WO2020094156A1

WO2020094156A1 - Diheterocycle-substituted pyridine-2(1h)-ketone derivative, preparation method therefore and pharmaceutical use thereof

Info

Publication number: WO2020094156A1
Application number: PCT/CN2019/117221
Authority: WO
Inventors: 胡斌; 朱经峰; 方志华; 杨斐; 林崇懒; 华默嘉; 刘洋; 关慧平
Original assignee: 上海海雁医药科技有限公司; 扬子江药业集团有限公司
Priority date: 2018-11-11
Filing date: 2019-11-11
Publication date: 2020-05-14
Also published as: CN111727186A; CN111727186B

Abstract

Provided is a diheterocycle-substituted pyridine-2(1H)-ketone derivative, a preparation method therefore and a pharmaceutical use thereof. Specifically, provided are a compound of formula (I) or pharmaceutically acceptable salts thereof, a stereoisomer or a solvate, a preparation method therefor and an application thereof. (I)

Description

Pyridine-2 (1H) -one derivative substituted with double heterocyclic ring, its preparation method and medical application

Technical field

The present invention relates to a new class of bicyclic heterocyclic substituted pyridine-2 (1H) -one derivatives, its preparation method and pharmaceutical composition containing the derivatives and its use as a therapeutic agent, especially as a factor XIa inhibitor and in Use in preparing medicine for treating and preventing thromboembolism and other diseases.

Background technique

Every year, cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis and other cardiovascular and cerebrovascular diseases take nearly 12 million lives, close to 1/4 of the world's total deaths, and become the number one enemy of human health. The number of people dying of cardiovascular disease in China each year reaches more than 2.6 million, and 75% of the surviving patients are disabled, and more than 40% of them are severely disabled. The thrombosis problem caused by cardiovascular and cerebrovascular diseases and diabetes and its complications has become an urgent problem to be solved today.

The human blood coagulation system consists of two processes: intrinsic pathway (extrinsic pathway) and extrinsic pathway (extrinsic pathway) and a common pathway. The exogenous pathway is also called tissue factor pathway. As an exogenous pathway, under injury and various external stimuli, the complex of tissue factor and activated factor VIIa (FVIIa) activates factor X (FX) to form factor Xa (FXa), activated FXa can convert prothrombin (PT) into thrombin (thrombin). Thrombin acts as the central catalytic enzyme in the coagulation process, catalyzing the formation of fibrinogen by fibrinogen to play a role in blood coagulation. The number of enzymes involved in this process is small, and the effect is fast. The endogenous pathway belongs to the body's inherent pathway. All the factors involved in coagulation come from the blood. Through the cascade reaction, the factors XII (FXII), Factor XI (FXI), and Factor IX (FIX) are activated, which in turn activates FXa to convert the downstream prothrombin PT) is converted to thrombin, which in turn can activate FXI. The number of enzymes involved in this process is large, and the effect is slow.

In the whole coagulation process, FXI and FXIa play an extremely important role. As co-regulators of exogenous and endogenous coagulation pathways, their antagonists are widely developed for the treatment of various thrombosis. There are a variety of FXa antagonists on the market, which occupy the majority of the cardiovascular and cerebrovascular market due to their significant effectiveness. However, their side effects are becoming more and more significant. Among them, the "bleeding risk" is the most serious problem.

In order to solve this problem, the recent target FXIa has become a research hotspot of major companies and research institutions. Studies have found that severe FXI deficiency can cause hemophilia C, which occurs mostly in Jews (1: 450). The symptoms of hemophilia C are milder than those of hemophilia A and B, and spontaneous bleeding occurs slightly. Even if the body's hemostatic function is not affected during injury or surgery, patients with hemophilia C can be delivered normally in pregnancy. Therefore, FXIa security is significantly better than FXa. The study found that in the thrombosis model, the inhibition of FXIa factor can effectively inhibit the formation of thrombus, but in the case of more serious thrombosis, FXIa has little effect. Clinical statistics show that increasing the amount of FXIa will increase the prevalence of VTE, and those with severe FXIa deficiency will have a reduced risk of DVT.

As an emerging target, FXIa has not yet announced the drugs that have entered the clinical stage, but Bristol-Myers Squibb's BMS-654457 and BMS-262084 may have begun clinical research, and its clinical results have not been published. In addition to Bristol-Myers Squibb, seven other companies, including Isis Pharmaceuticals, LG Life Science, Trigen, Shifa Biomedical, and LegoChem, have also entered clinical compound research for FXIa modulators. Patent applications WO9630396, WO9941276, WO2011001402, WO2011016534, WO2012162611, WO2012143483, WO2013093484, WO2004002405, WO2015120777, WO2013056060, and US20050171148 disclose compounds having factor XIa inhibitory activity.

Many anti-cancer drugs show a relatively high anti-cancer activity during the development or clinical research stage, but due to their excessive hydrophilicity or lipophilicity, low targeting, and high cytotoxicity, they cause adverse reactions. The present invention has designed a new compound small molecule FXIa antagonist which, as a prodrug, has a better exposure level for in vivo administration and exhibits excellent effects and effects. It can be used to effectively treat cardiovascular and cerebrovascular diseases and thrombotic symptoms.

Summary of the invention

The object of the present invention is to provide a novel compound which can be used as an XIa inhibitor.

The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:

In the formula,

R ₁ and R ₂ are each independently hydrogen or C _1-10 alkyl, or R ₁ and R ₂ together with the connected carbon and nitrogen atoms form pyridine-2 (1H) -one, the pyridine-2 (1H ) -Ketone is substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, C _1-10 alkoxy, optionally substituted C _1-10 alkyl, halogenated C _1-10 alkyl, Halogenated C _1-10 alkoxy; said optionally substituted means unsubstituted or substituted with 1-3 substituents selected from the group consisting of: C _1-10 alkoxy, -NR ₁₁ R ₁₂ , -CONR ₂₁ R ₂₂ , -C (O) OC _1-10 alkyl, -SO ₂ C _1-10 alkyl, -SO ₂ NR ₁₁ R ₁₂ ;

R ₃ is -L ₁ -R _c ; L ₁ is a bond, C (O) or (CR ₃₁ R ₃₂ ) _q ; R _c is hydrogen, phenyl, 5 to 6 membered monocyclic heteroaromatic ring, 3 to 6 Single saturated heterocyclic ring, C _3-8 cycloalkyl, C _1-10 alkoxy, -NR ₁₁ R ₁₂ , -CONR ₂₁ R ₂₂ , -C (O) OC _1-10 alkyl, -SO ₂ C _1-10 alkyl, -SO ₂ NR ₁₁ R ₁₂ , -CONR ₁₃ SO ₂ R ₀ , -SO ₂ NR ₁₃ COC _1-10 alkyl, -NR ₁₁ (CH ₂ ) _p NHR ₁₄ , -NR ₁₁ (CH ₂ ) _p CONR ₁₅ R ₁₆ , -NR ₁₁ (CH ₂ ) _p CR ₁₅ R ₁₆ ; the phenyl group, 5 to 6 membered monocyclic heteroaromatic ring, 3 to 6 membered saturated monoheterocyclic ring, C _3-8 ring The alkyl group is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkoxy, C _1-10 alkyl, halogenated C _1-10 alkyl, -NR ₁₁ R ₁₂ , -COC _1-10 alkyl, -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl, -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl;

R ₄ is hydrogen or C _1-10 alkyl;

Or R ₃ and R ₄ together with the connected carbon atoms form a 3- to 6-membered saturated monoheterocycle or a 3- to 6-membered saturated monocyclic ring; Substituted or substituted by 1-3 substituents selected from the group consisting of halogen, C _1-10 alkoxy, C _1-10 alkyl, and halogenated C _1-10 alkyl;

The structure shown in formula (A), formula (B) or formula (C):

Where Z ₁ is NR ₅ , S or CR ₅ R ₆ ;

Z ₂ is N or CR ₆ ;

Z ₃ is a bond, C (O), C (R ₇ R ₈ ) or S (O) ₂ ;

Z ₄ is N or CR ₆ ;

Z ₅ is CR ₉ ;

Z ₆ is N or CR ₆ ;

Z ₇ is NR ₅ , S or CR ₅ R ₆ ;

Z ₈ is a bond, C (O), C (R ₇ R ₈ ) or S (O) ₂ ;

Ring B is a 4- to 6-membered saturated or unsaturated monocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring;

Ring C and the heterocyclic ring together form a 9 to 10 membered bicyclic heteroaryl ring;

Ring D is a 4- to 6-membered saturated or unsaturated monocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring;

It is a single bond or a double bond;

R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are each independently hydrogen, halogen, C _1-10 alkyl, C _1-10 alkoxy, halogenated C _1-10 alkyl, -NR ₁₁ R ₁₂ , -COC _1-10 alkyl, -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl, -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl;

R ₃₁ and R ₃₂ are each independently hydrogen, halogen, C _1-10 alkyl, C _1-10 alkoxy, halogenated C _1-10 alkyl, -NR ₁₁ R ₁₂ , -NR ₁₃ COC _1-10 Alkyl, -NR ₁₃ SO ₂ R ₀ ;

R _b is halogen, CN, carboxyl, -NR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl, -SO ₂ C _1-10 alkyl, -SO ₂ NR ₁₁ R ₁₂ , -P (O) (OC _1-10 alkyl) ₂ , -P (O) (OH) ₂ , -CONR ₁₁ R ₁₂ , -CONR ₁₃ SO ₂ R ₀ , -SO ₂ NR ₁₃ COC _1-10 alkyl, -NR ₁₁ ( CH ₂ ) _p NHR ₁₄ , -NR ₁₁ (CH ₂ ) _p CONR ₁₅ R ₁₆ , -NR ₁₁ (CH ₂ ) _p CR ₁₅ R ₁₆ , halogenated C _1-10 alkyl-substituted hydroxymethyl or halogenated C _1-10 alkyl substituted hydroxyethyl; R ₀ is C _1-10 alkyl, -NR ₁₁ R ₁₂ or C _3-8 cycloalkyl;

R ₁₄ is -SO ₂ C _1-10 alkyl, -COC _1-10 alkyl;

R ₁₅ and R ₁₆ are each independently hydrogen or C _1-10 alkyl; or R ₁₅ and R ₁₆ form a 5- to 6-membered saturated monoheterocycle with the attached nitrogen or carbon atom; the 5- to 6-membered saturated mono Heterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkoxy, C _1-10 alkyl, halogenated C _1-10 alkyl, -NR ₁₁ R ₁₂ ;

R ₂₁ and R ₂₂ are each independently hydrogen or R ₂₁ , R ₂₂ and the connected nitrogen atom together form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or substituted by 1- Substituted by 3 -NR ₁₁ R ₁₂ or C _1-10 alkyl;

R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen, C _1-10 alkyl or halogenated C _1-10 alkyl;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

R _a is halogen, CN, C _1-10 alkyl or halogenated C _1-10 alkyl;

n is 0, 1, 2, 3 or 4.

The second aspect of the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

In the formula,

R ₃ is -L ₁ -R _c ; L ₁ is a bond, C (O) or (CR ₃₁ R ₃₂ ) _q ; R _c is hydrogen, phenyl, 5- to 6-membered monocyclic heteroaromatic ring (preferably pyridine Ring or pyrazole ring), 3 to 6 membered saturated monoheterocycle (preferably epoxyhexane), C _3-8 cycloalkyl (preferably C _3-6 cycloalkyl), C _1-8 alkoxy (Preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), -NR ₁₁ R ₁₂ , -CONR ₂₁ R ₂₂ , -C (O) OC _1-10 alkyl (preferably- C (O) OC _1-6 alkyl, more preferably -C (O) OC _1-3 alkyl), -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more Preferably -SO ₂ C _1-3 alkyl), -SO ₂ NR ₁₁ R ₁₂ , -CONR ₁₃ SO ₂ R ₀ , -SO ₂ NR ₁₃ COC _1-10 alkyl (preferably -SO ₂ NR ₁₃ COC _{1 -6} alkyl, more preferably -SO ₂ NR ₁₃ COC _1-3 alkyl), -NR ₁₁ (CH ₂ ) _p NHR ₁₄ , -NR ₁₁ (CH ₂ ) _p CONR ₁₅ R ₁₆ , -NR ₁₁ (CH ₂ ) _p CR ₁₅ R ₁₆ ; the phenyl group, 5 to 6 membered monocyclic heteroaromatic ring (preferably pyridine ring or pyrazole ring), 3 to 6 membered saturated monoheterocyclic ring (preferably epoxyhexane) C _3-8 cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkyl Oxy, More preferably, it is C _1-3 alkoxy), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), halogenated C _1-10 alkyl (preferably Halogenated C _1-6 alkyl, more preferably halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -COC _1-10 alkyl (preferably -COC _1-6 alkyl, more preferably- COC _1-3 alkyl), -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _1-6 alkyl, more preferably -C (O) OC _{1 -3} alkyl), -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl);

R ₄ is hydrogen or C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl);

Or R ₃ and R ₄ together with the connected carbon atoms form a 3- to 6-membered saturated monoheterocycle or a 3- to 6-membered saturated monocyclic ring; Substituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _{1- 3} alkoxy), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), halogenated C _1-10 alkyl (preferably halogenated C _1-6 Alkyl, more preferably halogenated C _1-3 alkyl);

R ₀₁ , R ₀₂ , R ₀₃ are each independently hydrogen, halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy Group), optionally substituted C _1-10 alkyl (preferably optionally substituted C _1-6 alkyl, more preferably optionally substituted C _1-3 alkyl), halogenated C _1-10 alkyl (Preferably halogenated C _1-6 alkyl, more preferably halogenated C _1-3 alkyl) or halogenated C _1-10 alkoxy (preferably halogenated C _1-6 alkoxy, more preferably Halogenated C _1-3 alkoxy); the optionally substituted means unsubstituted or substituted with 1-3 substituents selected from the group consisting of: C _1-10 alkoxy (preferably C _{1- 6} alkoxy, more preferably C _1-3 alkoxy), -NR ₁₁ R ₁₂ , -CONR ₂₁ R ₂₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _{1 -6} alkyl, more preferably -C (O) OC _1-3 alkyl), -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl), -SO ₂ NR ₁₁ R ₁₂ ;

The structure shown in formula (A), formula (B) or formula (C):

Where Z ₁ is NR ₅ , S or CR ₅ R ₆ ;

Z ₂ is N or CR ₆ ;

Z ₃ is a bond, C (O), C (R ₇ R ₈ ) or S (O) ₂ ;

Z ₄ is N or CR ₆ ;

Z ₅ is CR ₉ ;

Z ₆ is N or CR ₆ ;

Z ₇ is NR ₅ , S or CR ₅ R ₆ ;

Z ₈ is a bond, C (O), C (R ₇ R ₈ ) or S (O) ₂ ;

It is a single bond or a double bond;

R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are each independently hydrogen, halogen (preferably F or Cl), C _1-10 alkyl (preferably C _1-6 alkyl, and more preferably C _{1 -3} alkyl), C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), halogenated C _1-10 alkyl (preferably halogenated C _1-6 alkyl, more preferably halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -COC _1-10 alkyl (preferably -COC _1-6 alkyl, more preferably -COC _{1- 3} alkyl), -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _1-6 alkyl, more preferably -C (O) OC _1-3 alkyl Radical), -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl);

R ₃₁ and R ₃₂ are each independently hydrogen, halogen (preferably F or Cl), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), C _{1- 10} alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), halogenated C _1-10 alkyl (preferably halogenated C _1-6 alkyl, more preferably Halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -NR ₁₃ COC _1-10 alkyl (preferably -NR ₁₃ COC _1-6 alkyl, more preferably -NR ₁₃ COC _1-3 alkyl ), NR ₁₃ SO ₂ R ₀ ;

R _b is halogen (preferably F or Cl), CN, carboxyl, -NR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _1-6 alkyl, more preferably Is -C (O) OC _1-3 alkyl), -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl), -SO ₂ NR ₁₁ R ₁₂ , -P (O) (OC _1-10 alkyl) ₂ (preferably -P (O) (OC _1-6 alkyl) ₂ , more preferably -P (O) (OC _1-3 alkyl) ₂ ), -P (O) (OH) ₂ , -CONR ₁₁ R ₁₂ , -CONR ₁₃ SO ₂ R ₀ , -SO ₂ NR ₁₃ COC _1-10 alkyl (preferably -SO ₂ NR ₁₃ COC _1-6 alkyl, more preferably -SO ₂ NR ₁₃ COC _1-3 alkyl), -NR ₁₁ (CH ₂ ) _p NHR ₁₄ , -NR ₁₁ (CH ₂ ) _p CONR ₁₅ R ₁₆ ,- NR ₁₁ (CH ₂ ) _p CR ₁₅ R ₁₆ , halogenated C _1-10 alkyl substituted hydroxymethyl or halogenated C _1-10 alkyl substituted hydroxyethyl; R ₀ is C _1-10 alkyl ( Preferably it is C _1-6 alkyl, more preferably C _1-3 alkyl), -NR ₁₁ R ₁₂ , C _3-8 cycloalkyl (preferably C _3-6 cycloalkyl);

R ₁₄ is -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl), -COC _1-10 alkyl (preferably- COC _1-6 alkyl, more preferably -COC _1-3 alkyl);

R ₁₅ and R ₁₆ are each independently hydrogen or C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl); or R ₁₅ , R ₁₆ and the attached nitrogen atom or Carbon atoms form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), halogenated C _1-10 alkyl (preferably halogenated C _1-6 alkyl, more preferably halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ ;

R ₂₁ and R ₂₂ are each independently hydrogen or R ₂₁ , R ₂₂ and the connected nitrogen atom together form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or substituted by 1- Substituted by 3 -NR ₁₁ R ₁₂ or C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl);

R ₁₁ , R ₁₂ and R ₁₃ are each independently hydrogen, C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl) or halogenated C _1-10 alkyl ( It is preferably a halogenated C _1-6 alkyl, and more preferably a halogenated C _1-3 alkyl);

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

R _a is halogen (preferably F or Cl), CN, C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl) or halogenated C _1-10 alkyl ( It is preferably a halogenated C _1-6 alkyl, and more preferably a halogenated C _1-3 alkyl);

n is 0, 1, 2, 3 or 4.

In another preferred example, R ₀₁ and R ₀₃ are hydrogen; R ₀₂ is halogen (preferably F or Cl) or C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _{1 -3} alkoxy, most preferably methoxy).

In another preferred example, R ₀₁ is hydrogen, F or Cl; R ₀₂ is F, Cl, methyl or methoxy; R ₀₃ is hydrogen.

In another preferred example, R ₃ is -CH ₂ -R _c ; R _c is phenyl; the phenyl is unsubstituted or substituted with 1-3 halogens.

In another preferred example, R ₃ is -CH ₂ -R _c ; R _c is a 5- to 6-membered monocyclic heteroaromatic ring (preferably a pyridine ring, a pyrazole ring) or a 3- to 6-membered saturated monoheterocyclic ring (preferably For epoxy hexane).

In another preferred example, R ₄ is hydrogen.

In another preferred embodiment, R _a is F or Cl.

In another preferred embodiment, R _a is Cl.

In another preferred example, n is 1.

In another preferred example, in formula (A), Z ₁ is NR ₅ , S or CR ₅ R ₆ ; Z ₂ is N or CR ₆ ; Z ₃ is a bond;

Is a single bond or a double bond; ring B is a 4- to 6-membered saturated or unsaturated single heterocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ and R ₆ are as defined in the description.

In another preferred example, in formula (A), Z ₁ is NR ₅ or S; Z ₂ is N or CR ₆ ; Z ₃ is a bond;

Is a double bond; ring B is a 4- to 6-membered unsaturated monocyclic ring, a 4- to 6-membered unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ , R ₆ As defined in the instructions.

In another preferred example, in formula (A), Z ₁ is NR ₅ ; Z ₂ is N or CR ₆ ; Z ₃ is C (O), C (R ₇ R ₈ ), or S (O) ₂ ;

Is a single bond or a double bond; ring B is a 4- to 6-membered saturated or unsaturated single heterocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ , R ₆ , R ₇ and R ₈ are as defined in the specification.

Is a double bond; ring B is a 4- to 6-membered unsaturated monocyclic ring, a 4- to 6-membered unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ , R ₆ , R ₇ and R ₈ are as defined in the specification.

In another preferred example, in formula (A), Z ₁ is NH; Z ₂ is N; Z ₃ is C (O) or a bond;

Is a double bond; ring B is a benzene ring; R _b and m are as defined in the specification.

Is a double bond; ring B is a benzene ring; R _b is a carboxyl group, -CONHSO ₂ N (CH ₃ ) ₂ , -CONHSO ₂ CH ₃ , -P (O) (OH) ₂ , NH ₂ , -NHCH ₂ CONH ₂ , -NH (CH ₂ ) ₂ CONH ₂ or -CONH ₂ ; m is 1 or 2.

In another preferred example, in formula (A), Z ₁ is NH; Z ₂ is N; Z ₃ is C (O);

Is a double bond; ring B is a benzene ring; R _b is a carboxyl group, -CONHSO ₂ N (CH ₃ ) ₂ , -CONHSO ₂ CH ₃ , -P (O) (OH) ₂ , NH ₂ , -NHCH ₂ CONH ₂ , -NH (CH ₂ ) ₂ CONH ₂ or -CONH ₂ ; m is 1.

