WO2019134707A1

WO2019134707A1 - Immunomodulator

Info

Publication number: WO2019134707A1
Application number: PCT/CN2019/070791
Authority: WO
Inventors: 李进; 张登友; 潘飞; 冯静超; 李应飞; 朱文吉; 李偲; 张毅; 魏用刚; 陈伟
Original assignee: 成都先导药物开发股份有限公司
Priority date: 2018-01-08
Filing date: 2019-01-08
Publication date: 2019-07-11
Also published as: CN110016021B; CN110016021A

Abstract

Provided are a compound as presented in formula (I), a tautomer and enantiomer thereof, or a pharmaceutically acceptable salt, a cristal form, a hydrate or a solvate thereof. The compound of formula (I) can be effectively combined with STING, and act as a STING agonist for treating various STING-associated diseases.

Description

Immunomodulator

Technical field

The present invention relates to an immunomodulator.

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

The present invention provides a compound of formula I, and tautomers, enantiomers thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof:

among them,

s is 0 or 1;

Ring B is substituted with 0 to 4 R ^{5 5} ~ 6 membered aromatic ring, substituted with 0 to 4 R ^{5 5} ~ 6 membered aromatic heterocyclic ring;

R ^{5 is} independently selected from C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl, -(CH ₂ ) _n OR ^a , -(CH ₂ ) _n NR ^a R ^b , -(CH ₂ ) _n NR ^a C(O)R ^b , -(CH ₂ ) _n C(O)NR ^a R ^b , -(CH ₂ ) _n C(O)OR ^a , -(CH ₂ ) _n OC(O)R ^a ;

R ^{8 is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

R ^{4 is} selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl;

R ^{2 is} selected from -CONR ^a R ^b ;

R ¹ and R ³ are each independently selected from the group consisting of hydrogen, halogen, and C ₁ -C ₆ alkyl;

R ^t is selected from 0 to 2 substituents R ^f is C ₁ ~ C ₆ alkenyl group, substituted with 0 to 2 substituents R ^f is C ₁ ~ C ₆ alkynyl _{_{group, - (CH 2) m R}} g, -O ( CH ₂ ) _m R ^g , -S(CH ₂ ) _n R ^f ;

R ^{f is} selected from -OR ^a , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -C(O)NR ^a R ^b , -C(O)OR ^{^{a, -OC (O) R a}} , -OC (O) NR a R b, substituted with 0-4 R ^c 3 ~ 10 membered cycloalkyl, substituted with 0 to 4 substituents R ^c of 4 to 10-membered Heterocycloalkyl;

Each m, n is independently 0, 1, 2, 3, 4, 5 or 6;

When m is 0, R ^g is selected from 0 to 4 substituents R ^c is 3 to 10-membered cycloalkyl, substituted with 0 to 4 R ^c 3 to 10-membered heterocycloalkyl;

When m is 4, 5 or 6, R ^g is selected from 0 to 4 substituents R ^c of 3 to 6-membered cycloalkyl, substituted with 0 to 4 R ^c substituted 4-membered heterocyclic ring An alkyl group, a 7-10 membered heterocycloalkyl group substituted by 0 to 4 R ^c ;

R ^{c is} 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, C ₁ -C ₆ alkyl;

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

Further, B ring is substituted with 0 to 2 R ⁵ 5 to 6-membered aromatic ring is substituted with 0 to 2 R ⁵ substituted 5- to 6-membered aromatic heterocyclic ring;

R ^t is selected from 0 or 1 R ^f is substituted with C ₁ ~ C ₆ alkenyl group, substituted with 0 or 1 R ^f is substituted with C ₁ ~ C ₆ alkynyl _{_{group, - (CH 2) m R}} g, -O ( CH ₂ ) _m R ^g , -S(CH ₂ ) _n R ^f ;

R ^{f is} selected from -OR ^a , -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , -C(O)NR ^a R ^b , -C(O)OR ^{^{a, -OC (O) R a}} , -OC (O) NR a R b, substituted with 0 to 2 R ^c 3 ~ 10 membered cycloalkyl, substituted with 0 to 2 substituents R ^c of 4 to 10-membered Heterocycloalkyl;

Each m, n is independently 0, 1, 2, 3, 4, 5 or 6;

When m is 0, R ^g is selected from 0 to 2 substituents R ^c is 3 to 10-membered cycloalkyl, substituted with 0 to 2 R ^c 3 to 10-membered heterocycloalkyl;

When m is 4, 5 or 6, R ^g is selected from 0 to 2 substituents R ^c of 3 to 6-membered cycloalkyl, substituted with 0 to 2 substituents R ^c 4 membered heterocyclic ring An alkyl group having 7 to 10 membered heterocycloalkyl groups substituted with 0 to 2 R ^c groups.

Further, the compound of formula I can be represented by formula II:

Where s is 0 or 1;

Ring B is selected from 0 to 2 R ⁵

X' is selected from O, alkynylene, S or none;

When X' is selected from O or no,

n ₁ is 0, 1, 2,

R ^{S is} selected from the group consisting of a 3- to 6-membered cycloalkyl group, a 4-membered heterocycloalkyl group, and a 7- to 10-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of hetero atoms is 1, 2;

When X' is selected from S or alkynylene,

n ₁ is 0, 1, 2,

R ^{S is} selected from -OR ^a , -NR ^a C(O)OR ^b , 4 to 10 membered heterocycloalkyl; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of heteroatoms is 1, 2;

Further, when X' is selected from O or not,

n ₁ is 0, 1, 2,

R ^{S is} selected from a 4-membered heterocycloalkyl group and a 7- to 10-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of heteroatoms is 1, 2;

When X' is selected from S or alkynylene,

n ₁ is 0, 1, 2,

R ^{S is} selected from the group consisting of -OH, -OCH ₃ , -NHC(O)OCH ₃ , and a 4- to 6-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of hetero atoms is 1, 2.

Further, the 7-10 membered heterocycloalkyl group is a spiro ring; wherein the spiro ring is

Further, the compound represented by Formula II is specifically:

Further, the compound of formula I can be represented by formula III:

among them,

B ring is selected from

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

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

When m is 1,2,3,4,5,6, A ring is selected from substituted with 0 to 4 R ^c 3 ~ 6 membered cycloalkyl, substituted with 0-4 R ^c 4 membered heterocyclic ring An alkyl group; R ^{c is} selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl;

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from hydrogen, C ₁ -C ₆ alkyl, halogen-substituted C ₁ -C ₆ alkyl;

R ^{2 is} selected from -CONR ^a R ^b ; wherein R ^a and R ^b are each independently selected from hydrogen, C ₁ -C ₆ alkyl.

Further, R ¹ , R ³ , R ⁷ and R ^{8 are} selected from hydrogen.

Further, R ⁵ and R ⁶ are each independently selected from a C ₁ -C ₆ alkyl group and a halogen-substituted C ₁ -C ₆ alkyl group.

Further, R ^{2 is} selected from -CONR ^a R ^b ; wherein R ^a and R ^b are each independently selected from hydrogen.

Further, R ^{4 is} selected from a C ₁ -C ₆ alkyl group.

Further, the 3- to 6-membered heterocycloalkyl group substituted by 0 to 4 R ^{c is} selected from heterocycloalkyl groups containing nitrogen, oxygen and sulfur; and R ^{c is} selected from hydrogen.

Further, the compound of Formula III can be further represented by Formula IIIa:

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

n is 0, 1, 2, 3;

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

R ¹ , R ³ , R ⁷ , and R ⁸ are each independently selected from hydrogen;

R ^{4 is} selected from C ₁ -C ₆ alkyl;

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

R ^{2 is} selected from -CONR ^a R ^b ; wherein R ^a , R ^b are each independently selected from hydrogen;

R ^{c is} independently selected from hydrogen, C ₁ -C ₆ alkyl.

Further, the compound of Formula III can be further represented by Formula IIIb:

Wherein, 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 ¹ , R ³ , R ⁷ , and R ⁸ are each independently selected from hydrogen;

R ^{4 is} selected from C ₁ -C ₆ alkyl;

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

R ^{c is} independently selected from hydrogen, C ₁ -C ₆ alkyl.

Further, the compound represented by Formula III can be specifically expressed as:

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 STING agonist.

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 or prophylactically related to STING activity The use of the disease in medicine.

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 an immunological composition or vaccine adjuvant Use in.

The experimental results show that the compound of the present invention can effectively bind to STING, and the compound of the present invention can be used as a STING agonist for the treatment of various diseases, especially for leukemia.

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 diseases and 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.

The "cycloalkane" or "cycloalkyl group" in the present invention means a saturated ring or a non-aromatic unsaturated ring formed by linking carbon atoms, and includes a monocyclic ring, a ring or a spiro ring.

"Heterocycle", "heterocycloalkane", "heterocycloalkyl" as used in the present invention means a saturated saturated ring or a non-aromatic unsaturated ring containing at least one hetero atom, including a monocyclic ring, a cyclic ring or a spiro ring. The hetero atom is a nitrogen atom, an oxygen atom or a sulfur atom.

In the present invention, "aromatic ring" and "aryl group" mean an aromatic unsaturated ring formed by linking carbon atoms.

The "aromatic heterocyclic ring" and "aromatic heterocyclic group" in the present invention means an aromatic unsaturated ring containing at least one hetero atom, wherein the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom.

Halogen is fluorine, chlorine, bromine or iodine.

"Alkenyl" in the present invention means a hydrocarbon group containing at least one carbon-carbon double bond.

The "alkynyl group" in the present invention means a hydrocarbon group containing at least one carbon-carbon triple 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.

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.

Detailed ways

The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD3OD), internal standard. It is tetramethylsilane (TMS).

The LC-MS was measured using a 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.

DMF: means N,N-dimethylformamide.

DMSO: refers to dimethyl sulfoxide.

DIPEA: refers to diisopropylethylamine.

Boc: refers to tert-butyloxycarbonyl.

TFA: refers to trifluoroacetic acid.

DBU: 1,8-diazabicycloundec-7-ene.

HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

Synthesis of intermediate 1c:

Step 1: Synthesis of 4-chloro-3-methoxy-5-nitrobenzamide

Compound 1a (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 m. solid.

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).

MS (ESI) m / z = 231 [M+H] ⁺ .

Step 2: Synthesis of 4-chloro-3-hydroxy-5-nitrobenzamide

Compound 1b (12.5 g, 54.1 mmol) was dispersed in dry DCM (150 ml), and then boron tribromide (200 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 (Compound 1c) ( 10 g, 46.2 mmol, 85.3% yield), pale yellow solid.

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

MS (ESI) m / z = 217 [M+H] ⁺ .

Synthesis of intermediate 1h:

Step 1:1:1 Synthesis of ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride

1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (4 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. DCM (20 ml) was added to the crude crystals and then evaporated to dryness crystals crystalsssssssssssssssssssssssssssss Used for the next reaction.

Step 2: Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate

Compound 1g (4.46g, 25.9mmol) was dissolved in dry acetone (20ml) and added dropwise to a solution of potassium thiocyanate (5g, 51.5mmol) in acetone (100ml), and stirred at room temperature for 3h. The inorganic salt was removed by filtration, and the crude product was purified by silica gel column (eluent ethyl acetate / petroleum ether, v/v = 1 / 15) to give 1-ethyl-3-methyl-1H-pyrazole. 5-5-Carbo-isothiocyanate (Compound 1h) (4 g, 20.4 mmol, 78.7%), clear brown-yellow liquid. MS (ESI) m / z = 196 [M+H] ⁺ .

Synthesis of intermediate 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate:

Step 1: Synthesis of 4-ethyl-2-methylthiazole-5-formyl chloride

4-Ethyl-2-methylthiazole-5-carboxylic acid (2 g, 11.7 mmol) was dissolved in dry DCM (40 ml), and oxalyl chloride (1.9 g, 15.1 mmol) and A catalytic amount of DMF. After reacting for 1 h at room temperature, the volatiles were evaporated under reduced pressure. DCM (20 ml) was added to EtOAc (EtOAc m.

Step 2: Synthesis of 4-ethyl-2-methylthiazole-5-carbonyl isothiocyanate

4-Ethyl-2-methylthiazole-5-formyl chloride (2.2 g, 11.7 mmol) was dissolved in dry acetone (10 ml) and added dropwise to potassium thiocyanate (2.3 g, 23.4 mmol) at 0 °. In a solution of acetone (50 ml), the mixture was stirred at room temperature for 3 h, and the reaction system was filtered to remove the inorganic salt. The crude product was purified by silica gel column (eluent ethyl acetate / petroleum ether, v/v = 1/15). 4-Ethyl-2-methylthiazole-5-carbonyl isothiocyanate (2.15 g, 10.2 mmol, yield 87%), clear brown-yellow liquid.

MS (ESI) m / z = 213 [M+H] ⁺ .

Synthesis of intermediate 2-amino-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

Step 1: Synthesis of methyl 4-chloro-3-hydroxy-5-nitrobenzoate

Methyl 4-chloro-3-methoxy-5-nitrobenzoate (10 g, 40.7 mmol) was dissolved in anhydrous dichloromethane (100 mL), and boron tribromide was slowly added dropwise in an ice bath ( 40.8 g, 162.8 mmol), and slowly added to room temperature after stirring, and the reaction was stirred overnight. After the reaction was completed, it was quenched by slowly dropwise adding methanol under an ice bath, and then it was dried. Methanol (100 mL) and concentrated sulfuric acid (0.2 mL) were added thereto, and the reaction mixture was heated to 75 ° C and stirred overnight. After cooling, the solvent was concentrated under reduced pressure, and then 150 mL of water was added, and the mixture was filtered, and then filtered, and the solid was washed with water, and the solid was dried to give methyl 4-chloro-3-hydroxy-5-nitrobenzoate (8.89 g). , 38.4mmol).

MS (ESI) m / z = 232 [M+H] ⁺ .

Step 2: Synthesis of methyl 4-chloro-3-nitro-5-(2-(oxetan-3-yl)ethoxy)benzoate

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 (2.2 g, 8.6 mmol) was used directly in the next reaction.

To a solution of methyl 4-chloro-3-hydroxy-5-nitrobenzoate (1.0 g, 3.9 mmol) in DMF (10 mL) EtOAc (EtOAc (EtOAc) And 2-(oxetan-3-yl)ethyl 4-methylbenzenesulfonate (1.1 g, 3.9 mmol) were reacted at 75 ° C for 12 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-( Methyl oxetane-3-yl)ethoxy)benzoate (1.2 g, yield 88%).

MS (ESI) m / z = 316 [M+H] ⁺ .

Step 3: Synthesis of methyl 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate

Add DIPEA to a solution of methyl 4-chloro-3-nitro-5-(2-(oxetan-3-yl)ethoxy)benzoate (1.2 g, 3.8 mmol) in DMSO (10 mL) (0.98 g, 7.6 mmol) and n-propylamine (0.67 g, 11.4 mmol) were reacted at 50 ° C for 3 h. After cooling, it was poured into ice water, and an orange-red solid precipitated. After filtration, it was dried to give 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4 Methyl (-propylamino)benzoate (1.28 g, 3.8 mmol, 100% yield), orange- red solid.

MS (ESI) m / z = 339 [M+H] ⁺ .

Step 4: Synthesis of methyl 3-amino-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate

Methyl 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate (1.28 g, 3.8 mmol) in methanol (15 mL) Add 10% Pd/C (0.13g) to the solution, hydrogenate and reduce for 3h, remove Pd/C by filtration, and concentrate the filtrate to obtain 3-amino-5-(2-(oxetan-3-yl)ethoxylate. Methyl 4-(propylamino)benzoate (1.1 g, 3.5 mmol) was used directly in the next step.

