WO2019134705A1 - Immunomodulator - Google Patents

Abstract

Disclosed are an immunomodulatory agent, and in particular an activating STING compound and uses thereof acting as an immunomodulatory agent in preparing a drug. Also disclosed is/are a compound represented by formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, or uses of a metabolite in preparing an STING-activating drug, and providing a new option for clinical screening and/or preparation of a drug for treating STING-associated diseases. (I)

Description

Immunomodulator Technical field

The present invention relates to an immunomodulator, and in particular to a compound which activates STING and its use as an immunomodulator in the preparation of a medicament.

Background technique

The body's immune system can usually be divided into "natural immune" and "adaptive immune" systems. The natural immune system plays an important role in the fight against infection, inhibition of tumor growth, and the pathogenesis of autoimmune diseases. It mainly recognizes pathogenic microorganisms and cancer cell components through pattern recognition receptors, initiates downstream signaling pathways, and ultimately induces cytokine expression. Kill pathogenic microorganisms and cancer cell components, as well as adapt to the immune system to promote antibody and specific T lymphocyte production.

STING (interferon gene stimulating factor, TMEM173, MITA, etc.) is a key node molecule for intracellular response to DNA invasion. Under cytoplasmic DNA stimulation, recognition of cytoplasmic DNA receptor signaling plays a key role in the process of inducing interferon production. . After the host cell's DNA recognition receptor recognizes the exogenous or endogenous "non-self" DNA, it transmits a signal to the node molecule STING, which then rapidly dimerizes and transfers from the endoplasmic reticulum to the nuclear peripheral body. Activation of STING leads to upregulation of the IRF3 and NKκB pathways, resulting in the induction of interferon-β and other cytokines.

The CDN was first discovered to be the second messenger responsible for controlling prokaryotic cell responses. Direct activation of bacterial CDN by STING has been verified by X-ray crystallography (Burdette DL et al. Nature Immunolog, 2013 (14): 19-26). The new CDN signal transduction molecule cGAMP has been found to activate STING, and its interaction with STING has also been verified by X-ray crystallography (Cai X et al. Molecular Cell, 2014 (54): 289-296).

Compounds that bind to STING and act as agonists have been shown to induce type 1 interferons and other cytokines when incubated with human PBMC. Compounds that induce human interferon can be used to treat various conditions, such as treating allergic diseases and other inflammatory conditions, such as allergic rhinitis and asthma, treating infectious diseases, neurodegenerative diseases, precancerous syndromes, and cancer, or Used as an immunological composition or vaccine adjuvant. Activation of STING may be a potential method for treating diseases associated with type 1 IFN pathways including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndrome, or as an immunological combination Or vaccine adjuvant.

Summary of the invention

In order to solve the above problems, the present invention provides an immunomodulator.

The present invention provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:

among them,

X ¹ , X ² , X ³ , X ⁴ , X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} are each independently selected from C or N;

B ring is selected from

Ring C is selected from 0 to 4 R ^{5 'is} an optionally substituted benzene ring, substituted with 0 to 4 R ^5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;

R ⁴ and R ^4' are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and halogen;

R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl;

R ¹ , R ² , R ³ , R ^{1 '} , R ^{2 '} , R ^{3 '} and R ^{5 '} are each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl, -C(O)NR ^a R ^b or none;

R ^a , R ^b , R ^d , R ^e are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

L is selected from R ⁿ 0-4 alkylene group optionally substituted with a C ₄ ~ C _6, and 0 to 4 being optionally substituted with R ⁿ C ₄ ~ C ₆ alkenylene group, substituted with 0 to 4 R ⁿ optionally substituted C ₄ -C ₆ alkynylene; wherein optionally substituted C ₄ -C ₆ alkylene, optionally substituted C ₄ -C ₆ alkenylene, optionally substituted The carbon atom in the alkynylene group of C ₄ to C ₆ may be substituted by -O-, -S-, -NR ^m - ;

R ^{m is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl;

When at least one of X ¹ , X ² , X ³ , X ⁴ , X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} is:

R ^s and R ^t are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -CO ₂ R ^f , -C(O)NR ^f R ^g , -NR ^f C(O)R ^g or none;

When C ¹ , X ² , X ³ , X ⁴ , X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} are all C:

R ^{t is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -CO ₂ R ^f , -C(O)NR ^f R ^g , -NR ^f C(O)R ^g or none;

R ^{s is} selected from

When m is 0, A is a ring selected from 0-4 R ^c optionally substituted 3- to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl 0-4 R ^c is optionally substituted; when m is 1,2,3,4,5,6, a ring is optionally selected from 0-4 R ^c substituted 3-6 membered cycloalkyl, optionally zero to four substituents R ^c 4 Metaheterocycloalkyl;

R ^{c is} independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl, -C(O)OR ^d ;

R ^f and R ^g are each independently selected from hydrogen, a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a benzene ring optionally substituted by 0 to 4 R ⁱ , and 0 to 4 R ⁱ is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R ⁱ optionally 3 to 6-membered cycloalkyl, optionally 0-4 R ⁱ is 3 to 6-membered heterocyclic ring alkyl;

R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -C(O)R ^j , -CO ₂ R ^j , -C(O)NR ^j R ^k , -NR ^j C(O)R ^k , substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R ⁱ is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R ⁱ ;

R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

R ^j and R ^k are each independently selected from hydrogen and a C ₁ -C ₆ alkyl group.

Further, the compound is as shown in Formula II:

among them,

At least one N of X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} ;

B ring is selected from

C ring selected from

R ¹⁵ , R ¹⁶ , R ¹⁷ , R ^{15 '} , R ^{16 '} and R ^{17 '} are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl;

R ¹⁴ and R ^{14 '} are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ¹¹ and R ¹³ are each independently selected from the group consisting of hydrogen, -OR ^d , halogen, -CN, C(O)OR ^d , and C ₁ -C ₆ alkyl;

R ^{11 '} and R ^{13 '} are each independently selected from the group consisting of hydrogen, -OR ^d , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl or none;

R ^{12 is} selected from the group consisting of hydrogen and -C(O)NR ^a R ^b ;

R ^{12 ' is} selected from hydrogen, -C(O)NR ^a R ^b or not;

R ^a , R ^b , and R ^d are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ^{t1 is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

R ^f is selected from hydrogen, substituted with 0 to 4 R ^h is an optionally substituted C ₁ ~ C ₆ alkyl, substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally substituted 5 to 6-membered aromatic heterocyclic ring, substituted with 0 to 4 R ⁱ optionally 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ⁱ optionally substituted 3- to 6-membered heterocyclic group;

R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -C(O)R ^j , -CO ₂ R ^j , -C(O)NR ^j R ^k , -NR ^j C(O)R ^k , substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R ⁱ is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R ⁱ ;

R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

R ^j and R ^k are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

L is selected from the group consisting of C ₄ to C ₆ alkenylene groups.

Further, the compound of formula II is:

Further, the compound is as shown in Formula III:

among them,

B ring is selected from

Ring C is selected from 0 to 4 R ^{5 'is} an optionally substituted benzene ring, substituted with 0 to 4 R ^5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;

R ²¹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ^{22 is} selected from the group consisting of -C(O)NR ^a R ^b , -C(O)OR ^d ;

R ^{21 '} , R ^{23 '} and R ^{5 '} are each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, C ₁ -C ₆ alkyl;

R ^{24 ' is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

R ^a , R ^b , R ^d , R ^e are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ^{22 ' is} selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl, -C(O)NR ^a R ^b ;

R ^{t2 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -C(O) OR ^f , -CONR ^f R ^g , -NR ^f COR ^g ;

R ^f and R ^g are each independently selected from hydrogen, a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a benzene ring optionally substituted by 0 to 4 R ⁱ , and 0 to 4 R ⁱ is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R ⁱ optionally 3 to 6-membered cycloalkyl, optionally 0-4 R ⁱ is 3 to 6-membered heterocyclic ring alkyl;

R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -COR ^j , -CO ₂ R ^j , -CONR ^j R ^k , -NR ^j COR ^k , benzene optionally substituted by 0 to 4 R ⁱ ring substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, substituted with 0 to 4 R ⁱ optionally 3 to 6-membered cycloalkyl, optionally zero to four substituents R ⁱ 3- to 6-membered heterocycloalkyl;

R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

R ^j and R ^k are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

L is selected from R ⁿ 0-4 alkylene group optionally substituted with a C ₄ ~ C _6, and 0 to 4 being optionally substituted with R ⁿ C ₄ ~ C ₆ alkenylene group, substituted with 0 to 4 R ⁿ optionally substituted C ₄ -C ₆ alkynylene; wherein optionally substituted C ₄ -C ₆ alkylene, optionally substituted C ₄ -C ₆ alkenylene, optionally substituted C The carbon atom in the alkynylene group of ₄ to C ₆ may be substituted by -O-, -S-, or -NR ^m - ;

R ^{m is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl.

Further, R ²¹ , R ²³ , R ²⁴ , and R ²⁷ are each independently selected from hydrogen;

R ²⁵ and R ²⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

R ^a and R ^b are each independently selected from hydrogen;

C ring selected from

s is 0, 1, 2, 3;

R ^{21 '} , R ^{23 '} and R ^{5 '} are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ^{24' is} selected from hydrogen;

R ^{22 ' is} selected from -C(O)NR ^a R ^b ;

R ^{t2 is} selected from the group consisting of hydrogen and -OR ^f ;

R ^{f is} selected from a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a 3 to 6 membered cycloalkyl group optionally substituted by 0 to 4 R ^{i , and is} optionally substituted with 0 to 4 R ⁱ a substituted 3-6-membered heterocycloalkyl group;

R ^h is selected from 0 to 4, optionally substituted with R ⁱ is 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ⁱ optionally substituted 3- to 6-membered heterocyclic group;

R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

L is selected from 0-4 R ⁿ optionally substituted C ₄ ~ C ₆ alkylene group, and is substituted with 0 to 4 R ⁿ is C alkylene optionally substituted alkenyl group of ₄ ~ C _6;

R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl.

Further, the compound is as shown in formula IIIa:

among them,

R ²¹ , R ²³ , R ²⁴ and R ²⁷ are each independently selected from hydrogen;

R ²⁵ and R ²⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

R ^{22 ' is} selected from -C(O)NR ^a R ^b ;

R ^a and R ^b are each independently selected from hydrogen;

X selects -C-, -O-, -NR ^z -, -S-;

R ^{z is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

m is 0, 1, 2, 3, 4, 5, 6;

n is 1, 2, 3, 4;

p is 0, 1, 2, 3, 4.

Further, the compound of formula IIIa is:

Further, the compound is as shown in formula IIIb:

among them,

R ²¹ , R ²³ , R ²⁴ and R ²⁷ are each independently selected from hydrogen;

R ²⁵ and R ²⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

R ^a and R ^b are each independently selected from hydrogen.

Further, the compound of the formula IIIb is:

Further, the compound is as shown in Formula IV:

among them,

B ring is selected from

When m is 0, A ring is selected from 0-4 optionally substituted by R ^c 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ^c optionally having 3 to 6-membered heterocyclic group;

When m is 5, 6, A is a ring selected from substituted with 0 to 4 R ^c optionally 3 to 6-membered cycloalkyl, substituted with 0-4 R ^c optionally 4-membered heterocycloalkyl;

R ³¹ , R ³³ and R ³⁴ are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl;

R ³⁵ , R ³⁶ and R ³⁷ are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ^{32 is} selected from -CONR ^a R ^b ;

R ^a and R ^b are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

R ^{c is} each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl, -C(O)OR ^d ;

R ^d and R ^e are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

Ring C is selected from 0 to 4 R ^{5 'is} an optionally substituted benzene ring, substituted with 0 to 4 R ^5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;

R ^{31 '} , R ^{33 '} and R ^{5 '} are each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, C ₁ -C ₆ alkyl;

R ^{34 ' is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

R ^{32 ' is} selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl, -C(O)NR ^a R ^b ;

R ^{t3 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -CO ₂ R ^f , -C(O)NR ^f R ^g , -NR ^f C(O)R ^g ;

R ^f and R ^g are each independently selected from hydrogen, a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a benzene ring optionally substituted by 0 to 4 R ⁱ , and 0 to 4 R ⁱ is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R ⁱ optionally 3 to 6-membered cycloalkyl, optionally 0-4 R ⁱ is 3 to 6-membered heterocyclic ring alkyl;

R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -C(O)R ^j , -CO ₂ R ^j , -C(O)NR ^j R ^k , -NR ^j C(O)R ^k , substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R ⁱ is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R ⁱ ;

R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

R ^j and R ^k are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

L is selected from R ⁿ 0-4 alkylene group optionally substituted with a C ₄ ~ C _6, and 0 to 4 being optionally substituted with R ⁿ C ₄ ~ C ₆ alkenylene group, substituted with 0 to 4 R ⁿ optionally substituted C ₄ -C ₆ alkynylene; wherein optionally substituted C ₄ -C ₆ alkylene, optionally substituted C ₄ -C ₆ alkenylene, optionally substituted C The carbon atom in the alkynylene group of ₄ to C ₆ may be substituted by -O-, -S-, or -NR ^m - ;

R ^{m is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl.

Further, R ³¹ , R ³³ and R ³⁴ are each independently selected from hydrogen and halogen;

R ^{37 is} independently selected from hydrogen;

R ³⁵ and R ³⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

R ^a and R ^b are each independently selected from hydrogen;

The A ring is selected from a 3- to 6-membered cycloalkyl group or a 4-membered heterocycloalkyl group optionally substituted by 0 to 4 R ^c ;

C ring selected from

s is 0, 1, 2, 3;

R ^{31 '} , R ^{33 '} and R ^{35 '} are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl;

R ^{34 ' is} selected from hydrogen;

R ^{32 ' is} selected from -NR ^d R ^e , -C(O)NR ^a R ^b ;

R ^{t3 is} selected from the group consisting of hydrogen and -OR ^f ;

R ^{f is} selected from a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a 3 to 6 membered cycloalkyl group optionally substituted by 0 to 4 R ^{i , and is} optionally substituted with 0 to 4 R ⁱ a substituted 3-6-membered heterocycloalkyl group;

R ^h is selected from -OR ^j, substituted with 0 to 4 R ⁱ optionally 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ⁱ optionally substituted 3- to 6-membered heterocyclic group;

L is selected from R ⁿ 0-4 alkylene optionally substituted C ₄ ~ C _6, and is 0 to 4 R ⁿ is C alkylene optionally substituted alkenyl group of ₄ ~ C _6.

Further, the compound is as shown in formula IVa:

among them,

R ³¹ , R ³³ , R ³⁴ and R ³⁷ are each independently selected from hydrogen;

R ³⁵ and R ³⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

R ^a and R ^b are each independently selected from hydrogen;

m is 0, 1, 2, 3, 4, 5, 6;

n is 0, 1, 2, 3;

p is 0, 1, 2, 3, 4;

R ^{c is} each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl, -C(O)OR ^d ;

R ^d and R ^e are each independently selected from hydrogen and C ₁ -C ₆ alkyl.

Further, the compound of the formula IVa is:

Further, the compound is as shown in formula IVb:

among them,

R ³¹ , R ³³ and R ³⁴ are each independently selected from hydrogen and halogen;

R ^{37 is} independently selected from hydrogen;

R ³⁵ and R ³⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

R ^a and R ^b are each independently selected from hydrogen;

X selects -O-, -NR ^y -, -S-;

NR ^{y is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

When m is 0, n and q are added to 2, 3, 4;

When m is 1, 2, 3, 4, 5, 6, n and q are added to 2;

p is 0, 1, 2, 3, 4;

R ^{c is} each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl;

R ^d and R ^e are each independently selected from hydrogen and C ₁ -C ₆ alkyl.

Further, the compound of formula IVb is:

The present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the preparation of a medicament for activating STING .

The present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the preparation of a disease associated with STING activity Use of the drug.

Further, the disease associated with STING activity is one or more of diseases associated with inflammatory, autoimmune diseases, infectious diseases, cancer, precancerous syndrome.

The present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a therapeutic inflammatory, autoimmune Use in medicines for diseases, infectious diseases, cancer or precancerous syndrome.

The present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of an immunoadjuvant.

The present invention also provides a drug which is a compound of the foregoing, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, A preparation prepared from a pharmaceutically acceptable excipient.

The disease associated with STING activity as defined in the present invention is a disease in which STING plays an important role in the pathogenesis of the disease.

Diseases associated with STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndrome.

"Cancer" or "malignant tumor" refers to any of a variety of diseases characterized by abnormal proliferation of uncontrolled cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other sites. The body (ie, metastasis) and any of a number of characteristic structures and/or molecular features. "Cell cancer cells" refers to cells that undergo early, intermediate or late stages of multi-step tumor progression. Cancer includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer. In some embodiments, the compound of Formula I is for use in treating a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma. In some embodiments, the cancer is selected from the group consisting of melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer. In some embodiments, the cancer treated is a metastatic cancer.

Inflammatory diseases include a variety of conditions characterized by histopathological inflammation. Examples of inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, Airway inflammation and interstitial cystitis caused by house dust mites. There is a significant overlap between inflammatory diseases and autoimmune diseases. Some embodiments of the invention relate to the treatment of inflammatory disease asthma. The immune system usually involves inflammatory diseases, which are manifested in allergic reactions and some myopathy, and many immune system diseases cause abnormal inflammation.

The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definitions of terms of use in connection with the present invention: Unless otherwise stated, the initial definitions provided herein by the group or term apply to the group or term of the entire specification; for terms not specifically defined herein, it should be based on the disclosure and context. Given the meanings that those skilled in the art can give to them.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C _a - C _b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms. Thus, for example, (C ₁ -C ₄ )alkyl means an alkyl group containing from 1 to 4 carbon atoms.

In the present invention, C _a to C _b alkoxy, C _a to C _b alkyl ester group, C _a to C _b alkylamino group, and C _a to C _b acyl group respectively mean "a" to "b" carbon atoms. a group obtained by linking an alkyl group to a corresponding oxygen atom, ester group, amino group, or acyl group.