In another preferred example, in formula (A), Z ₁ is NH; Z ₂ is N; Z ₃ is a bond;

In another preferred example, in formula (A),

(a) Z ₁ is NH; Z ₂ is N; Z ₃ is a bond;

Is a double bond; ring B is a benzene ring; R _b is a carboxyl group, -CONHSO ₂ N (CH ₃ ) ₂ , -CONHSO ₂ CH ₃ , -P (O) (OH) ₂ , NH ₂ , -NHCH ₂ CONH ₂ , -NH (CH ₂ ) ₂ CONH ₂ or -CONH ₂ ; m is 1 or 2; or

(b) Z ₁ is NH; Z ₂ is N; Z ₃ is C (O);

In another preferred example, in formula (B), Z ₄ is N or CR ₆ ; Z ₅ is CR ₉ ; ring C and the heterocyclic ring together form a 9 to 10 membered bicyclic heteroaryl ring; R _b , m , R ₆ and R ₉ are as defined in the specification.

In another preferred example, in formula (C), Z ₆ is N or CR ₆ ; Z ₇ is NR ₅ , S or CR ₅ R ₆ ; Z ₈ is a bond;

Is a single bond or a double bond; ring D is a 4 to 6 membered saturated or unsaturated single heterocyclic ring, a 4 to 6 membered saturated or unsaturated single ring, a 5 to 6 membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ and R ₆ are as defined in the description.

In another preferred example, in formula (C), Z ₆ is N or CR ₆ ; Z ₇ is NR ₅ or S; Z ₈ is a bond;

Is a double bond; ring D is a 4- to 6-membered unsaturated monocyclic ring, a 4- to 6-membered unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ , R ₆ As defined in the instructions.

In another preferred example, in formula (C), Z ₆ is N or CR ₆ ; Z ₇ is NR ₅ ; Z ₈ is C (O), C (R ₇ R ₈ ) or S (O) ₂ ;

Is a single bond or a double bond; ring D is a 4 to 6 membered saturated or unsaturated single heterocyclic ring, a 4 to 6 membered saturated or unsaturated single ring, a 5 to 6 membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ , R ₆ , R ₇ and R ₈ are as defined in the specification.

Is a double bond; ring D is a 4- to 6-membered unsaturated monocyclic ring, a 4- to 6-membered unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring; R _b , m, R ₅ , R ₆ , R ₇ and R ₈ are as defined in the specification.

In another preferred example, in formula (C), Z ₆ is N; Z ₇ is NH; Z ₈ is C (O);

Is a double bond; D ring is a benzene ring; R _b and m are as defined in the specification.

Is a double bond; D ring is a benzene ring; R _b is a carboxyl group, -CONHSO ₂ N (CH ₃ ) ₂ , -CONHSO ₂ CH ₃ , -P (O) (OH) ₂ , NH ₂ , -NHCH ₂ CONH ₂ , -NH (CH ₂ ) ₂ CONH ₂ or -CONH ₂ ; m is 1.

Is a double bond; ring B is a 4 to 6 membered unsaturated monocyclic ring, a 4 to 6 membered unsaturated monocyclic ring, a 5 to 6 membered monocyclic heteroaryl ring or a benzene ring; m is 1 or 2; R _b , m , R ₅ and R ₆ are as defined in the specification.

In another preferred example, formula (A) has the structure shown in formula (A1):

Formula (A1)

In the formula, Y ₁ is N or CR _a1 ; Y ₂ is N or CR _a2 ; Y ₃ is N or CR _a3 ; Y ₄ is N or CR _a4 ; and Y ₁ , Y ₂ , Y ₃ , and Y _{4 are} not simultaneously N, and containing up to 2 _{_{N; R a1, R a2,}} R a3, R a4 are each independently defined as R _b; Z _1, Z ₂ as defined in the specification.

In another preferred example, in formula (A1), Y ₁ is CR _a1 ; Y ₂ is N or CH; Y ₃ is CR _a3 ; Y ₄ is N or CH; R _a1 and R _a3 are each independently as R _b As defined; Z ₁ and Z ₂ are as defined in the specification.

Is a double bond; ring D is a 4- to 6-membered unsaturated monocyclic ring, a 4- to 6-membered unsaturated monocyclic ring, a 5 to 6-membered monocyclic heteroaryl ring or a benzene ring; m is 1 or 2; R ₅ , R ₆ As defined in the manual.

In another preferred example, formula (C) has the structure shown in formula (C1):

Formula (C1)

In the formula, Y ₅ is N or CR _a5 ; Y ₆ is N or CR _a6 ; Y ₇ is N or CR _a7 ; Y ₈ is N or CR _a8 ; and Y ₅ , Y ₆ , Y ₇ , and Y _{8 are} not simultaneously N, and containing up to 2 _{_{N; R a5, R a6,}} R a7, R a8 R _b are each independently as defined; Z _6, Z ₇ as defined in the specification.

In another preferred example, in formula (C1), Y ₅ is CR _a5 ; Y ₆ is N or CH; Y ₇ is CR _a7 ; Y ₈ is N or CH; R _a5 and R _a7 are each independently as R _b As defined; Z ₆ and Z ₇ are as defined in the specification.

The third aspect of the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

In the formula,

R ₃ is -L ₁ -R _c ; L ₁ is a bond, C (O) or (CR ₃₁ R ₃₂ ) _q ; R _c is hydrogen, phenyl, 5- to 6-membered monocyclic heteroaromatic ring (preferably pyridine Ring, pyrazole ring), 3 to 6 membered saturated monoheterocycle (preferably epoxyhexane), C _3-8 cycloalkyl (preferably C _3-6 cycloalkyl), C _1-8 alkoxy (Preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), -NR ₁₁ R ₁₂ , -CONR ₂₁ R ₂₂ , -C (O) OC _1-10 alkyl (preferably- C (O) OC _1-6 alkyl, more preferably -C (O) OC _1-3 alkyl), -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more Preferably -SO ₂ C _1-3 alkyl), -SO ₂ NR ₁₁ R ₁₂ , -CONR ₁₃ SO ₂ R ₀ , -SO ₂ NR ₁₃ COC _1-10 alkyl (preferably -SO ₂ NR ₁₃ COC _{1 -6} alkyl, more preferably -SO ₂ NR ₁₃ COC _1-3 alkyl), -NR ₁₁ (CH ₂ ) _p NHR ₁₄ , -NR ₁₁ (CH ₂ ) _p CONR ₁₅ R ₁₆ , -NR ₁₁ (CH ₂ ) _p CR ₁₅ R ₁₆ ; the phenyl group, 5 to 6 membered monocyclic heteroaromatic ring (preferably pyridine ring, pyrazole ring), 3 to 6 membered saturated monoheterocyclic ring (preferably epoxyhexane), C _3-8 cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkyl Oxy, Preferably a C _1-3 alkoxy), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), C _1-10 haloalkyl group (preferably a halogen Substituted C _1-6 alkyl, more preferably halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -COC _1-10 alkyl (preferably -COC _1-6 alkyl, more preferably -COC _1-3 alkyl), -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _1-6 alkyl, more preferably -C (O) OC _{1- 3} alkyl), -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl);

R ₀₁ and R ₀₃ are hydrogen; R ₀₂ is halogen (preferably F or Cl) or C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy, most Preferably methoxy);

The structure shown in formula (A) or formula (C):

Where Z ₁ is NR ₅ , S or CR ₅ R ₆ ;

Z ₂ is N or CR ₆ ;

Z ₃ is a key;

Z ₆ is N or CR ₆ ;

Z ₇ is NR ₅ , S or CR ₅ R ₆ ;

Z ₈ is a key;

It is a single bond or a double bond;

R ₅ and R ₆ are each independently hydrogen, halogen (preferably F or Cl), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), C _{1- 10} alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), halogenated C _1-10 alkyl (preferably halogenated C _1-6 alkyl, more preferably Halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -COC _1-10 alkyl (preferably -COC _1-6 alkyl, more preferably -COC _1-3 alkyl), -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _1-6 alkyl, more preferably -C (O) OC _1-3 alkyl), -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl (preferably -SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl);

R ₃₁ and R ₃₂ are each independently hydrogen, halogen (preferably F or Cl), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), C _{1- 10} alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), halogenated C _1-10 alkyl (preferably halogenated C _1-6 alkyl, more preferably Halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -NR ₁₃ COC _1-10 alkyl (preferably -NR ₁₃ COC _1-6 alkyl, more preferably -NR ₁₃ COC _1-3 alkyl ), -NR ₁₃ SO ₂ R ₀ ;

R ₂₁ and R ₂₂ are each independently hydrogen or R ₂₁ , R ₂₂ and the connected nitrogen atom together form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or is 1- Substituted by 3 -NR ₁₁ R ₁₂ or C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl);

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4.

In another preferred example, R _b is halogen, CN, carboxyl, NH ₂ , -C (O) OC _1-3 alkyl, -SO ₂ C _1-3 alkyl, -SO ₂ NH ₂ , -P ( O) (OC _1-3 alkyl) ₂ , -P (O) (OH) ₂ , -CONH ₂ , -CONHSO ₂ C _1-3 alkyl, -CONHSO ₂ NH ₂ , -CONHSO ₂ N (CH ₃ ) ₂ , -CONHSO ₂ C _3-6 cycloalkyl, -SO ₂ NHCOC _1-10 alkyl, -C (CF ₃ ) ₂ OH, -NHCH ₂ CONH ₂ , -NH (CH ₂ ) ₂ CONH ₂ , -NH (CH ₂ ) ₃ CONH ₂ , -NH (CH ₂ ) ₃ NHSO ₂ C _1-3 alkyl, -NH (CH ₂ ) ₂ NHSO ₂ C _1-3 alkyl, -NHCH ₂ NHSO ₂ C _1-3 alkyl Group, -NHCH ₂ NHCOC _1-3 alkyl, -NH (CH ₂ ) ₂ NHCOC _1-3 alkyl, -NH (CH ₂ ) ₃ NHCOC _1-3 alkyl, -NHCHR ₁₅ R ₁₆ or -NHCONR ₁₅ R ₁₆ ; R ₁₅ and R ₁₆ form a 5- to 6-membered saturated monoheterocycle with the attached nitrogen atom; the 5- to 6-membered saturated monoheterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of : Halogen, C _1-3 alkoxy, C _1-3 alkyl, halogenated C _1-3 alkyl, NH ₂ or N (CH ₃ ) ₂ .

In another preferred example, m is 0, 1, or 2.

In another preferred example, when the ring B and ring D are 4- to 6-membered unsaturated monoheterocycles, they are selected from: 1,2-dihydroazetidine, 1,2-dihydrooxane Butadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H -Pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine.

In another preferred example, when the B ring and the D ring are 4 to 6 membered unsaturated monocyclic rings, they are selected from cyclopentenyl ring, cyclohexenyl ring, and cyclohexadienyl ring.

In another preferred example, when the B ring and the D ring are 5 to 6 membered monocyclic heteroaryl rings, they are selected from: thiophene ring, N-alkane ring pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole Ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring Azole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring.

In another preferred example, the 9- to 10-membered bicyclic heteroaryl ring formed by the C ring and the heterocyclic ring is selected from: quinoline, quinazoline, pyrido [3,2-d] pyrimidine, pyridine [2,3-d] pyrimidine, pyrido [3,4-d] pyrimidine, pyrido [4,3-d] pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6- Naphthyridine, 1,5-naphthyridine.

In another preferred example,

For structure

In another preferred example, formula (A) or formula (C) is selected from the following group of structures:

In another preferred example, formula (B) is selected from the following group of structures:

In another preferred example, the structure represented by formula (A) or formula (C) is selected from the group consisting of:

In another preferred example, R ₃ is -CH ₂ -L ₁ ; L ₁ is phenyl; the phenyl is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), C _1-10 alkyl (preferably C _1-6 alkyl , More preferably C _1-3 alkyl), halogenated C _1-10 alkyl (preferably halogenated C _1-6 alkyl, more preferably halogenated C _1-3 alkyl), -NR ₁₁ R ₁₂ , -COC _1-10 alkyl (preferably -COC _1-6 alkyl, more preferably -COC _1-3 alkyl), -CONR ₁₁ R ₁₂ , -C (O) OC _1-10 alkyl (preferably -C (O) OC _1-6 alkyl, more preferably -C (O) OC _1-3 alkyl), -SO ₂ NR ₁₁ R ₁₂ or -SO ₂ C _1-10 alkyl (preferably- SO ₂ C _1-6 alkyl, more preferably -SO ₂ C _1-3 alkyl); R ₄ is hydrogen.

In another preferred example, R ₃ and R ₄ together with the connected carbon atoms form a 3 to 6 membered saturated monoheterocycle or a 3 to 6 membered saturated monocyclic; the 3 to 6 membered saturated monoheterocyclic or 3 to 6 The saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C _1-10 alkoxy (preferably C _1-6 alkoxy, More preferably, it is C _1-3 alkoxy), C _1-10 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 alkyl), halogenated C _1-10 alkyl (preferably Halogenated C _1-6 alkyl, more preferably halogenated C _1-3 alkyl).

In another preferred example, the 3 to 6-membered saturated monocyclic ring or 3 to 6-membered saturated monocyclic ring formed by R ₃ and R ₄ together with the connected carbon atoms is selected from the group consisting of propylene oxide and azetidine , Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thioxo Morpholine-1,1-dioxide, tetrahydropyran, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring.

In another preferred example, n is 1.

In another preferred example, the compound is selected from Table A, Table B, Table C, or Table D.

In another preferred example, the compound is selected from Table B, Table C, or Table D.

In another preferred embodiment, the compound is selected from Table B or Table C.

In another preferred embodiment, the compound is selected from Table E.

Table A

Table B

Table C

Table D

Table E

In another preferred example, the compound is selected from the following structures:

The fourth aspect of the present invention provides a pharmaceutical composition comprising the compound of the first, second or third aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvent thereof Chemical compounds; and pharmaceutically acceptable carriers.

The fifth aspect of the present invention provides the compound according to the first, second or third aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the medicament according to the fourth aspect of the present invention Application of the composition in the preparation of XIa inhibitors.

The sixth aspect of the present invention provides the compound according to the first, second or third aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the medicament according to the fourth aspect of the present invention Use of the composition in the preparation of a medicament for inhibiting factor XIa.

The seventh aspect of the present invention provides the compound according to the first, second or third aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the medicament according to the fourth aspect of the present invention Use of the composition in the preparation of a medicament for preventing and / or treating Factor XIa-mediated diseases.

The eighth aspect of the present invention provides the compound according to the first, second or third aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the medicament according to the fourth aspect of the present invention Use of the composition in the preparation of a medicament for preventing and / or treating cardiovascular and cerebrovascular diseases.

In another preferred example, the cardiovascular and cerebrovascular diseases are preferably thromboembolic diseases, more preferably myocardial infarction, angina pectoris, angioplasty or aortic coronary artery shunt, re-occlusion and restenosis, diffuseness Intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

The ninth aspect of the present invention provides a method for preventing and / or treating a factor XIa-mediated disease, comprising administering to a desired patient a therapeutically effective amount of the compound of the first, second or third aspect of the present invention, or A pharmaceutically acceptable salt, stereoisomer or solvate, or the pharmaceutical composition according to the fourth aspect of the invention.

The tenth aspect of the present invention provides a method for preventing and / or treating cardiovascular and cerebrovascular diseases, comprising administering to a desired patient a therapeutically effective amount of the compound of the first, second or third aspect of the present invention, or a pharmaceutical thereof Acceptable salt, stereoisomer or solvate, and optionally another therapeutically active agent.

In another preferred example, the cardiovascular and cerebrovascular diseases are preferably thromboembolic diseases, more preferably myocardial infarction, angina pectoris, angioplasty or aortic coronary artery shunt, reocclusion and restenosis, disseminated blood vessels Internal coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep venous thrombosis.

It should be understood that, within the scope of the present invention, the above technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other, thereby forming a new or preferred technical solution. Due to space limitations, I will not repeat them here.

detailed description

After extensive and in-depth research, the inventor unexpectedly discovered such bicyclic heterocyclic substituted pyridine-2 (1H) -one derivatives, especially pyridine-2 (1H) -one substituted bicyclic heterocyclic Pyridine-2 (1H) -one derivatives have higher inhibitory activity on factor XIa and can effectively inhibit platelet aggregation. In addition, the compounds of the present invention have excellent pharmacokinetic properties. Therefore, this series of compounds is expected to be developed into drugs for the treatment and prevention of diseases such as thromboembolism. On this basis, the inventor completed the present invention.

Definition of Terms

As used herein, "alkyl" refers to a linear and branched saturated aliphatic hydrocarbon group, C _1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C _1-6 alkyl, more preferably C _1-3 alkyl, similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , N-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2 , 4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3 -Dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethyl Hexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethyl Amylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethyl Hexyl, 2,2-diethylhexyl, and various branched isomers thereof are more preferred.

As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C _3-8 cycloalkyl" refers to a cyclic hydrocarbon group containing 3 to 8 carbon atoms, preferably a C _3-6 ring Alkyl is defined similarly. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , Cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, cyclohexenyl.

As used herein, "C _1-8 alkoxy" refers to -O- (C _1-8 alkyl), where alkyl is as defined above. C _1-6 alkoxy is preferred, and C _1-3 alkoxy is more preferred. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, pentoxy, and the like.

As used herein, "C _3-8 cycloalkoxy" refers to -O- (C _3-8 cycloalkyl), where cycloalkyl is as defined above. C _3-6 cycloalkoxy is preferred. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

As used herein, "C _6-10 aryl" refers to an all-carbon monocyclic or fused polycyclic (that is, a ring that shares adjacent pairs of carbon atoms) groups with a conjugated π electron system, meaning that it contains 6 to 10 Carbon atom aryl; phenyl and naphthyl are preferred, and phenyl is more preferred.

As used herein, "a bond" refers to two groups connected by a covalent bond.

As used herein, "halogen" refers to fluorine, chlorine, bromine, or iodine.

As used herein, "halo" refers to the replacement of one or more (eg 1, 2, 3, 4, or 5) hydrogen in a group with a halogen.

For example, "halo C _1-10 alkyl" means that the alkyl is substituted with one or more (eg 1, 2, 3, 4, or 5) halogens, where alkyl is as defined above. The halogenated C _1-6 alkyl group is selected, and the halogenated C _1-3 alkyl group is more preferable. Examples of halogenated C _1-8 alkyl include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

For another example, "halo C _1-10 alkoxy" refers to alkoxy substituted by one or more (eg 1, 2, 3, 4 or 5) halogen, wherein alkoxy is defined as described above. It is preferably a halogenated C _1-6 alkoxy group, and more preferably a halogenated C _1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, etc.

As used herein, "amino" refers to NH _2, "cyano" refers to the CN, "Nitro" refers to NO _2, "benzyl" refers to -CH ₂ - phenyl, "carboxy" refers to -C (O) OH, ""Acetyl" refers to -C (O) CH ₃ , "hydroxymethyl" refers to -CH ₂ OH, "hydroxyethyl" refers to -CH ₂ CH ₂ OH, "hydroxy" refers to -OH, as used herein, "heteroaromatic""Basering" is used interchangeably with "heteroaryl" and "heteroaryl ring" and refers to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl; 6, 10, or 14 π electrons are shared in the ring array; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms. "Hetero atom" means nitrogen, oxygen or sulfur.

As used herein, "5 to 6 membered monocyclic heteroaryl ring" refers to a heteroaryl group containing 5 to 6 ring atoms. Examples of 5- to 6-membered monocyclic heteroaromatic rings include (but are not limited to): pyrazole, 1-methylpyrazole, imidazole, pyrrole, 1-methylpyrrole, isothiazole, thiazole, isoxazole, 1,2 , 3-triazole, 2-methyl-1,2,3-triazole, 1,2,4-triazole, thiophene, pyridine, pyrimidine and pyridazine etc.

As used herein, "3- to 6-membered saturated monocyclic ring" refers to a saturated all-carbon monocyclic ring containing 3 to 6 ring atoms. Examples of the 3- to 6-membered saturated monocyclic ring include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring and the like.

As used herein, "3- to 6-membered (5 to 6-membered) saturated monoheterocycle" means that 1, 2, or 3 carbon atoms in the 3- to 6-membered monocyclic ring are selected from nitrogen, oxygen, or S (O) _t (Where t is an integer 0 to 2) substituted by a heteroatom, but does not include the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 yuan. Examples of 3- to 6-membered saturated monoheterocycles include, but are not limited to, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxane Pentane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, etc.

As used herein, "4- to 6-membered saturated or unsaturated monocyclic ring" refers to a saturated or partially unsaturated all-carbon monocyclic ring containing 4 to 6 ring atoms. Examples of 4- to 6-membered saturated or partially unsaturated monocyclic rings include (but are not limited to): cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring , Cycloheptyl ring, cycloheptatrienyl ring, cyclooctyl ring, etc.

As used herein, "4- to 6-membered saturated or unsaturated monoheterocycle" means that 1, 2, or 3 carbon atoms in the 4- to 6-membered monocyclic ring are selected from nitrogen, oxygen, or S (O) _t (where t It is substituted with a hetero atom of the integer 0 to 2), but does not include the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members. Examples of 4- to 6-membered saturated or unsaturated monoheterocycles include, but are not limited to, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine , Piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine Diene, 1,2-dihydrooxetene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro- 1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydro Pyridine etc.

As used herein, "5 to 6 membered monocyclic heteroaryl ring" refers to a monoheteroaryl ring containing 5 to 6 ring atoms, including, for example, but not limited to: thiophene ring, N-alkane ring pyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5- Triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, etc.

