. Add water (20 mL), and extract with ethyl acetate (20 mL 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-8 Preparation of H- [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 were sequentially added into a 20mL single-necked bottle (5 mL). 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 (ammonium bicarbonate)) to obtain compound 15 .

LCMS: m/z = 495.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.05(d, J =8.9Hz, 1H), 8.27(s, 1H), 7.91(d, J =3.2Hz, 2H), 7.52(d, J =8.9Hz ,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-tetra Hydrogen- 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) in step 13 with (4,6-dichloro-pyrimidine-2-methyl)-tert-butylamine pyrimidine to obtain compound 16 .

LCMS: m/z = 481.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.06(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-8 H - [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) δ 9.10(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- 8 H- [1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 18 )

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 )δ 9.14(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- 8 H- [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 )δ 9.13(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-8 H - [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 ) δ 9.15(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

(10 R )-3-((6-chloro-2-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetra Hydrogen- 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-8 H- [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-8 H -[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-(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 )δ 9.14(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 )δ 9.14(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, 4.4 Hz,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 )δ 9.14(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-8 H- [1,4] Diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 22 )

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

LCMS: m/z = 440.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.18(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

(10 R )-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 )

Dissolve tert-butyl 2,6-dimethylpiperazine-1-carboxylate 23a (250 mg, 1.17 mmol) in dichloromethane (5 mL), and add 4,6-dichloropyrimidine- 2-Formaldehyde (206mg, 1.17mmol), sodium triacetyloxyborohydride (492mg, 2.33mmol), and 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 (50 mL), extract with dichloromethane (50 mL X 3), dry the organic phase, filter and 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 (ammonium bicarbonate)) to obtain compound 23 .

LCMS: m/z = 522.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.15(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-8 H -[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 (50 mL), and extract with ethyl acetate (100 mL 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 )

Dissolve compound 24b (240mg, 1.09mmol) in N,N-dimethylformamide (10mL), add compound 1m (100mg, 0.353mmol) and potassium carbonate (500mg, 3.68mmol) to it, and react at 100°C 5 hours. After filtration, concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonium bicarbonate)) to give compound 24 .

LCMS: m/z = 454.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.13(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, 6.4 Hz, 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 obtain 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 )

Compound 25b (190mg, 0.73mmol) was dissolved in N,N -dimethylformamide (5mL), compound 1m (100mg, 0.35mmol) and potassium carbonate (804mg, 5.82mmol) were added thereto, and reaction 3 at 100°C Hour. After filtration and concentration under reduced pressure, the residue was purified by preparative liquid phase (C18, acetonitrile/water (ammonium bicarbonate)) to obtain compound 25 .

LCMS: m/z = 508.3 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 8.93(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, add 2-methyl-1,2-propanediol (1.50g, 16.64mmol), tetrahydrofuran (7mL) and potassium tert-butoxide (1.87g, 16.64mmol) successively in a 25mL three-necked flask, and replace with nitrogen three times , cooled to -78°C, added compound 24a (4.16g, 18.31mmol), and reacted at this temperature for 3 hours. Add water (50 mL) to quench, ethyl acetate (50 mL X 3) to extract. The organic phase was dried, filtered and 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-neck flask, replaced with nitrogen three times, and stirred at 90°C for 10 minute. 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, concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonium bicarbonate)) to give compound 26 .

LCMS: m/z = 484.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.14(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-8 H- [ 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 )δ 9.19(d, J =8.9Hz,1H),8.08(s,1H),8.04(d, J =9.2Hz,1H),7.94(d, J =9.2 Hz,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-8 H- [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 )δ 9.19(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-8 H- [ 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 )δ 9.18(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- 8 H- [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 (710 mg, 17.74 mmol, 60%) and tetrahydrofuran (10 mL) were added to a 50 mL three-necked flask, and after cooling down to 0 ° C, tetrahydrofuran ( 3mL) solution, stirred at this temperature for 0.5 hours. After cooling down to -65°C, a solution of compound 2,4,6-trichloropyrimidine 30a (1.57g, 8.54mmol) in tetrahydrofuran (10mL) was added dropwise, and reacted at this temperature for 3 hours. Pour into ice water (200 mL) slowly, 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 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, add compound 1m (100mg, 0.35mmol), compound 30b (87mg, 0.39mmol), potassium carbonate (488mg, 3.53mmol) and N,N -dimethylformamide (10mL) into a 25mL single-necked bottle , replace nitrogen 3 times, heat up to 80°C, and stir for 16 hours. After filtration, concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonium bicarbonate)) to give compound 30 .