In the present invention -C(O)NR ^a R ^b , -C(O)OR, -C(O)R, -NRC(O)R -C(O)- represents a double atom through carbon and oxygen A carbonyl group (-C=O-) bonded by a bond.

The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.

The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium. The salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound. An acid salt, an oxalate salt, a malate salt, a succinate salt, a fumarate salt, a maleate salt, a tartrate salt or a trifluoroacetate salt.

In certain embodiments, one or more compounds of the invention may be used in combination with one another. Alternatively, the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition that modulates cellular function or treats a disease. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.

The present invention discloses a compound of the formula I, and discloses the use of the compound for the preparation of a medicament for treating a disease associated with STING activity, in particular for the preparation of a medicament for the treatment of inflammatory, allergic, autoimmune diseases, infectious diseases Use in drugs for cancer, cancer or precancerous syndrome, and in the preparation of immunological adjuvants. A new option for drugs for clinical screening and/or preparation of diseases associated with STING activity is provided.

It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

DRAWINGS

Figure 1 is a graph showing the effect of different concentrations of the compounds prepared in Example 2 on CT-26 tumor volume.

Figure 2 is a graph showing the effect of the compound prepared in Example 2 at a concentration of 1 mg/kg on the CT-26 tumor volume.

Detailed ways

The raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). The internal standard is tetramethylsilane (TMS).

The LC-MS was measured by Shimadzu LC-MS 2020 (ESI).

The HPLC was measured using Shimadzu High Pressure Liquid Chromatograph (Shimadzu LC-20A).

Reverse phase preparative chromatography was performed using a Gilson GX-281 reverse phase preparative chromatograph.

The thin layer chromatography silica gel plate is separated from the Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate by thin layer chromatography, and the specification is 0.4mm to 0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as Anike Chemical, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

There is no special description in the examples, and M is a mole per liter.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

The overnight stay was 12 ± 1 h.

PE means petroleum ether; EA means ethyl acetate; DCM means dichloromethane; MeOH means methanol; DMF means N,N-dimethylformamide; DMSO means dimethyl sulfoxide; DMAP means 4-dimethylaminopyridine; DIPEA means diisopropylethylamine; Boc means t-butyloxycarbonyl; TFA means trifluoroacetic acid; DBU means 1,8-diazabicycloundecene- 7-ene; HATU means 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

Preparation of the compounds of the invention

Synthesis of Intermediate Compound 1a: 4-Chloro-3-methoxy-5-nitrobenzamide

4-Chloro-3-methoxy-5-nitrobenzyl ester (18.5 g, 75.3 mmol) was added to a one-neck bottle containing aqueous ammonia (200 mL) and stirred at 60 ° C for 3 h. The reaction mixture was concentrated to EtOAc (EtOAc)EtOAc.

MS (ESI) m / z = 231 [M + H] ⁺ ,

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.29 (s, 1H), 8.04 (d, 1H), 7.78 (d, 1H), 7.78 (s, 1H), 4.01 (s, 3H).

Synthesis of intermediate compound 2: 4-chloro-3-hydroxy-5-nitrobenzamide

Intermediate compound 1a (7.5 g, 32.5 mmol) was dispersed in dry DCM (90 mL), and then boron tribromide (120 mL, 1 M) was slowly added dropwise thereto. After the addition was completed, the ice bath was removed, protected with nitrogen, and allowed to react at room temperature overnight. After the reaction was completed, the reaction liquid was poured into ice water, stirred vigorously for 30 min, filtered, and the filter cake was washed with water, and the filter cake was dried to give 4-chloro-3-hydroxy-5-nitrobenzamide (6.00 g, 27.7) M, 85.3% yield), pale yellow solid.

MS (ESI) m/z = 217 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.73 (s, 1H), 8.21. (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.66 (s, 1H).

Synthesis of intermediate compound 3: 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate

1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (4.00 g, 25.9 mmol) was dissolved in dry DCM (80 mL), and oxalyl chloride (3.9 g) , 31.1 mmol) and a catalytic amount of DMF. After reacting for 1 h at room temperature, the volatiles were evaporated under reduced pressure. Add DCM (20 mL) to EtOAc EtOAc (EtOAc) reaction.

1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (4.46 g, 25.9 mmol) was dissolved in dry acetone (20 mL) and added dropwise to potassium thiocyanate (5.0 g). , 51.5 mmol), a solution of acetone (100 ml), stirred at room temperature for 3 h, the reaction system was filtered to remove inorganic salts, and the crude product was purified by silica gel column (eluent: ethyl acetate / petroleum ether (v / v) 1-1/15) 1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (4.0 g, 20.4 mmol, 78.7%).

MS (ESI) m / z = 196 [M+H] ⁺ .

Synthesis of Intermediate Compound 4: 4-Chloro-3-nitro-5-(oxetan-3-yloxy)phenyl)amino)benzamide

To a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (1.0 g, 4.6 mmol) in EtOAc (30 mL) 1.27 g, 6.9 mmol), reacted at 100 ° C for 24 h. After the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column (DCM/MeOH=20/1, v/v) to give 4-chloro-3-nit. 5-O-(oxetane-3-yloxy)benzamide (0.8 g, 2.9 mmol, 63.9% yield), pale yellow solid.

MS (ESI) m / z = 273 [M+H] ⁺ .

Synthesis of Intermediate Compound 5: 4-Chloro-3-nitro-5-(oxetan-3-methyloxy)phenyl)amino)benzamide

To a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (400 mg, 1.85 mmol) in DMF <RTI ID=0.0> The benzenesulfonic acid (673 mg, 2.78 mmol) was reacted at 70 ° C overnight. After the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column (DCM/MeOH=20/1, v/v) to give 4-chloro-3-nit. 5-(Oxetane-3-yloxy)benzamide (226 mg, 0.79 mmol, 43% yield)

MS (ESI) m / z = 287 [M+H] ⁺ .

Synthesis of intermediate compound 6: (S)-4-chloro-3-nitro-5-((tetrahydrofuran-3-yl)oxy)benzamide

To a solution of (R)-3-hydroxytetrahydrofuran (1.09 g, 11.3 mmol) in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; g, 12.2 mmol), the reaction was carried out for 2 h at room temperature, and extracted with water and dichloromethane. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-3-hydroxytetrahydrofuran (2.2) g, 9.08 mmol), used directly in the next reaction.

To a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (0.65 g, 3.01 mmol) in EtOAc (10 mL) (R)-3-Tetrahydrofuran p-toluenesulfonate (0.73 g, 3.01 mmol) was reacted at 70 ° C for 24 h. After the completion of the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed successively with water and brine, and then dried and concentrated to give (S)-4-chloro-3-nitro-5- ((Tetrahydrofuran-3-yl)oxy)benzamide (0.54 g, 1.88 mmol).

MS (ESI) m / z = 287 [M+H] ⁺ .

Synthesis of intermediate compound 7: (R)-4-chloro-3-nitro-5-((tetrahydrofuran-3-yl)oxy)benzamide

To a solution of (R)-3-hydroxytetrahydrofuran (1.3 g, 13.5 mmol) in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; g, 14.6 mmol), reacted for 2 h at room temperature, extracted with water and dichloromethane. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-3-hydroxytetrahydrofuran (2.3) g, 9.08 mmol), used directly in the next reaction.

To a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (0.78 g, 3.6 mmol) in DMF (10 mL), EtOAc (EtOAc, EtOAc. (R)-3-Tetrahydrofuran p-toluenesulfonate (0.88 g, 3.6 mmol) was reacted at 70 ° C for 24 h. After the completion of the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed successively with water and brine, and then dried and concentrated to give (S)-4-chloro-3-nitro-5- ((Tetrahydrofuran-3-yl)oxy)benzamide (0.64 g, 2.25 mmol).

MS (ESI) m / z = 287 [M+H] ⁺ .

Intermediate Compound 8: 3-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide

To a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (1.41 g, 6.52 mmol) in DMF <RTI ID=0.0> Butyldimethylsilane (1.2 g, 4.7 mmol) was reacted at 70 ° C overnight. After the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed successively with water and saturated brine, and then dried and concentrated to give a crude product, which was purified by silica gel chromatography (eluent: PE/EA =5/1 to 2/1) 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide (1.7 g, 4.37) Mm).

MS (ESI) m / z = 381 [M+H] ⁺ .

Intermediate compound 9: 4-chloro-3-nitro-5-(2-(oxetan-3-yl)ethoxy)benzamide

To a solution of 2-(oxetan-3-yl)ethanol (1.0 g, 9.79 mmol) in dichloromethane <RTI ID=0.0>(20</RTI> <RTIgt; The reaction mixture was stirred at room temperature for 2 h, then extracted with water and dichloromethane. Ethyl 4-methylbenzenesulfonate was used directly in the next reaction.

Add potassium carbonate (1.08 g, 7.8 mmol), potassium iodide (0.12 g, 0.72 mmol) and 2 to a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (845 mg, 3.9 mmol) in DMF (10 mL) -(oxetan-3-yl)ethyl 4-methylbenzenesulfonate (1.0 g, 3.9 mmol) was reacted at 75 ° C for 24 h. After the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed successively with water and brine, and then dried and concentrated to give 4-chloro-3-nitro-5-(2-( Oxetane-3-yl)ethoxy)benzamide (0.86 g, yield 73.5%).

Synthesis of Intermediate Compound 10: 4-Chloro-3-(cyclopropylmethoxy)-5-nitrobenzamide

Potassium carbonate (1.27 g, 9.2 mmol) and (bromomethyl)cyclopropane were added to a solution of 4-chloro-3-methoxy-5-nitrobenzamide (1.0 g, 4.6 mmol) in DMF (30 mL) (0.92 g, 6.9 mmol), reacted at 70 ° C for 24 h. After the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column (eluent: ethyl acetate / petroleum ether, v/v = 3/1). 4-Chloro-3-(cyclopropylmethoxy)-5-nitrobenzamide (1.0 g, 80% yield), pale yellow solid.

MS (ESI) m / z = 271 [M+H] ⁺ .

Example 1

Step 1: Synthesis of (trans)-tert-butyl(4-(4-carbamoyl-2-methoxy-6-nitrophenyl)amino)-n-but-2-enyl)carbamate

4-Chloro-3-methoxy-5-nitrobenzamide (500 mg, 2.17 mmol) and (4-aminobut-2-en-1-yl)carbamic acid tert-butyl ester (966 mg, 4.34 mmol) The solution was dissolved in dimethyl sulfoxide (10 mL), and triethylamine (1.1 g, 10.84 mmol) was added dropwise to the reaction mixture. The reaction mixture was warmed to 115 ° C and stirred at this temperature overnight. After cooling to room temperature, it was diluted with water, a large amount of orange solid was precipitated, filtered, and the filter cake was washed with water (15 mL×3), and dried by a vacuum pump rotary evaporator to obtain (trans)-tert-butyl(4-(4-carbamoyl-2) -Methoxy-6-nitrophenyl)amino)n-but-2-enyl)carbamate (Compound 1b) (450 mg, yield 57%), orange-yellow solid.

MS (ESI) m / z = 381 [M+H] ⁺ .

Step 2: Synthesis of (trans)-tert-butyl(4-((2amino-4carbamoyl-6-methoxyphenyl)amino)-n-but-2-enyl)carbamate

Compound 1b (450 mg, 1.18 mmol) was dissolved in MeOH (15 mL), and then evaporated to EtOAc (EtOAc). The reaction mixture was stirred at 0 ° C for 1 h, and the color of the reaction mixture changed from orange-red to white. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (20 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate -tert-Butyl(4-((2amino-4carbamoyl-6-methoxyphenyl)amino)-n-but-2-enyl)carbamate (Compound 1c) (260 mg, yield 58%), White solid.

MS (ESI) m / z = 351 [M+H] ⁺ .

Step 3: (trans)-tert-Butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-methoxy Synthesis of -1H-benzimidazolyl)-n-but-2-enyl)carbamate

Compound 1c (260 mg, 0.742 mmol) and compound 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (145 mg, 0.74 mmol) were dissolved in N,N-dimethyl In amide (5 mL) and stirred at room temperature for 1 h, then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (338 mg, 0.89) Methyl) and 1,8-diazabicyclo [5.4.0]undec-7-ene (147 mg, 0.96 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. And washing with water (5 mL × 3), followed by reverse phase column separation (eluent: acetonitrile / water = 1/3, v / v) to give (trans)-tert-butyl (4-(5-carbamoyl)- 2-(1-Ethyl-3-methyl-1hydro-pyrazole-5-carboxamide)-7-methoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (compound) 1d) (313 mg, yield 82%), white solid.

MS (ESI) m/z = 512 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 8. s (s, 1H), 7.67 (s, 1H), 7.48 - 7.32 (m, 2H), 7.00 - 6.87 (m, 1H) ), 6.65 (s, 1H), 5.85 - 5.50 (m, 2H), 4.93 (d, 2H), 4.61 (q, 2H), 3.98 (s, 3H), 3.51 (m, 2H), 2.55 (m, 2H), 2.18 (s, 3H), 1.35 (t, 3H), 1.32 (s, 9H).

Step 4: (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of methoxy-l-hydrogen-benzimidazole-5-carboxamide

Compound 1d (290 mg, 0.57 mmol) was dissolved in methanol (10 mL). After the reaction solution was stirred at room temperature for 30 minutes, the mixture was warmed to 40 ° C and stirring was continued for 3 h. The reaction mixture was sparged, and the obtained crude product was separated and purified using a reversed phase column (eluent: water/acetonitrile = 50/50, v/v) to give compound (trans)-1-(4-amino-n-butyl-2-ene 2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 1e) (230 mg, yield 98%), light yellow solid.

MS (ESI) m / z = 412.0 [M+H] ⁺ .

Step 5: (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-yloxy)phenyl)amino)-n-but-2- Synthesis of alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide

Compound 1e (150 mg, 0.37 mmol), 4-chloro-3-nitro-5-(oxetan-3-yloxy)phenyl)amino)benzamide (100 mg, 0.37 mmol) and DIPEA ( 220 mg, 1.84 mmol) was dissolved in n-butanol (5 mL). The reaction mixture was warmed to 120 ° C and stirred at this temperature for 2 days. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (15 mL×2), dried over anhydrous sodium sulfate To give (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-yloxy)phenyl)amino)-n-but-2-ene 2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamido)-7-methoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 1f) (38 mg, yield 16%), light yellow solid.

MS (ESI) m/z =648.0 [M+H] ⁺ .

Step 6: (trans)-1-(4-(2-Amino-4-carboxamido-6-(oxetan-3-yloxy)phenyl)-n-but-2-enyl) Synthesis of -2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.08 mL, 0.56 mmol) was added dropwise to a solution of compound 1f (38 mg, 0.05 mmol) in methanol (5 mL), and the mixture was stirred for 5 min. The aqueous solution (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. The obtained crude material was purified by reversed column chromatography (eluent: acetonitrile/water = 50/50, v/v) to give (trans)-1-(4-(2-amino) 4-carboxamido-6-(oxetan-3-yloxy)phenyl)n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen- Pyrazole-5-carboxamido)-7-methoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 1 g) (26 mg, yield 74%).

MS (ESI) m / z = 618.0 [M+H] ⁺ .

Step 7: (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxa) Synthesis of cyclobutane-3-yloxy)phenyl)-1hydro-imidazole-5-carboxamide-7-methoxy-1hydro-benzimidazole-5-carboxamide

Compound 1g (26mg, 0.04mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (8.6mg, 0.05mmol) were dissolved in DMF (2mL), room temperature After stirring for 1 h, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol) and DIPEA (10 mg, 0.08 mmol), the resulting reaction mixture was stirred at room temperature for 2 h. The crude product obtained was dried <RTI ID=0.0></RTI> tojjjjjjjj

MS (ESI) m/z = 779.0 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ7.88 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.23 (s, 3H), 6.76 ( s, 1H), 6.44 (s, 2H), 5.92 - 5.65 (m, 2H), 5.31 - 5.17 (m, 1H), 4.96 (d, 2H), 4.89 (d, 2H), 4.80 (t, 2H) , 4.62–4.39 (m, 6H), 3.72 (s, 3H), 2.09 (s, 6H), 1.24 (t, 6H).

Example 2

Step 1: (trans)-tert-butyl(4-(4-carbamoyl-2-oxetanyloxy-6-nitrophenyl)amino)n-but-2-enyl)aminocarbyl Acid ester synthesis

4-Chloro-3-nitro-5-(oxetan-3-yloxy)phenyl)amino)benzamide (468 mg, 1.72 mmol) and (4-aminobutan-2-) at room temperature Tert-butyl-1-enylcarbamate (422 mg, 1.90 mmol) was dissolved in n-butanol (10 mL), and DIPEA (445 mg, 3.40 mmol) was added dropwise. The reaction mixture was warmed to 115 ° C and stirred at this temperature overnight. After cooling to room temperature, it was diluted with water, extracted with ethyl acetate and separated by column chromatography ( petroleum ether: ethyl acetate = 5: 1-3:1, v/v) to give (trans)-tert-butyl (4- (4-carbamoyl-2-oxetanyloxy-6-nitrophenyl)amino)n-but-2-enyl)carbamate (Compound 2b) (420 mg, yield 57.8%), Yellow solid.

MS (ESI) m / z = 445 [M+Na] ⁺ .

Step 2: (trans)-tert-Butyl (4-((2-amino-4-carbamoyl-6-oxetanyloxyphenyl)amino)-n-but-2-enyl)carbamate Ester synthesis

Compound 2b (210 mg, 0.5 mmol) was dissolved in methanol (10 mL), and the solution was cooled to 0 ° C, then aqueous ammonia (0.8 mL, 5.0 mmol) and sodium dithionite (435 mg, 2.5 mmol) aqueous solution (4 mL) The reaction was stirred at 0 ° C for 1 h. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (20 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate -tert-Butyl (4-((2-amino-4-carbamoyl-6 oxetanyloxyphenyl)amino)-n-but-2-enyl)carbamate (Compound 2c) (140 mg, Yield 72%), white solid.