MS (ESI) m / z = 308 [M+H] ⁺ .

Step 5: Synthesis of methyl 2-amino-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxylate

Methyl 3-amino-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate (472 mg, 1.53 mmol) and 1,3- Dicarboxymethyl-2-methyl-2-thioisourea (347.2 mg, 1.68 mmol) was dissolved in glacial acetic acid (5 mL) and the mixture was warmed to <RTIgt; After cooling to room temperature, it was diluted with water and extracted with ethyl acetate (30 mL×3). The organic phase was washed with water and dried over anhydrous sodium sulfate and then evaporated. Water = 30/70, v/v) Compound (125 mg, 0.37 mmol).

MS (ESI) m / z = 334 [M+H] ⁺ .

Synthesis of Intermediate 2-Ethyl-6-methylnicotinic Acid

Step 1: Synthesis of 2-ethyl-6-methylnicotinate methyl ester

Methyl 3-oxopentanoate (1 g, 7.68 mmol), 4-trimethylsilyl-3-butyn-2-one (1.13 g, 8.068 mmol) and ammonium acetate (1.78 g, 23.054 mmol) The reaction was heated to 60 ° C in a solution of methanol (50 mL) overnight. After cooling to room temperature, it was concentrated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and then evaporated to dryness to give the compound 2-ethyl-6-methyl-nicotinic acid methyl ester (585 mg, 3.26 mmol). One step reaction.

MS (ESI) m / z = 180 [M+H] ⁺ .

Step 2: Synthesis of 2-ethyl-6-methylnicotinic acid

The compound 2-ethyl-6-methyl-nicotinic acid methyl ester (585mg, 3.27mmol) was dissolved in THF (10ml), MeOH (5ml ) and H ₂ O (2ml), under ice-water cooled solution of lithium hydroxide was added ( 53.04 mg, 1.26 mmol), and allowed to react to room temperature overnight. The reaction mixture was diluted with HCl (1M) to pH = 4, and extracted with dichloromethane (30 mL × 4). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate -6-methylnicotinic acid (399 mg, 2.42 mmol), yield 74%.

MS (ESI) m / z = 166 [M+H] ⁺ .

Synthesis of intermediate 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate

Step 1: Synthesis of methyl 2-chloro-3-oxopentanoate

SO ₂ Cl ₂ (7.2 g, 58 mmol) was added dropwise to a solution of 1 (5 g, 38 mmol) in dichloromethane (100 mL), and the mixture was warmed to room temperature and stirred for 4 h, and the mixture was washed with saturated sodium carbonate The separated organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness to afford compound 2-chloro-3-oxopentanoate (6 g, 36.5 mmol). Used directly in the next step.

MS (ESI) m/z = 166.0 [M+H] ⁺

Step 2: Synthesis of methyl 2-acetoxy-3-oxopentanoate

TEA (12.5 mL) was added dropwise to a solution of acetic acid (12.5 mL) in DMF (63 mL), and the mixture was warmed to room temperature and then methyl 2-chloro-3-oxopentanoate (6 g, 36.5) Methyl) was added to the reaction mixture and stirred at room temperature overnight. The reaction was completed by TLC. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Methyl formate (3.0 g, 15.9 mmol), yellow oil, was used directly in the next step.

Step 3: Synthesis of methyl 4-ethyl-2-methyloxazole-5-carboxylate

Methyl 2-acetoxy-3-oxopentanoate (3.0 g, 15.9 mmol) was dissolved in acetic acid (50 mL) and then ammonium acetate (9.8 g, 127.6 mmol). The mixture was warmed to 120 ° C and stirred at this temperature for 4 hours. After concentrating the reaction mixture, it was diluted with water and extracted with ethyl acetate. The separated organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness. Agent: petroleum ether / ethyl acetate, 90/10) gave 4-ethyl-2-methyloxazole-5-carboxylic acid methyl ester (0.52 g, 3.1 mmol).

MS (ESI) m/z = 170.1 [M+H]+

^{1 H NMR (400MHz, CDCl3)} δ3.89 (s, 3H), 2.84 (q, J = 7.6Hz, 2H), 2.50 (s, 3H), 1.23 (t, J = 7.6Hz, 3H).

Step 4: Synthesis of 4-ethyl-2-methyloxazole-5-carboxylic acid

Methyl 4-ethyl-2-methyloxazole-5-carboxylate (323 mg, 1.9 mmol) was dissolved in THF / MeOH (10 mL / 5 mL), and hydrated lithium hydroxide (160 mg, 3.8 mmol). Stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated tolululululululululu

MS (ESI) m/z = 156.1 [M+H] ⁺

Step 5: Synthesis of 4-ethyl-2-methyloxazole-5-carbonyl isothiocyanate

4-Ethyl-2-methyloxazol-5-carboxylic acid (220 mg, 1.42 mmol) was dissolved in dry THF (10 ml), and oxalyl chloride (270 mL, 2. A catalytic amount of DMF. After reacting at room temperature for 30 min, the volatiles were evaporated under reduced pressure. To a crude product was added DCM (20 mL).

The yellow oil was dissolved in dry acetone (10 ml) and added dropwise to a solution of potassium thiocyanate (276 mg, 2.84 mmol) in acetone (15 ml), and stirred at room temperature for 3 h. The inorganic salt was removed by filtration and washed with n-hexane. The crude product was purified by silica gel column (eluent ethyl acetate / petroleum ether, v/v = 1/7) to give 4-ethyl-2-methyloxazole. 5-5-carbonyl isothiocyanate (176 mg, 63%), clear pale yellow liquid.

MS (ESI) m/z = 197.0 [M+H] ⁺

Example 1. Preparation of the compound of the present invention

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-yloxy)-1-propyl-1H-benzo [d]imidazole-5-carboxamide

Step 1: Synthesis of 4-chloro-3-nitro-5-(oxetan-3-yloxy)benzamide

Potassium carbonate (1.27 g, 9.2 mmol) and 3-iodooxybutane (1.27 g, 6.9 mmol) were added to a solution of compound 1c (1.0 g, 4.6 mmol) in DMF (30 ml). . 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-(oxe-butane-3- Benido)benzamide (Compound 1d) (0.8 g, 2.9 mmol, 63.9% yield), pale yellow solid.

MS (ESI) m / z = 273 [M+H] ⁺ .

Step 2: Synthesis of 3-nitro-5-(oxetan-3-yloxy)-4-(propylamino)benzamide

To a solution of Compound 1d (0.16 g, 0.62 mmol) in EtOAc (10 mL), DIPEA (0.15 g, 1.86 mmol) and n-propylamine (0.14 g, 1.86 mmol) were allowed to react at 50 ° C overnight. After cooling, it is poured into ice water, and an orange-red solid precipitates. After filtration, it is dried to give 3-nitro-5-(oxetan-3-yloxy)-4-(propylamino) Benzoylamide (Compound 1e) (0.14 g, 0.47 mmol), orange red solid.

¹ H NMR (400 MHz, DMSO): 8.23 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.31 (s, 1H), 7.08 (s, 1H), 5.41-5.36 (m, 1H) ), 4.96 (t, 2H), 4.64 (q, 2H), 3.58 (q, 2H), 3.33 (s, 1H), 1.61-1.56 (m, 2H), 0.89 (t, 3H).

MS (ESI) m / z = 296 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-5-(oxetan-3-yloxy)-4-(propylamino)benzamide

To a solution of the compound 1e (0.144 g, 0.62 mmol) in methanol and ethyl acetate was added 10% Pd/C (0.05 g), hydrogenation reduction for 3 h, Pd/C was removed by filtration, and the filtrate was concentrated to give compound 1i (0.12 g, 0.45 mmol) was used directly for the next reaction.

MS (ESI) m / z = 266 [M+H] ⁺ .

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

Compound 1h (0.092 g, 0.46 mmol) was added to compound 1i (0.12 g, 0.45 mmol) in DMF (5 mL). Then, HATU (0.19 g, 0.5 mmol) and DBU (0.1 g, 6.5 mmol) were added to the reaction mixture, and the mixture was reacted for 1 hour at room temperature. The reaction mixture was concentrated to give a crude compound. , 28.3% yield).

¹ H NMR (400 MHz, DMSO): 12.89 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.40 (s, 1H), 6.96 (s, 1H), 6.66 (s, 1H), 5.55-5.52 (m, 1H), 5.05 (t, 2H), 4.66-4.62 (m, 4H), 4.39 (t, 2H), 2.19 (s, 3H), 1.87-1.81 (m, 2H), 1.38 ( t, 3H), 0.98 (t, 3H).

MS (ESI) m / z = 427 [M+H] ⁺ .

Example 2 Preparation of the Compound of the Invention

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(cyclopropylmethoxy)-1-propyl-1H-benzo[d]imidazole- 5-carboxamide

Step 1: Synthesis of 4-chloro-3-(cyclopropylmethoxy)-5-nitrobenzamide

To a solution of Compound 1c (0.4 g, 1.85 mmol) in DMF (10 mL), EtOAc (EtOAc, EtOAc, 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-(cyclopropylmethoxy)-5-nitrobenzene. Formamide (Compound 2a) (0.31 g, 1.15 mmol, 62% yield), pale yellow solid.

MS (ESI) m / z = 271 [M+H] ⁺ .

Step 2: Synthesis of 3-(cyclopropylmethoxy)-5-nitro-4-(propylamino)benzamide

To a solution of compound 2a (0.17 g, 0.62 mmol) in EtOAc (10 mL), EtOAc (EtOAc) After cooling, pour it into ice water, precipitate with an orange-red solid, filter and dry to give 3-(cyclopropylmethoxy)-5-nitro-4-(propylamino)benzamide (compound) 2b) (160 mg, 0.54 mmol, 87% yield), orange- red solid.

¹ H NMR (400 MHz, DMSO) 8.20 (s, 1H) 7.98 (s, 1H) 7.92 (t, 1H) 7.49 (s, 1H) 3.92 (d, 2H) 3.58 (m, 2H) 1.55 to 1.64 (m, 2H) 1.23 to 1.31 (m, 1H) 0.88 (t, 3H) 0.61 (q, 2H) 0.36 (q, 2H).

MS (ESI) m / z = 294 [M+H] ⁺ .

Step 3: Synthesis of 3-(cyclopropylmethoxy)-5-amino-4-(propylamino)benzamide

Add 10% Pd/C (0.05 g) to a solution of compound 2b (0.15 g, 0.51 mmol) in methanol and ethyl acetate, hydrogenation reduction for 3 h, remove Pd/C by filtration, and concentrate the filtrate to give 3-(cyclopropyl) Methoxy)-5-amino-4-(propylamino)benzamide (Compound 2c) (0.130 g, 0.49 mmol, 96% yield).

MS (ESI) m / z = 264 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(cyclopropylmethoxy)-1-propyl-1H-benzo[d Synthesis of imidazole-5-carboxamide

Compound 1h (0.09 g, 0.46 mmol) was added to compound 2c (0.125 g, 0.47 mmol) in DMF (5 mL). Then, HATU (0.18 g, 0.47 mmol) and DBU (0.09 g, 0.58 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h, and the reaction mixture was concentrated to give a crude compound. , 25% yield).

¹ H NMR (400 MHz, DMSO) 7.97 (s, 1H) 7.66 (s, 1H) 7.35 (s, 2H) 6.64 (s, 1H) 4.63 (q, 2H) 4.35 (t, 2H) 4.06 (d, 2H) 2.18 (s, 3H) 1.78 to 1.87 (m, 2H) 1.36 (t, 3H) 1.29 to 1.34 (m, 1H): 0.96 (t, 3H): 0.65 (q, 2H) 0.41 (q, 2H).

MS (ESI) m / z = 425 [M+H] ⁺ .

Example 3 Preparation of a Compound of the Invention

Step 1: Synthesis of 4-chloro-3-nitro-5-((tetrahydrofuran-3-yl)oxy)benzamide

To a solution of 3-hydroxytetrahydrofuran (1 g, 11.3 mmol) in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was reacted for 2 h at room temperature, and washed with water and brine, and then dried over anhydrous sodium sulfate, filtered and concentrated to give 3-tetrahydrofuran p-tosylate (0.45 g, 1.85 mmol). .

Add cesium carbonate (1.2 g, 3.7 mmol) and 3-tetrahydrofuran p-toluenesulfonate (0.45 g, 1.85 mmol) to a solution of compound 1c (0.4 g, 1.85 mmol) in DMF (15 ml). . 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 3a) (0.3 g, 2.9 mmol, 56% yield), pale yellow solid.

MS (ESI) m / z = 287 [M+H] ⁺ .

Step 2: Synthesis of 3-nitro-4-(propylamino)-5-((tetrahydrofuran-3-yl)oxy)benzamide

To a solution of compound 3a (0.17 g, 0.62 mmol) in EtOAc (10 mL), EtOAc (EtOAc) After cooling, it was poured into ice water, and an orange-red solid precipitated. After filtration, it was dried to give 3-nitro-4-(propylamino)-5-((tetrahydrofuran-3-yl)oxy)benzene. Amide (Compound 3b) (0.16 g, 0.51 mmol, 83% yield).

MS (ESI) m / z = 310 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-4-(propylamino)-5-((tetrahydrofuran-3-yl)oxy)benzamide

To a solution of the compound 3b (0.15 g, 0.48 mmol) in methanol and ethyl acetate was added 10% Pd/C (0.015 g), hydrogenation reduction for 3 h, and Pd/C was removed by filtration, and the filtrate was concentrated to give 3-amino-4- (propylamino)-5-((tetrahydrofuran-3-yl)oxy)benzamide (Compound 3c) (0.13 g, 0.48 mmol, 99% yield).

MS (ESI) m / z = 310 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((tetrahydrofuran-3-yl)oxy)-1-propyl-1H-benzene And [d] Synthesis of imidazole-5-carboxamide

Compound 1h (0.085 g, 0.43 mmol) was added to compound 3c (0.12 g, 0.43 mmol) in DMF (5 mL). Then, HATU (0.165 g, 0.43 mmol) and DBU (0.08 g, 0.51 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h. , 96% purity, 24% yield).

^{1 H NMR (400MHz, DMSO)} 8.03 (s, 1H) 7.69 (s, 1H) 7.40 (s, 1H) 7.35 (s, 1H) 6.65 (s, 1H) 5.32 (s, 1H) 4.62 (q, 2H) 4.29 (t, 2H) 3.90 to 4.00 (m, 4H) 2.29 to 2.38 (m, 1H) 2.19 (s, 3H) 2.07 to 2.15 (m, 1H) 1.72 to 1.82 (m, 2H) 1.36 (t, 3H) 0.92 (t, 3H).

MS (ESI) m / z = 441 [M+H] ⁺ .

Example 4 Preparation of a Compound of the Invention

Step 1: Synthesis of 4-chloro-3-nitro-5-(oxetan-3-ylmethoxy)benzamide

To a solution of oxetane-3-ylmethanol (0.6 g, 6.81 mmol) in dichloromethane <RTI ID=0.0>(20</RTI> <RTI ID=0.0> (2.6g, 13.6mmol), reacted for 2h at room temperature, washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated to give oxetane-3-ylmethyl-p-toluenesulfonic acid The ester (1.2 g, 4.9 mmol, 71.9% yield) was used directly in the next step.

Add cesium carbonate (1.2 g, 3.7 mmol) and oxetane-3-ylmethyl p-toluenesulfonate (0.5 g, 2 mmol) to a solution of compound 1c (0.4 g, 1.85 mmol) in DMF (10 mL) , 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 to give 4-chloro-3-nitro-5-(oxe-butane-3- Benido)benzamide (Compound 4a) (0.21 g, 0.73 mmol, 39.5% yield).