LCMS: m/z = 470.1 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.13(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-8 H- [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 )δ 9.14(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-8 H- [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 )

Dissolve 2-methyl-1,2-propanediol (800mg, 8.87mmol) in N,N-dimethylformamide (50mL), and add cesium carbonate (8.68g, 26.6mmol) to the mixture, 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 and 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 )

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

LCMS: m/z = 484.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.05(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-8 H -[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 (10 mL), and extract with ethyl acetate (10 mL X 3). The organic phase was dried, filtered and 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 -8 H- [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 ). 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 (ammonium bicarbonate)) to obtain compound 33 .

LCMS: m/z = 468.0 (M+H) ⁺ .

¹ H NMR(400MHz,CD ₃ OD)δ 8.78(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-8 H - [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)δ 8.78(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 =7.1Hz, 3H).

Example 35

( R )-3-((2-Chloro-6-(methoxymethyl)pyrimidin-4-yl)oxy)-10-methyl-9,10,11,12-tetrahydro-8 H - [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, add 6-(chloromethyl)pyrimidine-2,4-diol 35a (1.00g, 6.15mmol) and sodium methoxide in methanol (10mL, 30%) to a 50ml single-necked bottle successively, and replace with nitrogen three times , and stirred at 70°C for 3 hours. Concentrated under reduced pressure, the residue was dissolved in water (50 mL), adjusted to pH~7 with 2N hydrochloric acid, and extracted 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, nitrogen replacement was performed three times, and the temperature was raised to 120°C for 5 hours. Concentrate under reduced pressure, add water (40 mL), and extract with dichloromethane (40 mL 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 8 H- [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 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, concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonium bicarbonate)) to give compound 35 .

LCMS: m/z = 440.0 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.17(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 (2.00 g, 10.90 mmol), stirred at room temperature for 16 hours. Add water (40 mL) to quench, extract with ethyl acetate (50 mL X 3), wash with saturated brine (50 mL X 3). The organic phase was dried, filtered and concentrated to obtain 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, sequentially add compound 1m (100mg, 0.35mmol), potassium carbonate (488mg, 3.53mmol) and N,N -dimethylformamide (3mL) into a 25ml single-necked bottle, nitrogen replacement three times, at 90°C Stir for 10 minutes. Cool to room temperature, add compound 36a (117mg, 0.53mmol), and stir at 90°C for 3 hours under nitrogen atmosphere. After filtration, 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 )δ 9.14(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-8 H- [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] quinoline-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 )δ 9.18(d, J =8.8Hz,1H),8.09(s,1H),8.03(d, J =9.2Hz,1H),7.91(d, J =9.2 Hz,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) δ 9.06(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-8 H- [ 1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one and ( R )-3-((4-chloro-5-( Trifluoromethyl)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 )δ 9.19(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) δ 9.06(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-8 H- [ 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 )δ 9.17(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-8 H- [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 tertiary 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), The temperature was raised to 90° C. for 3 hours. Filter, add water (20 mL), extract with ethyl acetate (20 mL 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-8 H- [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 give compound 42 .

LCMS: m/z = 451.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.03(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-8 H- [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 )δ 9.14(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-tetra Hydrogen- 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) was added and N,N-Diisopropylethylamine (34.89mL, 211.10mmol) was replaced with nitrogen three times, heated to 120°C and stirred for 16 hours. Saturated sodium bicarbonate solution was quenched, 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 X 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-methylpropane-2-amine ( 44d )

At room temperature, compound 44c (0.70g, 2.42mmol) was dissolved in acetonitrile (10mL), potassium carbonate (1.10g, 7.96mmol) and tertiary butylamine (0.22g, 3.01mmol) were added, and stirred at room temperature for 3 Hour. 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, and concentrate under reduced pressure, the residue is subjected to column chromatography (petroleum ether/ethyl acetate) to give 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, Preparation of 12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 44 )

Compound 1m (100 mg, 0.35 mmol), potassium carbonate (488 mg, 3.53 mmol), and N,N-dimethylformamide (3 mL) 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 give compound 44 .