MS (ESI) m / z = 393 [M+H] ⁺ .

Step 3: (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-oxocycle Synthesis of butanoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate

Compound 2c (140 mg, 0.357 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (70 mg, 0.357 mmol) were dissolved in N,N-dimethylformamide (5 mL), and stirred at room temperature for 1 h, then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) And DIPEA (65 mg, 0.5 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate, and then separated by reverse phase column (acetonitrile/water = 1/3, v/v) (trans) )-tert-Butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5carboxamide)-7-oxetanyloxy-1H- Benzimidazolyl) n-but-2-enyl)carbamate (Compound 2d) (150 mg, yield 77%), white solid.

MS (ESI) m / z = 554 [M+H] ⁺ .

Step 4: (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of -oxetanyloxy-1hydro-benzimidazole-5-carboxamide

Compound 2d (150 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 h. The reaction solution was sparged to give the compound (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide Base 7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 2e) (crude 120 mg) was used directly in the next step.

MS (ESI) m / z = 454 [M+H] ⁺ .

Step 5: (trans)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)-n-but-2-enyl)-2-(1-ethyl-3-A Synthesis of yl-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide

Compound 2e (120 mg, 0.26 mmol), 4-fluoro-3-nitro-benzamide (50 mg, 0.27 mmol) and DIPEA (110 mg, 0.92 mmol) were dissolved in dimethyl sulfoxide (5 mL) and heated to The reaction was carried out at 40 ° C overnight, the reaction was completed, and the mixture was cooled to room temperature. Water was added to precipitated as a white solid, and then filtered to give (trans)-1-(4-((4-carbamoyl-2-nitrophenyl)amino) n-butyl -2-alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-oxetanyloxy-1hydro-benzimidazole- 5-carboxamide (Compound 2f) (80 mg, yield 49%), pale yellow solid.

MS (ESI) m / z = 618 [M+H] ⁺ .

Step 6: (trans)-1-(4-(2-amino-4-carboxamidophenyl)-n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen Synthesis of pyrazole-5-carboxamido-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.17 mL, 1.3 mmol) was added dropwise to a solution of compound 2f (80 mg, 0.13 mmol) in methanol (5 mL), and the mixture was stirred for 5 min. The aqueous solution (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. At the end of the reaction, the methanol in the reaction mixture was distilled off, and extracted with n-butanol to give (trans)-1-(4-(2-amino-4-carboxamidophenyl)-n-but-2-enyl)- 2-(1-Ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 2g (56 mg, yield 73%), white solid.

MS (ESI) m/z = 495 [M+H] ⁺ .

Step 7: (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[ d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxyheterocycle Synthesis of butane-3-yloxy)-1H-benzo[d]imidazole-5-carboxamide

Compound 2g (56 mg, 0.09 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (19.5 mg, 0.1 mmol) were dissolved in DMF (2 mL). After stirring for 1 h, HATU (38 mg, 0.1 mmol) and DIPEA (19.4 mg, 0.15 mmol) were added, and the obtained mixture was stirred for 2 h at room temperature. Compound 2 (15 mg, yield 21%), white solid.

MS (ESI) m / z = 749 [M+H] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ12.89 (s, 2H), 7.99 (d, 1H), 7.96 (s, 2H), 7.73-7.70 (m, 2H), 7.43-7.35 (m, 3H ), 6.90 (d, 1H), 6.55 (d, 2H), 6.05-5.98 (m, 1H), 5.82-5.76 (m, 1H), 5.35-5.32 (m, 1H), 5.00 (d, 2H), 4.85-4.82 (m, 4H), 4.57-4.48 (m, 6H), 2.13 (s, 6H), 1.27 (t, 6H).

Example 3

Step 1: (trans)-tert-butyl(4-(4-carbamoyl-2-cyclopropylmethoxy-6-nitrophenyl)amino)-n-but-2-enyl)carbamic acid Ester synthesis

4-Chloro-3-(cyclopropylmethoxy)-5-nitrobenzamide (1.00 g, 3.7 mmol) and (4-aminobut-2-en-1-yl)carbamic acid at room temperature Butyl ester (830 mg, 3.72 mmol) was dissolved in n-butanol (15 mL), and DIPEA (1.2 g, 11.88 mmol) was added dropwise. The reaction mixture was warmed to 115 ° C and stirred at this temperature overnight. After cooling to room temperature, it was diluted with water, extracted with ethyl acetate (200 mL×3), and the organic phase was washed with water (60 mL×2), dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified on silica gel column (eluent: (trans)-tert-butyl(4-(4-carbamoyl-2-cyclopropylmethoxy-6-nitrophenyl)amino) is obtained after PE/EA = 1/5 to 1/1) n-But-2-enyl) carbamate (compound 3b) (675 mg, yield 43%), orange solid.

MS (ESI) m / z = 421 [M+H] ⁺ .

Step 2: Synthesis of (trans)-tert-butyl(4-((2amino-4carbamoyl-6cyclopropylmethoxyphenyl)amino)-n-but-2-enyl)carbamate

Compound 3b (670 mg, 1.59 mmol) was dissolved in MeOH (15 mL), and then evaporated to EtOAc. EtOAc (EtOAc, EtOAc, EtOAc The reaction mixture was stirred at 0 ° C for 1 h, and the color of the reaction mixture changed from orange-red to white. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (30 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate )-tert-Butyl (4-((2amino-4carbamoyl-6cyclopropylmethoxyphenyl)amino)-n-but-2-enyl)carbamate (Compound 3c) (388 mg, yield 62%), white solid.

MS (ESI) m / z = 391 [M+H] ⁺ .

Step 3: (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-cyclopropyl Synthesis of methoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate

Compound 3c (380 mg, 0.971 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (189 mg, 0.971 mmol) were dissolved in N,N-dimethylformamide (10 mL), and stirred at room temperature for 1 h, then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (370 mg, 0.973 mmol) And N,N-diisopropylethylamine (130 mg, 1.00 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 h, the reaction mixture was diluted with water, and the white solid was collected by filtration and washed with water (5mL×3) Chromatography (eluent: acetonitrile / water = 1/3, v / v) to give (trans)-tert-butyl (4-(5-carbamoyl-2-(1-ethyl-3-) Base-1 hydrogen-pyrazole-5-carboxamide)-7-cyclopropylmethoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (compound 3d) (440 mg, yield 82 %), white solid.

MS (ESI) m/z =552 [M+H] ⁺ .

Step 4: (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 -Synthesis of cyclopropylmethoxy-1hydro-benzimidazole-5-carboxamide

Compound 3d (430 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was sparged to give the compound (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide 7-cyclopropylmethoxy-1H-benzimidazole-5-carboxamide (Compound 3e) (350 mg, yield 99%), pale yellow solid.

MS (ESI) m / z = 452 [M+H] ⁺ .

Step 5: (trans)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropyl A Synthesis of oxy)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide

Compound 3e (340 mg, 0.75 mmol), 4-chloro-3-nitrobenzamide (150 mg, 0.75 mmol) and DIPEA (291 mg, 2.25 mmol) were dissolved in n-butanol (10 mL). The mixture was stirred at a temperature of 120 ° C for 2 days. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate (30 mL×4). The crude product obtained by spin-drying solvent was purified by reverse-phase column chromatography (eluent: acetonitrile/water = 30/70, v/v) to give trans-1-(4-((4-aminoformyl-2-) Nitrophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole- 5-carboxamido)-1 hydrogen-benzo[d]imidazole-5-carboxamide (Compound 3f) (307 mg, yield 65%), pale yellow solid.

MS (ESI) m / z = 616.0 [M+H] ⁺ .

Step 6: (trans)-1-(4-((4-carbamoyl-2-aminophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropyl A Synthesis of oxy)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.5 mL, 4.87 mmol) was added dropwise to a solution of compound 3f (300 mg, 0.487 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL), and the mixture was stirred for 5 min. (425 mg, 2.44 mmol) aqueous solution (3 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was spun dry. The obtained crude product was purified by reverse phase column (eluent: acetonitrile/water = 50/50, v/v) to give (trans)-1-(4-((4-amine) Formyl-2-aminophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 Hydrogen-pyrazole-5-carboxamide)-1 hydrogen-benzo[d]imidazole-5-carboxamide (compound 3g) (160 mg, yield 56%), white solid.

MS (ESI) m / z = 586 [M+H] ⁺ .

Step 7: (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxa) Synthesis of cyclobutane-3-yloxy)phenyl)-1hydro-imidazole-5-carboxamide-7-methoxy-1hydro-benzimidazole-5-carboxamide

Compound 3g (150mg, 0.256mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (50mg, 0.256mmol) were dissolved in DMF (2mL) at room temperature Stir for 1 h, then add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (98 mg, 0.256 mmol) and N,N-di Isopropylethylamine (67 mg, 0.512 mmol) was obtained. The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 747 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6): δ7.98 (s, 1H), 7.92 (br, 2H), 7.71 (t, 1H), 7.62 (t, 1H), 7.42 (t, 1H), 7.31 (br, 2H), 7.26 (s, 1H), 6.56 (d, 1H), 6.54 (s, 1H), 5.96 to 6.05 (m, 1H), 5.73 to 5.91 (m, 1H), 4.95 (m, 2H) ), 4.83 (d, 2H) 4.45 to 4.56 (m, 4H), 3.85 (d, 2H), 2.13 (s, 3H), 2.1 1 (s, 3H), 1.22 to 1.33 (m, 7H), 0.40 ( q, 2H), 0.20 (q, 2H).

Example 4

Step 1: (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-methyloxy)phenyl)amino)-n-butyl-2 Synthesis of 2-alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide

Compound 1e (256 mg, 0.62 mmol), 4-chloro-3-nitro-5-(oxetan-3-methyloxy)phenyl)amino)benzamide (178 mg, 0.62 mmol) and DIPEA (1.6g, 12.4mmol) was dissolved in n-butanol (3mL), the reaction mixture was heated to 120 ° C and stirred at this temperature for 2 days, cooled to room temperature, diluted with water, ethyl acetate (30mL × 3) The organic phase was extracted with saturated brine (15 mL×2), dried over anhydrous sodium sulfate and evaporated. /1+0.1,v/v) to give (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-methyloxy)phenyl) Amino) n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole -5-carboxamide (Compound 4a) (180 mg, yield 43%), pale yellow solid.

MS (ESI) m / z = 662.0 [M+H] ⁺ .

Step 2: (trans)-1-(4-(2-Amino-4-carboxamido-6-(oxetan-3-methyloxy)phenyl)-n-but-2-enyl Synthesis of 2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.43 mL, 3.0 mmol) was added dropwise to a solution of Compound 4a (180 mg, 0.05 mmol) in methanol (5 mL). The mixture was stirred for 5 min. The aqueous solution (5 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 h. Diluted with water, extracted with ethyl acetate (30 mL×5), dried over anhydrous sodium sulfate and evaporated to give (trans)-1-(4-(2-amino-4-carboxamido-6-) Heterocyclobutane-3-methyloxy)phenyl)n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)- 7-Methoxy-1hydro-benzimidazole-5-carboxamide (Compound 4b) (106 mg, yield 62%).

MS (ESI) m / z = 632.0 [M+H] ⁺ .

Step 3: (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxa) Synthesis of cyclobutane-3-methyloxy)phenyl)-1hydro-imidazole-5-carboxamide-7-methoxy-1hydro-benzimidazole-5-carboxamide

Compound 4b (100 mg, 0.16 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (30 mg, 0.16 mmol) were dissolved in DMF (2 mL) at room temperature After stirring for 1 h, HATU (60 mg, 0.16 mmol) and DIPEA (40 mg, 0.30 mmol) The reaction solution was diluted with water, ethyl acetate-n-butanol (6/1, v/v, 30 mL×3), and the obtained organic phase was dried and purified by reverse phase HPLC to give compound (trans). 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-yl) Oxy)phenyl)-1 hydrogen-imidazole-5-carboxamide)-7-methoxy-1 hydrogen-benzimidazole-5-carboxamide (Example Compound 4) (39 mg, yield 31%) White solid.

MS (ESI) m/z = 793.0 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (s, 1H), 7.78 (s, 1H), 7.67 (d, 1H), 7.66 (d, 1H), 7.48 - 7.35 (m, 3H), 7.33(d,1H), 6.55(s,1H), 6.52(s,1H), 5.77(m,2H),4.92(d,2H),4.89(d,2H),4.63 –4.45(m,6H) , 4.32 (t, 2H), 4.18 (d, 2H), 3.75 (s, 3H), 3.17 (m, 1H), 2.13 (s, 3H), 2.11 (s, 3H), 1.27 (m, 6H).

Example 5

Step 1: Synthesis of ethyl 3-(toluenesulfonyloxy)cyclobutanecarboxylate

To a solution of ethyl 3-hydroxycyclobutanecarboxylate (1.5 g, 10.4 mmol) in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0></RTI> <RTIgt; 2.38g, 12.5mmol), reacted for 2h at room temperature, after the reaction was completed, the reaction mixture was extracted with dichloromethane and water, and the organic phase was washed with water and saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated to give 3 Ethyl ((toluenesulfonyloxy)cyclobutanecarboxylate (Compound 5b) (1.1 g, 3.69 mmol) was used directly in the next step.

Step 2: Synthesis of ethyl 3-(5-carbamoyl-2-chloro-3-nitrophenoxy)cyclobutanecarboxylate

To a solution of 4-chloro-3-hydroxy-5-nitrobenzamide (0.8 g, 3.69 mmol) in DMF <RTI ID=0.0> , react at 90 ° C for 24 h. After the reaction, the inorganic salt was removed by filtration, and the filtrate was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column to give 4-chloro-3-nitro-5-((tetrahydrofuran-3-yl)oxy Benzoamide (Compound 5c) (0.53 g, 1.5 mmol, 42% yield), pale yellow solid.

MS (ESI) m/z = 343 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ8.30 (d, J = 15.9Hz, 1H), 8.06 (d, J = 1.8Hz, 1H), 7.80 (s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 5.18 - 5.05 (m, 1H), 3.33 (m, 2H), 3.22 (m, 1H), 2.75 (m, 2H), 2.45 (m, 2H), 1.27 - 1.19 (m, 3H) ).

Step 3: (E)-3-(5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[[d]imidazol-1-yl)but-2-en-1-yl)amino)-3-nitrophenoxy)cyclobutanecarboxylic acid Synthesis of ethyl ester

Compound 1e (304 mg, 0.74 mmol) was dissolved in n-butanol (5 mL), and DIPEA (952 mg, 7.38 mmol) and compound 5c (253 mg, 0.74 mmol) were added thereto, and the reaction flask was placed in an oil heated to 120 ° C. The mixture was stirred at room temperature for 24 hours. After cooling to room temperature, it was diluted with water and ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (15 mL×2) The crude product obtained by the solvent was purified by silica gel column chromatography (eluent: DCM/MeOH = 50/1, v/v) to afford (E)-3-(5-carbamoyl-2-((4-) 5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-7-methoxy-1H-benzo[[d]imidazol-1-yl Ethyl butan-2-enyl)amino)-3-nitrophenoxy)cyclobutanecarboxylate (Compound 5d) (150 mg, yield 28%).

MS (ESI) m/z = 718 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.82 (s, 1H), 8.11 (d, J = 1.8Hz, 1H), 8.01-7.93 (m, 1H), 7.76 (t, J = 6.4Hz, 1H), 7.64 (s, 1H), 7.34 (t, J = 5.5 Hz, 2H), 7.16 (s, 1H), 6.58 (s, 1H), 5.92 - 5.60 (m, 2H), 4.90 (d, J) = 5.3 Hz, 2H), 4.85 - 4.72 (m, 1H), 4.65 - 4.48 (m, 2H), 4.23 - 4.07 (m, 2H), 3.84 (d, J = 10.4 Hz, 2H), 3.06 - 2.94 ( m,1H), 2.63–2.51 (m, 2H), 2.37–2.20 (m, 2H), 2.15 (s, 2H), 1.31 (t, J = 7.1 Hz, 2H), 1.25–1.13 (m, 3H) .

Step 4: (E)-3-(3-Amino-5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole) -5-formylamino)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)phenoxy)cyclobutanecarboxylate Synthesis

Under ice bath, aqueous ammonia (0.3 mL, 2.0 mmol) was added dropwise to a solution of compound 5d (143 mg, 0.20 mmol) in methanol (5 mL), and the mixture was stirred for 5 min. The aqueous solution (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 h. Diluted with water, filtered, and the filtrate was diluted with water, extracted with ethyl acetate / n-butanol (5/1, v/v), and the organic phase was dried and dried to give (E)-3-(3-amino-5-aminomethyl) Acyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo) [d]Imidazol-1-yl)but-2-en-1-yl)amino)phenoxy)cyclobutanecarboxylate (Compound 5e) (127 mg, 93%)

MS (ESI) m / z = 688.3 [M+H] ⁺ .

Step 5: (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H- Synthesis of Ethyl Pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylate

Add 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (33 mg, 0.17 mmol) to compound 5e (120 mg, 0.17 mmol) in DMF (3 mL) In the solution, the reaction was continued for 20 min after the addition was completed. Then, HATU (65 mg, 0.17 mmol) and DIPEA (66 mg, 0.51 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h. 89% purity, 64% yield).

MS (ESI) m/z =849.3 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (d, J = 11.7 Hz, 2H), 7.64 (dd, J = 6.1, 1.2 Hz, 2H), 7.44 - 7.26 (m, 3H), 7.01 ( s, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 5.96 - 5.76 (m, 2H), 5.04 - 4.85 (m, 5H), 4.56 - 4.48 (m, 4H), 4.15 - 4.05 ( m, 2H), 3.75 (s, 3H), 2.99 - 2.87 (m, 1H), 2.60 - 2.53 (m, 2H), 2.26 - 2.13 (m, 2H), 2.12 (s, 2H), 2.08 (s, 3H), 1.32–1.19 (m, 8H).