As used herein, "9 to 10 membered bicyclic heteroaryl ring" refers to a biheteroaryl ring containing 9 to 10 ring atoms, including, for example (but not limited to): benzofuran, benzothiophene, indole, Isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, phthalazine, pyrido [3,2-d] pyrimidine, pyrido [ 2,3-d] pyrimidine, pyrido [3,4-d] pyrimidine, pyrido [4,3-d] pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine , 1,5-naphthyridine.

As used herein, "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other Are replaced by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

As used herein, any group herein may be substituted or unsubstituted. When the above group is substituted, the substituent is preferably 1 to 5 or less groups, independently selected from CN, halogen, C _1-8 alkyl (preferably C _1-6 alkyl, more preferably C _1-3 Alkyl), C _1-8 alkoxy (preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy), halogenated C _1-8 alkyl (preferably halogenated C _{1- 6} alkyl, more preferably halo C _1-3 alkyl), C _3-8 cycloalkyl (preferably C _3-6 cycloalkyl), halo C _1-8 alkoxy (preferably halo C _1-6 alkoxy, more preferably halogenated C _1-3 alkoxy), C _1-8 alkyl substituted amine group, amine group, halogenated C _1-8 alkyl substituted amine group, 3 To 6 membered saturated monoheterocycle, 5 to 6 membered monocyclic heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring, spiro ring, spiro heterocycle, bridged ring or bridged heterocycle.

The various types of substituent groups described herein above may themselves be substituted with the groups described herein.

When the 3- to 6-membered (5 to 6-membered) saturated monoheterocycles described herein are substituted, the position of the substituents may be at their possible chemical positions. Exemplary substitutions of exemplary monoheterocycles are shown below :

Where "Sub" represents the various substituents described herein; "

"Indicates connection with other atoms.

When the 4- to 6-membered saturated monoheterocycle described in the present invention is a substituent, it may itself be substituted or substituted with 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, C _{1- 3} alkyl, O =, NR _a0 R _b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C (O) OC _1-3 alkyl, acetyl, halogenated C _1-3 alkyl, C _1-3 Alkoxy, C _3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane Oxyhexacyclic, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxo Azole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring; where R _a0 And R _b0 are each independently hydrogen or C _1-3 alkyl.

The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.

"Pharmaceutically acceptable base addition salts" include, but are not limited to, inorganic base salts such as sodium, potassium, calcium, and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salts, triethylamine salts, lysine salts, arginine salts, etc.

The "solvate" mentioned in the present invention refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate out or crystallize out of the solvent. For example, a complex formed with water is called "hydrate". Solvates of compounds of formula (I) are within the scope of the present invention.

The compounds represented by formula (I) or formula (II) of the present invention may contain one or more chiral centers and exist in different optically active forms. When a compound contains a chiral center, the compound contains enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compound of formula (I) or formula (II) contains more than one chiral center, diastereomers may exist. The invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.

The present invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to obtain the parent compound. The specific prodrug preparation method can refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K .; Wu, D .; Royzen, MJ Med. Chem. 2000, 43, 475.).

Generally, the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like. The above dosage forms can be made from the active compound and one or more carriers or adjuvants through general pharmacological methods. The aforementioned carrier needs to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers used in liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, and polyethylene glycol. The active compound may form a solution or suspension with the above-mentioned carrier.

The composition of the present invention is formulated, quantified, and administered in a manner consistent with medical practice standards. The "therapeutically effective amount" of the administered compound is determined by factors such as the specific disorder to be treated, the individual being treated, the cause of the disorder, the target of the drug, and the mode of administration.

As used herein, "therapeutically effective amount" refers to a compound of the present invention that will elicit an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, relieving a disorder, slowing or delaying disease progression, or preventing disease the amount.

The therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg to 5 g / kg (body weight).

As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of auxiliary materials, which is compatible with the patient, most It is preferably a mammal, and more preferably a human, which is suitable for delivering an active agent to a target target without terminating the activity of the agent.

As used herein, "patient" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.

As used herein, "treatment" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or disorder (eg, cancer). Treatment also includes curing, preventing or alleviating one or more symptoms of the disease or condition to some extent.

Preparation

The experimental methods that do not indicate specific conditions in the following examples generally follow conventional conditions such as Sambrook et al. Molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer The recommended conditions.

Unless otherwise defined, the terms used herein have the same meaning as familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the contents described can be applied to the present invention.

The preparation method of the compound used in the present invention:

The compound represented by formula (I) of the present invention can be prepared by a known method, for example, by the following method, a method equivalent thereto, or the method described in the examples. In the following preparation method, the raw material compound may be in the form of a salt, and the salt may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (I) of the present invention.

The compound represented by the formula (I) (the compound represented by the formula (I-3)) in which R ₁ and R ₂ are each independently hydrogen or C _1-10 alkyl can pass the following reaction scheme (Ia), reaction scheme ( Ib) prepared by the method.

Reaction Scheme (Ia)

(In the above schemes, all symbols are as described above)

Specifically, the compound represented by formula (I-3) can be prepared by the amidation reaction of the compound represented by formula (I-1) and the compound represented by formula (I-2).

Reaction Scheme (Ib)

(In the above schemes, all symbols are as described above)

Specifically, the compound represented by formula (I-3) can be prepared by the amidation reaction of the compound represented by formula (I-4) and the compound represented by formula (I-2).

Where formula (A)

The compound represented by formula (II) where Z ₁ is NH, Z ₂ is N, and Z ₃ is a bond (the compound represented by formula (II-6)) can be subjected to the following reaction scheme (II) and reaction scheme (IV) Or prepared by the method shown in Reaction Scheme (V).

Reaction Scheme (Ⅱ)

(In the above schemes, all symbols are as described above.)

Specifically, the compound represented by the formula (II-6) can be prepared according to the following method: the compound represented by the formula (II-1) and the compound represented by the formula (II-2) are subjected to an amidation reaction to obtain the formula (II -3) In the compound represented by the formula (II-3), the carbonyl group and the amino group undergo dehydration condensation to form the compound represented by the formula (II-4), and the nitro group in the compound represented by the formula (II-4) occurs The reduction reaction forms a compound represented by formula (II-5). In the compound represented by formula (II-5), the amino group reacts with sodium azide and trimethyl orthoformate to form a compound represented by formula (II-6).

Reaction Scheme (Ⅳ)

(In the above schemes, all symbols are as described above)

Specifically, the compound represented by the formula (II-6) can be prepared according to the following method: the compound represented by the formula (IV-1) and the compound represented by the formula (II-2) are subjected to amidation reaction to obtain the formula (IV -2) In the compound represented by the compound represented by formula (IV-2), the carbonyl group and the amino group undergo a dehydration condensation reaction to form the compound represented by formula (II-6).

Reaction Scheme (Ⅴ)

(In the above schemes, all symbols are as described above)

Specifically, the compound represented by the formula (II-6) can be prepared according to the following method: the compound represented by the formula (V-1) and the compound represented by the formula (II-2) are subjected to an amidation reaction to obtain the formula (V -2) The compound represented by the formula (Ⅴ-2), the carbonyl group and the amino group undergo dehydration condensation reaction to form the compound represented by the formula (V-3), the compound represented by the formula (V-3) and the formula (Ⅴ- 4) The compound represented by Suzuki coupling reaction forms the compound represented by formula (II-5), and the compound represented by formula (II-5) undergoes a cyclization reaction between the amino group, sodium azide and trimethyl orthoformate to form the formula ( The compound represented by Ⅱ-6).

Among them (C)

The compound represented by formula (II) wherein Z ₆ is N, Z ₇ is NH, and Z ₈ is C (O) (the compound represented by formula (III-5)) can be prepared by the method represented by reaction scheme (III)

Reaction plan (Ⅲ)

(In the above schemes, all symbols are as described above.)

Specifically, the compound represented by the formula (III-5) can be prepared according to the following method: the compound represented by the formula (II-1) and the compound represented by the formula (III-1) are subjected to an amidation reaction to obtain the formula (III -2) The compound represented by the formula (III-2) undergoes a dehydration condensation reaction to form the compound represented by the formula (III-3), and the compound represented by the formula (III-3) undergoes a reduction reaction to form the formula (Ⅲ -4) The compound represented by the formula (III-4) in which the amino group reacts with sodium azide and trimethyl orthoformate to form the compound represented by the formula (III-5).

The compound represented by formula (II) can also be prepared by the method represented by reaction scheme (VI).

Reaction Scheme (Ⅵ)

(In the above schemes, all symbols are as described above.)

Specifically, the compound represented by formula (VI-6) can be prepared according to the following method: the corresponding compound represented by formula (VI-1) and the compound represented by formula (VI-2) are prepared by N-alkylation reaction The compound represented by formula (VI-3), the compound represented by formula (VI-3) and R ₃ Br or R ₃ OTf undergo substitution reaction to form the compound represented by formula (VI-4), the compound represented by formula (VI-4) Suzuki coupling reaction with the compound represented by the formula (Ⅴ-4) to form the compound represented by the formula (VI-5), the amino group in the compound represented by the formula (VI-5) and sodium azide, trimethyl orthoformate ring The chemical reaction forms the compound represented by formula (VI-6).

The compound represented by formula (II-1) in the above reaction scheme can be prepared by the method represented by reaction scheme (II-1a).

Reaction Scheme (II-1a)

(In each formula of the above scheme, all symbols are as described above, R is C _1-6 alkyl)

Specifically, the compound represented by the formula (II-1) can be prepared according to the following method: the corresponding compound represented by the formula (II-1-1) and the boric acid ester are borated to obtain the formula (II-1-2) The compound represented by formula (II-1-2) and the compound represented by formula (II-1-3) undergo Suzuki coupling reaction to form the compound represented by formula (II-1-4), formula (II-1 -4) The compound represented by the formula is dehydroxylated to form the compound represented by the formula (II-1-5), the compound represented by the formula (II-1-5) and the compound represented by the formula (II-1-6) generate N-alkyl groups The chemical reaction forms a compound represented by formula (II-1-7), and the decarboxylated protecting group of the compound represented by formula (II-1-7) forms a compound represented by formula (II-1).

The compound represented by formula (IV-1) in the above reaction scheme can be prepared by the method represented by the following reaction scheme (IV-1a) or reaction scheme (IV-1b).

Reaction Scheme (Ⅳ-1a)

(In each formula of the above scheme, all symbols are as described above, and R is C _1-6 alkyl.)

Specifically, the compound represented by formula (IV-1) can be prepared according to the following method: a compound represented by formula (IV-1-1) and a compound represented by formula (V-4) undergo Suzuki coupling reaction to form formula (IV -1-2) The compound represented by the formula ((IV-1-2) and the sodium azido ring undergo a cyclization reaction to form the compound represented by the formula (IV-1-3), the formula (IV-1-3 ) The compound represented by the decarboxylation protecting group forms the compound represented by formula (IV-1). The compound represented by formula (IV-1-1) can be represented by the compound represented by formula (VI-1) and formula (II-1-6) The compound represented by the N-alkylation reaction, or the compound represented by the formula (VI-1) and the compound represented by the formula (IV-1-4) N-alkylation reaction to form the formula (IV-1 -5) The compound represented by formula (IV-1-5) is prepared by substitution reaction with R ₃ OTf or R ₃ Br.

Reaction Scheme (Ⅳ-1b)

Specifically, the compound represented by formula (IV-1) can be prepared according to the following method: the compound represented by formula ((IV-1-2) is decarboxylated to form the compound represented by (IV-1-4), (IV- The compound represented by 1-4) undergoes a cyclization reaction with sodium azidocyclate to form the compound represented by formula (IV-1).

The amidation reaction is known and may be. For example, in the presence of a base in the presence of a base in an organic solvent (such as chloroform, dichloromethane, dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, etc.) at about 0 ° C to reflux temperature or without solvent In the case of pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), use a condensing agent (such as 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), N, N'-carbonyldiimidazole (CDI), 1-propylphosphonic anhydride (T ₃ P), etc.), with or without In the case of containing 1-hydroxybenzotriazole (HOBT), a carboxylic acid or sodium carboxylate is reacted with an amine.

The condensation reaction is known and may be. For example, under the catalysis of an acid (such as acetic acid), NH ₂ and -NHCO-condensation on the benzene ring dehydrate to form an imidazole ring.

The nitro reduction reaction is known and may be. For example, use (1) active metal reduction method (such as iron powder, zinc powder, tin particles, etc.), (2) metal hydride reduction (such as sodium borohydride, lithium tetrahydrogen aluminum, etc.), (3) catalytic hydrogenation reduction Method (using precious metal platinum, palladium or skeleton nickel as catalyst) or similar methods, reducing the nitro group on the benzene ring to an amino group.

The cyclization reaction is known and may be. For example, using a solvent (such as acetic acid, water, etc.) or no solvent, in the case of a catalyst (such as ferric oxide, indium trifluoromethanesulfonate, copper, etc.) or without a catalyst, NH ₂ on the benzene ring, stack The cyclization reaction of sodium nitride and trimethyl orthoformate forms a tetrazole ring.

The Suzuki coupling reaction is known and may be. In an organic solvent (such as toluene, dimethylformamide, dimethylacetamide, tetrahydrofuran, etc.), in the presence of a base (such as sodium carbonate, potassium carbonate, cesium carbonate, etc.), use a palladium catalyst (Pd (OAc ) 2, Ph (Ph3P) 4, Pd (Ph3P) 2Cl2, Pd (dppf) Cl2, Pd / C, etc.), aryl boric acid or aryl borate and cross-coupling with halogenated aromatic hydrocarbon.

The N-alkylation reaction is known and may be. For example, using a solvent (such as methanol, acetone, toluene, dimethylformamide, dimethylacetamide, tetrahydrofuran, etc.) or without a solvent, in the presence of a base (such as sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, etc.) In this case, an N-alkylation reaction occurs.

The substitution reaction is known and can be. For example, using a solvent (such as tetrahydrofuran, etc.), in the presence of a base (such as lithium hexamethyldisilazide, etc.), the hydrogen on the alkyl carbon is substituted.

The dehydroxylation protection reaction is known and may be. For example, using a solvent (such as dimethylformamide, dimethylacetamide, tetrahydrofuran, etc.), in the presence of an acid (such as phthalic acid, etc.), using a catalyst (aluminum trichloride), the 2-methyl The methyl group in the oxypyridine is removed to form 2-hydroxypyridine (also known as 2-pyridone).

The decarboxylation protection reaction is known and may be. For example, using a solvent (eg, 1,4-dioxane, methylene chloride, tetrahydrofuran, etc.), in the presence of an acid (eg, hydrochloric acid, trifluoroacetic acid, etc.), the ester group is deprotected to form a carboxyl group.

The borate reaction is known and may be. For example, use a solvent (such as 1,4-dioxane, methylene chloride, tetrahydrofuran, diethyl ether, toluene, etc.), and in the presence of a base (such as potassium acetate, lithium diisopropylamide, etc.), use a palladium catalyst (Pd (OAc) ₂ , Ph (Ph ₃ P) ₄ , Pd (Ph ₃ P) ₂ Cl ₂ , Pd (dppf) Cl ₂ , Pd / C, etc.) or no catalyst, boric acid or boric acid ester and halogenated aromatic hydrocarbon A coupling reaction occurred.

The compound having an amino group, a carboxyl group or a hydroxyl group used in the present invention can be prepared using a compound that has been protected by a protecting group commonly used for the group as needed, and after the reaction process through the above reaction scheme, known desorption can be performed Protection reaction.

The compounds represented by formula (I) and formula (II) other than the above compounds can be prepared by combining the examples described in this specification or combining known methods.

Compared with the prior art, the main advantages of the present invention are:

A series of novel bicyclic heterocyclic substituted pyridine-2 (1H) -one derivatives are provided, which have high inhibitory activity on coagulation factor XIa and can effectively inhibit platelet aggregation Pharmacokinetic properties. Therefore, it can be developed as a drug for the treatment and prevention of diseases such as thromboembolism.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. Unless otherwise stated, percentages and parts are calculated by weight.

As used herein, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, MeOH is methanol, AcOH or HOAc is acetic acid, NH ₄ OAc is ammonium acetate, KOAc is potassium acetate, ACN is acetonitrile, and NBS is N-bromine Succinimide, DCM is dichloromethane, AIBN is azobisisobutyronitrile, Pd (dppf) Cl ₂ is 1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, TFA Is trifluoroacetic acid, NCS is N-chlorosuccinimide, LiHMDS is lithium bis (trimethylsilyl) amide, DMAP is 4-dimethylaminopyridine, n-BuLi is n-butyl lithium, t- BuOH is t-butanol, t-BuOK is potassium t-butoxide, HATU is 2- (7-azobenzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate, DMF is N, N-dimethylformamide, DMSO is dimethylsulfoxide, DIEA (also known as DIPEA) is N, N-diisopropylethylamine, TCFH is N, N, N ', N' -Tetramethylchloroformamidine hexafluorophosphate, Raney Ni is Raney nickel, TEA is triethylamine, Dess-Martin is Dess-Martin oxidant, DBU is 1,8-diazabicyclo [5.4.0] Undec-7-ene, LDA is lithium diisopropylamide, Boc ₂ O is di-tert-butyl dicarbonate, SEM-Cl is 2- (trimethylsilyl) ethoxymethyl chloride, T ₃ P is 1-propyl Phosphoric anhydride, TMS-Br is trimethylbromosilane, Pd / C is palladium / carbon catalyst, TLC is thin layer chromatography, -OTf is trifluoromethanesulfonyl, and NMI is N-methylimidazole.

As used herein, room temperature refers to about 20-25 ° C.

Preparation of Intermediate 1-5

Step 1: Compound 1-1 (500 mg, 1.89 mmol) in DMF (15 mL) was added HATU (1.08 g, 2.83 mmol), DIPEA (731 mg, 5.67 mmol) and compound 1.1 (347 mg, 2.27 mmol) at 0 ° C under a nitrogen atmosphere ), The mixture was stirred at room temperature overnight. LC-MS followed until the reaction was complete. The mixture was poured into ice water, filtered, and the filter cake was washed with water and evaporated to dryness under reduced pressure to obtain a yellow solid compound 1-2 (720 mg, 95% yield). MS m / z (ESI): 401.2 [M + H] ⁺ .

Step 2: AcOH (15 mL) solution of compound 1-2 (680 mg, 1.7 mmol) was stirred at 70 ° C. overnight. LC-MS followed until the reaction was complete. After the mixture was concentrated, a saturated sodium carbonate solution was added to adjust the pH to 8, filtered, and the filter cake was washed with water and evaporated to dryness under reduced pressure to obtain a solid compound 1-3 (605 mg, 93% yield). MS m / z (ESI): 383.2 [M + H] ⁺ .

Step 3: A solution of compound 1-3 (100 mg, 0.26 mmol) in THF (8 mL) and methanol (2 mL) was added Raney Ni (30 mg), the mixture was stirred at room temperature in a hydrogen atmosphere for 3 h, and LC-MS followed until the reaction was complete. The mixture was filtered through celite, and the filtrate was concentrated to obtain brown solid compound 1-4, which was directly used in the next reaction. MS m / z (ESI): 353.2 [M + H] ⁺ .

Step 4: A solution of compound 1-4 (92 mg, 0.26 mmol) in methanol (3 mL) was added HCl / 1,4-dioxane (4M, 3 mL), and the mixture was stirred at room temperature for 3 h. LC-MS followed until the reaction was complete. The mixture was concentrated to give yellow solid compound 1-5 which was directly used in the next reaction. MS m / z (ESI): 253.1 [M + H] ⁺ .

Preparation of Intermediate 12-6

Step 1: Compound 1u-2 (2.6 g, 7.74 mmol), compound 12.1 (2.94 g, 11.61 mmol), Pd (dppf) Cl ₂ (285 mg, 0.39 mmol), cesium fluoride (2.94 g, 19.35 mmol), 1 A mixture of 4,4-dioxane (50 mL) and 10 mL of water was stirred at 90 ° C. overnight under an argon atmosphere. LC-MS followed until the reaction was complete. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated brine and concentrated, and combiflash purified to obtain compound 12-2 (1.92 g, 65% yield). MS m / z (ESI): 383.1 [M + H] ⁺ .

Step 2: Compound 12-2 (1.9g, 4.97mmol) in AcOH (30mL) was added _{_{CH (OCH 3) 3 (2.37g}} , 22.36mmol), stirred for 10min at room temperature was added NaN ₃ (1.45g, 22.36mmol), The mixture was stirred at room temperature overnight. LC-MS followed until the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, and concentrated under reduced pressure to obtain a yellow solid compound 12-3. MS m / z (ESI): 436.1 [M + H] ⁺ .

Step 3: A solution of compound 12-3 (2.1 g, 4.83 mmol) in THF (30 mL) and water (6 mL) was added LiOH (304 mg, 7.24 mmol) at 0 ° C, and the mixture was stirred at 0 ° C for 30 min. LC-MS followed until the reaction was complete. The reaction solution was adjusted to pH 3 with dilute hydrochloric acid, concentrated under reduced pressure to remove THF, extracted with ethyl acetate, the organic layer was washed with brine and concentrated under reduced pressure to obtain a yellow solid compound 12-4. MS m / z (ESI): 422.1 [M + H] ⁺ .

Steps 4 to 5: Refer to steps 1 to 2 in Intermediate 1-5, combiflash purification to obtain compound 12-6 (150 mg, 94% yield). MS m / z (ESI): 590 [M + H] ⁺ .

Preparation of Intermediate 1a

Step 1: The preparation method is the same as Step 2 of Intermediate 12-6. MS m / z (ESI): 307 [M + H] ⁺ .