MS (ESI) m / z = 287 [M+H] ⁺ .

^{1 HNMR (400MHz, DMSO):} 8.30 (s, 1H), 8.08 (d, 1H), 7.94 (d, 1H), 7.81 (s, 1H), 7.33 (s, 1H), 4.76 (q, 2H), 4.50-4.46 (m, 4H).

Step 2: Synthesis of 3-nitro-5-(oxetan-3-ylmethoxy)-4-(propylamino)benzamide

To a solution of Compound 4a (0.21 g, 0.73 mmol) in EtOAc (10 mL), DIPEA (0.18 g, 1.46 mmol) and n-propylamine (0.08 g, 1.46 mmol) were allowed to react at 50 ° C overnight. After cooling, it is poured into ice water, and an orange-red solid precipitates. After filtration, it is dried to give 3-nitro-5-(oxetan-3-yloxy)-4-(propylamino) Benzoylamide (Compound 4b) (202 mg, 0.65 mmol, 89% yield), orange red solid.

¹ H NMR (400 MHz, DMSO): 8.23 (s, 1H), 8. s (s, 1H), 7.85 (s, 1H), 7.59 (s, 1H), 7.33 (s, 1H), 4.77 (q, 2H), 4.46 (t, 2H), 4.31 (d, 2H), 3.50-3.41 (m, 3H), 1.57-1.51 (m, 2H), 0.85 (t, 3H).

MS (ESI) m / z = 310 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-5-(oxetan-3-ylmethoxy)-4-(propylamino)benzamide

To a solution of the compound 4b (202 mg, 0.65 mmol) in methanol and ethyl acetate was added 10% Pd / C (0.05 g), hydrogenation reduction for 3 h, Pd / C was removed by filtration, and the filtrate was concentrated to give compound 4c (0.18 g, 0.65) M, 100% yield), used directly in the next reaction.

MS (ESI) m / z = 280 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-ylmethoxy)-1-propyl- Synthesis of 1H-benzo[d]imidazole-5-carboxamide

Compound 1h (0.13 g, 0.67 mmol) was added to compound 4c (0.18 g, 0.65 mmol) in DMF (10 mL). Then, HATU (0.25 g, 0.67 mmol) and DBU (0.1 g, 0.67 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h. 37.3% yield).

¹ H NMR (400 MHz, DMSO): 12.87 (s, 1 H), 8.1 (s, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 6.64 (s, 1H), 4.82 (q, 2H), 4.66 (q, 2H), 4.55 (t, 2H), 4.43 (d, 2H), 4.31 (t, 2H), 3.56-3.53 (m, 1H), 2.19 (s, 3H) , 1.87-1.81 (m, 2H), 1.38 (t, 3H), 0.94 (t, 3H).

MS (ESI) m / z = 441 [M+H] ⁺ .

Example 5 Preparation of a Compound of the Invention

Step 1: Synthesis of 4-chloro-3-nitro-5-(oxetan-2-ylmethoxy)benzamide

To a solution of oxetane-2-ylmethanol (1 g, 11.3 mmol) in dichloromethane (20 ml), DIPEA (2.9 g, 22.6 mmol), DMAP (0.13 g, 1.1 mmol) and p-toluenesulfonyl chloride ( 2.35g, 12.4mmol), reacted for 2h at room temperature, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give oxetane-2-ylmethyl-p-tosylate (1.9 g, 7.91 mmol, 70% yield), used directly in the next step.

To a solution of compound 1c (0.3 g, 1.38 mmol) in DMF (15 mL), EtOAc (EtOAc, EtOAc, EtOAc ), 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 to give 4-chloro-3-nitro-5-(oxetane-2- Methoxy)benzamide (Compound 5a) (0.25 g, 0.87 mmol, 63% yield), pale yellow solid.

MS (ESI) m / z = 287 [M+H] ⁺ .

Step 2: Synthesis of 3-nitro-5-(oxetan-2-ylmethoxy)-4-(propylamino)benzamide

To a solution of compound 5a (0.25 g, 0.87 mmol) in EtOAc (10 mL), EtOAc (EtOAc, EtOAc. After cooling, it was poured into ice water, and an orange-red solid precipitated. After filtration, it was dried to give 3-nitro-5-(oxetan-2-ylmethoxy)-4-(propylamino) Benzoylamide (Compound 5b) (0.19 g, 95% yield), orange-red solid.

MS (ESI) m / z = 310 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-5-(oxetan-2-ylmethoxy)-4-(propylamino)benzamide

To a solution of compound 5b (0.18 g, 0.58 mmol) in methanol and ethyl acetate was added 10% Pd/C (0.05 g), hydrogenation reduction for 3 h, Pd/C was removed by filtration, and the filtrate was concentrated to give compound 5c (0.16 g). , 0.58 mmol, 99% yield), used directly in the next reaction.

MS (ESI) m / z = 280 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-2-ylmethoxy)-1-propyl- Synthesis of 1H-benzo[d]imidazole-5-carboxamide

Compound 1h (0.1 g, 0.51 mmol) was added to compound 5c (0.15 g, 0.53 mmol) in DMF (5 mL). Then, HATU (0.2 g, 0.52 mmol) and DBU (0.1 g, 0.64 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h. , 98% purity, 34% yield).

¹ H NMR (400 MHz, DMSO) 8.00 (s, 1H) 7.70 (s, 1H) 7.44 (s, 1H) 7.38 (s, 1H) 6.65 (s, 1H) 5.13 to 5.14 (m, 1H) 4.63 (q, 3H) ) 4.51 to 4.56 (m, 1H) 4.31 to 4.42 (m, 4H) 2.73 to 2.82 (m, 1H) 2.58 to 2.67 (m, 1H) 2.18 (s, 3H) 1.77 to 1.86 (m, 2H) 1.36 (t , 3H) 0.91 (t, 3H).

MS (ESI) m / z = 441 [M+H] ⁺ .

Example 6. Preparation of a compound of the invention

Step 1: Synthesis of 4-chloro-3-nitro-5-(N-tert-butoxycarbonylazetidin-3-ylmethoxy)benzamide

To a solution of N-tert-butoxycarbonylazetidin-3-propanol (1.0 g, 5.34 mmol) in dichloromethane (30 ml), DIPEA (1. <RTI ID=0.0> And p-toluenesulfonyl chloride (1.1 g, 5.87 mmol), and reacted at room temperature for 2 h, respectively, washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give N-t-butoxycarbonylazetidine. Alkyl-3-ylmethyl-p-toluenesulfonate (1.2 g, 4.9 mmol, 91% yield) was used directly in the next step.

Add cesium carbonate (0.7 g, 2.16 mmol) and N-tert-butoxycarbonylazetidin-3-ylmethyl-p-benzenesulfonate to a solution of compound 1c (0.23 g, 1.08 mmol) in DMF (15 mL) (0.55 g, 1.6 1 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 to give 4-chloro-3-nitro-5-(N-tert-butoxycarbonyl aza Cyclobutane-3-ylmethoxy)benzamide (Compound 6a) (0.25 g, 0.65 mmol, 60% yield)

MS (ESI) m / z = 386 [M+H] ⁺ .

Step 2: Synthesis of 3-nitro-5-(N-tert-butoxycarbonylazetidin-3-ylmethoxy)-4-(propylamino)benzamide

To a solution of compound 6a (0.245 g, 0.63 mmol) in EtOAc (10 mL), EtOAc (EtOAc) After cooling, it was poured into ice water, and an orange-red solid precipitated. After filtration, it was dried to give 3-nitro-5-(N-tert-butoxycarbonylazetidin-3-ylmethoxy)- 4-(propylamino)benzamide (Compound 6b) (0.21 g, 0.52 mmol, 82% yield).

MS (ESI) m / z = 409 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-5-(N-tert-butoxycarbonylazetidin-3-ylmethoxy)-4-(propylamino)benzamide

To a solution of compound 6b (0.2 g, 0.49 mmol) in methanol and ethyl acetate was added 10% Pd/C (0.06 g), hydrogenation reduction for 3 h, Pd/C was removed by filtration, and the filtrate was concentrated to give 3-amino- 5-(N-tert-Butoxycarbonylazetidin-3-ylmethoxy)-4-(propylamino)benzamide (Compound 6c) (0.14 g, 0.36 mmol, 75% yield) Used directly in the next step.

MS (ESI) m / z = 379 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(N-tert-butoxycarbonylazetidin-3-ylmethoxy) Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide

Compound 1h (0.066 g, 0.34 mmol) was added to EtOAc (EtOAc m. Then, HATU (0.13 g, 0.34 mmol) and DBU (0.063 g, 0.41 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated to give a crude compound. ).

¹ H NMR (400 MHz, DMSO) 1.99 (s, 1H) 7.69 (d, 1H) 7.42 (d, 1H) 7.38 (s, 1H) 6.63 (s, 1H) 4.63 (q, 2H) 4.34 (d, 2H) 4.30 (t, 2H) 4.04 (s, 2H) 3.79 (s, 2H) 3.04 to 3.12 (m, 1H) 1.72 to 1.82 (m, 2H) 1.40 (s, 9H) 1.36 (t, 3H) 0.91 (t, 3H) ).

MS (ESI) m / z = 540 [M+H] ⁺ .

Step 5: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(azetidin-3-ylmethoxy)-1-propyl- Synthesis of 1H-benzo[d]imidazole-5-carboxamide

To a solution of compound 6d (0.05 g, EtOAc. The reaction was carried out for 1 h at rt. EtOAc (m.)

^{1 HNMR (400MHz, DMSO) 8.83} (d, 2H) 8.00 (s, 1H) 7.70 (s, 1H) 7.43 (s, 1H) 7.41 (s, 1H) 6.64 (s, 1H) 4.63 (q, 2H) 4.41 (d, 2H) 4.28 (t, 2H) 4.10 to 4.18 (m, 2H) 3.88 to 3.95 (m, 2H) 3.32 to 3.39 (m, 1H) 2.18 (s, 3H) 1.77 (m, 2H) 1.35 (t , 3H) 0.91 (t, 3H).

MS (ESI) m / z = 440 [M+H] ⁺ .

Example 7. Preparation of a compound of the invention

Step 1: Synthesis of 4-chloro-3-nitro-5-(N-tert-butoxycarbonylazetidin-3-ylethoxy)benzamide

To a solution of N-tert-butoxycarbonylazetidin-3-ethanol (1.0 g, 4.9 mmol) in dichloromethane <RTI ID=0.0>(</RTI> <RTIgt; And p-toluenesulfonyl chloride (1.0 g, 5.3 mmol), and reacted at room temperature for 2 h, respectively, and washed with water and brine, and the organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to give N-t-butoxycarbonylazetidine. Alkyl-3-ylethyl p-benzenesulfonate (1.38 g, 3.9 mmol) was used directly in the next step.

To a solution of compound 1c (0.4 g, 1.85 mmol) in DMF (15 mL), EtOAc (EtOAc, EtOAc, EtOAc The ester (0.68 g, 1.9 mmol) was 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 to give 4-chloro-3-nitro-5-(N-tert-butoxycarbonyl aza Cyclobutane-3-ylethoxy)benzamide (Compound 7a) (0.52 g, 1.3 mmol, 70% yield)

MS (ESI) m / z = 400 [M+H] ⁺ .

Step 2: Synthesis of 3-nitro-5-(N-tert-butoxycarbonylazetidin-3-ylethoxy)-4-(propylamino)benzamide

To a solution of compound 7a (0.25 g, 0.62 mmol) in EtOAc (10 mL), EtOAc (EtOAc) After cooling, it is poured into ice water, and an orange-red solid precipitates. After filtration, it is dried to give 3-nitro-5-(oxetan-3-yloxy)-4-(propylamino) Benzoylamide (Compound 7b) (0.22 g, 0.52 mmol), orange red solid.

MS (ESI) m / z = 422 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-5-(N-tert-butoxycarbonylazetidin-3-ylethoxy)-4-(propylamino)benzamide

10% Pd/C (0.02 g) was added to a solution of the compound 7b (0.21 g, 0.49 mmol) in methanol and ethyl acetate, and hydrogenation reduction was carried out for 3 h, and Pd/C was removed by filtration, and the filtrate was concentrated to give compound 7c (0.19 g, 0.48 mmol) was used directly for the next reaction.

MS (ESI) m / z = 393 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(N-tert-butoxycarbonylazetidin-3-ylethoxy) Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide

Compound 1h (0.088 g, 0.45 mmol) was added to compound 7c (0.18 g, 0.45 mmol) in DMF (5 mL). Then, HATU (0.18 g, 0.47 mmol) and DBU (0.085 g, 0.55 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h, and the reaction mixture was concentrated to give a crude compound. ).

¹ H NMR (400 MHz, DMSO) 7.98 (s, 1H) 7.67 (d, 1H) 7.37 (d, 2H) 6.64 (s, 1H) 4.31 (t, 2H) 4.18 (t, 2) 3.90 (br, 2) 3.62 (br, 2) 2.71 - 2.78 (m, 1H) 2.18 (s, 3H) 2.14 (dd, 2H) 1.80 (dd, 2H) 1.38 (s, 9H) 1.35 (t, 3H) 0.93 (t, 3H).

MS (ESI) m / z = 554 [M+H] ⁺ .

Step 5: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(azetidin-3-ylethoxy)-1-propyl- Synthesis of 1H-benzo[d]imidazole-5-carboxamide

To a solution of compound 7d (0.02 g, EtOAc, EtOAc) The reaction was carried out for 1 h at rt.

¹ H NMR (400 MHz, DMSO) 8.66 (d, 2H) 7.79 (s, 1H) 7.67 (s, 1H) 7.38 (s, 1H) 6.64 (s, 1H) 4.63 (q, 2H) 4.31 (t, 2H) 4.18 (t, 2H) 4.03 to 4.10 (m, 2H) 3.76 to 3.85 (m, 2H) 2.97 to 3.05 (m, 1H) 2.18 (s, 3H) 2.16 (t, 1H) 1.80 (dd, 2H) 1.38 (s , 9H) 1.36 (t, 3H) 0.94 (t, 3H).

MS (ESI) m / z = 454 [M+H] ⁺ .

Example 8. Preparation of a compound of the invention

Step 1: Synthesis of 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 12 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 (Compound 8a) (0.86 g, yield 73.5%).

MS (ESI) m / z = 301 [M+H] ⁺ .

Step 2: Synthesis of 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzamide

To a solution of compound 8a (0.21 g, 0.73 mmol) in EtOAc (10 mL), EtOAc (EtOAc) After cooling, it was poured into ice water, and an orange-red solid precipitated. After filtration, it was dried to give 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4 -(propylamino)benzamide (Compound 8b) (202 mg, 0.65 mmol, 89% yield).

MS (ESI) m / z = 324 [M+H] ⁺ .

Step 3: Synthesis of 3-amino-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzamide

To a solution of the compound 8b (202 mg, 0.65 mmol) in methanol and ethyl acetate was added 10% Pd / C (0.05 g), hydrogenation reduction for 3 h, Pd / C was removed by filtration, and the filtrate was concentrated to give 3-amino-5- ( 2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzamide (Compound 8c) (0.18 g, 0.65 mmol, 100% yield) reaction.

MS (ESI) m / z = 294 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1 - Synthesis of propyl-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (0.13 g, 0.67 mmol) was added to compound 8c (0.18 g, 0.65 mmol) in DMF (10 mL) In the middle, the reaction was continued for 20 min after the addition was completed. Then, HATU (0.25 g, 0.67 mmol) and DBU (0.1 g, 0.67 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h. 37.3% yield).