LCMS: m/z = 481.1 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 9.15(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-8 H- [1,4]diazepine Epo[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 )δ 9.17(d, J =8.9Hz,1H),8.61(s,1H),8.02(d, J =9.2Hz,1H),7.92(d, J =9.2 Hz,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-8 H- [ 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, Compound 46 was obtained.

LCMS: m/z = 463.1 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 11.54(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-8 H- [ 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-oxobutyrate 47a (5.00 g, 30.12 mmol) in toluene (150 mL) at room temperature, add urea (3.62 g, 60.24 mmol) and sodium ethoxide in ethanol The solution (20% mass fraction, 20.48g, 60.24mmol) was 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 (100 mL), extract with ethyl acetate (70 mL X 2), wash with saturated brine (50 mL). 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 )δ 9.19(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-8 H- [1,4]diazepine Epo[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 (1.00g, 4.36mmol), benzyl Amine (0.47g, 4.36mmol) and methanol (10mL) were 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. The pH of the system was adjusted to neutral by adding saturated sodium bicarbonate solution, extracted with dichloromethane (50mL X 3), washed with saturated sodium chloride solution (50mL X 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated 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 (700mg, 2.19mmol), 10% palladium on carbon (70mg) and methanol (10mL) were sequentially added into a 25ml 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), heated to 65°C, stirred for 10 minutes, added 1 - Aminofuro[3,2-f]quinoline-2-carboxylic acid ethyl ester 1e (10.0 g, 39.02 mmol), react 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-binaphthyl-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 X 3), dry the organic phase, filter, and concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether/ethyl acetate) to obtain the 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 methanol (25 mL) solution of compound 48f (320 mg, 0.97 mmol) was added sodium methoxide (131 mg, 2.43 mmol) at room temperature, and reacted overnight at 70°C. Concentrate, add ice water (1.5mL), adjust pH~5 with 1N hydrochloric acid, and purify by prep-HPLC, C18, acetonitrile/water (formic acid) to obtain compound 48g .

LCMS: m/z = 284.1 (M+H) ⁺ .

Step 7: ( S )-10-(((tertiary butoxycarbonyl)oxy)methyl)-8-oxo-10,11-dihydro-8H-[1,4]diazepine[5 ',6': Preparation of di-tert-butyl 4,5]furo[3,2-f]quinoline-9,12-dicarboxylate ( 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 ( 2mL, 8.71mmol), reacted at 100°C for 60 hours. Concentrate, add water (20 mL), extract with ethyl acetate (40 mL X 3), dry the organic phase, filter, and concentrate under reduced pressure. 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 - Preparation of Tetrahydro-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 slurried with ether to obtain compound 48i .

LCMS: m/z = 600.3 (M+H) ⁺ .

Step 9: ( S )-10-(((tertiary butoxycarbonyl)oxy)methyl)-3-chloro-8-oxo-10,11-dihydro- 8H- [1,4]di Preparation of di-tert-butyl azepine[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] Preparation of diazepine[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 into dioxane (5 mL), Replaced with nitrogen 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, reacted overnight at 100°C. After filtration, concentration under reduced pressure, the residue was purified by preparative liquid chromatography (C18, acetonitrile/water (ammonium bicarbonate)) to obtain compound 48 .

LCMS: m/z = 411.0 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 10.87(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-8 H- [1,4]diazepine Epo[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 (26 mg, 0.17 mmol) and potassium carbonate (240 mg, 1.74 mmol) to a solution of compound 49a (52 mg, 0.17 mmol) in N,N -dimethylformamide (3 mL) 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) δ 9.06(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-8 H- [1,4]di Azepine[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 )δ 9.17(d, J =9.2Hz, 1H), 8.56(s, 1H), 8.01(d, J =9.2Hz, 1H), 7.89(d, J =9.2 Hz,1H),7.82(d, J =4.8 Hz,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), and N,N-diisopropylethylamine (1.97g, 15.30mmol) was added and compound 30a (800mg, 4.36mmol), 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, 10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 51 ) preparation

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, nitrogen Replaced three times, and reacted at 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) δ 9.03(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-8 H- [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 (50 mL), extract with ethyl acetate (20 mL X 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 )δ 9.15(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 (0.73 mL, 4.40mmol) and dimethylsulfoxide (10mL), replaced with nitrogen three times, and stirred at 90°C for 6 hours. Cool to room temperature, add water (100 mL), extract with ethyl acetate (50 mL X 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, 10,11,12-tetrahydro-8H-[1,4]diazepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 53 ) preparation

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 )δ 9.11(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-8 H- [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) δ 8.84(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 )δ 9.14(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-8 H- [1,4] Diazepine[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 obtain compound 56 .