Step 2: Compound 1a-2 (5g, 16.3mmol), ethyl acrylate (2.5g, 24.5mmol) and TEA (2.5g, 24.5mmol) in acetonitrile (50mL) were added compound Pd (OAc) ₂ under a nitrogen atmosphere (367mg, 1.6mmol), the mixture was microwaved at 80 ° C and stirred overnight. LC-MS followed until the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, evaporated to dryness under reduced pressure and purified by silica gel column chromatography to obtain compound 1a-3. MS m / z (ESI): 279 [M + H] ⁺ .

Step 3: Compound 1a-3 (4.5 g, 16.2 mmol) in methanol / water (50 mL / 5 mL) was added NaOH (710 mg, 17.8 mmol), and the mixture was stirred at room temperature overnight. LC-MS followed until the reaction was complete. The solvent was evaporated under reduced pressure to obtain compound 1a. MS m / z (ESI): 251 [M + H] ⁺ .

Preparation of Intermediate 1b

A solution of compound 1a (500 mg, 1.84 mmol) in water (3 mL) was added dropwise to HCl (0.8 mL), and the mixture was stirred at room temperature for 3 h. After filtering the reaction solution, it was washed with water to obtain a white solid compound 1b. MS m / z (ESI): 251 [M + H] ⁺ .

Preparation of Intermediate 1c

Step 1: A solution of SeO ₂ (0.65 g, 6 mmol) in 1,4-dioxane (25 mL) was heated to 65 ° C, compound 1c-1 (1 g, 4.5 mmol) was added, and the mixture was stirred at 80 ° C for 3 h. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated to obtain compound 1c-2. MS m / z (ESI): 236 [M + H] ⁺ .

Step 2: Compound 1c-2 (2.34 g, 10 mmol) in THF (40 mL) was added dropwise at 0 ° C. Compound 1c.1 (1 M in THF, 15 mL, 15 mmol), and the mixture was raised to room temperature for 1.5 h. The reaction solution was quenched with saturated ammonium chloride and ethyl acetate, extracted with ethyl acetate, the organic layer was concentrated and purified by silica gel column chromatography to obtain compound 1c-3 (2.5 g, 76.5% yield). MS m / z (ESI): 328 [M + H] ⁺ .

Step 3: Compound 1c-3 (1 g, 3.06 mmol) in DCM (20 mL) was added Dess-Martin (2.59 g, 6 mmol), and the mixture was stirred at room temperature for 1 day. LC-MS followed until the reaction was complete. Saturated sodium carbonate solution and dichloromethane were added to the reaction solution, the aqueous layer was extracted with dichloromethane, and the organic layer was concentrated to obtain compound 1c-4. MS m / z (ESI): 326 [M + H] ⁺ .

Step 4: A solution of compound 1c-4 (327 mg, 1 mmol) in THF / MeOH (10 mL / 1 mL) was added trans-bis (acetoxy) bis [2- [bis (2-methylphenyl) phosphino] benzyl ] Dipalladium (II) (47mg, 0.05mmol), tri-tert-butylphosphine tetrafluoroborate (29mg, 0.1mmol), Mo (CO) ₆ (528mg, 2mmol) and DBU (304mg, 2mmol), the mixture in Microwave reaction at 130 ° C for 10 min. LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified to obtain compound 1c-5. MS m / z (ESI): 306 [M + H] ⁺ .

Step 5: A solution of compound 1c-5 (70 mg, 0.23 mmol), NH ₄ OAc (88 mg, 1.15 mmol) and NaBH ₃ CN (71 mg, 1.15 mmol) in methanol (5 mL) was microwaved at 80 ° C. for 0.5 h. LC-MS followed until the reaction was complete. The mixture was concentrated and purified by column chromatography to obtain compound 1c (50 mg, 71% yield). MS m / z (ESI): 307 [M + H] ⁺ .

Preparation of Intermediate 1d

Step 1: Compound 1d-1 (10 g, 66.7 mmol) in CCl ₄ (10 mL) was added to compound SOCl ₂ (19.4 mL, 266.8 mmol), and the mixture was reacted at 65 ° C. for 3 h. To the reaction solution, CCl ₄ (40 mL), NBS (14.2 g, 80 mmol) and 48% HBr (10 drops) were added and the mixture was stirred overnight at 85 ° C. The system was cooled to 0 ° C and filtered through celite. After the filtrate was cooled to 0 ° C, methanol was slowly added until no gas was generated. After concentration, water was added, extracted with n-hexane, washed with saturated sodium bicarbonate solution, and the organic layer was concentrated. 1d-2 (9.2 g, 57% yield). MS m / z (ESI): 243/245 [M + H] ⁺ .

Step 2: Compound 1d.1 (600 mg, 2.7 mmol) in THF (10 mL) was added compound NaH (130 mg, 3.24 mmol) at 0 ° C under an argon atmosphere, and the mixture was reacted at room temperature for 2 h. 1d-2 (787 mg, 3.24 mmol) was added to the reaction solution, and stirred at room temperature for 3 days. LC-MS followed until the reaction was complete. The mixture was poured into ice water, extracted with dichloromethane, and the organic layer was concentrated and purified by combiflash to obtain compound 1d-3 (650 mg, 63% yield). MS m / z (ESI): 385 [M + H] ⁺ .

Step 3: Compound 1d-3 (250 mg, 0.65 mmol) in THF (10 mL) and water (8 mL) was added hydrated LiOH (41 mg, 0.97 mmol), and the mixture was reacted at room temperature for 2 h. Dilute hydrochloric acid solution was added to adjust the pH to 4, the THF was concentrated, the mixture was filtered, the filter cake was washed with water, and the solid was dried under reduced pressure to obtain compound 1d (210 mg, 87% yield). MS m / z (ESI): 371 [M + H] ⁺ .

Preparation of Intermediate 1e

Step 1: Compound 1e-1 (2.8 g, 20.1 mmol) in THF (25 mL) was added LDA (12 mL, 24.2 mmol) at -78 ° C, and stirred at -78 ° C to -20 ° C for 2 h, then at -78 A solution of compound 1e.1 (4.5g, 24.2mmol) in THF (5mL) was added at 0C, and the mixture was slowly raised to room temperature and stirred overnight. LC-MS followed until the reaction was complete. The reaction solution was quenched with water and extracted with ethyl acetate. The aqueous phase was added with dilute hydrochloric acid to adjust the pH to 7 and filtered to obtain compound 1e-2. MS m / z (ESI): 184 [M + H] ⁺ .

Step 2: The preparation method is the same as Step 1 in Intermediate 12-6, except that compounds 1u-2 and 12.1 are replaced with compounds 1e-2 and 1e.2 to obtain compound 1e-3. MS m / z (ESI): 295 [M + H] ⁺ .

Step 3: Compound 1e-3 (480 mg, 1.36 mmol) in DMF (30 mL) was added pyridine hydrochloride (1.57 g, 13.6 mmol), and the mixture was stirred at 100 ° C. overnight. LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by column chromatography to obtain compound 1e (440 mg, 96.3% yield). MS m / z (ESI): 281 [M + H] ⁺ .

Preparation of Intermediate 1f

A solution of compound 1f-1 (2.16g, 10mmol) and compound 1f.1 (3.05g, 12mmol) in 1,4-dioxane (40mL) plus KOAc (2.45g, 25mmol) and Pd (dppf) Cl ₂ ( 220 mg, 0.3 mmol), and the mixture was stirred overnight at 85 ° C under an argon atmosphere. LC-MS followed until the reaction was complete. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated and purified by combiflash to obtain compound 1f (2.42 g, 92% yield).

Preparation of Intermediate 1g

Step 1: The preparation method is the same as Step 1 in Intermediate 1k, except that compound 1k-1 is replaced with compound 1g-1 to obtain compound 1g-2. MS m / z (ESI): 250.1 [M + H] ⁺ .

Step 2: Compound 1g-2 (740 mg, 2.97 mmol), NBS (582 mg, 3.27 mmol) and AIBN (97 mg, 0.59 mmol) in CCl ₄ (10 mL) were stirred at 80 ° C. for 5 h. LC-MS followed until the reaction was complete. The system was cooled to 0 ° C, filtered and evaporated to dryness under reduced pressure to obtain compound 1g-3. MS m / z (ESI): 328 [M + H] ⁺ .

Step 3: Compound 1g-3 (800 mg, 2.45 mmol) and compound 1 g. 1 (292 mg, 1.22 mmol) and K ₂ CO ₃ (506 mg, 3.67 mmol) in ACN (10 mL) were stirred at room temperature overnight. LC-MS followed until the reaction was complete. The reaction solution was concentrated and purified by combiflash to obtain compound 1g-4. MS m / z (ESI): 487 [M + H] ⁺ .

Step 4: Under an argon atmosphere, to a solution of Compound 1g-4 (1312mg, 2.7mmol) and Compound 1g.2 (551mg, 3.24mmol) in THF (10mL) was added NaH (130mg, 3.24mmol) at 0 ° C, The mixture was reacted at 0 ° C for 3h. LC-MS followed until the reaction was complete. The mixture was poured into ice water, extracted with ethyl acetate, and the organic layer was concentrated and purified by combiflash to obtain compound 1g (908 mg, 63% yield). MS m / z (ESI): 577 [M + H] ⁺ .

Preparation of Intermediate 1i

Step 1: Compound 1i-1 (1g, 3.64mmol), NaOH (6N, 1.2mL, 7.28mmol) in 1,4-dioxane (3mL) was heated to 130 ° C and stirred for 4h. LC-MS followed until the reaction was complete. The reaction solution was added with water and extracted with ethyl acetate. The aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid under ice bath, and then filtered to obtain compound 1i-2. MS m / z (ESI): 273.9 [M + H] ⁺ .

Step 2: The preparation method is the same as Step 2 in Intermediate 1d, except that compound 1d.1 is replaced with compound 1i-2 to obtain compound 1i. MS m / z (ESI): 436 [M + H] ⁺ .

Preparation of Intermediate 1j

The preparation method is the same as that of intermediate 1i, except that compound 1i-1 is replaced with 2-fluoro-4iodo-5-methylpyridine to obtain compound 1j. MS m / z (ESI): 398 [M + H] ⁺ .

Preparation of Intermediate 1k

Step 1: A solution of compound 1k-1 (2 g, 16 mmol) in 1,4-dioxane (20 mL) was added Boc ₂ O (3.58 g, 16 mmol), and the mixture was refluxed for 4 h. LC-MS followed until the reaction was complete. After cooling, the mixture was concentrated under reduced pressure to remove the solvent, and purified by combiflash to obtain compound 1k-2. MS m / z (ESI): 225 [M + H] ⁺ .

Step 2: A solution of compound 1k-2 (1.6 g, 7.1 mmol) and tetramethylethylenediamine (3.4 mL, 22.1 mmol) in THF (10 mL) was added dropwise n-BuLi (10 mL, -78 ° C) under a nitrogen atmosphere at -78 ° C. 24mmol), slowly raised to -20 ° C and stirred for 3h, at -78 ° C was added I ₂ (2.164g, 8.52mmol) in THF (10mL) solution, the mixture was slowly raised to room temperature and stirred for 16h. LC-MS followed until the reaction was complete. The reaction solution was quenched with ammonium chloride solution and water. The aqueous layer was extracted with ethyl acetate. The organic layer was concentrated and purified by combiflash to obtain compound 1k-3. MS m / z (ESI): 351 [M + H] ⁺ .

Step 3: Prepare according to step 3 in intermediate 1v to obtain compound 1k-4. MS m / z (ESI): 251 [M + H] ⁺ .

Step 4: Compound 1k-4 (2.1g, 8.4mmol) in methanol (20mL) was added HCHO (1.26g, 42mmol), stirred for 1h after addition of _{NaBH 3 CN (1.588g, 25.2mmol)} , stirred at rt for 16h. LC-MS followed until the reaction was complete. The mixture was concentrated and purified by column chromatography to obtain compound 1k-5. MS m / z (ESI): 279 [M + H] ⁺ .

Step 5: A solution of compound 1k-5 (740 mg, 2.66 mmol) in HBr / HOAc (5Ml, 30%), the mixture was stirred at 80 ° C for 3 h, and LC-MS followed until the reaction was complete. The reaction solution was concentrated to obtain compound 1k-6. MS m / z (ESI): 265 [M + H] ⁺ .

Step 6: The preparation method is the same as Step 2 in Intermediate 1d, except that compound 1d.1 is replaced with compound 1k-6 to obtain compound 1k. MS m / z (ESI): 427.1 [M + H] ⁺ .

Preparation of intermediate 1m

Using the corresponding methyl ester as the raw material, refer to steps 2 to 4 in compound 1g to prepare compound 1m. MSm / z (ESI): 535 [M + H] ⁺ .

Preparation of Intermediate 1o

Using compound 1t-3 as a raw material and referring to the method of intermediate 12-6, compound 1o is obtained. MSm / z (ESI): 590 [M + H] ⁺ .

Preparation of Intermediate 1p

Step 1: A solution of compound 1p-1 (5 g, 37.6 mmol) in 1,4-dioxane (50 mL) was added malonic acid (39 g, 376 mmol), and the mixture was stirred at 130 ° C. for 24 h. LC-MS followed until the reaction was complete. The reaction solution was cooled and concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, and the organic layer was evaporated to dryness under reduced pressure to obtain compound 1p-2. MS m / z (ESI): 158 [M + H] ⁺ .

Step 2: Compound 1p-2 (1 g, 6.36 mmol) and DIPEA (1.8 mL, 12.72 mmol) in THF (15 mL) were added SEM-Cl (1.35 mL, 7.63 mmol) at 0 ° C, and the mixture was stirred at 40 ° C for 16 h . TLC followed until the reaction was complete. The reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated brine, the organic layer was evaporated to dryness under reduced pressure, and combiflash purified to obtain compound 1p-3. MS m / z (ESI): 288 [M + H] ⁺ .

Step 3: Dissolve compound 1p-3 (1.44g, 5mmol) in 20ml of DMF, add 10M NaOH aqueous solution and stir at 100 ° C overnight. After the reaction is completed, cool to room temperature. Ethyl acetate was extracted, dried and concentrated to obtain compound 1p-4, which was used directly in the next step without purification. MS m / z (ESI): 307.1 [M + H] ⁺ .

Steps 4 to 7: For the preparation method, refer to steps 1 to 4 in the intermediate 1g to obtain compound 1p. MS m / z (ESI): 708.1 [M + H] ⁺ .

Preparation of Intermediate 1q

Using 1p-3 and 4-bromo-5,6-dihydropyridine-2 (1H) -one as raw materials, the compound was prepared with reference to 1g of intermediate to obtain compound 1q. MS m / z (ESI): 549.1 [M + H] ⁺ .

Preparation of Intermediate 1r

Prepare by referring to the method of intermediate 1p, except that compound 1p-5 is replaced with methyl ester form, and 1- (bromomethyl) -4-fluorobenzene in step 7 of 1p is replaced with bromomethylbenzene to obtain compound 1r. MS m / z (ESI): 648.1 [M + H] ⁺ .

Preparation of Intermediate 1t

Step 1: Compound 1t-1 (2.3 g, 9.5 mmol) in AcOH (30 mL) was added with 12 mL of water, and the mixture was refluxed for 6 days. LC-MS followed until the reaction was complete. The reaction solution was concentrated to obtain compound 1t-2. MS m / z (ESI): 240 [M + H] ⁺ .

Steps 2 to 3: Prepare according to steps 2 to 3 in intermediate 1d to obtain compound 1t. MS m / z (ESI): 388 [M + H] ⁺ .

Preparation of Intermediate 20-4

Step 1: Compound 1e (440 mg, 1.57 mmol) was dissolved in 20 mL of THF, and sodium hydrogen (75 mg, 1.88 mmol) was added at 0 ° C. The reaction was stirred at room temperature for 2 hours, compound 1d-2 (419 mg, 1.72 mmol) was added, and the reaction was continued at room temperature for 18 hours. Add 20 mL of water, extract with EA (20 mL × 2), combine organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, using silica gel column chromatography with 0-60% The resulting residue was purified in PE to obtain compound 20-1 (150 mg, off-white solid), yield: 21.6%. MS “m / z (ESI): 443.1 [M-56 + 1].

Step 2: Compound 20-1 (140 mg, 0.32 mmol) was dissolved in 5 mL of methanol and 0.5 mL of water, sodium hydroxide (19 mg, 0.47 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to remove methanol, the pH was adjusted to 7 with 2M hydrochloric acid, extracted with EA (20 mL × 2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was decompressed Concentration gave crude compound 20-2 (130 mg, light yellow solid). MSm / z (ESI): 429.2 [M + 1].

Step 3: Compound 20-2 (130mg, 0.30mmol), compound 15.1 (126mg, 0.61mmol) and DIEA (157mg, 1.21mmol) was dissolved in 5mL DCM, 0 ℃ added _{T 3 P (193mg, 0.61mmol)} , The reaction was stirred at room temperature for 18 hours, 3 mL of saturated brine and 3 mL of water were added, extracted with DCM (15 mL × 2), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the compound 20-3 (180 mg, white solid), yield: 95.9%. MS m / z (ESI): 620.2 [M + 1].

Step 4: Compound 20-3 (180 mg, 1.20 mmol) was dissolved in 2 mL of acetic acid, and the reaction was stirred at 75 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified in 0-90% EA in PE by silica gel column chromatography to obtain intermediate compound 20-4 (170 mg, light yellow solid), yield: 97.3%. MS / m / z (ESI): 601.1 [M + 1].

Preparation of Intermediate 1u

Refer to the method of intermediate 20-4 for preparation. MS m / z (ESI): 494.1 [M + H] ⁺ .

Preparation of Intermediate 1v-1

Step 1: Dissolve 5-fluoro-4-iodopyridine-2 (1H) -one (5g, 20.9mmol) and tert-butyl bromoacetate (4.5g, 23.0mmol) in 30mL DMF, add potassium carbonate at 0 ° C ( 5.8g, 41.8mmol), stirred at room temperature for 4 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with 0-50% ethyl acetate in petroleum ether to obtain the product 2- (5-fluoro-4-iodo-2-oxopyridine- 1 (2H) -yl) tert-butyl acetate (6.0 g, white solid), yield: 81.2%. MS “m / z (ESI): 354 [M + 1].

Step 2: Dissolve tert-butyl 2- (5-fluoro-4-iodo-2-oxopyridine-1 (2H) -yl) acetate (2.0g, 5.66mol) and benzyl bromide (1156mg, 6.80mol) In 25mL of dimethylformamide, sodium hydrogen (340mg, 8.50mmol) was added at 0 ° C, the reaction was stirred at room temperature for 16 hours, 20mL of water and 20mL of 1M hydrochloric acid were added to the reaction solution, and extracted with ethyl acetate (50mL × 2 ), The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with 0-30% ethyl acetate in petroleum ether To give product 1v-1-a (163 mg, white solid), yield: 6.5%. MS / m / z (ESI): 444.0 [M + 1].

Step 3: Compound 1v-1-a (244mg, 0.55mmol), 4-chloro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) aniline (140mg, 0.55mmol) and potassium carbonate (190mg, 1.38mmol) were dissolved in 12mL dioxane and 2mL water, under the protection of nitrogen was added [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride (804mg, 0.11mmol), stirred at 100 ° C for 18 hours under nitrogen protection. After the reaction solution was cooled, 5mL saturated brine and 5mL water were added, extracted with ethyl acetate (20mL × 2), combined The organic phase was washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with 0-50% ethyl acetate in petroleum ether to obtain the product 1v-1-b (217 mg, light yellow solid), yield: 89.0%. MS “m / z (ESI): 443 [M + 1].

Step 4: In a 10 mL sealed tube, add: compound 1v-1-b (217 mg, 0.49 mmol), trimethyl orthoformate (470 mg, 4.42 mmol), sodium azide (288 mg, 4.42 mmol) and 2 mL of acetic acid, cover The lid was stirred at 90 ° C for 16 hours. 10 mL of water was added, extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and 5% by C18 column chromatography ~ 95% acetonitrile was purified the resulting residue in 0.5% ammonium bicarbonate solution to give product 1v-1-c (193 mg, light yellow solid). Yield: 79.6%. MS / m / z (ESI): 496 [M + 1].

Step 5: Compound 1v-1-c (193 mg, 0.39 mmol) was dissolved in 2 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with 0-15% methanol in methylene chloride to obtain the product 1v-1 (98 mg, off-white solid), yield: 57.0%. MS / m / z (ESI): 440 [M + 1].

Preparation of Intermediate 1v

Step 1: Under ice bath nitrogen protection, compound 1v-1 (200mg, 0.46mol), tert-butyl 3,4-diaminobenzoate (190mg, 0.92mmol), triethylamine (2.5mL) was dissolved in 10mL di To methyl chloride, propylphosphonic anhydride (1.5 mL) was added, and the temperature was raised to room temperature and the reaction was stirred for 16 hours. To the reaction solution was added 10 mL of ice water, extracted with dichloromethane (10 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product Compound 1v-2 (410 mg, yellow solid), the product was directly subjected to the next reaction without purification. MS / m / z (ESI): 630.2 [M + 1].

Step 2: Compound 1v-2 (410 mg, mmol) was dissolved in 5 mL of acetic acid, and the reaction was stirred at 75 ° C for 2 hours in a sealed tube. The reaction solution was poured into ice, extracted with ethyl acetate (5mL × 3), the organic phases were combined, washed sequentially with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and column chromatography was performed The method was purified with an eluent system (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain compound 1v-3 (242 mg, yellow solid), yield: 85.1%. MS / m / z (ESI): 612.2 [M + 1].