Example 6

Step 1: (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridyl Synthesis of oxazol-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylic acid

Lithium hydroxide monohydrate (17 mg, 0.4 mmol) was added to a solution of the compound of Example 5 (70 mg, 0.08 mmol) in tetrahydrofuran / water / MeOH (v / v = 2 / 1/2, 5 ml). After the reaction was completed, 0.5 M of diluted hydrochloric acid was added to adjust pH to 5, and then the obtained crude product was purified by reverse-phase HPLC to give the title compound 6 (17.5 mg, yield 27%) as white solid.

MS (ESI) m/z = 821 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 23.2 Hz, 2H), 7.64 (d, J = 6.3 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.03 (s, 1H), 6.52 (d, J = 14.9 Hz, 2H), 6.01 - 5.75 (m, 2H), 5.04 - 4.85 (m, 4H), 4.64 - 4.41 (m, 3H), 3.75 (s, 3H) ), 2.65–2.55 (m, 1H), 2.26–2.13 (m, 2H), 2.10 (m, 6H), 1.39–1.00 (m, 6H).

Example 7

Step 1: (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridyl Synthesis of Isoazol-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylic acid isopropyl ester

Potassium carbonate (1.68 mg, 0.012 mmol) and isopropyl iodide (2.07 mg, 0.012 mmol) were added to a solution of the title compound 6 (5 mg, 0.006 mmol) in DMF (0.5 mL). The reaction solution was directly purified by reverse-phase HPLC to give (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl)-2-(1-ethyl-3-methyl-1H) -pyrazole-5-formylamino)-7-methoxy-1H-benzo[[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl- 3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylic acid isopropyl ester (Example Compound 7) (1.1 mg ).

MS (ESI) m / z = 863 [M+H] ⁺ .

Example 8

Step 1: (S,E)-(4-((4-carbamoyl-2-nitro-6-((tetrahydrofuran-3-yl)oxy)phenyl)amino)but-2-ene-1 Synthesis of tert-butyl carbamate

To a solution of 4-chloro-3-nitro-5-(oxetan-3-yloxy)phenyl)amino)benzamide (540 mg, 1.88 mmol) in n-butanol (10 mL) DIPEA (608 mg, 4.71 mmol) and (4-aminobut-2-en-1-yl)carbamic acid tert-butyl ester (499 mg, 2.25 mmol) were added, and the reaction mixture was heated to 115 ° C and reacted at this temperature. 60 hours. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: Light yellow solid.

MS (ESI) m / z = 437 [M+Na] ⁺ .

Step 2: (S,E)-(4-((2-Amino-4-carbamoyl-6-((tetrahydrofuran-3-yl)oxy)phenyl)amino)but-2-en-1- Synthesis of tert-butyl carbamate

Compound 8b (380 mg, 0.88 mmol) was dissolved in methanol / THF (10 mL), and the solution was cooled to 0 ° C, then aqueous ammonia (1.0 mL, 8.8 mmol) and aqueous sodium dithionite (463 mg, 2.66 mmol) (1 mL) The reaction was stirred at 0 ° C for 0.5 h. The organic solvent was evaporated to dryness with EtOAc (EtOAc) (EtOAc m. Purification by MPLC (eluent: acetonitrile / water = 2/3, v/v) afforded compound 8c (164 mg, yield 45.5%) as a white solid.

MS (ESI) m/z = 407 [M+H] ⁺

Step 3: ((S,E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-7-((tetrahydrofuran) Synthesis of tert-butyl ester of -3-yl)oxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-ylcarbamate

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (78 mg, 0.40 mmol) was added to a solution of compound 8c (160 mg, 0.40 mmol) in DMF (3 mL) The reaction was carried out at this temperature for 0.5 h, then HATU (180 mg, 0.47 mmol) and DIPEA (180 mg, 1.39 mmol) were added to the reaction solution, and the reaction was continued at room temperature for 1 h. The reaction solution was directly separated by MPLC (acetonitrile/water = 1/3). , v/v) gave compound 8d (220 mg, yield 96%).

MS (ESI) m / z = 568 [M+H] ⁺ .

Step 4: (S,E)-1-(4-Aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) Synthesis of -7-((tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide

Compound 8d (220 mg, 0.38 mmol) was dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 0.5 h. The reaction solution was dried to give Compound 8e (yield: 180 mg).

MS (ESI) m / z = 468 [M+H] ⁺ .

Step 5: (S,E)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)-2-(1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-carboxamido)-7-((tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide

To a solution of compound 8e (180 mg, 0.38 mmol) in EtOAc (10 mL), EtOAc (EtOAc, EtOAc. After overnight, the reaction was completed, and the mixture was cooled to room temperature. Water was evaporated to give a white solid, which was filtered and purified to afford compound 8f (280 mg).

MS (ESI) m / z = 632 [M+H] ⁺ .

Step 6: (S,E)-1-(4-((2-Amino-4-carbamoylphenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3 Synthesis of -methyl-1H-pyrazole-5-carboxamido)-7-((tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.5 mL) was added dropwise to a solution of compound 8f (280 mg, 0.443 mmol) in methanol (2 mL) and THF (6 mL), and the mixture was stirred for 5 min. 1.33 mmol) aqueous solution (2 mL) was added slowly. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. At the end of the reaction, the methanol and THF in the reaction mixture were removed by rotary evaporation, and the crude solvent was obtained by diluting n-butanol with water to obtain a crude product, which was purified by reverse-phase MPLC (mobile phase: acetonitrile/water = 1/3, v/v) to give compound 8 g. (218 mg, yield 81%), white solid.

MS (ESI) m / z = 602 [M+H] ⁺ .

Step 7: (S,E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo [d]imidazol-1-yl)butyr-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(( Synthesis of Tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (70.7 mg, 0.36 mmol) was added to compound 8 g (210 mg, 0.36 mmol) in DMF (3 mL) In the solution, after 0.5 h of reaction, HATU (152 mg, 0.4 mmol) and DIPEA (148 mg, 1.15 mmol) were added successively, and the reaction was gradually warmed to room temperature for 1.5 h. The reaction solution was directly separated and purified by reverse-phase HPLC to give the compound. (29 mg), white solid.

MS (ESI) m/z = 749 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.81 (s, 2H), 7.97 (s, 2H), 7.94 (s, 1H), 7.71 (d, J = 8.2Hz, 1H), 7.65 (s, 1H), 7.45–7.31 (m, 2H), 7.27 (s, 1H), 6.52 (s, 2H), 6.03–5.87 (m, 1H), 5.83–5.69 (m, 1H), 5.24–5.07 (m, 1H), 4.91 (d, J = 4.7 Hz, 2H), 4.80 (d, J = 4.7 Hz, 2H), 4.68 - 4.39 (m, 4H), 3.93 - 3.56 (m, 4H), 2.23 - 2.17 (m , 1H), 2.17–2.03 (m, 6H), 1.95–1.81 (m, 1H), 1.37–1.15 (m, 6H).

Example 9

The starting material used in Example 9 was the reverse of the configuration of Example 8 as (S)-3-hydroxytetrahydrofuran, and the operation of the experimental procedure was the same. Finally, Example Compound 9 (25.5 mg) was obtained.

MS (ESI) m/z = 749 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 (d, J = 13.7 Hz, 2H), 7.97 (s, 2H), 7.94 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H) , 7.65 (s, 1H), 7.46 - 7.31 (m, 2H), 7.27 (s, 1H), 6.52 (s, 2H), 6.05 - 5.88 (m, 1H), 5.85 - 5.68 (m, 1H), 5.15 (s, 1H), 4.92 (s, 2H), 4.81 (d, J = 4.5 Hz, 2H), 4.66 - 4.38 (m, 4H), 3.92 - 3.55 (m, 4H), 2.24 - 2.01 (m, 7H) ), 1.94–1.81 (m, 1H), 1.39–1.01 (m, 6H).

Example 10

Step 1: (E)-1-(4-((2-Nitro-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl) Amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- Synthesis of 1H-benzo[d]imidazole-5-carboxamide

To a solution of compound 3e (160 mg, 0.35 mmol) in n-butanol (3 mL), DIPEA (140 mg, 1.08 mmol) and 3-(3-((tert-butyldimethylsilyl)oxy)propoxy -4-chloro-5-nitrobenzamide (140 mg, 0.36 mmol), the reaction mixture was warmed to 110 ° C and stirred at this temperature overnight, then cooled to room temperature, diluted with water, ethyl acetate (30 mL × 3) Extraction, the combined organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate and evaporated. 1,v/v) gives (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-methyloxy)phenyl)amino) n-But-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1 hydrogen-benzimidazole-5- Formamide (Compound 10b) (122 mg, yield 43%).

MS (ESI) m / z = 804 [M+H] ⁺ .

Step 2: (E)-1-(4-((2-Amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl) Amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H -Synthesis of benzo[d]imidazole-5-carboxamide

Under ice-cooling, a solution of the compound 10b (120 mg, 0.15 mmol) in methanol (1 mL) and THF (1 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 5 minutes, then sodium dithionite (120 mg, A 0.69 mmol) aqueous solution (1 mL) was added slowly. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, extracted with n-butanol (15 mL x 3), and the crude product obtained by spin-drying of organic phase was purified by reversed phase MPLC (mobile phase: acetonitrile/water = 2/3, v/v) to give 10c (61 mg, yield 52%) ).

MS (ESI) m / z = 774 [M+H] ⁺ .

Step 3: (E)-7-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-1-(4-(5-carbamoyl-7-(cyclopropyl) Oxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-1H-benzo[d]imidazol-1-yl)but-2-ene-1- Synthesis of 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H--benzo[d]imidazole-5-carboxamide

Add 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (15 mg, 0.078 mmol) to compound 10c (60 mg, 0.078 mmol) in DMF (2 mL) In the solution, after 0.5 h of reaction, HATU (36 mg, 0.094 mmol) and DIPEA (30 mg, 0.23 mmol) were sequentially added, and the mixture was slowly warmed to room temperature for 1.5 h. The reaction solution was directly purified by reverse phase HPLC to give Compound 10d (50 mg).

MS (ESI) m / z = 936 [M+H] ⁺ .

Step 4: (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-7-(3-hydroxyl) Propoxy)-1H-benzo[d]imidazolazine-1-yl)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

To a solution of the compound 10d (50 mg, EtOAc) (EtOAc) The crude product after concentration of the reaction mixture was purified by reversed-------

MS (ESI) m/z = 821 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.82 (s, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.33- 7.25 (m, 4H), 6.56 (s, 1H), 6.52 (s, 1H), 5.97-5.81 (m, 2H), 4.99-4.90 (m, 4H), 4.60-4.50 (m, 5H), 4.04 ( t, 2H), 3.81 (d, 2H), 3.40 (t, 2H), 2.15 (s, 3H), 2.12 (s, 3H), 1.68 (t, 2H), 1.32-1.25 (m, 6H), 1.03 -0.95 (m, 1H), 0.37 (q, 2H), 0.17 (q, 2H).

Example 11

Step 1: Synthesis of (E)-(4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester

To a solution of compound 11a (900 mg, 4.89 mmol) in DMSO (6 mL), DIPEA (3.16 g, 24.5 mmol) and tert-butyl (4-aminobut-2-en-1-yl)carbamate (910 mg) , 4.89 mmol), and the reaction mixture was stirred at room temperature overnight. Diluted with water, extracted with EtOAc EtOAc (EtOAc:EtOAc:EtOAc.

MS (ESI) m / z = 373.2 [M+Na] ⁺ .

Step 2: Synthesis of (E)-(4-((2-amino-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester

Compound 11b (1.07 g, 3.06 mmol) was dissolved in methanol (20 mL), and the solution was cooled to 0 ° C, then aqueous ammonia (4.5 mL, 30.06 mmol) and aqueous sodium dithionite (2.66 g, 15.3 mmol) (4 mL) The reaction was stirred at 0 ° C for 0.5 h. The organic solvent was evaporated to dryness with water, and the mixture was diluted with water and ethyl acetate (20 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate 11c (980 mg, yield 100%), white solid.

MS (ESI) m / z = 321.0 [M+H] ⁺ .

Step 3: (E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole Synthesis of -1-yl)but-2-en-1-yl)carbamic acid tert-butyl ester

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (598 mg, 3.06 mmol) was added to a solution of compound 11c (980 mg, 3.06 mmol) in DMF (6 mL) The reaction was carried out at this temperature for 0.5 h, then HATU (1.16 g, 3.06 mmol) and DIPEA (1.2 g, 9.18 mmol) were added to the reaction mixture, and the reaction was continued at room temperature for 1 h. The reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic phases were washed with EtOAc EtOAc (EtOAc m. .

MS (ESI) m / z = 482 [M+H] ⁺ .

Step 4: (E)-1-(4-Aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H -Synthesis of benzo[d]imidazole-5-carboxamide

To a solution of compound 11d (760 mg, 1.58 mmol) in dichloromethane (30 mL) It was then stirred to room temperature and stirred for 0.5 h. The reaction solution was dried to give Compound 11e (yield 590 mg).

MS (ESI) m / z = 382 [M+H] ⁺ .

Step 5: (E)-1-(4-((4-carbamoyl-2-nitro-6-(2-(oxetan-3-yl)ethoxy)phenyl)amino)) But-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide synthesis

To a solution of compound 11e (200 mg, 0.52 mmol) in EtOAc (5 mL), DIPEA (370 mg, 2.87 mmol) and 4-chloro-3-nitro-5-(2-(oxetane-3) - ethoxy)benzamide (158 mg, 0.52 mmol), heated to 120 ° C for 24 h, the reaction was completed, cooled to room temperature, water and ethyl acetate / n-butanol (5 / 1, v / v) The isolated organic phase was dried and purified by preparative thin layer chromatography to afford compound 11f (85 mg, yield 19.4%) as a yellow solid.

MS (ESI) m / z = 646 [M+H] ⁺ .

Step 6: (E)-1-(4-((2-Amino-4-carbamoyl-6-(2-(oxetan-3-yl)ethoxy)phenyl)amino) Synthesis of 2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.2 mL) was added dropwise to a solution of compound 11f (85 mg, 0.13 mmol) in methanol (10 mL), and the mixture was stirred for 5 min. 2mL) Add slowly. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. At the end of the reaction, the methanol in the reaction mixture was removed by rotary evaporation, and the mixture was diluted with n-butanol to extract the solvent. The crude product was purified by reversed phase MPLC (mobile phase: acetonitrile/water = 1/4, v/v) to give compound 11 g (60 mg, Yield 74%), white solid.

MS (ESI) m / z = 616 [M+H] ⁺ .

Step 7: (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d] Imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxygen) Synthesis of Heterocyclobutane-3-yl)ethoxy)-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (23 mg, 0.11 mmol) was added to compound 11 g (60 mg, 0.1 mmol) in DMF (3 mL) After 0.5 h of reaction, HATU (37 mg, 0.1 mmol) and DIPEA (37 mg, 0.3 mmol) were added, and the mixture was slowly warmed to room temperature and the reaction was continued for 1.5 h. The reaction mixture was directly purified by preparative HPLC to obtain the compound of Example 11 (6.0 mg, Yield 8%), white solid.

MS (ESI) m / z = 777 [M+H] ⁺ .

Example 12

Step 1: Synthesis of tert-butyl (4-fluoro-3-nitrophenyl)carbamate

To a solution of the compound 12a (3.0 g, 19.2 mmol) in THF (20 mL), EtOAc. The reaction mixture was concentrated and purified by column chromatography (PE/EA=20/1 to 5/1) to afford compound 12b (3.4 g, yield 69%).

Step 2: (E)-(4-((4-(5-carbamoyl-7-(cyclopropylmethoxy))-2-(1-ethyl-3-methyl-1H-pyrazole- Synthesis of tert-butyl 5-formylamino)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)-3-nitrophenyl)carbamate

Compound 3e (150 mg, 0.33 mmol) was added to n-butanol (5 mL), then DIPEA (148 mg, 1.15 mmol) and compound 12b (93 mg, 0.36 mmol). The reaction solution was heated to 100 ° C and stirred for 24 h. The crude product obtained by concentration was purified by reverse phase MPLC (mobile phase: acetonitrile/water = 2/3, v/v) to afford compound 12c (120mg, 0.17mmol).

MS (ESI) m / z = 688 [M+H] ⁺ .

Step 3: (E)-(3-Amino-4-((4-(5-carbamoyl-7-(cyclopropylmethoxy))-2-(1-ethyl-3-methyl-1H) Synthesis of tert-butyl ester of pyrazole-5-formylamino)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)phenyl)carbamate

Under ice-cooling, a solution of the compound 12c (120 mg, 0.17 mmol) in methanol (1 mL) and THF (1 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 5 minutes, then sodium dithionite (150 mg, A 0.85 mmol) aqueous solution (1 mL) was added slowly. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction, the organic solvent in the reaction mixture was evaporated under reduced pressure, diluted with water, and then purified and evaporated to ethylamine. The crude product was purified by reverse phase MPLC to afford compound 12d (52mg, yield 45%).

MS (ESI) m / z = 658 [M+H] ⁺ .

Step 4: (E)-(1-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5) -carboxamide)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Synthesis of Formamide--1H-Benzo[d]imidazol-5-yl)carbamic acid tert-butyl ester

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (15.4 mg, 0.079 mmol) was added to compound 12d (50 mg, 0.079 mmol) in DMF (2 mL) After the reaction for 0.5 h, HATU (30 mg, 0.0.079 mmol) and DIPEA (35 mg, 0.27 mmol) were added, and the reaction was slowly warmed to room temperature for 1.5 h. The reaction mixture was directly purified by preparative HPLC to give compound 12e (60 mg, Yield 92%).