¹ H NMR (400 MHz, DMSO): 12.85 (s, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 7.37 (m, 2H), 6.64 (s, 1H), 4.75 (t, 2H), 4.64(q,2H), 4.39(t,2H), 4.31(d,2H), 4.18(t,2H),3.24-3.19(m,1H), 2.25-2.21(m,5H),1.81(q, 2H), 1.38 (t, 3H), 0.95 (t, 3H).

MS (ESI) m / z = 455 [M+H] ⁺ .

Example 9. Preparation of a compound of the invention

Step 1: Synthesis of 2-(3-methyloxetan-3-yl)acetic acid ethyl acetate

Was added CuI (267mg, 1.4mmol) and Compound 9a (2.0g, 14.8mmol) to TMSCl (3.52g, 32.38mmol) in tetrahydrofuran (30ml) at -20 ℃ nitrogen and, five minutes later, the CH ₃ MgBr (42 mL, 42 mmol, 1 M in THF) was added dropwise to the mixture and maintained at -20 ° C. After the dropwise addition was completed, the reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and dichlorobenzene was added. The methane was extracted and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then purified on silica gel column ( petroleum ether / ethyl acetate = 20/1, v / v) Methyl oxetane-3-yl)acetate (Compound 9b) (1.2 g, 7.6 mmol, 53.9% yield).

MS (ESI) m/z = 159.2 [M+H] ⁺

Step 2: Synthesis of 2-(3-methyloxetan-3-yl)ethanol

(10ml) was added LiAlH ₄ (167mg, 4.4mmol) of compound 9b (580mg, 3.67mmol) in THF under ice-cooling, the reaction solution was slowly warmed to room temperature and stirred for 2h. The reaction solution was poured into a sodium sulfate decahydrate solid in an ice bath, stirred and quenched, then filtered, and the filter cake was washed several times with dichloromethane and methanol, and the obtained filtrate was dried to give 2-(3-methyloxa) Cyclobutane-3-yl)ethanol (Compound 9c) (430 mg, 100%) as a pale-yellow liquid, used directly in the next step.

MS (ESI) m/z = 117.0 [M+H] ⁺

Step 3: Synthesis of 2-(3-methyloxetan-3-yl)ethyl 4-methylbenzenesulfonate

TEA (800 mg, 7.34 mmol) and p-toluenesulfonyl chloride (698 mg, 3.67 mmol) were added to a solution of the compound 9c (426 mg, 3.67 mmol) in dichloromethane (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(3-methyl oxetane-3-yl)ethyl 4-methylbenzenesulfonate (Compound 9d) (650 mg, yield 65.5%) of a yellow oil.

MS (ESI) m/z = 271.0 [M+H] ⁺

Step 4: Synthesis of 4-chloro-3-(2-(3-methyloxetan-3-yl)ethoxy)-5-nitrobenzamide

Potassium carbonate (663 mg, 4.8 mmol) and Compound 1c (650 mg, 2.4 mmol) were added to a solution of compound 9d (521 mg, 2.4 mmol) in DMF (10 ml), and reacted at 75 ° C for 3 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 then recrystallized from ethyl acetate/ petroleum ether to give 4-chloro-3-(2-(3- Methyloxetan-3-yl)ethoxy)-5-nitrobenzamide (Compound 9e) (700 mg, 2.22 mmol, 93% yield)

MS (ESI) m/z = 315.0 [M+H] ⁺

Step 5: Synthesis of 3-(2-(3-methyloxetan-3-yl)ethoxy)-5-nitro-4-(propylamino)benzamide

To a solution of compound 9e (700 mg, 2.22 mmol) in EtOAc (10 mL) After cooling, pour it into ice water, precipitate with an orange-red solid, filter and dry to give 3-(2-(3-methyloxetan-3-yl)ethoxy)-5-nitrate 4-(propylamino)benzamide (Compound 9f) (700 mg, 2.08 mmol, yield 93%).

MS (ESI) m/z = 338.0 [M+H] ⁺

Step 6: Synthesis of 3-amino-5-(2-(3-methyloxetan-3-yl)ethoxy)-4-(propylamino)benzamide

Compound 9f (700 mg, 2.08 mmol) was dissolved in methanol (10 mL), and then evaporated to 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 ethyl acetate (20 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate 5-(2-(3-methyloxetan-3-yl)ethoxy)-4-(propylamino)benzamide (Compound 9g) (398 mg, yield 62%) Things.

MS (ESI) m/z = 308.0 [M+H] ⁺

Step 7: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(3-methyloxetan-3-yl)ethoxylate Synthesis of 1-propyl-1H-benzo[d]imidazole-5--carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (248 mg, 1.27 mmol) was added to compound 9 g (390 mg, 1.27 mmol) in DMF (5 mL) After the addition was completed, the reaction was continued for 20 min. Then, HATU (579 mg, 1.52 mmol) and DIPEA (491 mg, 3.81 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 h. The reaction mixture was diluted with water, and then a white solid was filtered, then recrystallized from dichloromethane/ petroleum ether. Compound 9 (280 mg, 0.60 mmol, 97% purity, 47% yield).

MS (ESI) m/z = 469.0 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.84 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 1.1Hz, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 6.62 (s, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.46 (d, J = 5.6 Hz, 2H), 4.33 - 4.16 (m, 5H), 2.28 - 2.09 (m, 4H), 1.79 (dq, J = 14.4, 7.3 Hz, 2H), 1.42 - 1.19 (m, 5H), 0.93 (t, J = 7.4 Hz, 3H).

Example 10 Preparation of a Compound of the Invention

Step 1:1:1 Synthesis of methyl 2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1H-pyrazole-5-carboxylate

Dissolve 3-methyl-1 hydrogen-pyrazole-5-carbonate (5.39 g, 38.46 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (11 g, 45.98 mmol) at room temperature Potassium carbonate (9.66 g, 70 mmol) was added to DMF (60 mL). The temperature was raised to 60 ° C for 12 h. Dilute with water, extract with ethyl acetate (200 mL×4), wash the organic phase with water (100 mL×3), dry over anhydrous sodium sulfate, and then evaporated under reduced pressure and purified by column chromatography (eluent ethyl acetate / petroleum ether =1/10,v/v)methyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1H-pyrazole-5-carboxylate (Compound 10a) (4.73 g, yield 41%) as a colorless oil.

MS (ESI) m / z = 299 [M+H] ⁺ .

Step 2: Synthesis of methyl 1-(2-hydroxyethyl)-3-methyl-1H-pyrazole-5-carboxylate

Compound 10a (3.7 g, 12.4 mmol) was dissolved in dichloromethane (25 mL). The reaction solution was stirred at room temperature for 30 minutes. The reaction mixture was sparged and purified by reverse phase (eluent acetonitrile/water = 30/70, v/v) to give 1-(2-hydroxyethyl)-3-methyl-1H-pyrazole-5-carboxyl. Methyl ester (compound 10b) (1.67 g, yield 73%), pale yellow solid.

MS (ESI) m / z = 185 [M+H] ⁺ .

Step 3: Synthesis of methyl 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylate

DAST (2.92 g, 18.13 mmol) was added dropwise to a solution of compound 10b (1.66 g, 9.06 mmol) and triethylamine (1.83 g, 18.13 mmol) in dichloromethane (20 mL). 12h. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc (EtOAc) /ethyl acetate = 1/3, v / v) Methyl 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylate (Compound 10c) (500 mg, yield 29 %), oily.

MS (ESI) m / z = 187 [M+H] ⁺ .

Step 4: Synthesis of 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid

An aqueous solution (2 mL) of lithium hydroxide (320 mg, 13.43 mmol) was added to a mixture of compound 10c (495 mg, 2.66 mmol) in tetrahydrofuran (3 mL) and methanol (2 mL). Diluted with 20 mL of water, the organic solvent was evaporated, and the mixture was extracted with ethyl acetate. The aqueous phase was adjusted to pH=4 with 1N HCl and then extracted with ethyl acetate (10×4). The organic phase was combined and washed with water. -(2-Fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid compound 10d (353 mg, yield 75%).

MS (ESI) m / z = 173 [M+H] ⁺ .

Step 5: Synthesis of 1-fluoroethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate

Compound 10d (350, 2.03 mmol) was dissolved in dry DCM (10 mL) and EtOAc (EtOAc, EtOAc, After reacting for 1 h at room temperature, the volatiles were evaporated under reduced pressure. DCM (20 mL) was added to EtOAc (EtOAc)EtOAc. .

1-Fluoroethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (386 mg, 2.03 mmol) was dissolved in dry acetone (5 mL) and added dropwise to potassium thiocyanate (395 mg). , 4.07 mmol) in acetone (15 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 = 1/15) 1-Fluoroethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (Compound 10e) (400 mg, 1.88 mmol, 92%).

MS (ESI) m / z = 214 [M+H] ⁺ .

Step 6: 2-(1-(2-Fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)B Synthesis of oxy)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

The compound 1-fluoroethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (75 mg, 0.351 mmol) was added dropwise to 3-amino-5-(2-) under ice bath. (N-N-dimethylformamide) (100 mg, 0.341 mmol) in N,N-dimethylformamide (1 mL) h. Then, HATU (130 mg, 0.341 mmol) and N,N-diisopropylethylamine (130 mg, 1.01 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h, and the reaction mixture was separated by column chromatography (eluent acetonitrile / water = 1/3, v/v) gave compound 10 (14 mg) as a white solid.

MS (ESI) m / z = 473 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) 0.93 (t, J = 7.0 Hz, 3H) 1.75 - 1.84 (m, 2H) 2.20 (s, 3H) 3.16 - 3.25 (m, 1H) 4.15 (t, J = 6.4 Hz, 2H) 4.31 (t, J = 7.0 Hz, 2H) 4.37 to 4.42 (m, 3H) 4.71 to 4.75 (m, 4H) 4.86 (t, J = 5.0 Hz, 1H) 4.93 (t, J = 4.2 Hz, 1H) 4.99 (t, J = 4.2 Hz, 1H) 6.69 (s, 1H) 7.33 (d, J = 11.6 Hz, 1H) 7.37 (s, 1H) 7.67 (s, 1H) 7.97 (d, J = 6.8 Hz, 1H) ) 12.83(s,1H)

Example 11 Preparation of a Compound of the Invention

Synthesis of methyl 1-(2-(2-difluoroethyl)-3-methyl-1H-pyrazole-5-carboxylate

3-Methyl-1 hydrogen-pyrazole-5-carbonate (2.8 g, 19.98 mmol) and 2-bromo-1,1-difluoroethane (3.18 g, 21.94 mmol) were dissolved in DMF at room temperature. In 30 mL), potassium carbonate (4.14 g, 30 mmol) was further added. The temperature was raised to 50 ° C for 12 h. Dilute with water, extract with ethyl acetate (200 mL×4), wash the organic phase with water (100 mL×3), dry over anhydrous sodium sulfate, and then evaporated under reduced pressure and purified by column chromatography (eluent ethyl acetate / petroleum ether =1/10,v/v) Methyl 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5-carboxylate (Compound 11a) (2.4 g, yield 58 %), colorless oil.

MS (ESI) m / z = 205 [M+H] ⁺ .

Step 2: Synthesis of 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid

An aqueous solution (10 mL) of lithium hydroxide (1.09 g, 25.95 mmol) was added to a mixture of compound 11a (1.06 g, 5.19 mmol) in tetrahydrofuran (10 mL) and methanol (5 mL). The reaction solution was stirred at room temperature for 2 h. After drying the organic solvent, the organic phase was extracted with ethyl acetate. The aqueous phase was acidified to pH ≈4 with dilute hydrochloric acid (1M) and then extracted with ethyl acetate (10mL×3). The organic phase was combined and washed with water and brine Dry solvent gave 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid (Compound 11b) (950 mg, yield: 96%).

MS (ESI) m / z = 191 [M+H] ⁺ .

Step 3: Synthesis of 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate

Compound 11b (265, 1.39 mmol) was dissolved in dry DCM (5 mL) and EtOAc (EtOAc, EtOAc, After reacting for 1 h at room temperature, the volatiles were evaporated under reduced pressure. DCM (20 mL) was added to EtOAc EtOAc (EtOAc m. Used directly in the next step.

1-2,2-Difluoroethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (289 mg, 1.39 mmol) was dissolved in dry acetone (5 mL) and added dropwise to thiocyanate at 0 °C. Potassium acid (270 mg, 2.78 mmol) in acetone (10 mL) was stirred at room temperature for 3 h. The reaction system was filtered to remove inorganic salts. The filtrate was concentrated and purified on silica gel column (eluent: ethyl acetate / petroleum ether, v/ v=1/15) 1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (Compound 11c) (250 mg, 1.08 mmol, 77%) ), a clear brownish yellow liquid.

MS (ESI) m / z = 232 [M+H] ⁺ .

Step 4: 2-(1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetane-3- Synthesis of ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

The compound 1-fluoroethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (50 mg, 0.216 mmol) was added dropwise to 3-amino-5-(2-( A solution of oxetane-3-yl)ethoxy)-4-(propylamino)benzamide (63 mg, 0.216 mmol) in N,N-dimethylformamide (1 mL) . Then, HATU (88 mg, 0.216 mmol) and N,N-diisopropylethylamine (85 mg, 0.65 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h, and the reaction mixture was directly used for reverse phase HPLC purification (eluent: acetonitrile / Water = 1/3, v/v) Compound 11 (18.42 mg, yield 17%).

MS (ESI) m / z = 491 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) 12.86 (s, 1H) 7.98 (s, 1H) 7.67 (s, 1H) 7.37 (s, 2H) 6.73 (s, 1H) 6.40 (t, J = 55.6 Hz, 1H) 5.11 ( t, J = 12.4 Hz, 2H) 4.72 (t, J = 6.8 Hz, 2H) 4.38 (t, J = 5.6 Hz, 2H) 4.31 (t, J = 6.4 Hz, 2H) 4.15 (t, J = 6.0 Hz) , 2H) 3.16 to 3.23 (m, 1H) 2.18 to 2.24 (m, 2H) 2.20 (s, 3H) 1.79 (q, J ₁ = 6.8 Hz, J ₂ = 13.6 Hz, 2H) 0.93 (t, J = 7.2 Hz, 3H)

Example 12 Preparation of a Compound of the Invention

Step 1: Synthesis of 2-chloro-6-ethyl isonicotinic acid methyl ester

Methyl 2,6-dichloronicotinate (544 mg, 2.64 mmol) and diethyl zinc (2.64 mL, 2.64 mmol) were added to 1,4-dioxane (8 mL) at room temperature under nitrogen. Thereafter, Pd(dppf)Cl ₂ (70 mg, 0.264 mmol) was added, and the mixture was heated to 70 ° C under nitrogen to stir the reaction for 16 hours. After the reaction was completed, it was cooled to room temperature, and then extracted with ethyl acetate (20 mL×3), and the organic phase was combined and washed with water and brine, dried over anhydrous sodium sulfate and filtered. Deprotection: ethyl acetate/petroleum ether, v/v = 1/15) gave 2-chloro-6-ethyl isoniconic acid methyl ester (Compound 12a) (308 mg, 0.1.54 mmol), yield: 58%.

MS (ESI) m / z = 200 [M+H] ⁺ .

Step 2: Synthesis of (2-chloro-6-ethylpyridin-4-yl)methanol

Lithium aluminum hydride (71 mg, 1.87 mmol) was added to methyl 2-chloro-6-ethylisonicotinate (305 mg, 1.53 mmol) in tetrahydrofuran (3 mL). After the completion of the reaction, the mixture was quenched with EtOAc EtOAc (EtOAc) -Chloro-6-ethylpyridin-4-yl)methanol (Compound 12b) (200 mg, 1.17 mmol), yield 75%.

MS (ESI) m / z = 172 [M+H] ⁺ .