LCMS: m/z = 409.0 (M+H) ⁺ .

¹ H NMR (400MHz,DMSO- d ₆ )δ 10.80(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-8 H- [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 )δ 9.17(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- 8 H- [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 )δ 9.14(d, J =9.2Hz,1H),8.57(s,1H),7.99(d, J =9.2Hz,1H),7.87(d, J =9.2 Hz,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 =5.2,3.6 Hz, 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-8 H- [1,4]di Azepine[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 )δ 9.09(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-8 H- [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 )δ 9.19(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 )δ 9.14(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-8 H -[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 successively, and stirred at room temperature for 40 minute. Filtration and purification of the filtrate by preparative liquid chromatography (C18, acetonitrile/water (formic acid)) afforded compound 62 .

LCMS: m/z = 465.3 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.14(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-8 H- [ 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, 3.10 mmol), 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, amine water (1 mL) was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure, and the residue is 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 (61.14mg, 0.34mmol) was dissolved in 1,4-dioxane (1.5mL), compound 63b (60mg, 0.17mmol), cesium carbonate (337.02mg, 1.03mmol), 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 )δ 11.36(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-8 H- [1,4]di Azepine[5',6':4,5]furo[3,2-f]quinolin-8-one ( 64 )

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

LCMS: m/z = 396.2 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ )δ 9.00(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-8 H- [ 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 )δ 9.19(d, J =9.0Hz,1H),9.01(s,1H),8.05(d, J =9.2Hz,1H),7.96(d, J =9.2 Hz,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

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 an appropriate amount of kinase to 1-fold kinase buffer to prepare a 2.5-fold enzyme solution; prepare a 5-fold compound dilution (1-fold kinase buffer, 10% DMSO) for the compound test concentration, use the initial stock solution at 50 μM, and use 1:5; 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 stop the reaction, and centrifuged at 1000 rpm for 1 minute; finally, the conversion rate data was read on the 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.

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 inducing cells to produce cytokine TNF-α. In the experiment, the initial concentration of the test compound was 10000nM, 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 dilution and 50 μl LPS dilution (final concentration 0.1ng/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 80μL CellTiter-Glo® Reagent to each well to detect cell viability.

Inhibition of the compounds disclosed herein on the release of pro-inflammatory cytokines from PBMCs was determined by the above tests, and the measured IC ₅₀ values are shown in Table 2.

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

Test Example 3: Pharmacokinetic Evaluation in Rats

After the compound was made 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 given 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 dosing. Compartmental analysis was used to estimate pharmacokinetic parameters.

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

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

Claims (30)