Step 3: Compound 1v-3 (242 mg, 0.40 mmol) was dissolved in 1 mL of trifluoroacetic acid and 4 mL of dichloromethane, and the reaction was stirred at room temperature for 2 hours. The filtrate of the reaction solution was concentrated under reduced pressure to obtain crude compound 1v (230 mg, off-white solid). The product was directly subjected to the next reaction without purification. MS m / z (ESI): 556.2 [M + 1]. ¹ H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.14 (d, J = 5.7 Hz, 2H), 7.87 (d, J = 2.9 Hz, 2H), 7.85–7.81 (m, 2H ), 7.59 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.2 Hz, 2H), 6.44 (t, J = 10.7 Hz, 2H), 3.69 (d, J = 8.6 Hz, 1H), 3.53 (d, J = 3.5 Hz, 1H).

Preparation of Intermediate 1w

Using 4-iodo-5-methoxypyridine-2 (1H) -one as the raw material and referring to the method of intermediate 1v-1, compound 1w was obtained. MS / m / z (ESI): 452 [M + 1].

Preparation of Intermediate 1x

Step 1: Dissolve 4-chlorobenzoic acid (5.0 g, 31.9 mol) in concentrated H ₂ SO ₄ (80 mL). To this solution was added KNO ₃ (16.0 g, 114.9 mmol) in portions, and the temperature was kept below 40 ° C during the process. The mixture was heated to 140 ° C and stirred for 5 hours (a reflux condenser was connected). It was cooled to room temperature and poured into ice water, filtered, washed with cold water, and dried under vacuum to obtain 4-chloro-3,5-dinitrobenzoic acid (6.20 g, white solid), yield: 78.7%. MS m / z (ESI): 247.1 [M + 1].

Step 2: Dissolve 4-chloro-3,5-dinitrobenzoic acid (6.2 g, 25.2 mmol) in 100 mL of methanol, add 215 mL of ammonia water at 0 ° C, stir the reaction mixture at -20 ° C for 2.5 hours, and reflux 3 Hours and leave it for 14 hours. The formed precipitate was filtered off and the filtrate was evaporated to dryness. The solid residue was combined with the precipitate, and water (50 mL) and HCl (50 mL) were added. With stirring, the precipitate was filtered off and washed with water until neutral to give the product 4-amino-3,5-dinitrobenzoic acid (5.5 g, yellow liquid), yield: 96.3%. MS “m / z (ESI): 228.1 [M + 1].

Step 3: Dissolve 4-amino-3,5-dinitrobenzoic acid (5.5 g, 24.2 mmol) in 100 mL of methanol, add 5 mL of concentrated sulfuric acid, and stir at reflux for 16 hours. The reaction solution is concentrated under reduced pressure, and 50 mL of water is added , Extracted with EA (100 mL × 2), combined organic phases, washed with saturated sodium bicarbonate (20 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using silica gel column chromatography to 0-50% EA was used to purify the resulting residue in PE to obtain the product methyl 4-amino-3,5-dinitrobenzoate (4.5 g, light yellow solid), yield: 77.1%. MS / m / z (ESI): 242.1 [M + 1].

Step 4: 4-Amino-3,5-dinitrobenzoic acid methyl ester (2 g, 8.3 mmol) was dissolved in 20 mL of methanol, and 40 mL of cyclohexene and 1.3 g of palladium carbon were added. The reaction system was replaced with hydrogen. The reaction was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified in 0 to 60% EA in PE by silica gel column chromatography to obtain the product 3,4-diamino-5- Methyl nitrobenzoate 1x (900 mg, off-white solid), yield: 51.4%. MS / m / z (ESI): 212.1 [M + 1].

Example 1 (E) -N- (1- (7-amino-1H-benzo [d] imidazol-2-yl) -2-phenylethyl) -3- (5-chloro-2- (1H -Tetrazole-1-yl) phenyl) acrylamide

A solution of compound 1-5 (78 mg, 0.22 mmol) and compound 1a (54 mg, 0.2 mmol) in DCM (10 mL) was added TEA (1 mL) and T ₃ P (0.5 mL) under a nitrogen atmosphere at 0 ° C. The mixture was stirred at room temperature overnight. LC-MS followed until the reaction was complete. The reaction was quenched with water, and the system was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and saturated brine, concentrated, and purified by Prep-HPLC to obtain a white solid compound H-1 (19 mg, 20% yield). ¹ H NMR (400MHz, DMSO-d6) δ 11.81-12.02 (m, 1H), 9.85 (s, 1H), 8.79-8.91 (m, 1H), 7.92 (s, 1H), 7.70-7.75 (m, 2H), 7.32–7.06 (m, 5H), 6.88–6.77 (m, 3H), 6.61 (d, J = 7.9Hz, 1H), 6.31-6.36 (m, 1H), 5.28-5.35 (m, 1H) , 5.10-5.15 (m, 2H), 3.49–3.39 (m, 1H), 3.21–3.05 (m, 1H). MS m / z (ESI): 485.2 [M + H] ⁺ .

Example 2 (E) -2- (1- (3- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) acrylamido) -2-phenylethyl) -1H- Preparation of imidazo [4,5-C] pyridine 6-carboxylic acid

Steps 1 to 3: Prepare by referring to steps 1, 2 and 4 of intermediate 1-5, respectively, to obtain compound 11-3.

Step 4: Prepared according to the method of Example 1, and purified by combiflash to obtain compound 11-4 (50 mg, 64% yield). MS m / z (ESI): 529.2 [M + H] ⁺ .

Step 5: A solution of compound 11-4 (40 mg, 0.076 mmol) in THF (5 mL) and water (3 mL) was added KOH (85 mg, 1.52 mmol) at 0 ° C, and the mixture was stirred at room temperature for 4 h. LC-MS followed until the reaction was complete. The reaction solution was adjusted to pH 6-7 with dilute hydrochloric acid, concentrated under reduced pressure to remove THF, filtered, and purified by Prep-HPLC to obtain white solid compound H-11 (5 mg, 13% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.05–8.84 (m, 2H), 8.20 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.70-7.76 (m, 2H), 7.34–7.07 (m, 5H), 6.79-6.88 (m, 2H), 5.41-5.47 (m, 1H), 3.38-3.45 (m, 1H), 3.19 (dd, J = 13.8, 9.0 Hz, 1H). MS m / z (ESI): 515.2 [M + H] ⁺ .

Example 3 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2-oxopyridine-1 (2H-yl) -2-phenylethyl Group) -7-fluoro-1H-benzo [d] imidazole-5-carboxylic acid

Compound 12-6 (90 mg, 0.15 mmol), Mo (CO) ₆ (40 mg, 0.15 mmol), trans-di- (m) -bis [2- (di-o-tolylphosphine) benzyl] dipalladium acetate (II ) (14 mg, 0.015 mmol), TEA (45 mg, 0.45 mmol), a mixture of 1,4-dioxane (2.5 mL) and 3 mL of water was reacted in a microwave at 150 ° C. for 20 min under an argon atmosphere. LC-MS followed until the reaction was complete. The mixture was added with water (8 mL) and ethyl acetate (20 mL), filtered, the filtrate was extracted with ethyl acetate, the organic layer was concentrated and purified by Prep-HPLC to obtain white solid compound H-12 (10 mg, 12% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.89 (s, 1H), 7.84–7.73 (m, 3H), 7.71 (d, J = 1.6 Hz, 1H), 7.48 (d , J = 11.3 Hz, 1H), 7.23 (t, J = 7.3 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 7.06 (d, J = 7.1 Hz, 2H), 6.39–6.32 (m , 1H), 6.17 (d, J = 1.9 Hz, 1H), 5.85 (dd, J = 7.2, 2.0 Hz, 1H), 3.65 (dd, J = 13.8, 9.0 Hz, 1H), 3.49-3.45 (m, 1H). MS m / z (ESI): 556.2 [M + H] ⁺ .

Example 4 (E) -2- (1- (3- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) acrylamido) -2-phenethyl) -1H-benzene Preparation of P [[]] imidazole-5-carboxylic acid

Steps 1-2: Refer to Steps 1-2 in Intermediate 1-5 for preparation to obtain compound 4-3. MS m / z (ESI): 528.1 [M + H] ⁺ .

Step 3: Compound 4-3 (500 mg, 1.16 mmol) and Pd / C in methanol (5 mL) were stirred at room temperature overnight. LC-MS followed until the reaction was complete. The reaction solution was filtered and evaporated to dryness under reduced pressure to obtain compound 4-4. MS, m / z (ESI): 296.1 [M + H] +.

Steps 4 to 5: Prepare according to steps 5 and 6 of Example 12, and purify by Prep-HPLC to obtain compound H-4 as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 9.85 (s, 1H), 8.94 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 15.5 Hz, 2H), 8.04 (s, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 11.7 Hz, 1H), 7.73 (dd, J = 10.4, 5.4 Hz, 2H), 7.66 (s, 1H ), 7.51 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 6.5 Hz, 3H), 7.17 (d, J = 6.7 Hz, 1H), 6.83 (d, J = 6.4 Hz, 1H), 5.40 (s, 1H), 3.20–3.13 (m, 2H). MSm / z (ESI): 514.1 [M + H] ⁺ .

Example 5 (E) -2- (1- (3- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) acrylamido) -2-phenylethyl) -4, Preparation of 5,6,7-tetrahydro-1H-benzo [d] imidazole-5-carboxylic acid

Steps 1 to 2: The preparation method is similar to steps 2 to 3 in compound 1g to obtain compound 5-3. MS m / z (ESI): 320.1 [M + H] ⁺ .

Step 3: A solution of compound 5-3 (480 mg, 1.14 mmol) and NH ₄ OAc (882 mg, 11.45 mmol) in toluene (12 mL) was stirred at 110 ° C. for 6 h. LC-MS followed until the reaction was complete. After the mixture was concentrated, water was added and extracted with DCM. The organic layer was concentrated and purified by combiflash to obtain a white solid compound 5-4. MS m / z (ESI): 400.2 [M + H] ⁺ .

Steps 4 to 6: Same as Steps 3 to 5 of Example 2, except that Compound 11-2 was replaced with Compound 5-4. Purified by Prep-HPLC to obtain white solid compound H-5. ¹ H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.46 (s, 1H), 9.81 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.73–7.65 (m, 2H), 7.23–7.16 (m, 2H), 7.16–7.07 (m, 3H), 6.80–6.69 (m, 2H), 5.06 (dd, J = 14.5 , 8.3Hz, 1H), 3.18 (dd, J = 13.1, 5.2Hz, 1H), 2.95 (dd, J = 13.9, 8.9Hz, 1H), 2.62 (d, J = 13.3Hz, 3H), 2.48 (s , 1H), 2.03 (d, J = 13.2 Hz, 1H), 1.71 (s, 1H). MS m / z (ESI): 518.1 [M + H] ⁺ .

Example 6 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridinium-1 (2H) -yl)- Preparation of 2-phenylethyl) -N- (N, N-dimethylsulfamoyl) -1H-benzo [d] imidazole-5-carboxamide

Compound H-6 was prepared by using compound 1v and N, N-dimethylsulfonamide as raw materials and referring to compound H-22. MS m / z (ESI): 662.2 [M + 1]. ¹ H NMR (400MHz, dmso) δ 12.91 (s, 1H), 11.75 (s, 1H), 9.70 (s, 1H), 8.23 (s, 0.5H), 8.11 (d, 0.5H), 8.07 (m , 1H), 7.87-7.82 (m, 2H), 7.77 (t, 2H), 7.62 (d, 0.5H), 7.50 (d, 0.5H), 7.27 (t, 2H), 7.18 (t, 1H), 7.09 (d, 2H), 6.42 (dd, 1H), 6.36 (m, 1H), 3.66--3.61 (m, 1H), 3.52--3.48 (m, 1H), 2.79 (d, 6H).

Example 7 (E) -3- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -N- (1- (4-cyano-1H-benzo [d] imidazole- Preparation of 2-yl) -2-ethyl) acrylamide

Using compound 2,3-diaminobenzonitrile and compound 1-1 as raw materials, compound H-7 was prepared according to the method of Example 1. ¹ H NMR (400MHz, DMSO-d6) δ 12.96 (s, 1H), 9.81 (s, 1H), 8.99 (d, J = 8.0Hz, 1H), 7.92 (s, 1H), 7.84-7.56 (m , 4H), 7.38–7.02 (m, 6H), 6.90–6.67 (m, 2H), 5.46–5.26 (m, 1H), 3.45–3.32 (m, 1H), 3.19-3.12 (m, 1H) .MS m / z (ESI): 495 [M + H] ⁺ .

Example 8 (E) -N- (1- (1H-imidazo [4,5-c] pyridin-2-yl) -2-phenylethyl) -3- (5-chloro-2- (1H -Tetrazole-1-yl) phenyl) acrylamide

The compound 3,4-diaminopyridine was used as a raw material to prepare according to the method of Example 1, and purified by Prep-HPLC to obtain a white solid compound H-8. ¹ H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 9.84 (s, 1H), 8.99–8.77 (m, 2H), 8.27 (d, J = 5.5 Hz, 1H), 7.95 (d , J = 1.9Hz, 1H), 7.79–7.65 (m, 2H), 7.48 (s, 1H), 7.37–7.03 (m, 5H), 6.92–6.75 (m, 2H), 5.40 (dd, J = 14.2 , 8.4 Hz, 1H), 3.37-3.44 (m, 1H), 3.17 (dd, J = 13.7, 9.0 Hz, 1H). MS m / z (ESI): 471.2 [M + H] ⁺ .

Example 9 (E) -N- (1- (1H-benzo [d] imidazol-2-yl) -2-phenylethyl) -3- (5-chloro-2- (1H-tetrazole- Preparation of 1-yl) phenyl) acrylamide

Using o-phenylenediamine as a raw material, it was prepared according to the method of Example 1, and purified by Prep-HPLC to obtain a white solid compound H-9 (58.6 mg, 81% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.82 (s, 1H), 8.84 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.74–7.65 (m, 2H), 7.56 (d, J = 6.7Hz, 1H), 7.44–7.37 (m, 1H), 7.24–7.16 (m, 4H), 7.16–7.07 (m, 3H), 6.88– 6.75 (m, 2H), 5.35 (dd, J = 14.6, 8.4 Hz, 1H), 3.38 (dd, J = 13.8, 6.0 Hz, 1H), 3.13 (dd, J = 13.7, 8.8 Hz, 1H) .MS m / z (ESI): 470.2 [M + H] ⁺ .

Example 10 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -4,5,6,7-tetrahydro-1H-benzo [d] imidazole-5-carboxylic acid

Using compound 1v-1 and compound 5-2 as raw materials, and referring to the similar reaction conditions of steps 2 to 3 in Example 5, compound H-10-2 was prepared. MS / m / z (ESI): 574.2 [M + 1].

Using compound H-10-2 as a raw material and referring to the similar reaction conditions in step 6 of Example 5, compound H-10 was prepared. MS / m / z (ESI): 560.2 [M + 1].

Example 11 (E) -2- (1- (3- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) acrylamido) -2-phenylethyl) -7- Preparation of methyl-1H-benzo [d] imidazole 5-carboxylic acid

Using compounds 1c and 1a as raw materials, referring to the method of step 4 and step 5 in Example 2 to obtain compound H-2 ¹ H NMR (400MHz, DMSO-d6) δ 9.80 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), 8.36 (s, 2H), 8.22 (s, 1H), 7.94-7.91 (m, 2H), 7.69 (d, J = 6.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.18-7.12 (m, 5H), 6.89-6.75 (m, 2H), 5.33 ( s, 1H), 3.25-3.12 (m, 2H). MS m / z (ESI): 525 [M + H] ⁺ .

Example 12 (E) -2- (1- (3- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) acrylamido) -2-phenylethyl) -7- Preparation of fluoro-1H-benzo [d] imidazole 5-carboxylic acid

Steps 1-2: Refer to intermediate compounds 1-5 in steps 1-2 for a similar method to prepare compounds 3-3. MS m / z (ESI): 434.1 [M + H] ⁺ .

Step 3: Similar to the method of Example 3, except that compound 12-6 was replaced with compound 3-3 to obtain compound 3-4. MS m / z (ESI): 400.2 [M + H] ⁺ .

Step 4: Compound 3-4 (630 mg, 1.58 mmol) and concentrated H ₂ SO ₄ (1 mL) in methanol (15 mL) were stirred at 50 ° C. for 16 h. LC-MS followed until the reaction was complete. Ice was added to the system, the pH was adjusted to 8 with saturated sodium carbonate solution, the mixture was concentrated, extracted with DCM, the organic layer was evaporated to dryness under reduced pressure, and combiflash purified to obtain compound 3-5. MS m / z (ESI): 314.1 [M + H] +.

Steps 5 to 6: Refer to steps 4 to 5 in Example 2 for preparation to obtain compound H-3. ¹ H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.02 (d, J = 9.1 Hz, 1H), 7.95–7.84 (m, 2H), 7.70 (dt, J = 13.3, 5.3 Hz , 2H), 7.47 (d, J = 11.4 Hz, 1H), 7.21 (q, J = 7.6 Hz, 3H), 7.14 (dd, J = 11.1, 4.3 Hz, 1H), 6.86-6.74 (m, 2H) , 5.37 (dd, J = 14.7, 8.2Hz, 1H), 3.38–3.34 (m, 1H), 3.14 (dd, J = 13.5, 8.9Hz, 1H). MS m / z (ESI): 532.1 [M + H] ⁺ .

Example 13 7-amino-2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

The compound 12-4 was used as a raw material, and the compound H-25 was prepared according to the method, and purified by Prep-HPLC to obtain a white solid compound H-13 (1.4 mg, 2.2% yield). MS m / z (ESI): 553.2 [M + H] ⁺ .

Example 16 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methyl-2-oxopyridine-1 (2H) -yl) Preparation of -2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

The compound 1j was used as a raw material to prepare according to the method of compound H-12, and the compound H-16 was purified. ¹ H NMR (400MHz, DMSO-d6) δ 12.88 (s, 1H), 12.69 (s, 1H), 9.54 (s, 1H), 8.11 (s, 1H), 7.86-7.40 (m, 6H), 7.15 (m, 5H), 6.46 (s, 1H), 6.14 (d, J = 7.7Hz, 1H), 3.65-3.46 (m, 2H), 1.65 (s, 3H). MS m / z (ESI): 552.1 [M + H] ⁺ .

Example 17 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5- (dimethylamino) -2-oxopyridine-1 (2H ) -Yl) -2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

The compound 1k was used as a raw material to prepare according to the method of compound H-12, and the compound H-17 was purified. ¹ H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.13 (s, 1H), 7.88–7.53 (m, 5H), 7.34–6.98 (m, 6H), 6.36 (s, 1H) , 3.57 (d, J = 51.2 Hz, 2H), 1.91 (s, 6H). MS m / z (ESI): 581.1 [M + H] ⁺ .

Example 19 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Same as compound 1v. ¹ H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.14 (d, J = 5.7 Hz, 2H), 7.87 (d, J = 2.9 Hz, 2H), 7.85–7.81 (m, 2H ), 7.59 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.2 Hz, 2H), 6.44 (t, J = 10.7 Hz, 2H), 3.69 (d, J = 8.6 Hz, 1H), 3.53 (d, J = 3.5 Hz, 1H). MS m / z (ESI): 556 [M + H] ⁺ .

Example 20 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridine-1 (2H) -yl ) -2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Step 1: Compound 20-4 (170 mg, 0.28 mmol) in NH ₄ Cl (1 mL) in acetone (10 mL) was added Zn (93 mg, 1.41 mmol), the mixture was stirred at room temperature overnight, and LC-MS followed until the reaction was complete. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain brown solid compound 20-5, which was directly used in the next reaction without purification. MSm / z (ESI): 571 [M + H] ⁺ .

Step 2: Refer to Step 2 in Intermediate 12-6.

Step 3: Refer to the method of Step 3 in Intermediate 1v to obtain compound H-20 (41.69 mg, 69.4% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 9.58 (s, 1H), 8.15 (s, 1H), 7.85-7.80 (m, 3H), 7.64 (dd, J = 17.1, 4.8Hz, 2H), 7.33–7.27 (m, 3H), 7.16 (dt, J = 35.7, 7.0Hz, 4H), 6.44 (s, 2H), 3.72–3.67 (m, 1H), 3.61 (d, J = 10.0 Hz, 1H), 3.21 (s, 3H). MS m / z (ESI): 568 [M + H] ⁺ .

Example 21 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of methyl 2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylate

Compound H-21 is obtained by using compound 1v-1 and methyl 3,4-diaminobenzoate as raw materials and referring to step 1 and step 2 of the preparation method of compound 1v. MS m / z (ESI): 570.1 [M + H] ⁺ .

Example 22 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -N- (methylsulfonyl) -1H-benzo [d] imidazole-5-carboxamide

Compound 1v (50 mg, 0.09 mmol), N, N′-carbonyldiimidazole (44 mg, 0.27 mmol) was dissolved in 2 mL of N, N-dimethylformamide and stirred at room temperature for 1 hour. Methanesulfonamide (51 mg, 0.54 mmol) and 1,8-diazabicycloundec-7-ene (41 mg, 0.27 mmol) were added to the reaction solution, and the reaction was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate (5mL × 2), the organic phases were combined, washed successively with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the compound was obtained after preparation H-22 (8.96 mg, white solid), yield: 15.7%. MS m / z (ESI): 633.2 [M + 1]. ¹ H NMR (400MHz, DMSO-d6) δ 12.98 (d, 1H), 12.04 (s, 1H), 9.70 (s, 1H), 8.24 (s, 0.5H), 8.12 (d, 0.5H), 8.08 (d, 1H), 7.87–7.82 (m, 2H), 7.81–7.74 (m, 2H), 7.66 (d, 0.5H), 7.53 (d, 0.5H), 7.27 (t, 2H), 7.18 (t , 1H), 7.09 (d, 2H), 6.43 (dd, 1H), 6.39–6.33 (m, 1H), 3.63 (dd, 1H), 3.50 (dd, 1H), 3.25 (s, 3H).