Step 3: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro-6-ethylpyridine

tert-Butyldimethylchlorosilane (210 mg, 2.55 mmol) was added to (2-chloro-6-ethylpyridin-4-yl)methanol (195 mg, 1.16 mmol), imidazole (159 mg, 2.34). Methyl) and 4-dimethylaminopyridine (20mg, 0.16mmol) in dichloromethane (10mL), after the addition is completed, the temperature is raised to room temperature for 3h, after the reaction is completed, dilute with dichloromethane, wash with water and saturated brine, spin The crude product obtained by dry solvent was purified by silica gel column (eluent: ethyl acetate / petroleum ether v/v = 1/10) to give 4-(((tert-butyldimethylsilyl)oxy)methyl)- 2-Chloro-6-ethylpyridine (Compound 12c) (153 mg, 0.535 mmol), yield: 45%.

MS (ESI) m / z = 286 [M+H] ⁺ .

Step 4: 2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-ethylpyridin-2-yl)amino)-7-(2-(oxa) Synthesis of Methylcyclobutane-3-yl)ethoxy)-1-propyl-1H-methyl-benzo[d]imidazole-5-carboxylate

To compound 12c (78 mg, 0.272 mmol) and 2-amino-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d] at room temperature To a solution of methyl imidazole-5-carboxylate (91 mg, 0.273 mmol) in 1,4-dioxane (5 mL), potassium t-butoxide (53 mg, 0.546 mmol), Pd2 (dba) 3 (8.19 mg, 8.95) Umol) and Xantphos (10.4 mg, 17.99 umol), after nitrogen substitution, the temperature was raised to 100 ° C and the reaction was stirred for 16 h. After completion of the reaction, the mixture was cooled to room temperature, and then water was evaporated. Oxy)methyl)-6-ethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-methyl Methyl benzo[d]imidazole-5-carboxylate (Compound 12d) was used directly in the next reaction.

MS (ESI) m / z = 583 [M+H] ⁺ .

Step 5: 2-((6-Ethyl-4-(hydroxymethyl)pyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxylic acid

The crude compound 12d was dissolved in tetrahydrofuran (3 mL), and then aqueous solution (3Ml) of lithium hydroxide (34 mg, 0.819 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was purified by reverse-phase MPLC to give 2-((6-ethyl) 4-(hydroxymethyl)pyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d] Imidazole-5-carboxylic acid (Compound 12e) (26 mg, 0.057 mmol), 20% yield in two steps.

MS (ESI) m / z = 455 [M+H] ⁺ .

Step 6: 2-((6-ethyl-4-(hydroxymethyl)pyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxamide

Compound 12e (26 mg, 57.20 umol) and ammonium chloride (10 mg, 57.20 umol) were added to DMF (1 mL), and EDCI (17 mg, 57.20 umol) and HOAT (12 mg, 57.20 umol) were added. The reaction was stirred at room temperature for additional 18 h and then purified by EtOAc EtOAc (EtOAc)

MS (ESI) m / z = 454 [M+H] ⁺ .

¹ H NMR (DMSO, 400 MHz) 0.83 (t, J = 6.8 Hz, 3H), 1.23 (t, J = 8.0 Hz, 3H), 1.67 to 1.74 (m, 2H), 2.19 (q, J ₁ = 6.8 Hz, J ₂ = 14.0 Hz, 2H), 2.63 to 2.73 (m, 2H), 3.17 to 3.24 (m, 1H), 4.10 (t, J = 6.4 Hz, 2H), 4.38 (t, J = 6.0 Hz, 4H) , 4.45 to 4.53 (m, 2H), 4.71 (q, J ₁ = 6.0 Hz, J ₂ = 7.6 Hz, 2H), 5.35 (s, 1H), 6.79 (s, 1H), 7.16 (s, 1H), 7.23(s,1H), 7.68(s,1H), 7.88(s,1H), 7.91(s,1H), 9.50(s,1H)

Example 13, Preparation of the Compound of the Invention

Step 1: 2-((4,6-Dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H Synthesis of benzo[d]imidazol-5-carboxylic acid methyl ester

2-Bromo-4,6-lutidine (75 mg, 0.41 mmol), 2-amino-7-(2-(oxetan-3-yl)ethoxy)-1 at room temperature -propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (91 mg, 0.273 mmol) and cesium carbonate (178 mg, 0.546 mmol) were added to 1,4-dioxane (4.5 mL). After replacing the air with nitrogen, Pd2(dba)3 (8.19 mg, 8.95 umol) and Xantphos (10.4 mg, 17.99 umol) were added, and the mixture was heated to 100 ° C and stirred for 16 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc (EtOAc) (EtOAc) Petroleum ether, v/v = 1/5) gives 2-((4,6-dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxylate Methyl 1-propyl-1H-benzo[d]imidazole-5-carboxylate (Compound 13a) (60 mg, 0.136 mmol), yield: 45%.

MS (ESI) m / z = 437 [M+H] ⁺ .

Step 2: 2-((4,6-Dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H Synthesis of benzo[d]imidazole-5-carboxylic acid

An aqueous solution (1 mL) of lithium hydroxide (26 mg, 0.628 mmol) was added to a mixture of compound 13a (55 mg, 0.125 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with H2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ , dry solvent to give 2-((4,6-dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl -1H-Benzo[d]imidazole-5-carboxylic acid (Compound 13b) (50 mg, 0.117 mmol), white solid.

MS (ESI) m / z = 425 [M+H] ⁺ .

Step 3: 2-((4,6-Dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide

Compound 13b (45 mg, 0.106 mmol) and ammonium chloride (17 mg, 0.318 mmol) were added to DMF (1 mL) and EDCI (23 mg, 0.117 mmol), HOAT (16 mg, 0.117 mmol) and DIPEA ( 41 mg, 0.318 mmol). The reaction solution was stirred at room temperature for 18 h. After the reaction was completed, the reaction mixture was purified by Prep-HPLC to give compound 13 (21.74 mg, 51.

MS (ESI) m / z = 422 [M+H] ⁺ .

¹ H NMR (DMSO, 400 MHz) 0.85 (t, J = 6.8 Hz, 3H) 1.64 - 1.78 (m, 2H) 2.19 (q, J1 = 6.8 Hz, J2 = 13.6 Hz, 2H) 2.28 (s, 3H) 2.40 ( s, 3H) 3.17 to 3.24 (m, 1H) 4.11 (t, J = 6.0 Hz, 2H) 4.31 to 4.44 (m, 4H) 4.72 (dd, J1 = 6.4, J2 = 7.6 Hz, 2H) 6.65 (s, 1H) 7.19 (s, 1H) 7.26 (s, 1H) 7.68 (s, 1H) 7.91 (s, 1H)

Example 14, Preparation of the Compound of the Invention

Step 1: 2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxa) Synthesis of Ethylcyclobutane-3-yl)ethoxy)-1-propyl-1H-methyl-benzo[d]imidazole-5-carboxylate

2-Bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridine (85 mg, 0.268 mmol), 2-amino-7-(2- at room temperature (Oxetane-3-yl)ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (60 mg, 0.179 mmol) and cesium carbonate (117 mg, 0.36 mmol) Add to 1,4-dioxane (4.5 mL), add Pd2(dba)3 (8.19 mg, 8.95 umol) and Xantphos (10.4 mg, 17.99 umol) after nitrogen replacement system air, and heat up after nitrogen gas exchange. The reaction was stirred at 100 ° C for 16 h. After the reaction was completed, it was cooled to room temperature, EtOAc (EtOAc) (EtOAc) Ether, v/v = 1/5) gives 2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2-yl)amino)- Ethyl 7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-methyl-benzo[d]imidazole-5-carboxylate (Compound 14a) (50 mg , 0.087 mmol), yield: 48%.

MS (ESI) m / z = 569 [M+H] ⁺ .

Step 2: 2-((4-(Hydroxymethyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxylic acid

Compound 14a (49 mg, 0.086 mmol) was dissolved in EtOAc (1 mL) (EtOAc) The reaction solution was stirred at room temperature for 2 h. The organic solvent was diluted with water and extracted with EtOAc. EtOAc (EtOAc)EtOAc. Dry solvent to give 2-((4-(hydroxymethyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 -propyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 14b) (37 mg, 0.084 mmol), white solid.

MS (ESI) m / z = 441 [M+H] ⁺ .

Step 3: 2-((4-(Hydroxymethyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxamide

Compound 14b (35 mg, 0.079 mmol) and ammonium chloride (12 mg, 0.237 mmol) were added to DMF (1 mL) and EDCI (18 mg, 0.095 mmol) and HOAT (13 mg, 0.095 mmol). The mixture was stirred at room temperature for 1 h. After completion of the reaction, the obtained mixture was purified by Prep-HPLC to afford compound 14 (23 mg, 0.052 mmol) yield 46%.

MS (ESI) m / z = 440 [M+H] ⁺ .

¹ H NMR (DMSO, 400 MHz) 0.84 (t, J = 6.8 Hz, 3H) 1.67 - 1.74 (m, 2H) 2.19 (q, J1 = 6.0 Hz, J2 = 13.2 Hz, 2H) 2.41 (s, 3H) 3.16 - 3.24 (m, 1H) 4.10 (t, J = 6.0 Hz, 2H) 4.35 to 4.52 (m, 6H) 4.72 (dd, J1 = 6.0 Hz, J2 = 7.2 Hz, 2H) 5.37 (t, J = 6.0 Hz, 1H) 6.78(s,1H)7.16(s,1H)7.24(s,1H)7.69(s,1H)7.89(s,1H)7.95(s,1H)9.53(s,1H)

Example 15. Preparation of a Compound of the Invention

Step 1: Synthesis of 3-amino-5-(oxetan-3-yloxy)-4-(propylamino)benzamide

Aqueous ammonia (3.8 mL, 26 mmol) was added dropwise to 3-nitro-5-(oxetan-3-yloxy)-4-(propylamino)benzamide (770 mg, 2.6 mmol). In a solution of methanol (30 mL), after 5 min, an aqueous solution (10 mL) of the powder (2.27 mg, 13.0 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was filtered, and the obtained filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,, Yield 65%, yellow solid.

MS (ESI) m/z = 266.0 [M+H] ⁺

Step 2: N-(5-carbamoyl-7-(oxetan-3-yloxy)-1-propyl-1H-benzo[d]imidazol-2-yl)-4-ethyl Synthesis of benzyl-2-methyloxazole-5-carboxamide

4-Ethyl-2-methyloxazol-5-carbonyl isothiocyanate (44 mg, 0.23 mmol) was added dropwise to the compound 3-amino-5-(oxetan-3- in an ice bath Alkoxy)-4-(propylamino)benzamide (60 mg, 0.23 mmol) in DMF (2 mL) EtOAc EtOAc (EtOAc) (mmol), the resulting reaction mixture was stirred at room temperature for 2 h. A white solid gradually precipitated, and the filter cake was washed with methanol and water in turn, and the cake was dried to give N-(5-carbamoyl-7-(oxetan-3-yloxy)-1-propane. Base-1H-benzo[d]imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide (30 mg, yield 31%) as a white solid.

MS (ESI) m/z = 428.0 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 12.77 (s, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 5.66 - 5.39 (m) , 1H), 5.03 (t, J = 6.6 Hz, 2H), 4.63 (dd, J = 7.0, 4.9 Hz, 2H), 4.48 - 4.17 (m, 2H), 3.35 (s, 3H), 3.01 (dd, J = 14.7, 7.3 Hz, 2H), 2.44 (s, 3H), 1.90 - 1.70 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H).

Example 16. Preparation of a compound of the invention

4-Ethyl-2-methylthiazole-5-carbonyl isothiocyanate (49 mg, 0.23 mmol) was added dropwise to 3-amino-5-(oxetan-3-yloxy) under ice bath Benzyl-4-(propylamino)benzamide (60 mg, 0.23 mmol) in DMF (2 mL) EtOAc (EtOAc) Stirring was continued for 2 h at room temperature. The reaction solution was purified by reverse phase HPLC to give N-(5-carbamoyl-7-(oxetan-3-yloxy)-1-propyl-1H-benzo[d]imidazol-2-yl 4-ethyl-2-methylthiazole-5-carboxamide (34.3 mg, yield 34%), white solid.

MS (ESI) m/z = 444 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.83 (s, 1H), 7.97 (s, 1H), 7.67 (d, J = 1.0Hz, 1H), 7.38 (s, 1H), 6.95 (d, J = 0.8 Hz, 1H), 5.58–5.47 (m, 1H), 5.02 (t, J = 6.7 Hz, 2H), 4.69 - 4.57 (m, 2H), 4.33 (t, J = 7.2 Hz, 2H), 3.20 (q) , J = 7.5 Hz, 2H), 2.60 (s, 3H), 1.90 - 1.76 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H).

Example 17, Preparation of a Compound of the Invention

Step 1: Synthesis of 3-(2-oxaspiro[3.3]hept-6-yloxy)-4-chloro-5-nitrobenzamide

3-Nitro-4-chloro-5-hydroxybenzamide (454 mg, 2.1 mmol) and 2-oxaspiro[3.3]heptane-6-ol (240 mg, 2.1 mmol) in THF. Triphenylphosphine (825 mg, 3.2 mmol) was added to the solution (10 mL), and after DI was applied, DIAD (646 mg, 3.2 mmol) was slowly added dropwise. The reaction system was maintained under nitrogen. After the ice bath was removed, the temperature was raised to 50 ° C, and the reaction was stirred overnight. After completion of the reaction, the crude product obtained by concentration of the reaction mixture was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1/3, v/v) to give 3-(2-oxaspiro[3.3]-g- 6-Methoxy)-4-chloro-5-nitrobenzamide (350 mg, 1.12 mmol), yield 53.3%.

MS (ESI) m/z = 313 [M+H] ⁺

Step 2: Synthesis of 3-(2-oxaspiro[3.3]hept-6-yloxy)-5-nitro-4-(propylamino)benzamide

To a solution of 3-(2-oxaspiro[3.3]hept-6-yloxy)-4-chloro-5-nitrobenzamide (350 mg, 1.12 mmol) in DMSO (10 mL) 2.24 mmol) and n-propylamine (198 mg, 3.36 mmol) were reacted at 50 ° C overnight. After cooling, it was poured into ice water, and an orange-red solid precipitated. After filtration, it was dried to give 3-(2-oxaspiro[3.3]hept-6-yloxy)-5-nitro-4-( Propylamino)benzamide (300 mg, 0.9 mmol), orange-red solid.

MS (ESI) m/z = 336 [M+H] ⁺

Step 3: Synthesis of 3-(2-oxaspiro[3.3]hept-6-yloxy)-5-amino-4-(propylamino)benzamide

Aqueous ammonia (0.8 mL, 4.8 mmol) was added dropwise to 3-(2-oxaspiro[3.3]hept-6-yloxy)-5-nitro-4-(propylamino)benzamide under ice bath. (300 mg, 0.9 mmol) in a solution of methanol (10 mL). After 5 min, a solution (5 mL) of &lt The reaction solution was filtered, and the obtained filtrate was evaporated to dryness, diluted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. [3.3] Hept-6-yloxy)-5-amino-4-(propylamino)benzamide (270 mg, 0.89 mmol).

MS (ESI) m/z = 306.0 [M+H] ⁺

Step 4: 7-(2-oxaspiro[3.3]hept-6-yloxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1- Synthesis of propyl-1H-benzo[d]imidazole-5-carboxamide

1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (39 mg, 0.2 mmol) was added dropwise to compound 304b (60 mg, 0.2 mmol) in DMF (2 mL) The mixture was reacted for 20 min, then HATU (75 mg, 0.197 mmol) and DIPEA (41 mg, 0.32 mmol). The reaction mixture was purified by reverse-purpur[pi][pi

MS (ESI) m/z = 467.0 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.82 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 6.63 (s, 1H ), 4.89–4.75 (m, 1H), 4.67 (s, 2H), 4.65–4.59 (m, 2H), 4.58 (s, 2H), 4.29 (t, J = 7.2 Hz, 2H), 2.94–2.84 ( m, 2H), 2.38 - 2.25 (m, 2H), 2.17 (s, 3H), 1.76 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H) ).