MS (ESI) m / z = </RTI> [M+H] ⁺ .

Step 5: (E)-1-(4-(5-Amino-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole -1-yl)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide Synthesis of -1H-benzo[d]imidazole-5-carboxamide

To a solution of compound 12e (60 mg, 0.073 mmol) in dichloromethane (2 mL) Stir at room temperature for 0.5 h. The crude product obtained by concentration was purified by preparative HPLC to afford the compound compound 12 (20 mg).

MS (ESI) m/z = 719 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.82 (s, 1H), 12.36 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.32 (s, 1H), 7.28 ( s, 1H), 7.01 (d, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 6.48 (s, 1H), 6.42 (d, 1H), 6.00-5.94 (m, 1H), 5.89 -5.82 (m, 1H), 5.05 (s, br, 2H), 4.98 (d, 2H), 4.72 (d, 2H), 4.60-4.49 (m, 4H), 3.90 (d, 2H), 2.16 (s) , 3H), 2.11 (s, 3H), 1.31 (t, 3H), 1.25 (t, 3H), 1.10 (m, 1H), 0.45 (q, 2H), 0.25 (q, 2H).

Example 13

Step 1: 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-1 -yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-yloxy)-1H- Synthesis of benzo[d]imidazole-5-carboxamide

Add Pd/C (5 mg, 10%) to a solution of the title compound 2 (20 mg, 0.027 mmol) in methanol (5 mL) and ethyl acetate (5 mL). The carbon was filtered off, and the filtrate was concentrated and purified by reverse phase HPLC to give the compound of Example 13 (5 mg).

MS (ESI) m/z = 751 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ7.96 (d, 1H), 7.96 (s, 2H), 7.75-7.73 (m, 2H), 7.66-7.30 (m, 3H), 6.92 (d, 1H ), 6.59 (d, 2H), 5.43 (t, 1H), 4.91 (t, 2H), 4.58-4.53 (m, 6H), 4.43 (s, 2H), 4.27 (s, 2H), 2.09 (s, 6H), 1.90 (t, 4H) 1.30 (t, 6H).

Example 14

Step 1: 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-1 -yl)butyl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d] Synthesis of imidazole-5-carboxamide

Pd/C (5 mg, 10%) was added to a solution of the title compound 3 (20 mg, 0.027 mmol) in methanol (5 mL) and ethyl acetate (5 mL). The carbon was filtered off, and the filtrate was concentrated and purified by reverse phase HPLC to afford the compound of compound 14 (8 mg).

MS (ESI) m/z = 749 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 2H), 8.06 - 7.88 (m, 3H), 7.78 - 7.70 (m, 1H), 7.64 - 7.58 (m, 1H), 7.55 - 7.49 (m, 1H), 7.33 (s, 2H), 7.28 (s, 1H), 6.66 - 6.55 (m, 2H), 4.57 (m, 5H), 4.45 - 4.34 (m, 3H), 4.32 - 4.24 (m , 2H), 3.92 (d, J = 7.1 Hz, 2H), 2.19 - 2.03 (m, 6H), 1.90 (s, 4H), 1.36 - 1.26 (m, 6H), 1.16 - 1.04 (m, 1H), 0.51–0.35 (m, 2H), 0.31–0.20 (m, 2H).

Example 15

Step 1: trans-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-((3) Synthesis of 1-nitropyridin-2-yl)amino)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide

Compound 3e (280 mg, 0.507 mmol) in DMSO (2.5 mL), DIPEA (200 mg, 1.55 mmol) and 2-fluoro-3-nitropyridine (90 mg, 0.663 mmol) were added and allowed to react at room temperature for 1 h. Diluted with water, extracted with ethyl acetate (30 mL×4), and the combined organic layer was washed with brine (10 mL×2), dried over anhydrous sodium sulfate Light yellow solid.

MS (ESI) m / z = 574 [M+H] ⁺ .

Step 2: (E)-1-(4-((3-Aminopyridin-2-yl)amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-( Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

Under ice-cooling, aqueous ammonia (0.5 mL, 4.87 mmol) was added dropwise to a solution of compound 15a (300 mg, 0.487 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL). After 5 minutes, sodium dithionite (425 mg, 2.44 mmol) The aqueous solution (3 mL) was added slowly. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 544 [M+H] ⁺ .

Step 3: (E)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2) -(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl Synthesis of -1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (60 mg, 0.307 mmol) was added to compound 15b (160 mg, 0.299 mmol) in DMF (2.5 mL) The solution was stirred for 30 min then DIPEA (120 mg, 0.928 <RTI ID=0.0> The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 705 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) 0.20 - 0.23 (m, 2H) 0.39 - 0.43 (m, 2H) 1.04 - 1.12 (m, 1H) 1.26 (t, J = 4.6 Hz, 3H) 1.28 (t, J = 4.6 Hz, 3H) 2.10 (s, 3H) 2.13 (s, 3H) 3.87 (d, J = 7.2 Hz, 2H) 4.48 - 4.57 (m, 4H) 4.79 (d, J = 3.2 Hz, 2H) 4.96 ( d, J = 3.2 Hz, 2H) 5.89 - 6.00 (m, 2H) 6.53 (s, 1H) 6.55 (s, 1H) 7.22 ~ 7.26 (m, 2H) 7.30 (s, 1H) 7.62 (d, J = 1.2 Hz, 1H) 7.75 (dd, J1 = 0.8 Hz, J2 = 7.6 Hz, 1H) 7.91 (s, 1H) 8.15 (dd, J1 = 1.2 Hz, J2 = 5.2 Hz, 1H) 12.77 (s, 2H)

Example 16

Step 1: Synthesis of (E)-(4-((3-nitropyridin-2-yl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester

Compound 16a (2.63 g, 11.82 mmol) in DMF (10 mL), EtOAc (EtOAc m. Diluted with water, extracted with ethyl acetate (50 mL×4), and the combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate and evaporated to dryness to afford compound 16b (3.2 g, yield 92%) , light yellow solid.

MS (ESI) m / z = 308 [M+H] ⁺ .

Step 2: Synthesis of (E)-(4-((3-aminopyridin-2-yl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester

Compound 16b (3.2 g, 10.38 mmol) was dissolved in a solution of acetic acid (30 mL), and zinc powder (3.37 g, 51.89 mmol) was added to the reaction system, and stirring was continued at room temperature for 1 h. The mixture was dissolved in aqueous sodium hydrogencarbonate, and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with brine (30 mL×2), dried over anhydrous sodium sulfate Eluent: EA/PE = 10/1, v/v) Compound 16c (1.5 g, yield 52%) was obtained as white solid.

MS (ESI) m / z = 278 [M+H] ⁺ .

Step 3: (E)-tert-Butyl (4-(2-(1-ethyl-3-methyl-1H-pyrazol-5-carboxamido)-3H-imidazo[4,5-b] Synthesis of tert-butyl pyridin-3-yl)but-2-en-1-ylcarbamate

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (841.71 mg, 4.31 mmol) was added to compound 16c (1.2 g, 4.31 mmol) in DMF. In a solution of 15 mL), the reaction was stirred for 30 min then EtOAc EtOAc (EtOAc &lt The reaction mixture was purified by normal phase (PE/EA = 1/1, v/v) to afford compound 16d (1.5 g, yield 79%) as white solid.

MS (ESI) m/z = 440 [M+H] ⁺

Step 4: (E)-N-(3-(4-Aminobut-2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-carboxamide

To a solution of compound 16d (1. 5 g, 3.41 mmol) in DCM (10 mL).

MS (ESI) m/z = 340 [M+H] ⁺

Step 5: (E)-N-(3-(4-((4-carbamoyl)-2-(2-methoxyethoxy)-6-nitrophenyl)amino)but-2-ene Synthesis of -1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

To a solution of compound 16e (0.2 g, 0.59 mmol) in n-butanol (2 mL), DIPEA (152 mg, 1.18 mmol) and 4-chloro-3-(2-methoxyethoxy)-5-nitrobenzene Formamide (162 mg, 0.59 mmol). The mixture was heated to 120 ° C for 18 h, and the reaction was evaporated to dryness crystals crystals crystals

MS (ESI) m/z = 578 [M+H] ⁺

Step 6: (E)-N-(3-(4-((2-Amino-4-phenyl)-6-(2-methoxyethoxy)phenyl)amino)but-2-ene- Synthesis of 1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

Under ice-cooling, aqueous ammonia (2 mL) was added dropwise to a solution of compound 16f (70 mg, 0.12 mmol) in methanol (5 mL). After 5 min, aqueous solution of sodium dithionite (105 mg, 0.61 mmol) (4 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 548 [M+H] ⁺ .

Step 7: (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(2-methoxy B Synthesis of oxy)-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (7 mg, 0.037 mmol) was added to compound 16 g (20 mg, 0.037 mmol) in DMF (1 mL) The solution was stirred for 30 min, then DIPEA (10 mg, 0.073 mmol) and EtOAc (15 mg, EtOAc). The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m / z = 709 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d ₆ ) δ 12.70-12.88 (m, 2H), 8.16-8.17 (m, 1H), 7.90-8.00 (m, 1H), 7.72-7.80 (m, 1H), 7.62 7.67 (m, 1H), 7.30-7.38 (m, 2H), 7.21-7.27 (m, 1H), 6.50-6.57 (m, 2H), 5.89-5.98 (m, 2H), 4.89-4.96 (m, 2H) ), 4.74-4.83 (m, 2H), 4.46-4.59 (m, 4H), 4.11-4.19 (m, 2H), 3.52-3.61 (m, 2H), 3.14-3.22 (m, 3H), 2.07-2.17 (m, 6H), 1.20-1.33 (m, 6H).

Example 17

Step 1: (E)-N-(3-(4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)-3H Synthesis of imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

To a solution of the compound 16e (200 mg, 0.59 mmol) in EtOAc (EtOAc) . The mixture was heated to 120 ° C for 18 h, and the reaction was evaporated to dryness crystals crystals crystals crystals

MS (ESI) m/z = 534 [M+H] ⁺

Step 2: (E)-N-(3-(4-((2-Amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1-yl)-3H- Synthesis of Imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

Under ice-cooling, aqueous ammonia (2 mL) was added dropwise to a solution of Compound 17a (35 mg, 0.065 mmol) in methanol (4 mL). After 5 min, aqueous solution of sodium dithionite (57 mg, 0.328 mmol) (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 504 [M+H] ⁺ .

Step 3: (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-methoxy-1H-benzene And [d] Synthesis of imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (4 mg, 0.02 mmol) was added to compound 17b (10 mg, 0.02 mmol) in DMF (1 mL) The solution was stirred for 30 min, then DIPEA (5 mg, EtOAc (EtOAc) The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m / z = 665 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d ₆ ) δ 12.69-12.85 (m, 2H), 8.15-8.20 (m, 1H), 7.94-8.01 (m, 1H), 7.72-7.80 (m, 1H), 7.71 7.67 (m, 1H), 7.30-7.41 (m, 2H), 7.22-7.25 (m, 1H), 6.48-6.57 (m, 2H), 5.83-5.91 (m, 2H), 4.87-4.96 (m, 2H) ), 4.74-4.83 (m, 2H), 4.47-4.58 (m, 4H), 3.75-3.83 (m, 3H), 2.03-2.16 (m, 6H), 1.24-1.28 (m, 6H).

Example 18

Step 1: (E)-N-(3-(4-((4-carbamoyl-2-nitro-6-(oxetan-3-yloxy)phenyl)amino))- Synthesis of 2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

To a solution of compound 16e (200 mg, 0.59 mmol) in EtOAc (2 mL), DIPEA (152 mg, 1.18 mmol) and 4-chloro-3-methoxy-5-nitrobenzamide (160 mg, 0.59 mmol) . The mixture was warmed to 120 ° C for 18 h, and the reaction was completed and then evaporated to give a crude material, which was purified by silica gel column (eluent PE/EA =) to give compound 18a (116 mg, yield: 34%).

MS (ESI) m / z = 576 [M + H] ⁺

Step 2: ((E)-N-(3-(4-((2-Amino-4-carbamoyl-6-(oxetan-3-yloxy)phenyl)amino))- Synthesis of 2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

Under ice-cooling, aqueous ammonia (2 mL) was added dropwise to a solution of Compound 18a (52 mg, 0.09 mmol) in methanol (4 mL). After 5 min, aqueous sodium sulphate (79 mg, 0.45 mmol) (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 546 [M+H] ⁺ .

Step 3: ((E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-) -1H-pyrazole-5-carboxamido)--3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(oxeidine Synthesis of alk-3-yloxy)-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (4 mg, 0.016 mmol) was added to compound 18b (9 mg, 0.016 mmol) in DMF (1 mL) The solution was stirred for 30 min, then DIPEA (5 mg, EtOAc (EtOAc) The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m / z = 707 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d ₆ ) δ 12.68-12.87 (m, 2H), 8.15-8.16 (m, 1H), 7.90-7.97 (m, 1H), 7.74-7.76 (m, 1H), 7.66- 7.69 (m, 1H), 7.33-7.41 (m, 1H), 7.20-7.27 (m, 2H), 6.86-6.90 (m, 1H), 6.50-6.57 (m, 2H), 5.84-5.97 (m, 2H) ), 5.29-5.37 (m, 2H), 4.94-5.02 (m, 2H), 4.74-4.86 (m, 4H), 4.43-4.61 (m, 6H), 2.08-2.16 (m, 6H), 1.24-1.28 (m, 6H).

Example 19

Step 1: (E)-N-(3-(4-((4-carbamoyl-2-nitro-6-(oxetan-3-ylmethoxy)phenyl)amino)) Synthesis of 2--2-enyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

To a solution of compound 16e (260 mg, 0.767 mmol) in n-butanol (5mL), DIPEA (270.5mg, 2.09mmol) and 4-chloro-3-methoxy-5-nitrobenzamide (200mg, 0.697mmol) ). The mixture was warmed to 120 ° C for 18 h, and the reaction was completed and then evaporated to dryness to afford crude crystals eluted from silica gel column (eluent PE/EA=) to give compound 19a (107 mg, 0.181 mmol).

MS (ESI) m/z = 590 [M+H] ⁺

Step 2: (E)-N-(3-(4-((2-Amino-4-carbamoyl-6-(oxetan-3-ylmethoxy)phenyl)amino))- Synthesis of 2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide

Under ice bath, aqueous ammonia (0.2 mL, 1.94 mmol) was added dropwise to a solution of compound 19a (100 mg, 0.169 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL). After 5 min, sodium dithionite (100 mg, 0.568 mmol) The aqueous solution (1 mL) was added slowly. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 560 [M+H] ⁺ .

Step 3: (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(oxetane- Synthesis of 3-ylmethoxy)-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (20 mg, 0.103 mmol) was added to compound 19b (55 mg, 0.103 mmol) in DMF (1 mL) The solution was stirred for 30 min, then DIPEA (14 mg, 0.104 mmol) The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m / z = 721 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) 1.24 (t, J = 3.6 Hz, 3H) 1.27 (t, J = 3.6 Hz, 3H) 2.10 (s, 3H) 2.12 (s, 3H) 3.21 to 3.28 (m, 1H) 4.23 (d, J = 6.0 Hz, 2H) 4.34 (t, J = 6.0 Hz, 2H) 4.48 (d, J = 6.8 Hz, 2H) 4.52 (d, J = 7.2 Hz, 2H) 4.57 (dd, J1=6.0 Hz, J2=7.6 Hz, 2H) 4.75 (d, J=4.4 Hz, 2H) 4.91 (d, J=4 Hz, 2H) 5.69 to 5.79 (m, 1H) 5.80 to 5.90 (m, 1H) 6.52 (s, 2H) 7.23 (dd, J1 = 4.8 Hz, J2 = 7.6 Hz, 1H) 7.35 (s, 2H) 7.65 (s, 1H) 7.75 (d, J = 7.6 Hz, 1H) 7.96 (s, 1H) 8.16 (d, J = 4.0 Hz, 1H) 12.74 (s, 1H) 12.83 (s, 1H)

Example 20

Step 1: (E)-N-(3-(4-((4-carboyl-2-nitro-6-(2-(oxetan-3-yl)ethoxy)phenyl) Amino)but-2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5- Amide synthesis

To a solution of compound 16e (538 mg, 1.58 mmol) in n-butanol (10 mL), DIPEA (409 mg, 3.17 mmol) and 4-chloro-3-methoxy-5-nitrobenzamide (500 mg, 1.58 mmol) . The mixture was heated to 120 ° C for 18 h, and the reaction was completed and then evaporated to give a crude material, which was purified by silica gel column (eluent PE/EA = 1/3) to afford compound 20a (526 mg, yield 53%).

MS (ESI) m/z = 604 [M+H] ⁺

Step 2: ((E)-N-(3-(4-((2-Amino-4-carbamoyl-6-(2-(oxetan-3-yl)ethoxy)phenyl) Amino)but-2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5- Amide synthesis

Under ice-cooling, aqueous ammonia (5 mL) was added dropwise to a solution of Compound 20a ( 526 mg, 0.85 mmol) in methanol (10 mL). After 5 min, aqueous solution (3 mL) of sodium dithionite (740 mg, 4.25 mmol) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 574 [M+H] ⁺ .

Step 3: (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(2-(oxo-heterocycle) Synthesis of butane-3-yl)ethoxy)-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (56 mg, 0.29 mmol) was added to compound 20b (169 mg, 0.29 mmol) in DMF (2 mL) In the solution, the reaction was stirred for 30 min then EtOAc (EtOAc &lt The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 735 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68-12.90 (m, 2H), 8.13-8.20 (m, 1H), 7.90-7.98 (m, 1H), 7.73-7.80 (m, 1H), 7.61 - 7.67 (m, 1H), 7.30-7.38 (m, 1H), 7.20-7.29 (m, 2H), 6.49-6.58 (m, 2H), 5.76-5.96 (m, 2H), 4.86-4.96 (m, 2H), 4.73-4.82 (m, 2H), 4.46-4.60 (m, 6H), 4.10-4.25 (m, 2H), 3.82-3.98 (m, 2H), 2.92-3.04 (m, 2H), 2.07- 2.16 (m, 6H), 1.85-2.05 (m, 4H), 1.24-1.29 (m, 6H).