Example 23 2- (1- (5-chloro-4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -3-fluoro-2-oxopyridine-1 (2H) -Yl) -2-phenylethyl-1H-benzo [d] imidazole-5-carboxylic acid

The compound 1i was used as a raw material to prepare according to the method of compound H-12, and the compound H-23 was purified. ¹ H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 7.95–7.88 (m, 2H), 7.85 (d , J = 2.0 Hz, 1H), 7.81 (dd, J = 8.4, 1.4 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.20 (t , J = 7.4 Hz, 1H), 7.05 (d, J = 7.0 Hz, 2H), 6.49 (dd, J = 10.2, 5.5 Hz, 1H), 3.68 (dd, J = 13.9, 5.4 Hz, 1H), 3.55 (dd, J = 13.8, 10.4 Hz, 1H). MS m / z (ESI): 590.1 [M + H] ⁺ .

Example 25 7-amino-2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -Yl) -2-phenylethyl-1H-benzo [d] imidazole-5-carboxylic acid

Step 1: Compound 1v-1 (121mg, 0.28mmol), methyl 3,4,5-triaminobenzoate (50mg, 0.28mmol) and DIEA (107mg, 0.83mmol) were dissolved in 5mL DCM, added at 0 ℃ T ₃ P (263 mg, 0.83 mmol), stirred at room temperature for 18 hours, added 10 mL of saturated brine and 10 mL of water, extracted with DCM (25 mL × 2), combined organic phases, washed with saturated brine (5 mL), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 25-1 (150 mg, white solid). MS m / z (ESI): 603.1 [M + 1].

Step 2: Compound 25-1 (150 mg, 0.25 mmol) was dissolved in 5 mL of acetic acid, and the reaction was stirred at 70 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified in 0-90% EA in PE by silica gel column chromatography to obtain compound 25-2 (50 mg, light yellow solid), yield: 34.4%. MS / m / z (ESI): 585.1 [M + 1].

Step 3: Compound 25-2 (50 mg, 0.09 mmol) was dissolved in 2 mL of water, 2 mL of hydrogen chloride in dioxane was added, and the reaction was stirred at 90 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the title compound H-25 (11.9 mg, white solid) was obtained by preparative HPLC chromatography, yield: 24.4%. MS m / z (ESI): 571.1 [M + 1]. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.66 (s, 1H), 9.72 (s, 1H), 8.06 (d, J = 6.2 Hz, 1H), 7.89-7.80 (m, 3H), 7.29 ( t, J = 7.4Hz, 3H), 7.22 (d, J = 7.3Hz, 1H), 7.14 (d, J = 7.1Hz, 2H), 7.03 (s, 1H), 6.45 (d, J = 7.2Hz, 1H), 6.37 (s, 1H), 5.46 (s, 2H), 3.66 (dd, J = 13.9, 5.8 Hz, 3H).

Example 28 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridine-1 (2H) -yl ) -2-phenylethyl) -4-oxo-3,4-dihydroquinazoline-6-carboxylic acid

Step 1: Dissolve methyl 4-amino-3-cyanobenzoate (528 mg, 3 mmol) in 4 mL of dimethyl sulfoxide, add anhydrous potassium carbonate (42 mg, 0.3 mmol) and 0.5 mL of hydrogen peroxide, and stir the reaction at room temperature 2 hours. Purification by preparative chromatography gave methyl 4-amino-3-carbamoylbenzoate (450 mg, white solid), yield: 77.3%. MS / m / z (ESI): 195.1 [M + 1].

Step 2: Dissolve compound 20-2 (214 mg, 0.5 mmol) in 5 mL of tetrahydrofuran, add methyl 4-amino-3-carbamoylbenzoate (97 mg, 0.5 mmol) and 4- (4,6-dimethyl Oxytriazin-2-yl) -4-methylmorpholine hydrochloride (176 mg, 0.6 mmol) was refluxed for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 50: 1) to obtain compound 28-1 (240 mg, yellow solid), yield: 79.5%. MS / m / z (ESI): 605.2 [M + 1].

Step 3: Compound 28-1 (151 mg, 0.25 mmol) was dissolved in 10 mL of acetone, zinc powder (81 mg, 1.25 mmol) and ammonium chloride (66 mg, 1.25 mmol) were added, and the reaction was refluxed for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 28-2 (90 mg, yellow solid), yield: 62.6%. MS “m / z (ESI): 575.2 [M + 1].

Step 4: Compound 28-2 (90 mg, 0.16 mmol) was dissolved in 10 mL of ethanol, potassium hydroxide (44 mg, 0.78 mmol) was added, and the reaction was stirred at 80 ° C for 2 hours. Cool to room temperature, add concentrated hydrochloric acid to the reaction solution to adjust the pH to less than 3, extract with ethyl acetate (10mL × 3), combine the organic phases, and wash with water (5mL × 2) and saturated brine (5mL × 2) in sequence. It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 28-3 (76 mg, yellow solid), yield: 89.3%. MS m / z (ESI): 543.2 [M + 1]

Step 5: Compound 28-3 (76 mg, 0.14 mmol) was dissolved in 5 mL of acetic acid, trimethyl orthoformate (45 mg, 0.42 mmol) and sodium azide (27 mg, 0.42 mmol) were added, and the reaction was stirred at room temperature for 24 hours. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (15 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was used Purification by preparative chromatography gave compound H-28 (41 mg, white solid), yield: 49.2%. MS m / z (ESI): 596.2 [M + 1]. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 13.2 (br.s, 1H), 12.9 (s, 1H), 9.52 (s, 1H ), 8.63 (s, 1H), 7.88-7.68 (m, 4H), 7.36-7.18 (m, 6H), 6.37 (s, 1H), 6.16 (t, J = 8Hz, 1H), 3.52 (d, J = 8Hz, 2H), 3.25 (s, 3H).

Example 29 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) benzo [d] thiazole-5-carboxylic acid

Using 1g of the intermediate as a raw material, it was prepared by referring to the method of compound 12-4, and purified to obtain compound H-29. ¹ H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.71 (s, 1H), 8.49 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 5.7 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.92–7.77 (m, 3H), 7.39-7.17 (m, 5H), 6.52–6.47 (m, 2H), 3.84–3.52 ( m, 2H). MS m / z (ESI): 573.1 [M + H] ⁺ .

Example 30 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) benzo [d] thiazole-6-carboxylic acid

The intermediate 1m was used as a raw material to prepare according to the method of compound 12-4, and purified to obtain compound H-30. ¹ H NMR (400MHz, DMSO-d6) δ 13.11 (s, 1H), 9.71 (s, 1H), 8.72 (s, 1H), 8.10-8.04 (m, 3H), 7.99-7.70 (m, 3H) , 7.87-7.82 (m, 5H), 6.72–6.26 (m, 2H), 3.86–3.57 (m, 2H). MSm / z (ESI): 573.1 [M + H] ⁺ .

Example 32 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-1- (1- (5- (methylsulfonyl) -1H-benzo [ d) Preparation of imidazol-2-yl) -2-phenethyl) pyridine-2 (1H) -one

Compound 1t-3 and 3,4-diaminobenzyl sulfone were used as raw materials to prepare according to the method of compound 12-6, and purified to obtain compound H-32. ¹ H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.12–8.04 (m, 2H), 7.87–7.82 (m, 2H), 7.79 (d, J = 1.8 Hz, 1H), 7.76 –7.69 (m, 2H), 7.28 (t, J = 7.4Hz, 2H), 7.19 (t, J = 7.4Hz, 1H), 7.11 (d, J = 7.2Hz, 2H), 6.43 (d, J = 7.2Hz, 1H), 6.39 (dd, J = 9.7, 5.2Hz, 1H), 3.67 (dd, J = 14.1, 5.5Hz, 1H), 3.51 (dd, J = 13.8, 10.0Hz, 1H), 3.18 ( s, 3H). MS m / z (ESI): 590.1 [M + H] ⁺ .

Example 33 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -1H-benzo [d] imidazole-5-sulfonamide

Compound 1t-3 and 3,4-diaminobenzenesulfonamide were used as raw materials to prepare according to the method of compound 12-6, and purified to obtain compound H-33. ¹ H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.70 (s, 1H), 8.08 (d, J = 6.3 Hz, 1H), 7.98 (s, 1H), 7.87-7.81 (m , 2H), 7.79 (d, J = 1.9 Hz, 1H), 7.65 (s, 2H), 7.26 (dd, J = 14.1, 6.5 Hz, 4H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.0 Hz, 2H), 6.43 (d, J = 7.2 Hz, 1H), 6.37 (dd, J = 9.9, 6.4 Hz, 1H), 3.66 (dd, J = 14.0, 5.8 Hz, 1H) , 3.53–3.46 (m, 1H). MSm / z (ESI): 591.1 [M + H] ⁺ .

Example 35 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -1Hbenzo [d] imidazole-5-phosphate diethyl ester

The compound 1o and diethyl phosphite were used as raw materials to prepare according to the method of compound 12-2, and the compound H-35 was purified. ¹ H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.07 (d, J = 6.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.79 (s, 1H), 7.49 (s , 2H), 7.29–7.25 (m, 2H), 7.21–7.16 (m, 2H), 7.10 (d, J = 6.9Hz, 2H), 6.42 (d, J = 7.1Hz, 1H), 6.37 (s, 1H), 3.95 (dd, J = 13.9, 7.0Hz, 4H), 3.65 (d, J = 8.5Hz, 1H), 3.49 (d, J = 3.9Hz, 1H), 1.18 (t, J = 7.0Hz, 6H). MS m / z (ESI): 648.2 [M + H] ⁺ .

Example 36 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2- (4-fluorophenyl) (1H) -1H-benzo [d] imidazole-5-carboxylic acid

Steps 1 and 2: Starting from compound 1p, refer to steps 1 to 2 in intermediate 12-6.

Step 3: Prepare according to step 3 in intermediate 1v, and purify to obtain compound H-36. 1H NMR (400MHz, DMSO-d6) δ 12.96 (br, 1H), 12.73 (br, 1H), 9.76 (s, 1H), 8.08 and 8.22 (s, 1H), 8.10-8.12 (m, 1H), 7.80-7.91 (m.4H), 7.70 and 7.56 (d, J = 8.4Hz, 1H), 7.10-7.18 (m, 4H), 6.45 and 6.47 (s, 1H), 6.41 (br, 1H), 3.65-3.69 (m, 1H), 3.54-3.57 (m, 1H), MS m / z (ESI): 574.1 (M + H ] ⁺ .

Example 38 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -1H-benzo [d] imidazol-5-ylphosphonic acid

Compound H-35 (10 mg, 0.015 mmol), TMS-Br (47 mg, 0.3 mmol), DCM / MeCN (1 mL / 2 mL) was stirred at 70 ° C. for 16 h under a nitrogen atmosphere. LC-MS followed until the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, washed with dichloromethane, and the filter cake was purified by Prep-HPLC to obtain a white solid compound H-38 (2.68 mg, 30% yield). ¹ H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.08 (d, J = 6.1 Hz, 1H), 7.85–7.80 (m, 2H), 7.78 (s, 1H), 7.52 (s , 2H), 7.38 (s, 1H), 7.28-7.21 (m, 2H), 7.18-7.14 (m, 1H), 7.08 (d, J = 7.2Hz, 2H), 6.40 (d, J = 7.2Hz, 1H), 6.38–6.33 (m, 1H), 3.64–3.59 (m, 1H), 3.49 (s, 1H). MS m / z (ESI): 592.1 [M + H] ⁺ .

Example 40 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -3H-imidazo [4,5-c] pyridine-6-carboxylic acid

Steps 1 and 2: Compounds 1v-1 and 4,5-diamino-2-pyridinecarboxylic acid ethyl ester are used as raw materials, and reference is made to steps 3 and 4 of intermediate 20-4.

Step 3: Prepare according to step 3 of intermediate 1v, and purify to obtain compound H-40. ¹ H NMR (400MHz, DMSO-d6) δ 9.69 (s, 1H), 8.81 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 6.4Hz, 1H), 7.86-7.82 (m , 2H), 7.80 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 10.4, 4.4 Hz, 2H), 7.21–7.18 (m, 1H), 7.08 (d, J = 7.0 Hz, 2H) , 6.41 (d, J = 7.1 Hz, 1H), 6.39-6.35 (m, 1H), 3.66 (d, J = 8.7 Hz, 1H), 3.52 (s, 1H). MS m / z (ESI): 557.1 [M + H] ⁺ .

Example 41 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2-phenylethyl) -1H-benzo [d] imidazole-5-carboxamide

Using compound 1v as a raw material and referring to the preparation method of compound H-44, the title compound H-41 was prepared. MS m / z (ESI): 555.1 [M + 1]; ¹ H NMR (400 MHz, DMSO-d6) δ 12.87 (d, 1H), 9.70 (s, 1H), 8.18 (s, 0.5H), 8.10 (t, 1H), 7.99 (d, 0.5H), 7.93 (d, 1H), 7.87–7.68 (m, 4H), 7.62 (d, 0.5H), 7.47 (d, 0.5H), 7.30–7.15 ( m, 4H), 7.09 (d, 2H), 6.42 (dd, 1H), 6.37 (m, 1H), 3.63 (dd, 1H), 3.48 (dd, 1H).

Example 42 7-((2-amino-2-acetyl) amino) -2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5- Preparation of methoxy-2-oxopyridine-1 (2H) -yl) -2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Step 1: Dissolve methyl 3,4-diamino-5-nitrobenzoate 1x (182mg, 0.86mmol), compound 1w (390mg, 0.86mmol) and DIEA (558mg, 4.32mmol) in 10mL DCM, 0 T ₃ P (1.37 g, 4.32 mmol) was added at ℃, the reaction was stirred at room temperature for 18 hours, 10 mL of saturated brine and 10 mL of water were added, extracted with DCM (25 mL × 2), the organic phases were combined, washed with saturated brine (5 mL), without It was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 42-1 (550 mg, light yellow solid). MS m / z (ESI): 645.2 [M + 1].

Step 2: Compound 42-1 (550 mg, 0.83 mmol) was dissolved in 5 mL of acetic acid, and the reaction was stirred at 130 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by PE column chromatography with 0-50% EA in PE Compound to give compound 42-2 (380 mg, white solid), yield: 71.1%. MS “m / z (ESI): 627.2 [M + 1].

Step 3: Compound 42-2 (380 mg, 0.61 mmol) and SEM-Cl (202 mg, 1.21 mmol) were dissolved in DMF, DIPEA (313 mg, 2.42 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography with 0-50% EA in PE to obtain compound 42-3 (440 mg, light yellow solid), yield: 95.9%. MS / m / z (ESI): 757.3 [M + 1].

Step 4: Compound 42-3 (440 mg, 0.58 mmol) and ammonium chloride (155 mg, 2.91 mmol) were dissolved in 10 mL of acetone and 1 mL of water, zinc powder (190 mg, 2.91 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was filtered, the filter cake was rinsed with acetone, the filtrate was concentrated under reduced pressure, 5 mL of ammonium bicarbonate solution was added, extracted with EA (10 mL × 2), the organic phases were combined, washed with saturated brine (5 mL × 2), and dried over anhydrous sodium sulfate , Filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 42-4 (410 mg, white solid), yield: 97.0%. MS / m / z (ESI): 727.1 [M + 1].

Step 5: Add compound 42-4 (170 mg, 0.23 mmol), 2-bromoacetamide (322 mg, 2.34 mmol), potassium carbonate (161 mg, 1.17 mmol), potassium iodide (8 mg, 0.05 mmol) and 2 mL to a 10 mL microwave tube Acetonitrile, covered with a lid, microwave stirring at 130 ° C for 45 minutes. 10mL of water was added, extracted with EA (10mL × 2), the organic phases were combined, washed with saturated brine (5mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using silica gel column chromatography at 0-90% EA was purified in PE to obtain compound 42-5 (80 mg, white solid), yield: 43.6%. MS / m / z (ESI): 784.3 [M + 1].

Step 6: Compound 42-5 (80 mg, 0.10 mmol) was dissolved in 1.5 mL of DCM, 3 mL of TFA was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by C18 column chromatography with 5% to 95% acetonitrile in 0.5% formic acid aqueous solution to obtain compound 42-6 (50 mg, white solid), yield: 74.95%. MS / m / z (ESI): 654.2 [M + 1].

Step 7: Compound 42-6 (50 mg, 0.08 mmol) was dissolved in 5 mL of methanol and 1 mL of water, sodium hydroxide (31 mg, 0.76 mmol) was added, and the reaction was stirred at room temperature for 18 hours. The pH was adjusted to 7 with 1M hydrochloric acid, concentrated under reduced pressure, and the title compound H-42 (2.92 mg, white solid) was obtained by preparative HPLC chromatography, yield: 5.94%. MS m / z (ESI): 640.2 [M + 1]; 1H NMR (400MHz, DMSO-d ₆ ) δ 12.67 (s, 1H), 9.59 (s, 1H), 8.41 (s, 1H), 7.80 ( s, 2H), 7.67 (s, 1H), 7.40 (s, 3H), 7.32–7.27 (m, 2H), 7.23–7.17 (m, 2H), 7.14 (d, J = 7.5Hz, 3H), 6.82 (s, 1H), 6.42 (s, 1H), 5.84 (s, 1H), 4.57 (s, 2H), 3.81 (d, J = 5.1 Hz, 3H), 3.49 (s, 2H).

Example 43 7-((3-amino-3-propionyl) amino) -2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5- Preparation of methoxy-2-oxopyridine-1 (2H) -yl) -2-phenylethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Using compound 42-4 and 3-bromopropionamide as raw materials, referring to steps 5-7 of compound H-42, the title compound H-43 was prepared, MS m / z (ESI): 654.2 [M + 1].

Example 44 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridine-1 (2H) -yl ) -2-phenylethyl) -4-oxo-1,4-dihydroquinazoline-6-carboxamide

Compound H-28 (20 mg, 0.034 mmol) was dissolved in 2 mL of DMF, and ammonium bicarbonate (14 mg, 0.17 mmol), HATU (19 mg, 0.051 mmol), and DIPEA (9 mg, 0.068 mmol) were added. Stir at room temperature for 2 hours, quench with water, extract with ethyl acetate, dry, and purify by preparative chromatography to obtain the title compound H-44 (11 mg, white solid), yield: 54.5%. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.81 (s, 1H), 9.52 (s, 1H), 8.63 (s, 1H), 8.25-8.23 (m, 2H), 7.77 (s, 1H) , 7.68 (s, 2H), 7.49 (s, 1H), 7.27-7.18 (m, 6H), 6.37 (s, 1H), 6.16 (t, J = 8Hz, 1H), 3.52 (d, J = 8Hz, 2H), 3.25 (s, 3H).

Example 45 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-methoxy-2-oxopyridine-1 (2H) -yl ) -2-phenylethyl) -1H-benzo [d] imidazole-5-carboxamide

Compound H-20 (30mg, 0.05mmol), ammonium bicarbonate (13mg, 0.16mmol) and DIEA (20mg, 0.16mmol) were dissolved in 5mL DCM, HATU (24mg, 0.06mmol) was added, the reaction was stirred at room temperature for 4 hours The reaction solution was concentrated under reduced pressure, and the title compound H-45 (9.48 mg, white solid) was obtained by HPLC chromatography, yield: 31.65%. MS / m / z (ESI): 567.2 [M + 1].

Example 48 4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-1- (1- (6- (1,1,1,3,3,3 -Hexafluoro-2-hydroxypropane-2-yl) -1H-benzo [d] imidazol-2-yl) -2-phenethyl) pyridin-2 (1H) one

Step 1: Combine 2,1,3-benzothiadiazole-5-carboxylic acid 48-1 (500 mg, 2.78 mmol), pentafluorophenol (767 mg, 4.17 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (801 mg, 4.17 mmol), DMAP (68 mg, 0.56 mmol) was dissolved in 20 mL DMF, and the reaction was stirred at room temperature for 16 hours. To the reaction solution was added 20 mL of ice water, and a yellow solid precipitated. After filtration and drying, Compound 48-2 (730 mg, yellow solid) was obtained. Yield: 75.9%.

Step 2: Dissolve compound 48-2 (630mg, 1.82mmol) in toluene (15mL), add (trifluoromethyl) trimethylsilane (1.55g, 10.92mmol) and 1M A solution of butyl ammonium fluoride in THF (0.91 mL, 0.91 mmol) was added. After the addition, the reaction solution was reacted at room temperature for 16 hours. The reaction solution was added with water, and then extracted with EA (15mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (15mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then prepared by preparative HPLC chromatography to obtain compound 48-3 (260 mg, off-white solid), yield: 47%. MS / m / z (ESI): 303.0 [M + 1].

Step 3: Compound 48-3 (150 mg, 0.49 mmol) and zinc powder (323 mg, 4.90 mmol) were dissolved in 5 mL of acetic acid, and the reaction was stirred at 80 ° C. for 1 hour. The reaction solution was diluted with EA and filtered. The filtrate was washed with saturated sodium bicarbonate solution (10 mL). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 48-4. (149 mg, yellow solid), the product was directly subjected to the next reaction without purification. MS / m / z (ESI): 275.0 [M + 1].