Example 18 Preparation of a Compound of the Invention

4-Ethyl-2-methyloxazol-5-carbonyl isothiocyanate (32 mg, 0.16 mmol) was added dropwise to compound 304b (50 mg, 0.16 mmol) in DMF (2 mL) After 20 min, HATU (75 mg, 0.197 mmol) and DIPEA (41 mg, 0.32 mmol Gradually, a white solid precipitated, and the filter cake was washed with methanol and water in turn, and the filter cake was dried to obtain 3-(2-oxaspiro[3.3]hept-6-yloxy)-5-amino-4-(propyl Benzoamino)benzamide (25.4 mg, yield 34%), white solid.

MS (ESI) m/z = 468.0 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 4.93 - 4.75 (m) , 1H), 4.67 (s, 2H), 4.58 (s, 2H), 4.36 - 4.12 (m, 2H), 3.00 (q, J = 7.4 Hz, 2H), 2.94 - 2.83 (m, 2H), 2.44 ( s, 3H), 2.35 - 2.24 (m, 2H), 1.75 (dq, J = 15.0, 7.4 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H) ).

Example 19 Preparation of a Compound of the Invention

4-Ethyl-2-methylthiazole-5-carbonyl isothiocyanate (32 mg, 0.16 mmol) was added dropwise to 3-(2-oxaspiro[3.3]hept-6-yloxyl under ice bath 5-Amino-4-(propylamino)benzamide (60 mg, 0.2 mmol) in DMF (2 mL) EtOAc (EtOAc) Then, it was warmed to room temperature and stirred for 2 h. The reaction mixture was purified by EtOAc EtOAc EtOAc EtOAc

MS (ESI) m/z = 484 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.78 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 1.2Hz, 1H), 7.37 (s, 1H), 7.13 (d, J = 1.0 Hz, 1H), 4.89 - 4.74 (m, 1H), 4.67 (s, 2H), 4.58 (s, 2H), 4.32 - 4.16 (m, 2H), 3.20 (q, J = 7.5 Hz, 2H), 2.95 –2.82(m,2H), 2.59(s,2H), 2.37–2.23(m,2H), 1.84–1.68(m,2H), 1.22(t,J=7.5Hz,3H),0.92(t,J =7.4Hz, 3H).

Example 20 Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 1-propyl-7-((tetrahydrofuran-3-yl)thiomethylmethyl)-1H-benzo[d]imidazole-5-carboxylate

To the compound 7-bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamide 3-Acetyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (80 mg, 0.138 mmol) in dioxane (2 mL) was added sequentially to 3- acetyl thiol tetrahydrofuran (20 mg, 0.138) Mp), Pd ₂ (dba) ₃ (13 mg, 0.014 mmol), xantphos (8 mg, 0.014 mmol), K ₃ PO ₄ (36 mg, 0.166 mmol), and reacted at 110 ° C overnight under nitrogen atmosphere. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

MS (ESI) m/z = 602 [M+H] ⁺

Step 2: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydrofuran-3-yl)thio)-1H-benzo[d]imidazole-5-carboxylic acid

To 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1- Methyl propyl-7-((tetrahydrofuran-3-yl)thiomethylmethyl)-1H-benzo[d]imidazole-5-carboxylate (34 mg, 0.055 mmol) in methanol / THF / water (1 /1/1 mL) LiOH (5 mg, 0.11 mmol) was added to the solution, and the reaction was carried out at 50 ° C for 2 h, and the reaction was completed. The pH was adjusted to 5-6 with a 1M aqueous solution of hydrochloric acid, and the mixture was concentrated to give the title compound (33 mg, yield: 99%).

MS (ESI) m/z = 588 [M+H] ⁺

Step 3: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydrofuran-3-yl)thio)-1H-benzo[d]imidazole-5-carboxamide

To the compound 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamide)-1 - propyl -7 - ((tetrahydrofuran-3-yl) thio) lH-benzo [d] imidazole--5- DMF-carboxylic acid (33mg, 0.05mmol) (2mL) was added sequentially a solution of NH ₄ Cl ( 4 mg, 0.07 mmol), HATU (26 mg, 0.07 mmol), DIPEA (22 mg, 0.15 mmol). After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated

MS (ESI) m / z = 587 [M + H] ⁺

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-((tetrahydrofuran-3-yl)thio)-1H-benzene And [d] Synthesis of imidazole-5-carboxamide

To the compound 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamide)-1 Add a solution of propyl-7-((tetrahydrofuran-3-yl)thio)-1H-benzo[d]imidazole-5-carboxamide (20 mg, 0.03 mmol) in EtOAc. The reaction was carried out at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated and evaporated tolululululululululululululululululululululululululululu

MS (ESI) m/z = 457 [M+H] ⁺

¹ H NMR (DMSO-d6, 400 MHz) δ 12.93-13.04 (m, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.44 (s, 1H), 6.66 (s, 1H), 4.53-4.71 (m, 4H), 3.79-3.91 (m, 2H), 3.49-3.57 (m, 1H), 3.30-3.34 (m, 2H), 2.19 (s, 3H), 1.74 -1.87 (m, 4H), 1.52-1.63 (m, 2H), 1.30-1.44 (m, 3H), 0.92-1.00 (m, 3H).

Example 21, Preparation of a Compound of the Invention

Step 1: Synthesis of methyl 3-bromo-5-nitro-4-(propylamino)benzoate

To a solution of methyl 3-bromo-4-fluoro-5-nitrobenzoate (1 g, 3.42 mmol) in DMF (20 mL), DMEEA (1.33 g, 10.27 mmol) and propylamine (404 mg, 6.85 mmol) 2h, the reaction was completed. After adding water, EA was extracted, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to give ethyl 3-bromo-5-nitro-4-(propylamino)benzoate (compound 21a) (1.16 g) , yield 99%).

MS (ESI) m / z = 317 [M + H] ⁺ , 319 [M+H+2] ⁺

Step 2: Synthesis of methyl 3-amino-5-bromo-4-(propylamino)benzoate

Zn (1.19 g, 18.3 mmol) was added to a solution of Compound 21a (1.16 g, 3.42 mmol) in AcOH (20 mL). Filtration, the filtrate was spun dry, and the obtained crude product was purified by normal phase column (eluent: PE/EA=3/1, v/v) to give methyl 3-amino-5-bromo-4-(propylamino)benzoate. (Compound 21b) (320 mg, yield 31%).

MS (ESI) m / z = 287 [M + H] ⁺ , 289 [M+H+2] ⁺

Step 3: 7-Bromo-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid Synthesis of methyl ester

1-Ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (218 mg, 1.11 mmol) was added to compound 21b (320 mg, 1.11 mmol) in DMF (5 mL) The solution was stirred for 30 min, then DIPEA (288 mg, 2.22 mmol) Add 50 mL of water, precipitate a solid, filter the solid and dry to give 7-bromo-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H - Methyl benzo[d]imidazole-5-carboxylate (Compound 21c) 484 mg, yield 97%).

MS (ESI) m / z = 448 [M+H] ⁺ , 450[M+H+2] ⁺ .

Step 4: 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-A Synthesis of Methyl Amido)-1-propyl-1H-benzo[d]imidazole-5-carboxylate

(10 mL) was added _{_{Cs 2 CO 3 (1.06g, 3.24mmol}} ) and SEMCl (270mg, 1.62mmol) in THF Compound 21c (484mg, 1.08mmol) is stirred at rt overnight. After the completion of the reaction, water was added, and the mixture was extracted with EtOAc. EtOAc (EtOAc m.) 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamide) Methyl 1-propyl-1H-benzo[d]imidazole-5-carboxylate (Compound 21d) (530 mg, yield 84%).

MS (ESI) m / z = 578 [M + H] ⁺ , 580 [M+H+2] ⁺

Step 5: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylate

2-Hydroxyethanethiol (11 mg, 0.14 mmol), Pd ₂ (dba) ₃ (13 mg, 0.014 mmol), xantphos (8 mg) was added sequentially to a solution of compound 21d (80 mg, 0.14 mmol) in dioxane (2 mL). , 0.014 mmol), K ₃ PO ₄ (36 mg, 0.166 mmol), reacted at 110 ° C overnight under nitrogen atmosphere, and the reaction was completed. After cooling to room temperature, the reaction mixture was concentrated to give a crude material which was purified on a normal phase column (eluent: PE/EA = 1/3, v/v) to give 2-(1-ethyl-3-methyl-N- ((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-((2-hydroxyethyl)thio)-1-propyl Methyl-1H-benzo[d]imidazole-5-carboxylate (Compound 21e) (28 mg, yield 45%).

MS (ESI) m / z = 576 [M + H] ⁺

Step 6: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid

To a solution of the compound 21e (28 mg, 0.063 mmol) in methanol / THF / water (1/1/1mL) was added LiOH (6 mg, 0.126 mmol), and reacted at 50 ° C for 2 h, and the reaction was completed. The reaction was stopped, the pH was adjusted to 5-6 with 1M aqueous hydrochloric acid, and then the mixture was concentrated to give 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)) ethoxy Methyl)-1H-pyrazole-5-carboxamido)-7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 21f) (26 mg, yield 95%) was used directly in the next step.

MS (ESI) m/z = 562 [M+H] ⁺

Step 7: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

NH ₄ Cl (5 mg, 0.09 mmol), HOAT (10 mg, 0.07 mmol), EDCI (14 mg, 0.07 mmol), DIPEA (24 mg, 0.18 mmol) was added to a solution of compound 21f (26 mg, 0.06 mmol) in DMF (2 mL). ), react at room temperature overnight. After the completion of the reaction, the reaction mixture was concentrated, evaporated with ethyl acetate, and washed with water and brine, and the organic phase was concentrated to give crude 2-(1-ethyl-3-methyl-N-((2-) Silyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d Imidazole-5-carboxamide (Compound 21 g) (20 mg, yield 86%).

MS (ESI) m / z = 561 [M + H] ⁺

Step 8: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((2-hydroxyethyl)thio)-1-propyl-1H-benzene And [d] Synthesis of imidazole-5-carboxamide

To a solution of compound 21 g (20 mg, 0.05 mmol) eluted elut elut elut elut elut elut elut elut elut Water = 2/1, v/v) Compound 21 (6.34 mg, yield 24%) was isolated.

MS (ESI) m/z = 431 [M+H] ⁺

¹ H NMR (DMSO-d6, 400 MHz) δ 12.97 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 6.66 (s) , 1H), 4.93-5.02 (m, 1H), 4.51-4.71 (m, 4H), 3.53-3.64 (m, 2H), 3.13-3.23 (m, 2H), 2.19 (s, 3H), 1.73-1.92 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H).

Example 22, Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylate

Were added to a solution of Compound 21d (50mg, 0.086mmol) in dioxane (2mL) 2- acetyl-mercaptoethyl ether _{(12mg, 0.086mmol), Pd 2} (dba) 3 (9mg, 0.009mmol), xantphos _{(6mg, 0.009mmol), K 3} PO 4 (22mg, 0.104mmol), 110 ℃ reaction overnight under nitrogen, the reaction was complete. The reaction solution was concentrated to give a crude material which was purified on a normal phase column (eluent: PE/EA = 1/1, v/v) to give 2-(1-ethyl-3-methyl-N-((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-((2-methoxyethyl)thio)-1-propyl-1H Methyl benzo[d]imidazole-5-carboxylate (Compound 22a) (30 mg, yield 58%).

MS (ESI) m/z = 590 [M+H] ⁺

Step 2: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid

LiOH (5 mg, 0.10 mmol) was added to a solution of Compound 22a (30 mg, 0.05 mmol) in methanol/THF/water (1/1/1 mL), and the reaction was carried out at 50 ° C for 2 h. The pH was adjusted to 5-6 with a 1M aqueous solution of hydrochloric acid, and then the mixture was concentrated to give crude 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)) Methyl)-1H-pyrazole-5-carboxamido)-7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 22b) (28 mg, yield 99%).

MS (ESI) m / z = 576 [M + H] ⁺

Step 3: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

NH ₄ Cl (4 mg, 0.07 mmol), HOAT (8 mg, 0.06 mmol), EDCI (12 mg, 0.06 mmol), DIPEA (19 mg, 0.15 mmol) was added to a solution of compound 22b (28 mg, 0.05 mmol) in DMF (2 mL). ), reacted at room temperature overnight, and the reaction was completed. The reaction solution was concentrated, washed with ethyl acetate and washed with water and brine, Ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole -5-carboxamide (compound 22c) (26 mg, yield 93%).

MS (ESI) m/z = 575 [M+H] ⁺

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((2-methoxyethyl)thio)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide

To a solution of Compound 22c (26 mg, EtOAc) The reaction mixture was concentrated and concentrated to give purified crystals crystals crystals crystals

MS (ESI) m/z = 445 [M+H] ⁺

¹ H NMR (DMSO-d6, 400 MHz) δ 12.95 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.41 (s, 1H), 6.66 (s) , 1H), 4.48-4.72 (m, 4H), 3.49-3.57 (m, 2H), 3.27-3.32 (m, 2H), 3.23 (s, 3H), 2.19 (s, 3H), 1.73-1.89 (m , 2H), 1.37 (t, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H).

Example 23, Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 1-propyl-7-((tetrahydro-2H-pyran-4)yl)thio)-1H-benzo[d]imidazole-5-carboxylate

Were sequentially added 4-acetyl-mercapto-pyran (23mg, 0.138mmol) of compound 21d (80mg, 0.138mmol) in dioxane _{(2mL), Pd 2 (dba} ) 3 (13mg, 0.014mmol), xantphos (8mg , 0.014 mmol), K ₃ PO ₄ (36 mg, 0.166 mmol), reacted at 110 ° C overnight under nitrogen atmosphere, and the reaction was completed. The reaction solution was concentrated to give a crude material which was purified on a normal phase column (eluent: PE/EA = 1/1, v/v) to give 2-(1-ethyl-3-methyl-N-((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1-propyl-7-((tetrahydro-2H-pyran-4)yl)sulfide Methyl-1H-benzo[d]imidazole-5-carboxylate (Compound 23a) (34 mg, yield 40%).

MS (ESI) m/z = 616 [M+H] ⁺

Step 2: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydro-2H-pyran-4-)yl)thio)-1H-benzo[d]imidazole-5-carboxylic acid

To a solution of the compound 23a (34 mg, 0.055 mmol) in methanol / THF / water (1/1/1mL) was added LiOH (5 mg, 0.11 mmol), and reacted at 50 ° C for 2 h, and the reaction was completed. The pH was adjusted to 5-6 with a 1M aqueous solution of hydrochloric acid, and then the mixture was concentrated to give crude 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)) Methyl)-1H-pyrazole-5-carboxamido)-1-propyl-7-((tetrahydro-2H-pyran-4-)yl)thio)-1H-benzo[d]imidazole -5-carboxylic acid (compound 23b) (30 mg, yield 91%).

MS (ESI) m/z = 602 [M+H] ⁺

Step 3: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydro-2H-pyran-4-yl)thio)-1H-benzo[d]imidazole-5-carboxamide

NH ₄ Cl (4 mg, 0.07 mmol), HOAT (9 mg, 0.06 mmol), EDCI (12 mg, 0.06 mmol), DIPEA (20 mg, 0.15 mmol) was added to a solution of compound 23b (30 mg, 0.05 mmol) in DMF (2 mL) ), react at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated, evaporated, evaporated, evaporated, evaporated Silyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1-propyl-7-((tetrahydro-2H-pyran-4-yl)thio)-1H -Benzo[d]imidazole-5-carboxamide (Compound 23c) (20 mg, yield 67%).