Example 21

Step 1: (E)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(( Synthesis of 2-nitropyridin-3-yl)amino)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide

Compound 3e (116 mg, 0.26 mmol) in n-butanol (5 mL) was added DIPEA (95 mg, 0.78 mmol) and 2-fluoro-3-nitropyridine (35 mg, 0.25 mmol), and reacted at 90 ° C for 3 h. Diluted with water, extracted with ethyl acetate (30 mL×4), and the combined organic layer was washed with brine (10 mL×2), dried over anhydrous sodium sulfate Light yellow solid.

MS (ESI) m / z = 574 [M+H] ⁺ .

Step 2: (E)-1-(4-((2-Aminopyridin-3-yl)amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-( Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide

Compound 21a (120 mg, 0.21 mmol) was dissolved in EtOAc (10 mL). The organic layer was washed with saturated aqueous sodium chloride (30 mL×3), and the combined organic layer was washed with brine (10 mL×2), dried over anhydrous sodium sulfate Eluent: DCM / MeOH = 10/1, v / v) Compound 21b (70 mg, yield: 61.5%).

MS (ESI) m / z = 544 [M+H] ⁺ .

Step 3: (E)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2) -(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-imidazo[4,5-b]pyridin-1-yl)but-2-en-1-yl Synthesis of -1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (25 mg, 0.128 mmol) was added to compound 21b (70 mg, 0.128 mmol) in DMF (5 mL) The solution was stirred for 30 min, then DIPEA (33 mg, EtOAc. The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 705 [M+H] ⁺

Example 22

Step 1: Synthesis of 6-chloro-2-methoxynicotinic acid

Anhydrous methanol (1.6 mL, 40.0 mmol) was added to dry THF (15 mL), and then NaH (0.96 g, 40.0 mmol). After stirring for 30 minutes in an ice bath, 22a (1.9 g, 10.0 mmol) was added. The reaction was then stirred at 60 ° C overnight. After cooling to room temperature, the reaction was quenched with water, and the pH was adjusted to 6 to 7 with dilute hydrochloric acid (3M). Then extracted with dichloromethane (10mL×3), and the organic phase was washed with brine (10mL×1) The aqueous solution was dried over sodium sulfate and evaporated to dryness]]]]]]]]]] This crude product was used in the next step without purification.

MS (ESI) m / z = 188 [M+H] ⁺ .

Step 2: Synthesis of methyl 6-chloro-2-methoxynicotinate

Oxalyl chloride (3.4 mL, 40 mmol) was added dropwise to a solution of the crude compound 22b (2.5 g, 13.4 mmol, 60% purity) in dichloromethane, and then DMF (200 uL). After stirring for 2 h in an ice bath. The reaction solution was sparged under reduced pressure, and the residue after spin-drying was dissolved in dichloromethane, and then this dichloromethane solution was added to anhydrous methanol. It was then stirred at room temperature for 1.5 h. Diluted with water and extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (10 mL×1), dried over anhydrous sodium sulfate and evaporated to dryness. The eluent: acetonitrile / water = 30 / 80, v / v) purified product 6-chloro-2-methoxynicotinic acid methyl ester (compound 22c), 1.3 g, yield 87%.

MS (ESI) m / z = 202 [M+H] ⁺ .

Step 3: Synthesis of methyl 6-chloro-2-methoxy-5-nitronicotinate

HNO ₃ (1.3 mL) was added dropwise to a solution of compound 6-chloro-2-methoxynicotinic acid methyl ester (1.3 g, 6.5 mmol) in trifluoroacetic acid anhydride (40 mL). Stir in an ice salt bath for 3 h. The reaction solution was slowly poured into ice water, and the pH was adjusted to 7-8 with saturated sodium carbonate to precipitate a yellow solid. Filtration and dissolving the solid with water, then filtered and evaporated to dryness mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS (ESI) m / z = 247 [M+H] ⁺ .

Step 4: E)-6-((4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Synthesis of Methylcarboxamide)-1H-benzo[d]imidazole-piperazin-1-yl)but-2-en-1-yl)amino)-2-methoxy-5-nitronicotinate

Methyl 6-chloro-2-methoxy-5-nitronicotinate (330 mg, 1.3 mmol) was added to a solution of compound 1e (604 mg, 1.3 mmol) and DIPEA (503 mg, 3.9 mmol) in DMF (10 mL) The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, diluted with water, ethyl acetate (30 mL×4), and the combined organic phase was washed with brine (10 mL×2), dried over anhydrous sodium sulfate The obtained crude product was separated by reverse phase column chromatography (eluent: acetonitrile/water = 30/70, v/v) to afford (E)-6-((4-(5-carbamoyl-7-(cyclopropyl) Methoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-piperazin-1-yl)butyl-2 Methyl 1-en-1-ylamino)-2-methoxy-5-nitronicotinate (Compound 22e) 390 mg, pale yellow solid, yield 44%.

MS (ESI) m / z = 662.0 [M+H] ⁺ .

Step 5: (E)-5-Amino-6-((4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-) Synthesis of pyrazole-5-carboxamido)-1H-benzo[methyl]d]imidazol-1-yl)but-2-en-1-yl)amino)-2-methoxynicotinate

To a solution of the compound 22e (390 mg, 0.59 mmol) in methanol (10 mL), ethyl acetate (2mL) and iron powder (165.2mg, 2.95mmol), and the reaction mixture was warmed to 60 ° C, and the reaction was stirred for 2 h. After the completion of the reaction, the methanol in the reaction mixture was evaporated to dryness, and the obtained crude product was purified by ethyl acetate (yield: acetonitrile/water = 50/50, v/v) to afford (E)-5- Amino-6-((4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)) -1H-benzo[methyl]d]imidazol-1-yl)but-2-en-1-yl)amino)-2-methoxynicotinate methyl ester (Compound 22f) 180 mg, white solid, yield 48%.

MS (ESI) m / z = 632 [M+H] ⁺ .

Step 6: (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Formamide)-1H-benzo[d]imidazol-1-methyl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5 Synthesis of methyl 3-formylamino)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carboxylate

The compound 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (57 mg, 0.29 mmol) was added dropwise to (E)-3-(4-( 5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole -1-methyl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-5-methoxy-3H -Methyl imidazo[4,5-b]pyridine-6-carboxylate 22f (180 mg, 0.29 mmol) in N,N-dimethylformamide (10 mL) Then, HATU (122 mg, 0.32 mmol) and N,N-diisopropylethylamine (124 mg, 0.96 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h, and the reaction mixture was directly dried under reduced pressure and then purified by column chromatography. Acetonitrile/water = 1/3, v/v) to give (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3) -methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-methyl)but-2-en-1-yl)-2-(1-ethyl- Methyl 3-methyl-1H-pyrazole-5-formylamino)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carboxylate (Compound 22 g) 70 mg, white solid The yield was 31%.

MS (ESI) m / z = 793 [M+H] ⁺ .

Step 7: (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Formamide)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-A Synthesis of Amido)-5-Methoxy-3H-imidazo[4,5-b]pyridine-6-carboxylic Acid

The compound 22h (70mg, 0.09mmol) was dissolved in a mixed solvent of THF (1mL) and methanol (1mL), and a solution of lithium hydroxide (19mg, 0.81mmol) was added at room temperature, stirred at room temperature for 1h, and the reaction solution was added. 1N hydrochloric acid adjusted to pH=5-6, and then directly dried to obtain a crude salt (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1) -ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1- Ethyl-3-methyl-1H-pyrazole-5-formylamino)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (compound 22h) 160 mg, 40% purity, yield 93%, white solid.

MS (ESI) m / z = 773 [M+H] ⁺ .

Step 8: (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Formamide)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-A Synthesis of Amido)-5-Methoxy-3H-imidazo[4,5-b]pyridine-6--carboxamide

Under ice-cooling, HATU (38 mg, 0.10 mmol) was added to a solution of compound 22h (purified by pure product) (160×40% mg, 0.08 mmol) in DMF (1 mL). 12.8 mg, 0.24 mmol) and N,N-diisopropylethylamine (52 mg, 0.40 mmol). The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 778 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.81 (s, 2H), 8.24 (s, 1H), 7.92 (s, 1H), 7.70-7.61 (m, 3H), 7.29 (d, J = 17.4 Hz, 2H), 6.54 (d, J = 9.4 Hz, 2H), 6.04 - 5.96 (m, 2H), 4.99 (d, J = 5.3 Hz, 2H), 4.76 (d, J = 5.3 Hz, 2H), 4.53 (dq, J = 14.4, 7.6, 7.2 Hz, 4H), 3.87 - 3.85 (m, 5H), 2.12 (d, J = 3.2 Hz, 6H), 1.28 (q, J = 6.7 Hz, 7H), 1.08 (s, 1H), 0.42 (d, J = 7.6 Hz, 2H), 0.22 (d, J = 5.0 Hz, 2H).

Example 23

Step 1: (trans)-tert-butyl(4-(4-carbamoyl-2-cyclopropylmethoxy-6-nitrophenyl)amino)-n-but-2-enyl)carbamic acid Synthesis of ester (compound 23b)

4-Chloro-3-cyclopropylmethoxy-5-nitrobenzamide (1.0 g, 3.7 mmol) and tert-butyl (4-aminobut-2-en-1-yl)carbamate at room temperature ( 830 mg, 3.72 mmol) was dissolved in n-butanol (15 mL), and DIPEA (1.2 g, 11.88 mmol) was added dropwise to the reaction mixture. The reaction mixture was warmed to 115 ° C and stirred at this temperature overnight. After cooling to room temperature, it was diluted with water, extracted with ethyl acetate (200 mL×3), and the organic phase was washed with water (60 mL×2), dried over anhydrous sodium sulfate, evaporated under reduced pressure, and purified on silica gel column (eluent: (trans)-tert-butyl(4-(4-carbamoyl-2-cyclopropylmethoxy-6-nitrophenyl)amino) is obtained after PE/EA = 1/5 to 1/1) n-But-2-enyl)carbamate (Compound 23b) 675 mg, orange-yellow solid, yield 43%.

MS (ESI) m / z = 421 [M+H] ⁺ .

Step 2: (trans)-tert-butyl(4-((2-amino-4carbamoyl-6cyclopropylmethoxyphenyl)amino)-n-but-2-enyl)carbamate (compound) Synthesis of 23c)

Aqueous ammonia (1.62 mL, 11.80 mmol) was added to a solution of compound 23b (670 mg, 1. After 5 min, an aqueous solution (6 mL) of sodium dithionite (1.22 g, 7.01 mmol) was slowly added dropwise. After 1 h of reaction, the color of the reaction solution changed from orange-red to white. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (30 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate )-tert-Butyl (4-((2-amino-4carbamoyl-6cyclopropylmethoxyphenyl)amino)-n-but-2-enyl)carbamate (Compound 23c) as a white solid 388mg The yield was 62%.

MS (ESI) m / z = 391 [M+H] ⁺ .

Step 3: (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-cyclopropyl Synthesis of methoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (Compound 23d)

The compound 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (189 mg, 0.971 mmol) was added dropwise to compound 23c (380 mg, 0.971 mmol). In a solution of N-dimethylformamide (10 mL), the reaction was carried out for 0.5 h. Then, HATU (370 mg, 0.973 mmol) and N,N-diisopropylethylamine (130 mg, 1.00 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and filtered ×3) Washing, followed by column chromatography (eluent: acetonitrile / water = 1/3, v / v) to give (trans)-tert-butyl (4-(5-carbamoyl-2-) -ethyl-3-methyl-1hydro-pyrazole-5-carboxamide)-7-cyclopropylmethoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (Compound 23d 440 mg, white solid, yield 82%.

MS (ESI) m/z =552 [M+H] ⁺ .

Step 4: (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of cyclopropylmethoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 23e)

Compound 23d (430 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was sparged to give the compound (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide Base 7-cyclopropylmethoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 23e) 350 mg, light yellow solid, yield 99%.

MS (ESI) m / z = 452 [M+H] ⁺ .

Step 5: (trans)-1-(6-((5-nitro-nicotinate methyl)amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy) Synthesis of -2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide (Compound 23f)

Add 6-chloro-5-nicotinic acid methyl ester (162 mg, 0.75 mmol) to a solution of compound 23e (340 mg, 0.75 mmol) and DIPEA (291 mg, 2.25 mmol) in DMF (10 mL) After the reaction was completed, it was diluted with water, and extracted with ethyl acetate (30 mL×4). The combined organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate and evaporated to dryness Separation and separation (eluent: acetonitrile / water = 30 / 70, v / v) to give trans)-1-(6-((5-nitro-nicotinate)amino)butyl-2-ene -1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d Imidazole-5-carboxamide (Compound 23f) 307 mg, pale yellow solid, yield 65%.

MS (ESI) m / z = 632.0 [M+H] ⁺ .

Step 6: (trans)-1-(6-((5-Amino-methylnicotinate)amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy) Synthesis of -2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide (Compound 23g)

To a solution of the compound 23f (300 mg, 0.47 mmol) in methanol (10 mL), ethyl acetate (2 mL) and iron powder (135 mg, 2.41 mmol), and the mixture was warmed to 60 ° C and stirred for 2 h. After the completion of the reaction, the methanol in the reaction mixture was evaporated to dryness, and the obtained crude product was purified by ethyl acetate (yield: acetonitrile/water = 50/50, v/v) to afford trans. (6-((5-Amino-methylnicotinate)Amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3 -Methyl-1 -hydropyrazol-5-carboxamido)-1 -hydro-benzo[d]imidazole-5-carboxamide (Compound 23 g) 210 mg, white solid, yield 71%.

MS (ESI) m / z = 602 [M+H] ⁺ .

Step 7: (trans)-methyl-3-(4-(5-aminoformyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen) -pyrazole-5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1 Synthesis of Hydrogen-pyrazole-5-aminoformyl)-3hydro-imidazole [4,5-pyro]pyridine-6-methyl carbonate (Compound 23h)

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (67 mg, 0.34 mmol) was added dropwise to the compound 23 g (206 mg, 0.34 mmol) of N, N. In a solution of dimethylformamide (10 mL), the reaction was carried out for 0.5 h. Then, HATU (130 mg, 0.34 mmol) and N,N-diisopropylethylamine (130 mg, 1.00 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h, the reaction mixture was diluted with water, ×3) Washing, followed by column chromatography (eluent acetonitrile / water = 1/3, v / v) to give (trans)-methyl-3-(4-(5-aminoformyl-7-) (cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazol-1-yl) Benz-2-en-1-yl)-2-(1-ethyl-3-methyl-1hydro-pyrazol-5-aminocarbonyl)-3hydro-imidazole [4,5-b]pyridine -6-Methyl carbonate (Compound 23h) 110 mg, white solid, yield 42%.

MS (ESI) m / z = 763 [M+H] ⁺ .

Step 8: (trans)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole- 5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole Synthesis of 5-5-carboxamido)-3hydro-imidazole [4,5-pyro]pyridine-6-carboxylic acid (Compound 23i)

The compound 23h (110mg, 0.14mmol) was dissolved in a mixed solvent of THF (1mL) and methanol (1mL), and added to the aqueous solution of lithium hydroxide (31mg, 1.28mmol) at room temperature, stirred at room temperature for 1h, the reaction solution was added After adjusting the pH of 1N hydrochloric acid, the solid was precipitated, suction filtered, and the filter cake was washed with water and dried to give (trans)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-( 1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2- (1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamido)-3hydro-imidazole [4,5-pyro]pyridine-6-carboxylic acid (Compound 23i) 100 mg, white solid The rate is 92%.

MS (ESI) m / z = 749 [M+H] ⁺ .

Step 9: (trans)-3-(4-(5-aminoformyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole) -5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyridyl Synthesis of oxazol-5-carboxamido)-3hydro-imidazole [4,5-pyro]pyridine-6-carboxamide (Compound 23)

Under ice-cooling, HATU (50 mg, 0.133 mmol) was added to a solution of compound 23i (100 mg, 0.133 mmol) in DMF (1 mL) and stirred for 0.2 h, then ammonium chloride (35 mg, 0.665 mmol) and N,N- Diisopropylethylamine (35 mg, 0.256 mmol) was obtained. The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 748 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6): δ12.8 (s, 1.5H), 8.69 (d, 1H), 8.13 (d, 2H), 7.93 (d, 1H), 7.62 (d, 1H), 7.53 (s, 1H), 7.33 to 7.26 (m, 2H), 6.53 (d, 2H), 5.94 to 5.69 (m, 2H), 5.03 to 4.89, (m, 3H), 4.55 to 4.48 (m, 4H) , 4.13 to 4.01 (m, 2H), 3.86 (d, 1H), 2.11 (s, 6H), 1.29 to 1.24 (m, 6H), 1.20 to 1.03 (m, 1H), 0.40 (q, 2H), 0.21 (q, 2H).

Example 24

Step 1: (trans)-methyl-6-((4-((tert-butoxycarbonyl)amino)-n-but-2-yl-1-yl)amino)-5-nitronicotinic acid (Compound 24b) )Synthesis

Methyl 6-chloro-5-nitronicotinate (1000 mg, 4.6 mmol) and tert-butyl (4-aminobut-2-en-1-yl)carbamate (1026 mg, 4.6 mmol) were dissolved in DMF at room temperature In (20 mL), triethylamine (1400 mg, 13.8 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, it was diluted with water, extracted with ethyl acetate (200 mL×3), and the organic phase was washed with water (60 mL×2), dried over anhydrous sodium sulfate, and evaporated to dryness /EA = 1/5 to 1/1) to give (trans)-methyl-6-((4-((tert-butoxycarbonyl)amino)-n-but-2-yl-1-yl)amino) -5-Nitronicotinic acid (Compound 24b) 1500 mg, orange-yellow solid, yield 89%.