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

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, the Alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^1A , each R ^1A independently selected from halogen, hydroxyl, pendant oxygen, nitro, cyano or amine; Alternatively, any adjacent ^R1 and adjacent carbon atoms form a 3 to 6 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl, which is optionally substituted by one or more ^R1B , R ^1B is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy, the alkyl or alkyl oxygen is optionally replaced by one Or more substituted by halogen, hydroxyl, side oxygen, nitro, cyano or amino; R ² and R ³ are independently selected from hydrogen or C _1-6 alkyl, which is optionally selected from one or more of halogen, hydroxyl, cyano or amine; R ⁴ are each independently selected from halogen, side oxygen (=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 ) _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 substituted by one or more R ^4A , each R ^4A is independently selected from halogen , hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, C _1-6 alkoxy, 3 to 6 1-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 Substitution, R ^5A is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl; R ⁵ 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^2A , each R ^2A independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine; 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^3A , each R ^3A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine; T is selected from a bond or -L-X-; L is selected from a bond or C _1-3 (alkylene) alkylene, which is optionally substituted by one or more R ^6A , and each R ^6A is independently selected from halogen, hydroxyl, side oxygen, nitric acid Group, cyano group, amino group, 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 replaced 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, side oxygen, 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, the alkane Alkyloxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^7A , each R ^7A is independently selected from halogen, hydroxyl, pendant oxygen, 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 , and each R ^8A is independently selected from halogen, hydroxyl, pendant Oxygen, 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 as described in claim item 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, the Alkyl, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^1A , each R ^1A independently selected from halogen, hydroxyl, pendant oxygen, nitro, cyano or amine; 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; R ⁴ are each independently selected from halogen, side oxygen (=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 substituted by one or more R ^4A , each R ^4A is independently selected from halogen, hydroxyl, side oxygen, 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 Substitution, R ^5A is each independently selected from halogen, hydroxyl, side oxygen, nitro, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered cycloalkyl; R ⁵ 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^2A , each R ^2A independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine; 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, the alkyl, Alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^3A , each R ^3A is independently selected from halogen, hydroxyl, side oxygen, nitro, cyano or amine; T is selected from a bond or -L-X-; L is selected from a bond or C _1-3 (alkylene) alkylene, which is optionally substituted by one or more R ^6A , and each R ^6A is independently selected from halogen, hydroxyl, side oxygen, nitric acid Group, cyano group, amino group, 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, which is optionally replaced by one or more groups selected from halogen, hydroxyl, side oxygen, 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, the alkane Alkyloxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R ^7A , each R ^7A is independently selected from halogen, hydroxyl, pendant oxygen, 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 , and each R ^8A is independently selected from halogen, hydroxyl, pendant Oxygen, 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 as claimed in item 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, the (alkylene group) Optionally replaced by 1-3 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 as described in any one of claims 1 to 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 a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, wherein ^each R 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 in Claim 1 or 2. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein ^each R 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 ^3A , and R ^3A is as defined in Claim 1 or 2. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein R ² is selected from C _1-6 alkyl, and the alkyl is optionally replaced by 1-3 selected from halogen, hydroxyl or amine Substituted by a radical group; further, ^R2 is preferably methyl, ethyl, hydroxyethyl, difluoromethyl or trifluoromethyl. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein R ² is selected from hydrogen. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein R ¹ is selected from C _1-6 alkyl or C _1-6 alkoxy, the alkyl or alkoxy 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 as described in any one of claims 1 to 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 a pharmaceutically acceptable salt thereof as claimed in any one of claims 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 as described in any one of claim 1, 2 or 10, wherein the compound of formula I is selected from:

Wherein, R ¹ , R ² , R ⁴ , ring A, and m are as defined in Claim 1 or 2. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, wherein each R ⁴ is independently selected from halogen, hydroxyl or amino. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, wherein ^each R is independently selected from C _1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycle Alkyl, 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 as claimed in any one of claims 1 to 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 in claim 1 or as defined in 2. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, wherein any adjacent two R ⁴ and adjacent atoms form a 3 to 6 membered cycloalkyl group or a 3 to 6 membered heterocycloalkyl group , the cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 R ^5A , and R ^5A is as defined in Claim 1 or 2. The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 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, the 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 as described in any one of claims 1 to 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 - replaced by 3 R ^8A , R ^8A as defined in claim 1 or 2. The compound or pharmaceutically acceptable salt thereof as claimed in any one of claim 1, 2 or 17, wherein each R ^7A is 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 as claimed in any one of claim 1, 2 or 14, wherein R ^4A is each independently selected from halogen, hydroxyl, cyano, C _1-6 alkyl, 3 to 6 membered ring Alkyl, 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 as described in any one of claims 1, 2 or 18, wherein each R ^8A is 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 as claimed in item 1, wherein R ⁴ are each independently selected from halogen, side oxygen (=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 hetero Cycloalkylamino, 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 as described in claim item 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 as described in claim item 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 as described in any one of claims 1 to 24, wherein the compound shown in the formula I is selected from:

The compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 25, wherein the compound shown in the formula I is selected from:

An isotopic substitution of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, preferably, the isotopic substitution is a deuterated substance. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 26, or an isotope substitution as described in claim 27, and a pharmaceutically acceptable Accepted excipients. A compound as described in any one of claim items 1 to 26 or a pharmaceutically acceptable salt thereof, or an isotope substitution as described in claim item 27, or a pharmaceutical composition as described in claim item 28 is used for preventing And/or use in medicines for treating MK2-mediated diseases. A compound as described in any one of claim items 1 to 26 or a pharmaceutically acceptable salt thereof, or an isotope substitution as described in claim item 27, or a pharmaceutical composition as described in claim item 28 is used for preventing And/or use in medicines for the treatment of autoimmune diseases, inflammatory diseases, fibrotic diseases or metabolic diseases.