Step 4: Dissolve compound 48-4 (139 mg, 0.251 mmol), intermediate 1v-1 (111 mg, 0.25 mmol) and TEA (2 mL) in 10 mL DCM, add T ₃ P (1 mL) at 0 ° C, and stir the reaction at room temperature 16 hours. 10 mL of water was added, extracted with DCM (15 mL × 2), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 48-5 (180 mg, yellow oil), The product was directly subjected to the next reaction without purification. MS m / z (ESI): 696.1 [M + 1].

Step 5: Compound 48-5 (175 mg, 0.25 mmol) was dissolved in 3 mL of acetic acid, heated at 75 ° C and stirred for 2 hours. The reaction solution was concentrated to dryness and obtained by preparative HPLC chromatography to obtain the title compound H-48 (38.24 mg, white solid), yield: 22%. MS m / z (ESI): 678.1 [M + 1]; 1H NMR (400MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.75 (s, 1H), 8.78 (s, 1H), 8.13 ( d, 1H), 7.91–7.84 (m, 3H), 7.82 (d, 1H), 7.67 (s, 1H), 7.51 (d, 1H), 7.31 (t, 2H), 7.22 (t, 1H), 7.14 (d, 2H), 6.46 (d, 1H), 6.44–6.37 (m, 1H), 3.69 (dd, 1H), 3.52 (dd, 1H).

Example 50 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 3-methoxypropyl) -1H-benzo [d] imidazole-5-carboxylic acid

Step 1: -20 ℃, DCM ethylene glycol monomethyl ether solution of 50-1 (2g, 26.3mmol) and 2,6-lutidine (4.2g, 39.4mmol) was added (TfO) ₂ O (11.1g, 39.4mmol), react at -20 ° C for 1 hour. After the reaction was completed, the reaction solution was diluted with DCM and washed with water and dilute hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 50-2 (1 g, brown oil) with a yield of 18.28%.

Step 2: To a solution of compound 54-1 (500 mg, 1.48 mmol) in THF, LiHMDS (2.8 mL, 2.83 mmol) was added dropwise at -70 ° C. After the mixture was reacted at -70 ° C for 30 min, a solution of compound 50-2 (589 mg, 2.83 mmol) in THF was added. After the mixture was reacted at -70 ° C for 30 min, it was further reacted at 0 ° C for 1 hour. After the reaction was monitored by LC-MS, the reaction was quenched by adding dilute hydrochloric acid, and extracted by EA. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (PE: EA = 100/0 ～ 80/20) to obtain compound 50-3 (185 mg, yellow oil), yield 28.9 %. MS m / z (ESI): 356 [M ⁺¹ -56].

Step 3: Compound 50-3 (185 mg, 0.45 mmol) in DCM was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 1.5 hours. LC-MS followed until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain crude compound 50-4 (200 mg, yellow oil). MS “m / z (ESI): 356 [M + 1].

Step 4: Compound 50-4 (120 mg, 0.34 mmol) and compound 15.1 (105 mg, 0.51 mmol) in acetonitrile were added 1-methylimidazole (98 mg, 1.2 mmol) and TCFH (249 mg, 0.51 mmol) at room temperature. The mixture was reacted at room temperature for 3 hours. LC-MS followed until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent, and EA and water were added to the residue. The organic layer was washed with saturated sodium bicarbonate and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 50-5 (250 mg, crude product). MS “m / z (ESI): 546 [M + 1].

Step 5: A solution of compound 50-5 (250 mg, 0.46 mmol) in acetic acid was stirred at 70 ° C for 16 hours. LC-MS followed until the reaction was complete. The reaction was concentrated under reduced pressure and then subjected to column chromatography (PE: EA = 100/0 to 50/50) to obtain compound 50-6 (160 mg, yellow solid), yield: 66.7%. MS / m / z (ESI): 528 [M + 1].

Step 6: Under nitrogen protection, compound 50-6 (160mg, 0.3mmol), compound 12.1 (115mg, 0.45mmol), Pd (dppf) Cl2 (9.5mg, 0.015mmol), cesium fluoride (80mg, 0.91mmol) , A mixture of 1,4-dioxane (2ml) and H2O (0.4ml) was stirred at 90 ° C for 3h under an argon atmosphere. After the reaction was completed, the reaction solution was cooled and filtered. The filtrate was concentrated and purified by column chromatography (PE: EA = 100/0 to 70/30) to obtain the crude compound 50-7 (150 mg, brown solid). MS “m / z (ESI): 527 [M + 1].

Step 7: The acetic acid solution of compound 50-7 (150 mg, 0.28 mmol) was added trimethyl orthoformate (362 mg, 3.4 mmol), stirred at room temperature for 10 min, and then added sodium azide (221 mg, 3.4 mmol). The mixture was stirred at 70 ° C for 16h. After the reaction was completed, the reaction solution was quenched with cold water and extracted with EA. The organic layer was washed with water, saturated sodium bicarbonate and brine, and the filtrate was concentrated under reduced pressure to obtain compound 50-8 (100 mg, yellow solid). The yield was 60.6%. MS “m / z (ESI): 580 [M + 1].

Step 8: Compound 50-8 (100 mg, 0.20 mmol) in DCM was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain the title compound H-50 (29.75 mg) as a white solid. Yield: 32.95%. MS m / z (ESI): 524 [M + 1]; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.76 (br, 1H), 9.81 (s, 1H), 8.13 (s, 1H), 7.99 (d, J = 6.4Hz, 1H), 7.87–7.92 (m, 3H), 7.82 (dd, J = 8.0Hz & 1.6Hz, 1H), 7.60 (d, J = 8.0Hz, 1H), 6.55 (d , J = 7.2 Hz, 1H), 6.25 (m, 1H), 3.31-3.38 (m, 1H), 3.21-3.25 (m, 1H), 3.21 (s, 3H), 2.54-2.61 (m, 2H).

Example 54 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2- (pyridin-2-yl) ethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Step 1: Under the protection of ice bath nitrogen, compound 1t-2 (5.4g, 22.69mmol), potassium carbonate (6.264g, 45.38mmol) was dissolved in 45mL DMF, 2-tert-butyl 2-bromoacetate (5.293g, 27.23) was added mmol), warmed to room temperature and stirred for 2 hours. To the reaction solution was added 30 mL of ice water, extracted with EA (25 mL × 2), the organic phases were combined, washed twice with water (20 mL × 2), washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and reduced pressure After concentration, the crude product was obtained, which was then slurried with PE (25 mL) to obtain compound 54-1 (6.49 g, white solid). Yield: 81%. MS m / z (ESI): 297.9 [M-56 + 1].

Step 2: Dissolve compound 54-1 (1g, 2.83mmol) in THF (50mL), and dropwise add lithium hexamethyldisilazide (7mL, 7.08mmol) under nitrogen protection at -78 ° C. After the addition is complete The reaction solution was reacted at -78 ° C for 1.5 hours. Then, 2- (bromomethyl) pyridine hydrobromide (852 mg, 3.40 mmol) was added. After the addition, the reaction solution was reacted at -78 ° C for 1 hour, and then raised to room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution at 0 ° C, and then extracted with EA (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The crude product 54-2 (1.3 g, black oil), the product was directly subjected to the next reaction without purification. MS / m / z (ESI): 445.0 [M + 1].

Step 3: Compound 54-2 (650 mg, 1.46 mmol), intermediate 12.1 (555 mg, 2.19 mmol), Pd (dppf) Cl ₂ (110 mg, 0.15 mmol), cesium fluoride (444 mg, 2.92 mmol) were dissolved in 15 mL 1,4-Dioxane and 3mL water, heated at 90 ° C under nitrogen protection, and stirred for 4 hours. Ice water was added to the reaction solution, the organic phase was extracted with EA (20 mL × 2), and the combined organic phase was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography at 30% ~ Purification of 80% EA in PE gave compound 54-3 (310 mg, brown solid), yield: 48%. MS m / z (ESI): 444.1 [M + 1].

Step 4: Compound 54-3 (300 mg, 0.68 mmol), sodium azide (264 mg, 4.06 mmol), trimethyl orthoformate (430 mg, 4.06 mmol) were dissolved in 7 mL of acetic acid and stirred at room temperature for 16 hours. Water was added to the reaction solution, the organic phase was extracted with EA (10 mL × 2), the combined organic phase was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 54-4 (275 mg, yellow solid) , Yield: 81.5%. MS / m / z (ESI): 497.1 [M + 1].

Step 5: Compound 54-4 (270 mg, 0.54 mmol) was dissolved in 10 mL of 4M hydrochloric acid dioxane solution, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness, and the residue was slurried with DCM (10 mL) and filtered to obtain compound 54-5 (280 mg, yellow solid), yield: 100%. MS / m / z (ESI): 441.0 [M + 1].

Step 6: Compound 54-5 (140 mg, 0.32 mmol), compound 15.1 (133 mg, 0.64 mmol) and TEA (2 mL) were dissolved in 5 mL DCM, T3P (1 mL) was added at 0 ° C, and the reaction was stirred at room temperature for 16 hours. 5 mL of water was added, extracted with DCM (10 mL × 2), the organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 54-6 (202 mg, brown oil), The product was directly subjected to the next reaction without purification. MS / m / z (ESI): 631.2 [M + 1].

Step 7: Compound 54-6 (202 mg, 0.32 mmol) was dissolved in 2 mL of acetic acid, heated at 60 ° C. and stirred for 1 hour. 5 mL of water was added, extracted with EA (5 mL × 2), the organic phases were combined, washed with saturated sodium bicarbonate solution (5 mL), saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and thin layer was used Chromatography was purified with a developing agent system (dichloromethane: methanol = 13: 1) to obtain product 54-7 (70 mg, yellow solid), yield: 35.7%. MSm / z (ESI): 613.2 [M + 1].

Step 8: Compound 54-7 (70 mg, 0.11 mmol) was dissolved in 2 mL of 4M dioxane hydrochloride solution, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness, and the title compound H-54 (20.56 mg, white solid) was obtained by preparative HPLC chromatography, yield: 34%. MS m / z (ESI): 557.1 [M + 1]; 1H NMR (400MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.45 (d ,, 1H), 8.07 (d, 2H), 7.88 –7.74 (m, 4H), 7.68 (td, 1.8Hz, 1H), 7.54 (d, 1H), 7.23–7.18 (m, 1H), 7.13 (d, 1H), 6.67–6.59 (m, 1H), 6.42 (d, 1H), 3.83–3.78 (m, 1H), 3.67 (d, 1H).

Example 55 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2- (1-methyl-1H-pyrazol-4-yl) ethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Step 1: (1-methyl-1H-pyrazol-4-yl) methanol (1 g, 20.9 mmol) was dissolved in 5 mL of hydrogen bromide acetic acid solution, and the reaction was stirred at 115 ° C for 16 hours. The reaction was followed to completion by TLC plate, and the reaction solution was concentrated under reduced pressure to obtain crude 4- (bromomethyl) -1-methyl-1H-pyrazole hydrobromide 55-1 (1.1 g, yellow solid).

Step 2: Dissolve compound 54-1 (918 mg, 6.80 mol) in 20 mL of THF, add LiHMDS (4.3 mL, 4.25 mmol) at -78 ° C, stir the reaction at -78 ° C for 1 hour, and add compound 55-1 (-78 ° C) 725mg, 2.83mol), stirred at room temperature for 3 hours, quenched the reaction with saturated ammonium chloride solution, extracted with EA (50mL × 2), combined organic phases, washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, Filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified in 0 to 30% EA in PE by silica gel column chromatography to obtain compound 55-2 (510 mg, white solid), yield: 80.5%. MS / m / z (ESI): 448.1 [M + 1].

Step 3: 55-2 (200 mg, 0.45 mmol) was dissolved in 1 mL of DCM and 1 mL of TFA, the reaction was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure to obtain crude compound 55-3 (160 mg, light yellow solid). MS / m / z (ESI): 391.9 [M + 1].

Step 4: Compound 55-3 (160 mg, 0.41 mmol), compound 15.1 (170 mg, 0.82 mmol) and NMI (100 mg, 1.23 mmol) were dissolved in 10 mL of DCM, TCFH (230 mg, 0.82 mmol) was added at 0 ° C, and the reaction was stirred at room temperature After 3 hours, 10 mL of saturated brine and 10 mL of water were added, extracted with DCM (25 mL × 2), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 55- 4 (220 mg, light yellow solid). MS / m / z (ESI): 582.0 [M + 1].

Step 5: Compound 55-4 (220 mg, 0.38 mmol) was dissolved in 5 mL of acetic acid, and the reaction was stirred at 70 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with 0-15% methanol in DCM to obtain compound 55-5 (211 mg, off-white solid), yield: 99.0%. MS / m / z (ESI): 564.0 [M + 1].

Step 6: Compound 55-5 (211 mg, 0.37 mmol), compound 12.1 (95 mg, 0.37 mmol) and potassium carbonate (155 mg, 1.12 mmol) were dissolved in 10 mL of dioxane and 2 mL of water, and Pd (dppf) was added under nitrogen protection Cl ₂ (30mg, 0.04mmol), stirred at 100 ° C for 18 hours under nitrogen protection. After the reaction solution was cooled, 5mL saturated brine and 5mL water were added, extracted with EA (30mL × 2), the organic phases were combined and washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with 0-10% methanol in DCM to obtain compound 55-6 (210 mg, off-white solid), yield: 99.5%. MS m / z (ESI): 563.2 [M-82 + 1].

Step 7: In a 10 mL sealed tube, add: compound 55-6 (210 mg, 0.37 mmol), trimethyl orthoformate (356 mg, 3.36 mmol), sodium azide (218 mg, 3.36 mmol) and 2 mL of acetic acid, and close the lid. The reaction was stirred at 90 ° C for 18 hours. 10mL of water was added, extracted with EA (10mL × 2), the organic phases were combined, washed with saturated brine (5mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using silica gel column chromatography at 0-90% EA purified the resulting residue in PE to give compound 55-7 (200 mg, off-white solid), yield: 87.0%. MS / m / z (ESI): 616.2 [M + 1].

Step 8: Compound 55-7 (80 mg, 0.13 mmol) was dissolved in 1 mL of DCM, 1 mL of TFA was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the title compound H-55 (21.17 mg, white solid) was obtained by preparative HPLC chromatography, yield: 29.1%. MS m / z (ESI): 560.2 [M + 1]; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.82 (s, 1H), 8.18 (d, J = 30.0 Hz, 1H), 8.09 (d, J = 6.2Hz, 1H), 7.93–7.86 (m, 3H), 7.83 (d, J = 8.6Hz, 1H), 7.61 (s, 1H), 7.24 (s, 1H ), 7.18 (s, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.29-6.21 (m, 1H), 3.81 (s, 3H), 3.55-3.48 (m, 2H).

Example 56 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -yl)- Preparation of 2- (1-methyl-1H-pyrazol-4-yl) ethyl) -1H-benzo [d] imidazole-5-carboxamide

Compound H-55 (80mg, 0.14mmol), ammonium chloride (38mg, 0.71mmol) and DIEA (111mg, 0.86mmol) were dissolved in 5mL DMF, HATU (109mg, 0.29mmol) was added, the reaction was stirred at room temperature for 3 hours, The reaction solution was concentrated under reduced pressure, and the title compound H-56 (32.76 mg, white solid) was obtained by HPLC chromatography, yield: 41.0%. MS m / z (ESI): 559.2 [M + 1]; ¹ H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.14–8.07 (m, 2H), 7.99 (s, 1H), 7.93–7.86 (m, 3H), 7.78 (dd, J = 8.5, 1.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.24 (s, 1H), 7.17 (s, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.28–6.21 (m, 1H), 3.81 (s, 3H), 3.52–3.47 (m, 2H).

Example 58 and Example 59 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -5-fluoro-2-oxopyridine-1 (2H) -Yl) -2- (tetrahydro-2H-pyran-2-yl) ethyl) -1H-benzo [d] imidazole-5-carboxylic acid H-58 (diastereomer D1) and H -59 (Diastereomer D2) Preparation

Step 1: Under the protection of nitrogen at -20 ° C, (tetrahydro-2H-pyran-2-yl) methanol 58-1 (500mg, 4.31mmol), 2,6-lutidine (691mg, 6.46mmol) Dissolve in 20mL DCM, add trifluoromethanesulfonic anhydride (1.8g, 6.46mmol) dropwise, and maintain the reaction at -20 ° C with stirring for 2 hours. To the reaction solution was added 20 mL of ice water, extracted with DCM (10 mL × 2), the organic phases were combined, washed with 1 M hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (10 mL), saturated sodium chloride solution (15 mL ), Dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 58-2 (950 mg, brown oil), yield: 89%, the product was directly subjected to the next reaction without purification.

Step 2: Compound 54-1 (985 mg, 2.79 mmol) was dissolved in THF (45 mL), and lithium hexamethyldisilazide (7 mL, 6.98 mmol) was added dropwise under nitrogen protection at -78 ° C. The reaction solution was reacted at -78 ° C for 1.5 hours. A solution of compound 58-2 (900 mg, 3.63 mmol) and THF (5 mL) was added dropwise, and after the addition, the reaction solution was reacted at -78 ° C for 1 hour and then raised to room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution at 0 ° C, and then extracted with EA (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. It was purified in PE by silica gel column chromatography with 10% to 20% EA to obtain crude compound 58-3 (360 mg, yellow oil), yield: 28.6%. MS “m / z (ESI): 395.9 [M-56 + 1].

Step 3: Compound 58-3 (350 mg, 0.78 mmol), compound 12.1 (295 mg, 1.16 mmol), Pd (dppf) Cl ₂ (57 mg, 0.078 mmol), cesium fluoride (237 mg, 1.56 mmol) were dissolved in 10 mL 1 , 4-dioxane and 2 mL of water, heated at 90 ° C. under nitrogen protection and stirred for 3 hours. Add water to the reaction solution, extract with EA (15 mL × 2), combine organic phases, wash with saturated sodium chloride solution (15 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column chromatography at 10% to 50 % EA was purified in PE to obtain compound 58-4 (250 mg, brown oil), yield: 71%. MS m / z (ESI): 451.1 [M + 1].

Step 4: Compound 58-4 (240 mg, 0.53 mmol), sodium azide (208 mg, 3.20 mmol), trimethyl orthoformate (339 mg, 3.20 mmol) were dissolved in 6 mL of acetic acid and stirred at room temperature for 16 hours. Water was added to the reaction solution, extracted with EA (10 mL × 2), and the combined organic phase was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product compound 58-5 (242 mg, brown solid) ), Yield: 90.8%. MS / m / z (ESI): 504.2 [M + 1].

Step 5: Compound 58-5 (237 mg, 0.47 mmol) was dissolved in 2 mL of DCM solution, 1 mL of TFA was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness to obtain compound 58-6 (160 mg, yellow solid), yield: 76%. MS / m / z (ESI): 448.1 [M + 1].

Step 6: Dissolve compound 58-6 (140 mg, 0.31 mmol), compound 15.1 (129 mg, 0.62 mmol), TCFH (174 mg, 0.62 mmol), NMI (76 mg, 0.93 mmol) in 6 mL of acetonitrile, and stir at room temperature for 3 hours . The reaction solution was concentrated to dryness, 10 mL of water was added, extracted with EA (5 mL × 2), the organic phases were combined, washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 58-7 (200 mg, Yellow solid), the product was directly subjected to the next reaction without purification. MS / m / z (ESI): 638.2 [M + 1].

Step 7: Dissolve compound 58-7 (200 mg, 0.31 mmol) in 3 mL of acetic acid, and stir at 60 ° C. for 1 hour. 5mL of water was added, extracted with EA (5mL × 2), the organic phases were combined, washed with saturated sodium bicarbonate solution (5mL), saturated sodium chloride (5mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 58 -8 (90 mg, yellow solid), yield: 46.3%. MS / m / z (ESI): 620.2 [M + 1].

Step 8: Compound 58-8 (85mg, 0.14mmol) was dissolved in 2mL of 4M dioxane hydrochloride solution, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness and obtained by preparative HPLC chromatography:

Diastereomer D1 product H-58 (34.12 mg, white solid). MS m / z (ESI): 564.1 [M + 1]; 1H NMR (400MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.10 (s, 1H), 7.97 (d, 1H), 7.90– 7.85 (m, 3H), 7.83 (dd, 1H), 7.60 (d, 1H), 6.53 (d, 1H), 6.13 (s, 1H), 3.80 (d, 1H), 3.16 (td, 1H), 2.87 (t, 1H), 2.51 (d, 1H), 2.36–2.28 (m, 1H), 1.76 (d, 1H), 1.55–1.38 (m, 4H), 1.23 (dd, 1H). Diastereomer D2 product H-59 (20.69 mg, white solid). MS m / z (ESI): 564.1 [M + 1]; 1H NMR (400MHz, DMSO-d ₆ ) δ 12.72 (s, 1H), 9.77 (s, 1H), 8.10 (s, 1H), 7.98 ( d, 1H), 7.90–7.81 (m, 3H), 7.79 (dd, 1H), 7.58 (d, 1H), 6.50 (d, 1H), 6.33 (t, 1H), 3.85–3.78 (m, 1H) , 3.20–3.14 (m, 1H), 3.10–3.03 (m, 1H), 2.55–2.48 (m, 1H), 2.19–2.09 (m, 1H), 1.75–1.66 (m, 1H), 1.56 (d, 1H), 1.39 (s, 3H), 1.19 (dd, 1H).