MS (ESI) m / z = 367 [M+H] ⁺ .

Step 2: Synthesis of (trans)-6-((4-((tert-butoxycarbonyl)amino)-n-but-2-en-1-yl)amino)-5-nitronicotinic acid (Compound 24c)

The compound 24b (1500 mg, 4.09 mmol) was dissolved in a mixed solvent of THF (4 mL) and methanol (4 mL), and a solution of lithium hydroxide (860 mg, 20.5 mmol) was added at room temperature, stirred at room temperature for 1 h, and the reaction mixture was added. After adjusting the pH of 1N hydrochloric acid, the solid precipitated, suction filtration, and the filter cake was washed with water and dried to give (trans)-6-((4-((tert-butoxycarbonyl)amino)-n-but-2-en-1-yl) Amino)-5-nitronicotinic acid (Compound 24c) 1300 mg, white solid, yield 90%.

MS (ESI) m/z =353 [M+H] ⁺ .

Step 3: (trans)-tert-butyl(4-((5-carbamoyl-3-nitropyridin-2-yl)amino)-n-but-2-en-1-yl)carbamate ( Synthesis of Compound 24d)

HATU (1406 mg, 3.7 mmol) was added to a solution of compound 24c (1300 mg, 3.69 mmol) in DMF (15 mL), and stirred for 0.2 h, then ammonium chloride (900 mg, 18.45 mmol) and N,N- Diisopropylethylamine (1439 mg, 11.07 mmol) was obtained. The reaction mixture was diluted with water and extracted with ethyl acetate (200 mL×3). The organic phase was washed with water (60mL×2), dried over anhydrous sodium sulfate, and evaporated under reduced pressure and purified on silica gel column (eluent: PE/EA =1/5 to 1/1) to give (trans)-tert-butyl(4-((5-carbamoyl-3-nitropyridin-2-yl)amino)-n-but-2-ene-1 -Base) Carbamate (Compound 24d) 1030 mg, white solid, yield 80%.

MS (ESI) m / z = 352 [M+H] ⁺ .

Step 4: (trans)-tert-butyl(4-((3-amino-5-carbamoylpyridin-2-yl)amino)butyl-2-en-1-yl)carbamate (compound) Synthesis of 24f)

Compound 24d (670 mg, 1.91 mmol) was dissolved in MeOH (15 mL), EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at 0 ° C for 1 h, and the color of the reaction mixture changed from orange-red to white. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (30 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate )-tert-Butyl (4-((3-amino-5-carbamoyridin-2-yl)amino)butyl-2-en-1-yl)carbamate (Compound 24f) as a white solid 320mg The yield was 62%.

MS (ESI) m / z = 322 [M+H] ⁺ .

Step 5: (trans)-tert-butyl (4-(6-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-3 hydrogen-imidazole) Synthesis of [4,5-and]pyridin-3-yl)butyl-2-en-1-yl)carbamate (Compound 24g)

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (193 mg, 0.99 mmol) was added to compound 24f (320 mg, 0.99 mmol) in DMF (10 mL) After stirring at room temperature for 0.5 h, HATU (376 mg, 0.99 mmol) and N,N-diisopropylethylamine (130 mg, 1.00 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h. The resulting white solid was collected, washed with water (5 mL×3) and then purified by column chromatography (eluent acetonitrile/water = 1/3, v/v) to give (trans)-tert-butyl (4-(6) -carbamoyl-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamide)-3hydro-imidazole [4,5-pyridin-3-yl)butyl- 2-Alken-1-yl)carbamate (Compound 24 g) 392 mg, white solid, yield 82%.

MS (ESI) m / z = 483 [M+H] ⁺ .

Step 6: (trans)-3-(4-aminobutyric-2-en-1-yl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carbamoyl Synthesis of -3 hydrogen-imidazole [4,5-pyro]pyridine-6-carbamate (compound 24h)

Compound 24 g (392 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was sparged to give the compound (trans)-3-(4-aminobutyric-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5 -carbamoyl)-3 hydrogen-imidazole [4,5-pyro]pyridine-6-carbamate (compound 24h) 307 mg, pale yellow solid, yield 99%.

MS (ESI) m / z = 381 [M+H] ⁺ .

Step 7: (trans)-3-(4-((4-carbamoyl-2-nitrophenyl)amino)-n-but-2-en-1-yl)-2-(1-ethyl- Synthesis of 3-methyl-1hydro-pyrazol-5-carbamoyl)-3hydro-imidazole [4,5-pyro]pyridine-6-carbamate (Compound 24i)

4-Fluoro-3-nitrobenzamide (158 mg, 0.85 mmol) and DIPEA (330 mg, 4.93 mmol) were added to a solution of compound 2h (198 mg, 0.51 mmol) in dimethylsulfoxide (6 mL). At 50 ° C and stirring at this temperature overnight, after cooling to room temperature, without any treatment, direct reverse phase column chromatography (eluent: acetonitrile / water = 30 / 70, v / v) to give (trans) -3- (4-((4-carbamoyl-2-nitrophenyl)amino)-n-but-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole -5-carbamoyl)-3 hydrogen-imidazole [4,5-pyridin-6-carbamate (compound 24i) 264 mg, pale yellow solid, yield 93%.

MS (ESI) m / z = 564 [M+H] ⁺ .

Step 8: (trans)-3-(4-((2-amino-4-carbamoylphenyl)amino)-n-but-2-en-1-yl)-2-(1-ethyl-3 Synthesis of -methyl-1 -hydropyrazol-5-carbamoyl)-3hydro-imidazole [4,5-pyro]pyridine-6-carbamate (Compound 24j)

To a solution of the compound 24i (300 mg, 0.47 mmol) in methanol (10 mL), ethyl acetate (2 mL) and iron powder (135 mg, 2.41 mmol), and the mixture was warmed to 60 ° C and stirred for 2 h. After the completion of the reaction, the methanol in the reaction mixture was evaporated to give a crude product, and the crude product was purified by reversed column chromatography (eluent: acetonitrile/water = 50/50, v/v) to give (trans)-3-(4) -((2-amino-4-carbamoylphenyl)amino)n-but-2-en-1-yl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5- Carbamoyl)-3 hydrogen-imidazole [4,5-pyridin-6-carbamate (compound 24j) 150 mg, white solid, yield 60%.

MS (ESI) m / z = 517 [M+H] ⁺ .

Step 9: (trans)-3-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-1 hydrogen-benzene [ And] imidazol-1-yl)n-but-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-3 hydrogen-imidazole [ Synthesis of 4,5-and]pyridine-6-carbamate (Compound 24)

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (50 mg, 0.29 mmol) was added to compound 24j (150 mg, 0.29 mmol) in DMF (2 mL) In the solution, the reaction was stirred for 0.5 h, then EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt;&gt; The reaction solution was purified by reverse phase HPLC to give (trans)-3-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1-hydro-pyrazole-5-carboxamide) -1 hydrogen-benzene[and]imidazol-1-yl)n-but-2-en-1-yl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamide) -3 Hydrogen-imidazole [4,5-pyro]pyridine-6-carbamate (Example Compound 24) 12.60 mg, white solid, yield 6%.

MS (ESI) m/z = 678 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) 8.72 (d, 1H), 8.15 (s, 1H), 8.13 (d, 1H), 7.97 (d, 1H), 7.94 (s, 1H), 7.72 (dd, 1H) ), 7.54 (s, 1H), 7.45 (d, 1H), 7.34 (s, 1H), 6.55 (d, 2H), 5.97 to 6.04 (m, 1H), 5.845.91 (m, 1H), 4.82 ( Dd, 2H), 4.49 to 4.56 (m, 6H), 2.12 (s, 6H), 1.26 to 1.30 (m, 6H).

Example 25

Step 1: (trans)-tert-butyl(4-(4-carbamoyl-2-oxetanyloxy-6-nitrophenyl)amino)n-but-2-enyl)aminocarbyl Synthesis of acid ester (compound 25b)

4-Chloro-3-oxetanyloxy-5-nitrobenzamide (468 mg, 1.72 mmol) and tert-butyl (4-aminobut-2-en-1-yl)carbamate at room temperature ( 422 mg, 1.90 mmol) was dissolved in n-butanol (10 mL), and DIPEA (445 mg, 3.40 mmol) was added dropwise to the reaction mixture. The reaction mixture was warmed to 115 ° C and stirred at this temperature overnight. After cooling to room temperature, it was diluted with water, extracted with ethyl acetate and separated by column chromatography ( petroleum ether: ethyl acetate = 5: 1-3:1, v/v) to give (trans)-tert-butyl (4- (4-carbamoyl-2-oxobutoxy-6-nitrophenyl)amino)n-but-2-enyl)carbamate (compound 25b) 420 mg, yellow solid, yield 57.8 %.

MS (ESI) m / z = 445 [M+Na] ⁺ .

Step 2: (trans)-tert-Butyl (4-((2-amino-4-carbamoyl-6-oxetanyloxyphenyl)amino)-n-but-2-enyl)carbamate Synthesis of ester (compound 25c)

Compound 25b (210 mg, 0.5 mmol) was dissolved in MeOH (10 mL). EtOAc was evaporated. EtOAc EtOAc EtOAc. The reaction was stirred at 0 ° C for 1 h. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (20 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate a white solid of -tert-butyl(4-((2-amino-4-carbamoyl-6 oxetanyloxyphenyl)amino)-n-but-2-enyl)carbamate (compound 25c) 140 mg, yield 72%.

MS (ESI) m / z = 393 [M+H] ⁺ .

Step 3: (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-oxocycle Synthesis of butanoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (Compound 25d)

Compound 25c (140 mg, 0.357 mmol) and 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (70 mg, 0.357 mmol) were dissolved in N,N-dimethyl The mixture was stirred at room temperature for 1 h, then HATU (190 mg, 0.5 mmol) and DIPEA (65 mg, 0.5 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. Chromatography (acetonitrile / water = 1/3, v / v) to give (trans)-tert-butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen) -Pyrazole-5-carboxamide)-7-oxetanyloxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (Compound 25d) 150 mg, white solid, yield 77%.

MS (ESI) m / z = 554 [M+H] ⁺ .

Step 4: (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of oxetaneoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25e)

Compound 25d (150 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 h. The reaction solution was sparged to give the compound (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide Base, 7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25e), crude 120 mg, was used directly in the next step.

MS (ESI) m / z = 454 [M+H] ⁺ .

Step 5: (trans)-1-(6-((3-nicotinic acid methyl ester-5-nitropyridine)amino)-n-but-2-enyl)-2-(1-ethyl-3- Methyl-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (compound 25f)

To a solution of compound 25e (120 mg, 0.26 mmol) in dimethyl sulphoxide (5 mL), DIPEA (110 mg, 0.92 mmol) and 6-chloro-5-nitronicotinic acid methyl ester (58 mg, 0.27 mmol). The reaction was heated to 40 ° C overnight, the reaction was completed, cooled to room temperature, and a white solid was precipitated with water, and then filtered to give (trans)-1-(6-((3-nicotinic acid methyl ester-5-nitropyridine)amino group. n-Butyl-2-alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzene Imidazole-5-carboxamide (Compound 25f) 150 mg, pale yellow solid, yield 91%.

MS (ESI) m / z = 634[M+H] ⁺ .

Step 6: (trans)-1-(6-((3-nicotinic acid methyl ester-5-aminopyridine)amino)-n-but-2-enyl)-2-(1-ethyl-3-methyl Base-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (compound 25g)

To a solution of the compound 25f (120 mg, 0.26 mmol) in methanol (l.lmL), ethyl acetate (l.lmL) and iron powder (36 mg, 0.65 mmol), and the reaction mixture was warmed to 60 ° C, and the reaction was stirred for 2 h. At the end of the reaction, the methanol in the reaction mixture was evaporated, and extracted with ethyl acetate to give (trans)-1-(6-((3-methylnicotinate-5-aminopyridine)amino)-n-but-2- Alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-oxetanyloxy-1hydro-benzimidazole-5- Amide (Compound 25 g) 95 mg, white solid, yield 83%.

MS (ESI) m / z = 604 [M+H] ⁺ .

Step 7: (trans)-1-(6-(3-nicotinylmethyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-pyridine Synthesis of 1-hydrogen-imidazole-5-carboxamide-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide (Compound 25h)

Compound 25g (95mg, 0.16mmol) and compound 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (30.7mg, 0.16mmol) were dissolved in DMF (2mL). After stirring at room temperature for 1 h, HATU (60.8 mg, 0.16 mmol) and DIPEA (25.8 mg, 0.2 mmol) The crude product obtained by spin-drying was purified by reverse phase HPLC to give (trans)-1-(6-(3-nicotinic acid methyl-2-(1-ethyl-3-methyl-1H-pyrazole) -5-carboxamido)-7-pyridine)-1 hydrogen-imidazole-5-carboxamide)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25h) 86mg , white solid, yield 70%.

MS (ESI) m / z = 765 [M+H] ⁺ .

Step 8: (trans)-1-(6-(3-carboxylic acid-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-pyridine)-1 Synthesis of hydrogen-imidazole-5-carboxamide-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25i)

The compound 25h (86mg, 0.11mmol) was dissolved in a mixed solvent of THF (2mL) and methanol (2mL), and a solution of lithium hydroxide (9mg, 0.22mmol) was added at room temperature, stirred at room temperature for 1h, and the reaction solution was added 1N. After adjusting the pH of hydrochloric acid, the solid is precipitated, suction filtration, and the filter cake is washed with water and dried to obtain (trans)-1-(6-(3-carboxylic acid-2-(1-ethyl-3-methyl-1H-pyridyl) Oxazol-5-carboxamido)-7-pyridine)-1hydro-imidazole-5-carboxamide)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25i) 60 mg, white solid, yield 73%.

MS (ESI) m / z = 751 [M+H] ⁺ .

Step 9: (trans)-1-(6-(3-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-pyridine)- Synthesis of 1H-imidazole-5-carboxamide-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide (Compound 25)

Under ice bath, HATU (30.4 mg, 0.08 mmol) was added to a solution of compound 25i (60 mg, 0.08 mmol) in DMF (5 mL), stirred for 0.2 h, then ammonium chloride (8.56 mg, 0.16 mmol) and N. N-Diisopropylethylamine (20.64 mg, 0.16 mmol). The crude product obtained by spin-drying was purified by reverse phase HPLC to give (trans)-1-(6-(3-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5) -carboxamido)-7-pyridine)-1hydro-imidazole-5-carboxamide)-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide (Example Compound 25) 36 mg , white solid, yield 60%.

MS (ESI) m/z: 750 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.87 (s, 2H), 8.71 (s, 1H), 8.15 (d, 2H), 7.95 (s, 1H), 7.68 (s, 1H), 7.54 ( s, 1H), 7.38 (s, 1H), 6.90 (d, 1H), 6.55 (d, 2H), 5.96 to 5.87 (m, 2H), 5.35 (t, 1H), 5.00 (d, 2H), 4.84 ～4.80 (m, 4H), 4.56 to 4.46 (m, 6H), 2.13 (s, 6H), 1.30 to 1.25 (m, 6H).

The beneficial effects of the present invention will be described below by way of experimental examples:

Experimental Example 1: Protein Thermal Transfer Experiment (TSA)

The binding of the compound to the Sting protein was determined by TSA assay, and 100 ug/ml Sting protein was mixed with different concentrations of the compound and 5X SYPRO Orange dye in 20 mM Hepes, 150 mM NaCl, 1 mM MgCl ₂ , 1 mM DTT, pH=7.5 buffer. The dissolution profile of the protein was determined on a qPCR instrument, and the Tm value was fitted using Protein Thermal Shift Software 1.3 software to calculate the difference in Tm of the protein when different concentrations of the compound were added and when no compound was added, and Kd was fitted according to the change in the concentration of the compound according to ΔTm. The maximum right shift ΔTm of the compound of Example 1 of the present invention was 9.6 °C.

Example	Maximum ΔTm	Kd (μM)
1	9.6	10.3
2	11.0	1.4
3	8.8	1.9
4	10.5	1.2
5	10.2	1.3
6	9.9	3.5
7	9.2	2.2
8	12.6	1.3
9	12.7	1.2
10	14.4	2.9
11	11.4	11.89
12	5.42	-
13	8.4	1.2
14	11.0	2.7
15	6.09	4.35

16	5.52	6.14
17	3.84	10.28
18	6.42	3.34
19	6.26	4.6
20	7.98	3.37
twenty one	4.05	8.44
twenty two	5.14	2.01
twenty three	9.9	-
twenty four	8.6	50
25	12.5	1.1

The test results indicate that the compound of the present invention can interact with STING and may be used for the preparation of a medicament for regulating diseases associated with STING activity.

Experimental Example 2: Cell experiment

This experiment evaluates the function of sting agonists by detecting changes in CXCL10 (IP10) cytokines produced by compounds that stimulate human peripheral blood mononuclear cell line THP1 cells (Shanghai Cell Bank). On the first day of the experiment, the ELISA plate was coated according to the IP10 ELISA test kit (BD, #550926). The compound DMSO was dissolved into a stock solution, and diluted with a medium to a working concentration of 2X, and added to a 96-well plate at 100 μL per well; the THP1 cells in the logarithmic growth phase were counted and diluted to a concentration of 2*10 ⁶ /mL, and the above-mentioned inclusion was added. In a 96-well plate of the compound, 100 μL per well was mixed, and cultured in a 37 ° C, 5% CO ₂ incubator for 18 hours. On the next day, the above cell culture supernatant was taken, 100 uL per well, and tested according to the IP10 ELISA test kit (BD, #550926). The OD450 value was read, converted to IP10 concentration according to the standard curve, and the drug effect curve was fitted with GraphPad 5.0. Calculate the EC50 value. The compounds of the examples of the present invention strongly stimulate the release of CXCL-10 by THP-1 with an EC50 value of less than 10 μM.