MS (ESI) m/z = 601 [M+H] ⁺

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-((tetrahydro-2H-pyran-4-yl)sulfide Synthesis of -1H-benzo[d]imidazole-5-carboxamide

To a solution of compound 23c (20 mL,EtOAc. After completion of the reaction, the reaction mixture was concentrated and concentrated to give purified crystals. Pyrazole-5-carboxamido)-1-propyl-7-((tetrahydro-2H-pyran-4-yl)thio)-1H-benzo[d]imidazole-5-carboxamide compound 23 (0.85 mg, yield 7%).

MS (ESI) m/z = 471 [M+H] ⁺

Example 24 Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 7-((2-morpholinoethyl)thio)-1-propylmethyl-1H-benzo[d]imidazole-5-carboxylate

To a solution of compound 21d (80 mg, 0.138 mmol) in dioxane (2 mL), N- acetyl ethyl morpholine (26 mg, 0.138 mmol), Pd ₂ (dba) ₃ (13 mg, 0.014 mmol), xantphos 8 mg, 0.014 mmol), K ₃ PO ₄ (36 mg, 0.166 mmol), reacted at 110 ° C overnight under nitrogen atmosphere, and the reaction was completed. The reaction solution was concentrated to give a crude material which was purified on a normal phase column (eluent: PE/EA = 1/1, v/v) to give 2-(1-ethyl-3-methyl-N-((2- (Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-((2-morpholinoethyl)thio)-1-propylmethyl -1H-Benzo[d]imidazole-5-carboxylic acid methyl ester (Compound 24a) (89 mg, yield 99%).

MS (ESI) m/z = 645 [M+H] ⁺

Step 2: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-morpholinoethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid

To a solution of the compound 24a (89 mg, 0.138 mmol) in MeOH / THF / water (1/1/1mL) was added LiOH (12 mg, 0.276 mmol), and reacted at 50 ° C for 2 h, and the reaction was completed. The pH was adjusted to 5-6 with a 1M aqueous solution of hydrochloric acid, and then the mixture was concentrated to give crude 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)) Methyl)-1H-pyrazole-5-carboxamido)-7-((2-morpholinoethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 24b) (80 mg, yield 91%). .

MS (ESI) m/z = 631 [M+H] ⁺

Step 3: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-morpholinoethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

NH ₄ Cl (11 mg, 0.19 mmol), HATU (58 mg, 0.152 mmol), DIPEA (50 mg, 0.38 mmol), and then reacted at room temperature for 2 h. . The reaction solution was concentrated, washed with ethyl acetate and washed with water and brine, Ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-((2-morpholinoethyl)thio)-1-propyl-1H-benzo[d]imidazole -5-carboxamide (compound 24c) (65 mg, yield 81%).

MS (ESI) m/z = 630 [M+H] ⁺

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((2-morpholinoethyl)thio)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide

To a solution of compound 24c (65 mg, 0.1 mmol),EtOAc. After completion of the reaction, the reaction mixture was concentrated and evaporated tolululululululululululululululululululululululululululululululululululu

MS (ESI) m/z = 500 [M+H] ⁺

¹ H NMR (DMSO-d6, 400 MHz) δ 12.83-13.09 (m, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.41 (s, 1H), 6.66 (s, 1H), 4.49-4.74 (m, 4H), 3.40-3.46 (m, 4H), 3.19-3.29 (m, 2H), 2.53-2.59 (m, 2H), 2.25-2.38 (m, 4H) , 2.19 (s, 3H), 1.73-1.90 (m, 2H), 1.31-1.44 (m, 3H), 0.91-1.04 (m, 3H).

Example 25 Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-vinyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 25a)

4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.6 g, 10.4 mmol), Pd(dppf) ₂ (at room temperature) 380.6 mg, 0.52 mmol) was added to a solution of the compound 21d (3.0 g, 5.2 mmol) in dioxane (20 mL), and then a solution of Na ₂ CO ₃ (1.4 g, 13 mmol) (10 mL). ₂ The air in the reaction flask was replaced three times under protection. The reaction was carried out in an oil bath at 80 ° C overnight. The reaction was cooled to room temperature, diluted with water and adjusted to pH 5-6 using HCl (3M). The organic phase was washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate and evaporated to dryness to give the crude 2-(1-ethyl-3-methyl-N- ((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1-propyl-7-vinyl-1H-benzo[d]imidazole -5-carboxylic acid (compound 25a) (2.6 g, 65% purity), yield 64%. This crude product was used in the next step without purification.

MS (ESI) m / z = 512 [M+H] ⁺ .

Step 2: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-vinyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25b)

HATU (2.1 g, 5.6 mmol) was added to a solution of compound 25a (2.6 g, 5.1 mmol) in DMF (30 mL), and stirred for 0.3 h, then ammonium chloride (826.2 mg, 15.3 mmol) and N,N-Diisopropylethylamine (3.4 g, 25.5 mmol). The reaction was quenched with EtOAc (EtOAc)EtOAc. v/v = 1/2) gives 2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5 -Carboxamido)-1-propyl-7-vinyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25b) (1.2 g, 2.4 mmol), yield 71%.

MS (ESI) m / z = 511 [M+H] ⁺ .

Step 3: 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-formyl-1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25c)

NMO (561.6 mg, 4.8 mmol) was dissolved in 8 mL of water at room temperature, and potassium citrate dihydrate (88.3 mg, 0.24 mmol) was dissolved in 5 mL of water and added to compound 25b (1.2 g, 2.4 mmol) of acetonitrile ( The solution was diluted with water and extracted with dichloromethane (10 mL×2). The organic phase was washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate This intermediate was dissolved in dichloromethane (15 mL) then aqueous sodium iodate (1.0 g, 4.8 mmol) (6 mL) was added at room temperature. The mixture was reacted at room temperature for about 1.5 hours. It was diluted with water and extracted with dichloromethane (10 mL×2). The organic phase was washed with saturated brine 2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-7-formyl-1-propyl-1H-benzo[d]imidazole- 5-carboxamide (Compound 25c) (1.1 g) was used in the next step without purification.

MS (ESI) m / z = 513 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-formyl-1-propyl-1H-benzo[d]imidazole-5- Synthesis of amide (compound 25d)

The compound 25c (450 mg, 0.88 mmol) was dissolved in ethyl acetate (4M) EtOAc. -pyrazole-5-carboxamido)-7-formyl-1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25d) (480 mg, 70% purity), yield 91% .

MS (ESI) m / z = 381 [M+H] ⁺ .

Step 5: 7-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25)

Add 2-oxa-6-azaspiro[3.3]heptane (34.5 mg, 0.35 mmol) to a solution of compound 25d (160×70% mg, 0.29 mmol) in methanol (10 mL) After adding acetic acid (100 uL) for 1 h, sodium cyanoborohydride (54.8 mg, 0.87 mmol) was added and stirring was continued at room temperature for 3 h. Diluted with water, extracted with ethyl acetate (10 mL×2), washed with brine (10 mL×1), dried over anhydrous sodium sulfate and evaporated. Separation (eluent: acetonitrile / water = 1/3, v / v) to give 7-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-2-(1-B 3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25) (19.7 mg), white solid The rate is 12%.

MS (ESI) m / z = 466 [M+H] ⁺ .

^{1 H NMR (400MHz, Methanol-} d 4) δ8.08 (d, J = 1.5Hz, 1H), 7.86-7.81 (m, 1H), 6.77 (s, 1H), 4.83 (s, 4H), 4.80 ( s, 2H), 4.72 (q, J = 7.1 Hz, 2H), 4.52 (s, 4H), 4.40 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.84 (q, J = 7.4) Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.4 Hz, 3H).

Example 26, Preparation of a Compound of the Invention

7-(6-oxa-2-azaspiro[3.4]oct-2-ylmethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)- Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 26)

6-oxa-2-azaspiro[3.4]octane (39.6 mg, 0.35 mmol) was added to a solution of compound 25e (160×70% mg, 0.29 mmol) in methanol (10 mL) After adding acetic acid (100 uL) for 1 h, sodium cyanoborohydride (54.8 mg, 0.87 mmol) was added and stirring was continued at room temperature for 3 h. Diluted with water, extracted with ethyl acetate (10 mL×2), washed with brine (10 mL×1), dried over anhydrous sodium sulfate and evaporated Oxa-2-azaspiro[3.4]oct-2-ylmethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl- 1H-Benzo[d]imidazole-5-carboxamide (Compound 26) (35.5 mg), white solid.

MS (ESI) m/z = 495 [M+H] ⁺ .

^{1 H NMR (400MHz, Methanol-} d 4) δ8.10 (d, J = 1.6Hz, 1H), 7.89 (d, J = 1.7Hz, 1H), 6.79 (s, 1H), 4.88 (s, 2H) , 4.74 (q, J = 7.1 Hz, 2H), 4.55 - 4.24 (m, 6H), 3.96 (s, 2H), 3.84 (t, J = 7.0 Hz, 2H), 2.34 (d, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.86 (h, J = 7.4 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H).

Example 27, Preparation of a Compound of the Invention

7-(2-oxa-6-azaspiro[3.4]oct-6-ylmethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)- Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 27)

Add 2-oxa-6-azaspiro[3.4]octane (39.6 mg, 0.35 mmol) to a solution of compound 25d (160×70% mg, 0.29 mmol) in methanol (10 mL) After adding acetic acid (100 uL) for 1 h, sodium cyanoborohydride (54.8 mg, 0.87 mmol) was added and stirring was continued at room temperature for 3 h. Diluted with water, extracted with EtOAc (10 mL×2), EtOAc (EtOAc)EtOAc. ), white solid, yield 19%.

MS (ESI) m/z = 495 [M+H] ⁺ .

^{1 H NMR (400MHz, Methanol-} d 4) δ8.11 (d, J = 1.7Hz, 1H), 8.00 (d, J = 1.7Hz, 1H), 6.79 (d, J = 0.8Hz, 1H), 4.80 (s, 2H), 4.79 - 4.70 (m, 4H), 4.67 (s, 2H), 4.45 (t, J = 7.5 Hz, 2H), 3.74 (d, J = 36.9 Hz, 2H), 3.57 (s, 2H), 2.51 (d, J = 37.3 Hz, 2H), 2.30 (s, 3H), 1.94 - 1.77 (m, 2H), 1.47 (t, J = 7.1 Hz, 3H), 1.06 (td, J = 7.4) , 1.8Hz, 3H).

Example 28 Preparation of a Compound of the Invention

Step 1: 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-A Synthesis of Amido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (Compound 28b)

Compound 28a' (435 mg, 2.8 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (49 mg, 0.07 mmol), CuI (27 mg, 0.14 mmol), t-Bu ₃ P (28 mg, 0.14 mmol), DIPEA (903mg, 7mmol added to compound 28a (810mg, 1.4mmol) in DMF (10mL) solution, then three times with replacement air in the reaction flask under N _2. 100 deg.] C overnight in an oil bath. the reaction was cooled to The mixture was diluted with water and extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (10 mL×1) and dried over anhydrous sodium sulfate. Ethyl ester/petroleum ether, v/v = 1/3) gives the compound 7-bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl))ethoxy) )methyl)-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (compound 28b) (430 mg, 0.66 mmol) yield 47 %.

MS (ESI) m / z = 653 [M+H] ⁺ .

Step 2: 7-(3-((tert-Butoxycarbonyl)amino)prop-1-yn-1-yl)-2-(1-ethyl-3-methyl-N-((2-(3) Methylsilyl)ethoxy)methyl)-1H--pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (compound 28c) synthesis

Compound 28b (430mg, 0.66mmol) was dissolved in 5mL of methanol was added LiOH.H ₂ O (83mg, 1.98mmol) in water (3mL). The reaction overnight at room temperature. The pH of the reaction mixture was adjusted to 5 to 6 with HCl (3M), EtOAc (EtOAc (EtOAc) Product 7-(3-((tert-Butoxycarbonyl)amino)prop-1-yn-1-yl)-2-(1-ethyl-3-methyl-N-((2-(trimethyl)) Silyl)ethoxy)methyl)-1H--pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 28C) (320 mg, 0.5 mmol), yield 76%.

MS (ESI) m / z = 639 [M+H] ⁺ .

Step 3: tert-Butyl (3-(5-carbamoyl-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)) -1H-pyrazole-5-carboxamido)-1-propyl-1H--benzo[d]imidazol-7-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (Compound 28d )Synthesis

Add HATU (209 mg, 0.55 mmol) to a solution of compound 28b (320 mg, 0.5 mmol) in DMF (10 mL). Ethylethylamine (323 mg, 2.5 mmol) was obtained. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Carbamoyl-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamide) The yield of 1-propyl-1H-benzo[d]imidazol-7-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (Compound 28d) (310 mg, 0.49 mmol) was 98%.

MS (ESI) m / z = 638 [M+H] ⁺ .

Step 4: 7-(3-Aminoprop-1-yn-1-yl)-2-(((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)- Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 28e)

28d (160 mg, 0.25 mmol) was dissolved in 5 mL of dichloromethane at room temperature and then trifluoroacetic acid (5 mL) was added. After the completion of the reaction, direct distillation under reduced pressure gave the crude product 7-(3-aminoprop-1-yn-1-yl)-2-(((1-ethyl-3-methyl-1H-pyrazole-5-) Methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxamide (compound 28e) (130 mg, 0.33 mmol), purity 70%, yield 92%, no purification, Used directly in the next step.

MS (ESI) m / z = 394 [M+H] ⁺ .

Step 5: Methyl (3-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[ Synthesis of d]imidazolium-7-yl)prop-2-yn-1-yl)carbamic acid (Compound 28)

DIPEA (148 mg, 1.15 mmol), 28e' (27 mg, 0.28 mmol) was added to a solution of compound 28e (130 mg x 70%, 0.23 mmol) in dichloromethane (8 mL). h. Diluted with water, extracted with dichloromethane (10 mL × 2), EtOAc (EtOAc m. /water = 50/50, v/v) isolated methyl (3-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)) 1-propyl-1H-benzo[d]imidazol-7-yl)prop-2-yn-1-yl)carbamic acid (Compound 28) (51 mg, 0.11 mmol), yield 48%.

MS (ESI) m / z = 466 [M+H] ⁺ .

^{1 H NMR (400MHz, DMSO-} d 6) δ12.96 (s, 1H), 8.04 (d, J = 30.8Hz, 2H), 7.83 (d, J = 5.8Hz, 2H), 7.39 (s, 1H) , 6.67 (s, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.46 (t, J = 7.3 Hz, 2H), 4.15 (d, J = 5.8 Hz, 2H), 3.59 (s, 3H) , 2.19 (s, 3H), 1.80 (dt, J = 16.8, 8.4 Hz, 2H), 1.36 (t, J = 7.0 Hz,

3H), 0.95 (t, J = 7.5 Hz, 3H).

Example 29 Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-methylcarboxylate

Methyl 3-amino-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate (350 mg, 1.1 mmol) was dissolved in DMF (10 mL) In the mixture, 1-ethyl-3-methyl-1H-pyrazole-5-formyl isothiocyanate (221.33 mg, 1.1 mmol) was added at 0 ° C for 30 min. The reaction mixture was added to HATU (517.5 mg, 1.36 mmol) at 0 ° C and allowed to warm to room temperature overnight. Diluted with water, extracted with ethyl acetate (20 mL×3), EtOAc (EtOAc)EtOAc. Water = 30/70, v/v) 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetane-3-) The yield of methyl ethoxy)-1-propyl-1H-benzo[d]imidazol-5-methylcarboxylate (461 mg, 0.98 mmol) was 86.5%.