Example	EC 50 (μM)
1	0.32
2	0.18
3	0.14
4	0.55
5	0.10

6	2.70
7	0.15
8	0.32
9	0.33
10	0.0086
11	0.76
12	0.13
13	0.30
14	0.12
15	0.2
16	0.36
17	0.84
18	0.87
19	-
20	0.49
twenty one	-
twenty two	0.33
twenty three	0.19
twenty four	1.2
25	0.27

The test results indicate that the compound prepared by the present invention has an activating effect on STING and can be used for the preparation of a drug that activates STING or a disease associated with STING activity.

Experimental Example 3: Animal experiment

In this experiment, the efficacy of the compound was evaluated by CT-26 colon cancer homologous mouse model. CT-26 colon cancer cells were inoculated into Balb/C mice, and the compounds prepared in Example 2 were sequentially administered intratumorally for three times on the first, fourth, and seventh days after the tumor volume reached 100 mm ³ . The doses administered per group were 0.01 mg per mouse, 0.03 mg per mouse, and 0.1 mg per mouse. Measurement of tumor volume was performed at the beginning of treatment. After the start of dosing, the mouse tumor gradually subsided to completely disappear. The result is shown in Figure 1.

In this experiment, the efficacy of the compound was evaluated by CT-26 colon cancer homologous mouse model. CT-26 colon cancer cells were inoculated into Balb/C mice, and 1 mg/kg of the compound prepared in Example 2 was intraperitoneally administered every two days after the tumor volume reached 100 mm ³ , and ML-RR-S2CDA was used as a control. Measurement of tumor volume was performed at the beginning of treatment. After the start of administration, the tumor growth rate of the mice was slowed, and on the 29th day, the tumor growth inhibition was 89%. The results are shown in Figure 2. ADU-S100 is a clinical compound of Aduro Biotech.

Animal test results indicate that the compounds prepared according to the invention have an inhibitory effect on tumors.

In summary, the present invention discloses a compound of the formula I, and discloses the use of the compound for the preparation of a medicament for treating a disease associated with STING activity, in particular for the preparation of a therapeutic inflammatory, allergic, autoimmune disease, Use in drugs for infectious diseases, cancer or precancerous syndrome, and in the preparation of immunological adjuvants. A new option for drugs for clinical screening and/or preparation of diseases associated with STING activity is provided.

Claims (21)

1. a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:

   

   among them,

   X ¹ , X ² , X ³ , X ⁴ , X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} are each independently selected from C or N;

   B ring is selected from

   

   Ring C is selected from 0 to 4 R ^{5 'is} an optionally substituted benzene ring, substituted with 0 to 4 R ^5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;

   R ⁴ and R ^4' are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, and halogen;

   R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl;

   R ¹ , R ² , R ³ , R ^{1 '} , R ^{2 '} , R ^{3 '} and R ^{5 '} are each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl, -C(O)NR ^a R ^b or none;

   R ^a , R ^b , R ^d , R ^e are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   L is selected from R ⁿ 0-4 alkylene group optionally substituted with a C ₄ ~ C _6, and 0 to 4 being optionally substituted with R ⁿ C ₄ ~ C ₆ alkenylene group, substituted with 0 to 4 R ⁿ optionally substituted C ₄ -C ₆ alkynylene; wherein optionally substituted C ₄ -C ₆ alkylene, optionally substituted C ₄ -C ₆ alkenylene, optionally substituted The carbon atom in the alkynylene group of C ₄ to C ₆ may be substituted by -O-, -S-, -NR ^m - ;

   R ^{m is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

   R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl;

   When at least one of X ¹ , X ² , X ³ , X ⁴ , X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} is:

   R ^s and R ^t are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -CO ₂ R ^f , -C(O)NR ^f R ^g , -NR ^f C(O)R ^g or none;

   When C ¹ , X ² , X ³ , X ⁴ , X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} are all C:

   R ^{t is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -CO ₂ R ^f , -C(O)NR ^f R ^g , -NR ^f C(O)R ^g or none;

   R ^{s is} selected from

   

   When m is 0, A is a ring selected from 0-4 R ^c optionally substituted 3- to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl 0-4 R ^c is optionally substituted; when m is 1,2,3,4,5,6, a ring is optionally selected from 0-4 R ^c substituted 3-6 membered cycloalkyl, optionally zero to four substituents R ^c 4 Metaheterocycloalkyl;

   R ^{c is} independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl, -C(O)OR ^d ;

   R ^f and R ^g are each independently selected from hydrogen, a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a benzene ring optionally substituted by 0 to 4 R ⁱ , and 0 to 4 R ⁱ is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R ⁱ optionally 3 to 6-membered cycloalkyl, optionally 0-4 R ⁱ is 3 to 6-membered heterocyclic ring alkyl;

   R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -C(O)R ^j , -CO ₂ R ^j , -C(O)NR ^j R ^k , -NR ^j C(O)R ^k , substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R ⁱ is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R ⁱ ;

   R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

   R ^j and R ^k are each independently selected from hydrogen and a C ₁ -C ₆ alkyl group.
2. The compound of claim 1 wherein said compound is as shown in formula II:

   

   among them,

   At least one N of X ^{1 '} , X ^{2 '} , X ^{3 '} , X ^{4 '} ;

   B ring is selected from

   

   C ring selected from

   

   R ¹⁵ , R ¹⁶ , R ¹⁷ , R ^{15 '} , R ^{16 '} and R ^{17 '} are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl;

   R ¹⁴ and R ^{14 '} are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   R ¹¹ and R ¹³ are each independently selected from the group consisting of hydrogen, -OR ^d , halogen, -CN, C(O)OR ^d , and C ₁ -C ₆ alkyl;

   R ^{11 '} and R ^{13 '} are each independently selected from the group consisting of hydrogen, -OR ^d , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl or none;

   R ^{12 is} selected from the group consisting of hydrogen and -C(O)NR ^a R ^b ;

   R ^{12 ' is} selected from hydrogen, -C(O)NR ^a R ^b or not;

   R ^a , R ^b , and R ^d are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   R ^{t1 is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

   R ^f is selected from hydrogen, substituted with 0 to 4 R ^h is an optionally substituted C ₁ ~ C ₆ alkyl, substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally substituted 5 to 6-membered aromatic heterocyclic ring, substituted with 0 to 4 R ⁱ optionally 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ⁱ optionally substituted 3- to 6-membered heterocyclic group;

   R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -C(O)R ^j , -CO ₂ R ^j , -C(O)NR ^j R ^k , -NR ^j C(O)R ^k , substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R ⁱ is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R ⁱ ;

   R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

   R ^j and R ^k are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   L is selected from the group consisting of C ₄ to C ₆ alkenylene groups.
3. The compound according to claim 2, wherein the compound of formula II is:

   

   
4. The compound of claim 1 wherein said compound is as shown in formula III:

   

   among them,

   B ring is selected from

   

   Ring C is selected from 0 to 4 R ^{5 'is} an optionally substituted benzene ring, substituted with 0 to 4 R ^5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;

   R ²¹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ²⁷ are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   R ^{22 is} selected from the group consisting of -C(O)NR ^a R ^b , -C(O)OR ^d ;

   R ^{21 '} , R ^{23 '} and R ^{5 '} are each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, C ₁ -C ₆ alkyl;

   R ^{24 ' is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

   R ^a , R ^b , R ^d , R ^e are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   R ^{22 ' is} selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl, -C(O)NR ^a R ^b ;

   R ^{t2 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -C(O) OR ^f , -CONR ^f R ^g , -NR ^f COR ^g ;

   R ^f and R ^g are each independently selected from hydrogen, a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a benzene ring optionally substituted by 0 to 4 R ⁱ , and 0 to 4 R ⁱ is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R ⁱ optionally 3 to 6-membered cycloalkyl, optionally 0-4 R ⁱ is 3 to 6-membered heterocyclic ring alkyl;

   R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -COR ^j , -CO ₂ R ^j , -CONR ^j R ^k , -NR ^j COR ^k , benzene optionally substituted by 0 to 4 R ⁱ ring substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, substituted with 0 to 4 R ⁱ optionally 3 to 6-membered cycloalkyl, optionally zero to four substituents R ⁱ 3- to 6-membered heterocycloalkyl;

   R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

   R ^j and R ^k are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   L is selected from R ⁿ 0-4 alkylene group optionally substituted with a C ₄ ~ C _6, and 0 to 4 being optionally substituted with R ⁿ C ₄ ~ C ₆ alkenylene group, substituted with 0 to 4 R ⁿ optionally substituted C ₄ -C ₆ alkynylene; wherein optionally substituted C ₄ -C ₆ alkylene, optionally substituted C ₄ -C ₆ alkenylene, optionally substituted C The carbon atom in the alkynylene group of ₄ to C ₆ may be substituted by -O-, -S-, or -NR ^m - ;

   R ^{m is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

   R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl.
5. The compound according to claim 4, characterized in that:

   R ²¹ , R ²³ , R ²⁴ and R ²⁷ are each independently selected from hydrogen;

   R ²⁵ and R ²⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

   R ^a and R ^b are each independently selected from hydrogen;

   C ring selected from

   

   s is 0, 1, 2, 3;

   R ^{21 '} , R ^{23 '} and R ^{5 '} are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

   R ^{24' is} selected from hydrogen;

   R ^{22 ' is} selected from -C(O)NR ^a R ^b ;

   R ^{t2 is} selected from the group consisting of hydrogen and -OR ^f ;

   R ^{f is} selected from a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a 3 to 6 membered cycloalkyl group optionally substituted by 0 to 4 R ^{i , and is} optionally substituted with 0 to 4 R ⁱ a substituted 3-6-membered heterocycloalkyl group;

   R ^h is selected from 0 to 4, optionally substituted with R ⁱ is 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ⁱ optionally substituted 3- to 6-membered heterocyclic group;

   R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

   L is selected from 0-4 R ⁿ optionally substituted C ₄ ~ C ₆ alkylene group, and is substituted with 0 to 4 R ⁿ is C alkylene optionally substituted alkenyl group of ₄ ~ C _6;

   R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl.
6. The compound according to claim 5, wherein the compound is as shown in formula IIIa:

   

   among them,

   R ²¹ , R ²³ , R ²⁴ and R ²⁷ are each independently selected from hydrogen;

   R ²⁵ and R ²⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

   R ^{22 ' is} selected from -C(O)NR ^a R ^b ;

   R ^a and R ^b are each independently selected from hydrogen;

   X selects -C-, -O-, -NR ^z -, -S-;

   R ^{z is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

   m is 0, 1, 2, 3, 4, 5, 6;

   n is 1, 2, 3, 4;

   p is 0, 1, 2, 3, 4.
7. The compound according to claim 6, wherein the compound of the formula IIIa is:

   
8. The compound according to claim 5, wherein the compound is as shown in formula IIIb:

   

   among them,

   R ²¹ , R ²³ , R ²⁴ and R ²⁷ are each independently selected from hydrogen;

   R ²⁵ and R ²⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

   R ^a and R ^b are each independently selected from hydrogen.
9. The compound according to claim 8 wherein the compound of formula IIIb is:

   
10. The compound of claim 1 wherein said compound is as shown in formula IV:

    

    among them,

    B ring is selected from

    

    When m is 0, A ring is selected from 0-4 optionally substituted by R ^c 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ^c optionally having 3 to 6-membered heterocyclic group;

    When m is 5, 6, A is a ring selected from substituted with 0 to 4 R ^c optionally 3 to 6-membered cycloalkyl, substituted with 0-4 R ^c optionally 4-membered heterocycloalkyl;

    R ³¹ , R ³³ and R ³⁴ are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl;

    R ³⁵ , R ³⁶ and R ³⁷ are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

    R ^{32 is} selected from -CONR ^a R ^b ;

    R ^a and R ^b are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

    R ^{c is} each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl, -C(O)OR ^d ;

    R ^d and R ^e are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

    Ring C is selected from 0 to 4 R ^{5 'is} an optionally substituted benzene ring, substituted with 0 to 4 R ^5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;

    R ^{31 '} , R ^{33 '} and R ^{5 '} are each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, C ₁ -C ₆ alkyl;

    R ^{34 ' is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

    R ^{32 ' is} selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, -CN, C(O)OR ^d , C ₁ -C ₆ alkyl, -C(O)NR ^a R ^b ;

    R ^{t3 is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl optionally substituted by 0 to 4 R ^h , -OR ^f , -NR ^f R ^g , -C(O)R ^f , -CO ₂ R ^f , -C(O)NR ^f R ^g , -NR ^f C(O)R ^g ;

    R ^f and R ^g are each independently selected from hydrogen, a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a benzene ring optionally substituted by 0 to 4 R ⁱ , and 0 to 4 R ⁱ is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R ⁱ optionally 3 to 6-membered cycloalkyl, optionally 0-4 R ⁱ is 3 to 6-membered heterocyclic ring alkyl;

    R ^{h is} selected from the group consisting of halogen, -OR ^j , -NR ^j R ^k , -C(O)R ^j , -CO ₂ R ^j , -C(O)NR ^j R ^k , -NR ^j C(O)R ^k , substituted with 0 to 4 R ⁱ optionally substituted benzene ring, substituted with 0 to 4 R ⁱ optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R ⁱ is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R ⁱ ;

    R ^{i is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl, cyano;

    R ^j and R ^k are each independently selected from hydrogen, C ₁ -C ₆ alkyl;

    L is selected from R ⁿ 0-4 alkylene group optionally substituted with a C ₄ ~ C _6, and 0 to 4 being optionally substituted with R ⁿ C ₄ ~ C ₆ alkenylene group, substituted with 0 to 4 R ⁿ optionally substituted C ₄ -C ₆ alkynylene; wherein optionally substituted C ₄ -C ₆ alkylene, optionally substituted C ₄ -C ₆ alkenylene, optionally substituted C The carbon atom in the alkynylene group of ₄ to C ₆ may be substituted by -O-, -S-, or -NR ^m - ;

    R ^{m is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

    R ^{n is} selected from the group consisting of halogen, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, halogen-substituted C ₁ -C ₆ alkyl.
11. The compound according to claim 10, characterized in that:

    R ³¹ , R ³³ and R ³⁴ are each independently selected from hydrogen and halogen;

    R ^{37 is} independently selected from hydrogen;

    R ³⁵ and R ³⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

    R ^a and R ^b are each independently selected from hydrogen;

    The A ring is selected from a 3- to 6-membered cycloalkyl group or a 4-membered heterocycloalkyl group optionally substituted by 0 to 4 R ^c ;

    C ring selected from

    

    s is 0, 1, 2, 3;

    R ^{31 '} , R ^{33 '} and R ^{35 '} are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl;

    R ^{34 ' is} selected from hydrogen;

    R ^{32 ' is} selected from -NR ^d R ^e , -C(O)NR ^a R ^b ;

    R ^{t3 is} selected from the group consisting of hydrogen and -OR ^f ;

    R ^{f is} selected from a C ₁ -C ₆ alkyl group optionally substituted by 0 to 4 R ^h , a 3 to 6 membered cycloalkyl group optionally substituted by 0 to 4 R ^{i , and is} optionally substituted with 0 to 4 R ⁱ a substituted 3-6-membered heterocycloalkyl group;

    R ^h is selected from -OR ^j, substituted with 0 to 4 R ⁱ optionally 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ⁱ optionally substituted 3- to 6-membered heterocyclic group;

    L is selected from R ⁿ 0-4 alkylene optionally substituted C ₄ ~ C _6, and is 0 to 4 R ⁿ is C alkylene optionally substituted alkenyl group of ₄ ~ C _6.
12. The compound according to claim 11, wherein said compound is as shown in formula IVa:

    

    among them,

    R ³¹ , R ³³ , R ³⁴ and R ³⁷ are each independently selected from hydrogen;

    R ³⁵ and R ³⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

    R ^a and R ^b are each independently selected from hydrogen;

    m is 0, 1, 2, 3, 4, 5, 6;

    n is 0, 1, 2, 3;

    p is 0, 1, 2, 3, 4;

    R ^{c is} each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl, -C(O)OR ^d ;

    R ^d and R ^e are each independently selected from hydrogen and C ₁ -C ₆ alkyl.
13. The compound according to claim 12, wherein the compound of the formula IVa is:

    
14. The compound of claim 11 wherein said compound is as shown in formula IVb:

    

    among them,

    R ³¹ , R ³³ and R ³⁴ are each independently selected from hydrogen and halogen;

    R ^{37 is} independently selected from hydrogen;

    R ³⁵ and R ³⁶ are each independently selected from a C ₁ -C ₆ alkyl group;

    R ^a and R ^b are each independently selected from hydrogen;

    X selects -O-, -NR ^y -, -S-;

    NR ^{y is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

    When m is 0, n and q are added to 2, 3, 4;

    When m is 1, 2, 3, 4, 5, 6, n and q are added to 2;

    p is 0, 1, 2, 3, 4;

    R ^{c is} each independently selected from the group consisting of hydrogen, -OR ^d , -NR ^d R ^e , halogen, =O, C ₁ -C ₆ alkyl;

    R ^d and R ^e are each independently selected from hydrogen and C ₁ -C ₆ alkyl.
15. The compound according to claim 14 wherein the compound of formula IVb is:

    

    
16. The compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of an activated STING Use in medicine.
17. The compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a treatment and STING Use in medicines for activity-related diseases.
18. The use according to claim 17, wherein the disease associated with STING activity is one or more of diseases associated with inflammatory, autoimmune diseases, infectious diseases, cancer, and precancerous syndrome. Kind.
19. The compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the preparation of a therapeutic inflammatory Use in drugs for autoimmune diseases, infectious diseases, cancer or precancerous syndrome.
20. The compound according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for preparing an immunoadjuvant Use in.
21. A pharmaceutical composition according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a precursor thereof A preparation prepared from a drug, or a metabolite thereof, in addition to a pharmaceutically acceptable adjuvant.

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