MS (ESI) m / z = 470 [M+H] ⁺ .

Step 2: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-methylcarboxylic acid

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1-propane yl -1H- benzo [d] imidazole-5-carboxylic acid methyl ester (100mg, 0.213mmol) was dissolved in THF (3ml), MeOH (1ml ) and H ₂ O (1ml), was added ice-water cooling Lithium hydroxide (22.4 mg, 0.53 mmol) was allowed to react to room temperature overnight. The reaction mixture was adjusted to pH 4 with dilute HCl (1M), and extracted with dichloromethane (10 mL×4). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo [d] Imidazole-5-methylcarboxylic acid (116 mg, overweight, containing a portion of the inorganic salt) was used in the next reaction without further purification.

MS (ESI) m / z = 456 [M+H] ⁺ .

Step 3: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-formylamino)-N-methyl-7-(2-(oxetan-3-yl)B Synthesis of oxy)-1-propyl-1H-benzo[d]imidazole-5-carboxamide

Under ice bath, HATU (116.28 mg, 0.306 mmol) was added to 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetane) a solution of -3-yl)ethoxy)-1-propyl-1H-benzo[d]imidazole-5-methylcarboxylic acid (116 mg, 0.21 mmol) in DMF (2 mL) Methylamine hydrochloride (85.97 mg, 1.273 mmol) and N,N-diisopropylethylamine (164.52 mg, 1.27 mmol). The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 469 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ12.84 (s, 1H), 8.40 (q, J = 4.4Hz, 1H), 7.63 (d, J = 1.2Hz, 1H), 7.31 (d, J = 1.4 Hz, 1H), 4.73 (dd, J = 7.8, 5.8 Hz, 2H), 4.63 (q, J = 7.1 Hz, 2H), 4.39 (t, J = 6.1 Hz, 2H), 4.31 (t, J = 7.3) Hz, 2H), 4.15 (t, J = 6.4 Hz, 2H), 3.20 (tt, J = 8.0, 6.6 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 2.23 (t, J = 6.9) Hz, 2H), 2.18 (s, 3H), 1.80 (q, J = 7.4 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

Example 30, Preparation of a Compound of the Invention

Step 1: 2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy Synthesis of methyl-1-propyl-1H-benzo[d]imidazole-5-carboxylate

2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1-propane Base-1H-benzo[d]imidazol-5-methylcarboxylic acid (342 mg, 0.728 mmol) was dissolved in DMF (20 mL), EtOAc (EtOAc, EtOAc, Reaction for 3 h. It was diluted with water and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with water, dried over anhydrous sodium sulfate, and then evaporated to give the crude product to afford the title compound (244 mg, 0.5 mmol).

MS (ESI) m / z = 484 [M+H] ⁺ .

Step 2: 2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxylic acid

2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)- 1-propyl -1H- benzo [d] imidazole-5-carboxylate (244mg, 0.50mmol) was dissolved in THF (5ml), MeOH (2ml ) and H ₂ O (2ml) in a mixture, Lithium hydroxide (53.04 mg, 1.26 mmol) was added under ice cooling, and the mixture was allowed to react at room temperature overnight. The reaction mixture was adjusted to pH 4 with dilute HCl (1M), and extracted with dichloromethane (10 mL×3). The obtained organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. 0.47 mmol).

MS (ESI) m / z = 470 [M+H] ⁺ .

Step 4: 2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide

Under ice-cooling, HATU (214.78 mg, 1.414 mmol) was added to a solution of compound 1d (221 mg, 0.47 mmol) in DMF (5 mL), and stirred for 0.2 hr, then ammonium chloride (75.62 mg, 1.414 mmol) and N, N-Diisopropylethylamine (183.45 mg, 1.414 mmol). The reaction mixture was purified by EtOAc EtOAc EtOAc.

MS (ESI) m/z = 469 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ8.05 (s, 1H), 7.74 (d, J = 1.3Hz, 1H), 7.52-7.41 (m, 2H), 4.72 (dd, J = 7.8,5.8Hz , 2H), 4.56 (q, J = 7.1 Hz, 2H), 4.38 (t, J = 6.1 Hz, 2H), 4.21 (dt, J = 24.8, 6.4 Hz, 4H), 3.54 (s, 3H), 3.19 (tt, J = 7.7, 6.3 Hz, 1H), 2.22 (t, J = 6.9 Hz, 2H), 2.17 (s, 3H), 1.75 (q, J = 7.3 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H).

Example 31, Preparation of a Compound of the Invention

Step 1: 2-(2-Ethyl-6-methylnicotinyl)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo Synthesis of [d]imidazole-5-carboxylic acid methyl ester

Under ice bath, HATU (265.62 mg, 0.699 mmol) was added to a solution of the compound 2-ethyl-6-methylnicotinic acid (117.47 mg, 0.583 mmol) in DMF (10 mL). Amino-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (97 mg, 0.291 mmol) N,N-Diisopropylethylamine (188.23 mg, 1.45 mmol). The reaction mixture was purified by EtOAc EtOAcjjjjjjjj

MS (ESI) m / z = 481 [M+H] ⁺ .

Step 2: 2-(2-Ethyl-6-methylnicotinyl)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo [d] Synthesis of imidazole-5-carboxylic acid

2-(2-Ethyl-6-methylnicotinyl)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d ] imidazole-5-carboxylate (70mg, 0.146mmol) was dissolved in THF (3ml), MeOH (1ml ) and H ₂ O (1ml), was added lithium hydroxide (15.31mg, 0.365mmol) under ice-water cooling Raise to room temperature and react overnight. The reaction mixture was adjusted to pH 4 with dilute HCl (1M), and extracted with dichloromethane (30 mL×4). The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate The target compound (73 mg) was overweight containing an inorganic salt. It was used in the next reaction without further purification.

MS (ESI) m / z = 467[M+H] ⁺ .

Step 3: 2-(2-Ethyl-6-methylnicotinyl)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo [d]imidazole-5-carboxamide

Under ice bath, HATU (71.59 mg, 0.188 mmol) was added to 2-(2-ethyl-6-methylnicotinyl)-7-(2-(oxetan-3-yl)ethoxy a solution of 1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (73 mg, 0.157 mmol) in DMF (2 mL). And N,N-diisopropylethylamine (60.74 mg, 0.47 mmol), and the obtained mixture was stirred at room temperature for 3 h. The reaction mixture was purified by EtOAc EtOAc.

MS (ESI) m/z = 466 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d6) δ12.92 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 7.36 (d, J = 10.1Hz, 2H ), 7.22 (s, 1H), 4.72 (dd, J = 7.8, 5.8 Hz, 2H), 4.39 (t, J = 6.1 Hz, 2H), 4.31 (q, J = 6.5, 5.6 Hz, 2H), 4.16 (t, J = 6.4 Hz, 2H), 3.21 (dq, J = 14.3, 7.2 Hz, 3H), 2.22 (q, J = 6.8 Hz, 2H), 1.80 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

The advantageous effects of the present invention will be described below by way of test examples.

Test Example 1, Biological Test

(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. Determination of protein dissolution profile in qPCR instrument, fitted with a Tm value protein Thermal Shift software 1.3 software that calculates the difference between Tm and different concentrations of the compound when the compound was not added protein, Kd fitted with concentrations changes compound according _Δ Tm.

实施例Example	最大 _ΔTm Maximum _Δ Tm	Kd(μM)Kd (μM)
11	9.99.9	16.116.1
22	6.96.9	3.13.1
33	10.810.8	22.622.6
44	6.46.4	--
55	6.66.6	--
66	3.43.4	97.597.5
88	6.16.1	24.524.5
99	5.05.0	--
1010	1.81.8	6.76.7
1111	3.03.0	4.74.7
1616	5.55.5	11.711.7
1717	7.07.0	15.7515.75
21twenty one	5.45.4	34.834.8
22twenty two	3.23.2	--
23twenty three	1.671.67	--
24twenty four	4.34.3	24.524.5
2525	2.62.6	358.8358.8
2626	5.15.1	103.6103.6

27

5.3

91.2

(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 μL 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 EC ₅₀ value.

实施例Example	EC ₅₀(μM) EC ₅₀ (μM)
11	1.61.6
22	4.44.4
33	2.02.0
44	1.61.6
55	1.51.5
66	16.616.6
88	4.74.7
1010	6.06.0
21twenty one	2.92.9
2626	9.29.2

In conclusion, the compounds of the present invention are capable of effectively binding to STING, and the compounds of the present invention are useful as STING agonists for the treatment of various conditions, particularly for leukemia.

Claims

a compound of formula I, and its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof:

among them,

s is 0 or 1;

Ring B is substituted with 0 to 4 R 5 5 ~ 6 membered aromatic ring, substituted with 0 to 4 R 5 5 ~ 6 membered aromatic heterocyclic ring;

R 5 is independently selected from C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -(CH 2 ) n NR a C(O)R b , -(CH 2 ) n C(O)NR a R b , -(CH 2 ) n C(O)OR a , -(CH 2 ) n OC(O)R a ;

R 8 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 2 is selected from -CONR a R b ;

R 1 and R 3 are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;

R t is selected from 0 to 2 substituents R f is C 1 ~ C 6 alkenyl group, substituted with 0 to 2 substituents R f is C 1 ~ C 6 alkynyl group, - (CH 2) m R g, -O ( CH 2 ) m R g , -S(CH 2 ) n R f ;

R f is selected from -OR a , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -C(O)NR a R b , -C(O)OR a, -OC (O) R a , -OC (O) NR a R b, substituted with 0-4 R c 3 ~ 10 membered cycloalkyl, substituted with 0 to 4 substituents R c of 4 to 10-membered Heterocycloalkyl;

Each m, n is independently 0, 1, 2, 3, 4, 5 or 6;

When m is 0, R g is selected from 0 to 4 substituents R c is 3 to 10-membered cycloalkyl, substituted with 0 to 4 R c 3 to 10-membered heterocycloalkyl;

When m is 4, 5 or 6, R g is selected from 0 to 4 substituents R c of 3 to 6-membered cycloalkyl, substituted with 0 to 4 R c substituted 4-membered heterocyclic ring An alkyl group, a 7-10 membered heterocycloalkyl group substituted by 0 to 4 R c ;

R c is 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, C 1 -C 6 alkyl;

R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl.
The compound according to claim 1 or a tautomer, enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized by:

Ring B is substituted with 0 to 2 R 5 5 ~ 6 membered aromatic ring, substituted with 0 to 2 R 5 5 ~ 6 membered aromatic heterocyclic ring;

R t is selected from 0 or 1 R f is substituted with C 1 ~ C 6 alkenyl group, substituted with 0 or 1 R f is substituted with C 1 ~ C 6 alkynyl group, - (CH 2) m R g, -O ( CH 2 ) m R g , -S(CH 2 ) n R f ;

R f is selected from -OR a , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -C(O)NR a R b , -C(O)OR a, -OC (O) R a , -OC (O) NR a R b, substituted with 0 to 2 R c 3 ~ 10 membered cycloalkyl, substituted with 0 to 2 substituents R c of 4 to 10-membered Heterocycloalkyl;

Each m, n is independently 0, 1, 2, 3, 4, 5 or 6;

When m is 0, R g is selected from 0 to 2 substituents R c is 3 to 10-membered cycloalkyl, substituted with 0 to 2 R c 3 to 10-membered heterocycloalkyl;

When m is 4, 5 or 6, R g is selected from 0 to 2 substituents R c of 3 to 6-membered cycloalkyl, substituted with 0 to 2 substituents R c 4 membered heterocyclic ring An alkyl group having 7 to 10 membered heterocycloalkyl groups substituted with 0 to 2 R c groups.
A compound according to claim 2, and a tautomer, enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein: a compound of formula I Can be expressed as:

Where s is 0 or 1;

Ring B is selected from 0 to 2 R 5

R 5 is independently selected from C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -(CH 2 ) n NR a C(O)R b , -(CH 2 ) n C(O)NR a R b , -(CH 2 ) n C(O)OR a , -(CH 2 ) n OC(O)R a ;

X' is selected from O, alkynylene, S or none;

When X' is selected from O or no,

n 1 is 0, 1, 2,

R S is selected from the group consisting of a 3- to 6-membered cycloalkyl group, a 4-membered heterocycloalkyl group, and a 7- to 10-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of hetero atoms is 1, 2;

When X' is selected from S or alkynylene,

n 1 is 0, 1, 2,

R S is selected from -OR a , -NR a C(O)OR b , 4 to 10 membered heterocycloalkyl; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of heteroatoms is 1, 2;

R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl.
A compound according to claim 3, and a tautomer, enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein:

When X' is selected from O or no,

n 1 is 0, 1, 2,

R S is selected from a 4-membered heterocycloalkyl group and a 7- to 10-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of heteroatoms is 1, 2;

When X' is selected from S or alkynylene,

n 1 is 0, 1, 2,

R S is selected from the group consisting of -OH, -OCH 3 , -NHC(O)OCH 3 , and a 4- to 6-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of hetero atoms is 1, 2.
The compound according to claim 4, and tautomers, enantiomers thereof, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof, characterized in that said 7 to 10 a metaheterocycloalkyl group is a spiro ring; wherein the spiro ring is
A compound according to any one of claims 3 to 5, and a tautomer, enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein: The compound represented by formula II is specifically:
The compound according to claim 1 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, which is a compound of formula I Can be expressed as formula III:

among them,

B ring is selected from

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

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

When m is 1,2,3,4,5,6, A ring is selected from substituted with 0 to 4 R c 3 ~ 6 membered cycloalkyl, substituted with 0-4 R c 4 membered heterocyclic ring An alkyl group; R c is selected from the group consisting of hydrogen, C 1 -C 6 alkyl;

R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl;

R 2 is selected from -CONR a R b ; wherein R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized by: R 1 , R 3 And R 7 and R 8 are selected from hydrogen.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized by: R 5 , R 6 Each is independently selected from a C 1 -C 6 alkyl group and a halogen-substituted C 1 -C 6 alkyl group.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein R 2 is selected from the group consisting of CONR a R b ; wherein R a and R b are each independently selected from hydrogen.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein R 4 is selected from C 1 to C 6 alkyl.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, characterized by being 0 to 4 The R c substituted 3- to 6-membered heterocycloalkyl group is selected from heterocycloalkyl groups containing nitrogen, oxygen, and sulfur; and R c is selected from hydrogen.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, which is represented by formula III The compound can be further represented by formula IIIa:

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

n is 0, 1, 2, 3;

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

R 1 , R 3 , R 7 , and R 8 are each independently selected from hydrogen;

R 4 is selected from C 1 -C 6 alkyl;

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

R 2 is selected from -CONR a R b ; wherein R a , R b are each independently selected from hydrogen;

R c is independently selected from hydrogen, C 1 -C 6 alkyl.
The compound according to claim 7 or a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, which is represented by formula III The compound can be further represented by formula IIIb:

Wherein, 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 1 , R 3 , R 7 , and R 8 are each independently selected from hydrogen;

R 4 is selected from C 1 -C 6 alkyl;

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

R 2 is selected from -CONR a R b ; wherein R a , R b are each independently selected from hydrogen;

X selects -O-, -NR d -, -S-;

R c is independently selected from hydrogen, C 1 -C 6 alkyl.
A compound according to any one of claims 7 to 14, and a tautomer, enantiomer thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein: The compound of formula III can be specifically expressed as:
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 STING agonist the use of.
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 or prevention Use in drugs for diseases associated with STING activity.
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 immunological composition Or use in vaccine adjuvants.