Example 61 2- (1- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2-oxopyridine-1 (2H) -yl) -2-phenyl Preparation of ethyl) -1H-benzo [d] imidazole-5-carboxylic acid

Step 1: Compound 1u-3 (180 mg, 0.56 mmol) and DIPEA (216 mg, 1.68 mmol) were dissolved in 10 mL of DCM, HATU (276 mg, 0.73 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. Methyl 3,4-diaminobenzoate (93 mg, 0.56 mmol) was added, and the reaction was stirred at room temperature for 2 hours. 3 mL of saturated brine and 3 mL of water were added, and extracted with DCM (15 mL × 2). The organic phases were combined and saturated brine It was washed (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 61-1 (230 mg, light yellow solid). MS / m / z (ESI): 472.1 [M + 1].

Step 2: Compound 61-1 (230 mg, 0.49 mmol) was dissolved in 2 mL of acetic acid, and the reaction was stirred at 80 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified in 0-90% EA in PE by silica gel column chromatography to obtain compound 61-2 (130 mg, white solid), yield: 58.9%. MS / m / z (ESI): 452.1 [M + 1].

Step 3: Dissolve compound 61-2 (130 mg, 0.29 mmol), pinacol diborate (292 mg, 1.15 mmol) and potassium acetate (85 mg, 0.86 mmol) in 2 mL of dioxane and 2 mL of dimethyl sulfoxide Pd (dppf) Cl ₂ (21mg, 0.03mmol) was added under nitrogen protection, and the reaction was stirred at 100 ° C for 18 hours under nitrogen protection. After the reaction solution was cooled, 3mL of saturated saline and 3mL of water were added and extracted with EA (100mL × 2) The organic phases were combined, washed with saturated brine (3 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Usage The obtained residue was purified in PE with 0-50% EA in silica gel column chromatography to obtain compound 61-3 (140 mg, light yellow solid), yield: 97.5%. MS m / z (ESI): 419.1 [M-82 + 1].

Step 4: Dissolve compound 61-3 (140 mg, 0.28 mmol), compound 1a-2 (86 mg, 0.28 mmol) and cesium carbonate (274 mg, 0.84 mmol) in 5 mL of dioxane and 1 mL of water, and add Pd under the protection of nitrogen (dppf) Cl ₂ (20mg, 0.03mmol), stir the reaction at 100 ° C for 18 hours under the protection of nitrogen. After the reaction solution was cooled, add 5mL of saturated saline and 5mL of water, extract with EA (20mL × 2), combine the organic phase, saturated It was washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified in PE with 0 to 90% EA by silica gel column chromatography to obtain compound 61-34 (20 mg, white solid), yield: 12.9%. MS m / z (ESI): 553.1 [M + 1].

Step 5: Compound 61-4 (20 mg, 0.04 mmol) was dissolved in 2 mL of methanol and 0.5 mL of water, sodium hydroxide (3 mg, 0.07 mmol) was added, and the reaction was stirred at room temperature for 16 hours. It was concentrated under reduced pressure, and the title compound H-61 (1.52 mg, white solid) was obtained by preparative HPLC chromatography, yield: 7.8%. MS / m / z (ESI): 538.2 [M + 1].

Example 66: Reference compound H-42 is prepared, the difference is that intermediate 1v-1 is substituted for 1w, and N- (3-bromopropyl) methanesulfonamide is substituted for 2-bromoacetamide to prepare compound H -66.

Example 67: Reference compound H-42 is prepared, the difference is that the intermediate 1v-1 is substituted for 1w, and N- (3-bromopropyl) acetamide is substituted for 2-bromoacetamide, compound H- can be prepared 67.

Example 68: Refer to the preparation method of compound H-42, the difference is that intermediate 1v-1 is substituted for 1w, and N- (2-bromoethyl) methanesulfonamide is substituted for 2-bromoacetamide to prepare compound H -68.

Example 69: Reference compound H-42 is prepared, the difference is that the intermediate 1v-1 is substituted for 1w, and N- (2-bromoethyl) acetamide is substituted for 2-bromoacetamide, compound H- can be prepared 69.

Biological test

Test case for the detection of the inhibition of coagulation factor Ⅺ activity

In this experiment, substrate chromogenic method was used to detect the inhibition of coagulation factor Ⅺ activity. The reagents used were: coagulation factor Ⅺ (Sekisui Diagnostics 4011A) and FⅪ substrate S-2366 (Diapharma S821090).

The inhibitory effect of the test compound on coagulation factor XI was determined by the following method. The test compound was dissolved in dimethyl sulfoxide according to the concentration required in the experiment. Prepare 1 × and 2 × buffer, use 1 × buffer to prepare the appropriate concentration of factor Ⅺ dilution, and use 1 × and 2 × buffer to prepare FⅪ substrate S-2366 (1mM) reaction solution. Add 5 μl of test compound DMSO solution, 5 μl of factor Ⅺ dilution solution (only 5 μl of 1 × buffer in the background) and 5 μl of 1 × buffer to the 384-well plate (PE 6007640). After incubating for 15 minutes at ℃, add 35 μl of FⅪ substrate S-2366 diluted solution, shake and mix well, after incubating at 25 ℃ for 50 minutes, measure the absorbance at 405 nm with a microplate reader. Two parallel holes were set for different concentrations of each test compound. Calculate the inhibition rate of each concentration point of the compound according to the OD value. The calculation formula is as follows, where the negative control is substrate + buffer + DMSO, and the positive control is substrate + FXIa + DMSO: inhibition rate% = [1- (OD (compound) – OD (negative control)) / (OD (positive control) – OD (negative control))] × 100%. The calculated inhibition rate was calculated using XLFIT 5.0 software to calculate the IC ₅₀ value. The results are shown in Table 1:

Table 1 Compounds' inhibitory activity on coagulation factor XIa

Test Example 2 Activated partial thromboplastin time (APTT) test

1. Source of plasma

1.1 Rabbit plasma: rabbits are provided by the Experimental Animal Center of Shanghai University of Traditional Chinese Medicine, and blood samples and plasma are extracted by the company's laboratory staff.

1.2 Human plasma: provided by Shanghai Ruizhi Chemical Research Co., Ltd.

2. APTT reagent

Supplier: Nanjing Jiancheng Biological Engineering Research Institute, specifications: 40T, 2ml / 10 bottles / box.

3. Instruments

Name: Semi-automatic four-channel coagulation analyzer, Manufacturer: Nanjing Ruimai Technology Development Co., Ltd., Model: AYW8001

Fourth, the detection method

4.1 Turn on the instrument, preheat for 20 minutes, and set the detection index.

4.2 Dilute the compound solution with blank plasma to the required concentration, which is the plasma sample to be tested.

4.2 Equilibrate the APTT reagent to room temperature and preheat CaCl ₂ to 37 ° C.

4.3 Add 100μl of APTT reagent and 100μl of the plasma sample to be tested into the cuvette, mix well, and then place in the pre-warmed well for pre-warming.

4.4 After pre-warming, transfer the cuvette to the detection well, and then add 100 μl of CaCl ₂ to the cuvette for APTT detection.

4.5 Record and print the results. The results are shown in Table 2:

Table 2 Compound APTT test results

It can be seen from Tables 1 and 2 that the representative compounds of the present invention have high inhibitory activity on coagulation factor XIa and can effectively inhibit platelet aggregation. The study found that the presence or absence of substituents on pyridone has a significant effect on the inhibitory activity of the compound, especially after introducing a substituent at the 5-position of pyridone, the activity of the compound is significantly improved (for example, compounds H-13 and H-25, H -61 and compound H-19), in addition, the type of substituent also has a great influence on the activity, when the substituent is halogen or methoxy, its activity is significantly higher than the structure where the substituent is dimethylamino.

All documents mentioned in the present invention are cited as references in this application, just as each document is individually cited as a reference. In addition, it should be understood that, after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

In the formula,

R 3 is -L 1 -R c ; L 1 is a bond, C (O) or (CR 31 R 32 ) q ; R c is hydrogen, phenyl, C 3-8 cycloalkyl (preferably C 3- 6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -NR 11 R 12 , -CONR 21 R 22 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl ( It is preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , -CONR 13 SO 2 R 0 , -SO 2 NR 13 COC 1- 10 alkyl (preferably -SO 2 NR 13 COC 1-6 alkyl, more preferably -SO 2 NR 13 COC 1-3 alkyl), -NR 11 (CH 2 ) p NHR 14 , -NR 11 (CH 2 ) p CONR 15 R 16 , -NR 11 (CH 2 ) p CR 15 R 16 ; the phenyl and C 3-8 cycloalkyl are unsubstituted or substituted by 1-3 substituents selected from the group consisting of Substitution: halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl) , -NR 11 R 12 , -COC 1-10 alkyl (preferably- COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl , More preferably -C (O) OC 1-3 alkyl), -SO 2 NR 11 R 12 or -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl);

R 4 is hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);

Or R 3 and R 4 together with the connected carbon atoms form a 3- to 6-membered saturated monoheterocycle or a 3- to 6-membered saturated monocyclic ring; Substituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1- 3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl);

R 01 , R 02 , R 03 are each independently hydrogen, halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy Group), optionally substituted C 1-10 alkyl (preferably optionally substituted C 1-6 alkyl, more preferably optionally substituted C 1-3 alkyl), halogenated C 1-10 alkyl (Preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl) or halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably Halogenated C 1-3 alkoxy), and at least one of R 01 , R 02 , and R 03 is not hydrogen; the optionally substituted means unsubstituted or substituted by 1-3 selected from the group consisting of Substitution: C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -NR 11 R 12 , -CONR 21 R 22 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably- SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 ;

The structure shown in formula (A), formula (B) or formula (C):

Where Z 1 is NR 5 , S or CR 5 R 6 ;

Z 2 is N or CR 6 ;

Z 3 is a bond, C (O), C (R 7 R 8 ) or S (O) 2 ;

Z 4 is N or CR 6 ;

Z 5 is CR 9 ;

Z 6 is N or CR 6 ;

Z 7 is NR 5 , S or CR 5 R 6 ;

Z 8 is a bond, C (O), C (R 7 R 8 ) or S (O) 2 ;

Ring B is a 4- to 6-membered saturated or unsaturated monocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring;

Ring C and the heterocyclic ring together form a 9 to 10 membered bicyclic heteroaryl ring;

Ring D is a 4- to 6-membered saturated or unsaturated monocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring;

It is a single bond or a double bond;

R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, and more preferably C 1 -3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1- 3 alkyl), -CONR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl Radical), -SO 2 NR 11 R 12 or -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl);

R 31 and R 32 are each independently hydrogen, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1- 10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl ), -NR 13 SO 2 R 0 ;

R b is halogen (preferably F or Cl), CN, carboxyl, -NR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably Is -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , -P (O) (OC 1-10 alkyl) 2 (preferably -P (O) (OC 1-6 alkyl) 2 , more preferably -P (O) (OC 1-3 alkyl) 2 ), -P (O) (OH) 2 , -CONR 11 R 12 , -CONR 13 SO 2 R 0 , -SO 2 NR 13 COC 1-10 alkyl (preferably -SO 2 NR 13 COC 1-6 alkyl, more preferably -SO 2 NR 13 COC 1-3 alkyl), -NR 11 (CH 2 ) p NHR 14 , -NR 11 (CH 2 ) p CONR 15 R 16 ,- NR 11 (CH 2 ) p CR 15 R 16 , halogenated C 1-10 alkyl substituted hydroxymethyl or halogenated C 1-10 alkyl substituted hydroxyethyl; R 0 is C 1-10 alkyl ( Preferably it is C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 11 R 12 , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl);

R 14 is -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -COC 1-10 alkyl (preferably- COC 1-6 alkyl, more preferably -COC 1-3 alkyl);

R 15 and R 16 are each independently hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); or R 15 , R 16 and the attached nitrogen atom or Carbon atoms form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 ;

R 21 and R 22 are each independently hydrogen or R 21 , R 22 and the connected nitrogen atom together form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or is 1- Substituted by 3 -NR 11 R 12 or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);

R 11 , R 12 and R 13 are each independently hydrogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or halogenated C 1-10 alkyl ( It is preferably a halogenated C 1-6 alkyl, and more preferably a halogenated C 1-3 alkyl);

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

R a is halogen (preferably F or Cl), CN, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or halogenated C 1-10 alkyl ( It is preferably a halogenated C 1-6 alkyl, and more preferably a halogenated C 1-3 alkyl);

n is 0, 1, 2, 3 or 4.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R 01 and R 03 are hydrogen; R 02 is halogen (preferably F or Cl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy, most preferably methoxy).
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein in formula (A), Z 1 is NR 5 , S or CR 5 R 6 ; Z 2 is N or CR 6 ; Z 3 is a key;
It is a single bond or a double bond; ring B is a 4 to 6 membered saturated or unsaturated single heterocyclic ring, a 4 to 6 membered saturated or unsaturated single ring, a 5 to 6 membered monocyclic heteroaryl ring or a benzene ring.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein, in formula (A), Z 1 is NR 5 ; Z 2 is N or CR 6 ; Z 3 is C (O), C (R 7 R 8 ) or S (O) 2 ;
It is a single bond or a double bond; ring B is a 4 to 6 membered saturated or unsaturated single heterocyclic ring, a 4 to 6 membered saturated or unsaturated single ring, a 5 to 6 membered monocyclic heteroaryl ring or a benzene ring.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein, in formula (B), Z 4 is N or CR 6 ; Z 5 is CR 9 ; The C ring and the heterocyclic ring together form a 9 to 10 membered bicyclic heteroaryl ring.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein, in formula (C), Z 6 is N or CR 6 ; Z 7 is NR 5 , S or CR 5 R 6 ; Z 8 is a key;
It is a single bond or a double bond; ring D is a 4- to 6-membered saturated or unsaturated single heterocyclic ring, a 4- to 6-membered saturated or unsaturated single ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein, in formula (C), Z 6 is N or CR 6 ; Z 7 is NR 5 ; Z 8 is C (O), C (R 7 R 8 ) or S (O) 2 ;
It is a single bond or a double bond; ring D is a 4- to 6-membered saturated or unsaturated single heterocyclic ring, a 4- to 6-membered saturated or unsaturated single ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring.
A compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

In the formula,

R 3 is -L 1 -R c ; L 1 is a bond, C (O) or (CR 31 R 32 ) q ; R c is hydrogen, phenyl, C 3-8 cycloalkyl (preferably C 3- 6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -NR 11 R 12 , -CONR 21 R 22 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl ( It is preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , -CONR 13 SO 2 R 0 , -SO 2 NR 13 COC 1- 10 alkyl (preferably -SO 2 NR 13 COC 1-6 alkyl, more preferably -SO 2 NR 13 COC 1-3 alkyl), -NR 11 (CH 2 ) p NHR 14 , -NR 11 (CH 2 ) p CONR 15 R 16 , -NR 11 (CH 2 ) p CR 15 R 16 ; the phenyl and C 3-8 cycloalkyl are unsubstituted or substituted by 1-3 substituents selected from the group consisting of Substitution: halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl) , -NR 11 R 12 , -COC 1-10 alkyl (preferably- COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl , More preferably -C (O) OC 1-3 alkyl), -SO 2 NR 11 R 12 or -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl);

R 4 is hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);

Or R 3 and R 4 together with the connected carbon atoms form a 3- to 6-membered saturated monoheterocycle or a 3- to 6-membered saturated monocyclic ring; Substituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1- 3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 alkyl);

R 01 and R 03 are hydrogen; R 02 is halogen (preferably F or Cl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy, most Preferably methoxy);

The structure shown in formula (A) or formula (C):

Where Z 1 is NR 5 , S or CR 5 R 6 ;

Z 2 is N or CR 6 ;

Z 3 is a key;

Z 6 is N or CR 6 ;

Z 7 is NR 5 , S or CR 5 R 6 ;

Z 8 is a key;

Ring B is a 4- to 6-membered saturated or unsaturated monocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring;

Ring D is a 4- to 6-membered saturated or unsaturated monocyclic ring, a 4- to 6-membered saturated or unsaturated monocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring or a benzene ring;

It is a single bond or a double bond;

R 5 and R 6 are each independently hydrogen, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1- 10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halogenated C 1-3 alkyl), -NR 11 R 12 , -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 NR 11 R 12 or -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl);

R 31 and R 32 are each independently hydrogen, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1- 10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl ), -NR 13 SO 2 R 0 ;

R b is halogen (preferably F or Cl), CN, carboxyl, -NR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably Is -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , -P (O) (OC 1-10 alkyl) 2 (preferably -P (O) (OC 1-6 alkyl) 2 , more preferably -P (O) (OC 1-3 alkyl) 2 ), -P (O) (OH) 2 , -CONR 11 R 12 , -CONR 13 SO 2 R 0 , -SO 2 NR 13 COC 1-10 alkyl (preferably -SO 2 NR 13 COC 1-6 alkyl, more preferably -SO 2 NR 13 COC 1-3 alkyl), -NR 11 (CH 2 ) p NHR 14 , -NR 11 (CH 2 ) p CONR 15 R 16 ,- NR 11 (CH 2 ) p CR 15 R 16 , halogenated C 1-10 alkyl substituted hydroxymethyl or halogenated C 1-10 alkyl substituted hydroxyethyl; R 0 is C 1-10 alkyl ( Preferably it is C 1-6 alkyl, more preferably C 1-3 alkyl), -NR 11 R 12 , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl);

R 14 is -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -COC 1-10 alkyl (preferably- COC 1-6 alkyl, more preferably -COC 1-3 alkyl);

R 15 and R 16 are each independently hydrogen or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); or R 15 , R 16 and the attached nitrogen atom or Carbon atoms form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 ;

R 21 and R 22 are each independently hydrogen or R 21 , R 22 and the connected nitrogen atom together form a 5- to 6-membered saturated monoheterocycle; the 5- to 6-membered saturated monoheterocycle is unsubstituted or is 1- Substituted by 3 -NR 11 R 12 or C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);

R 11 , R 12 and R 13 are each independently hydrogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or halogenated C 1-10 alkyl ( It is preferably a halogenated C 1-6 alkyl, and more preferably a halogenated C 1-3 alkyl);

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

m is 0, 1, 2, 3 or 4;

R a is halogen (preferably F or Cl), CN, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or halogenated C 1-10 alkyl ( It is preferably a halogenated C 1-6 alkyl, and more preferably a halogenated C 1-3 alkyl);

n is 0, 1, 2, 3 or 4.
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R b is halogen, CN, carboxyl, NH 2 , -C (O) OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NH 2 , -P (O) (OC 1-3 alkyl) 2 , -P (O) (OH) 2 , -CONH 2 , -CONHSO 2 C 1-3 alkyl, -CONHSO 2 NH 2 , -CONHSO 2 N (CH 3 ) 2 , -CONHSO 2 C 3-6 cycloalkyl, -SO 2 NHCOC 1-10 alkyl, -C (CF 3 ) 2 OH, -NHCH 2 CONH 2 , -NH (CH 2 ) 2 CONH 2 , -NH (CH 2 ) 3 CONH 2 , -NH (CH 2 ) 3 NHSO 2 C 1-3 alkyl,- NH (CH 2 ) 2 NHSO 2 C 1-3 alkyl, -NHCH 2 NHSO 2 C 1-3 alkyl, -NHCH 2 NHCOC 1-3 alkyl, -NH (CH 2 ) 2 NHCOC 1-3 alkyl , -NH (CH 2) 3 NHCOC 1-3 alkyl, -NHCHR 15 R 16 or -NHCONR 15 R 16; R 15, R 16 with the nitrogen atom form a 5- to 6-membered saturated heteromonocyclic; the 5 Up to 6-membered saturated monoheterocycle is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1-3 alkyl, halogenated C 1-3 alkyl Radical, NH 2 or N (CH 3 ) 2 .
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein m is 0, 1, or 2.
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (A) or formula (C) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (A) or formula (C) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (A) or formula (C) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (A) or formula (C) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (A) or formula (C) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (B) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein formula (B) is selected from the following group of structures:
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R 3 is -CH 2 -L 1 ; L 1 is phenyl; Phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen (preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably Is C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halo C 1-3 alkyl), -NR 11 R 12 , -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1 -3 alkyl), -CONR 11 R 12 , -C (O) OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 Alkyl), -SO 2 NR 11 R 12 or -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); R 4 For hydrogen.
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R 3 and R 4 together with the connected carbon atoms form a 3 to 6-membered saturated monomer Heterocyclic ring or 3 to 6 membered saturated monocyclic ring; said 3 to 6 membered saturated single heterocyclic ring or 3 to 6 membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of: halogen ( Preferably F or Cl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 The alkyl group is more preferably a C 1-3 alkyl group) and a halogenated C 1-10 alkyl group (preferably a halogenated C 1-6 alkyl group, and more preferably a halogenated C 1-3 alkyl group).
The compound according to claim 1 or 9, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein n is 1.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from Table A, Table B, Table C or Table D.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from Table B, Table C or Table D.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from Table B or Table C.
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from the following structures:
A pharmaceutical composition comprising the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and a pharmaceutically acceptable carrier.
Use of the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 25 in the preparation of an XIa inhibitor.
The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 25 in the preparation for the inhibition of factor XIa Application of drugs.
The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 25 in the preparation of prophylactic and / or therapeutic XIa Use of drugs for factor-mediated diseases.
The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 25 in the preparation of prophylaxis and / or treatment Use in medicine for cerebrovascular diseases.
The use according to claim 29, characterized in that the cardiovascular and cerebrovascular diseases are preferably thromboembolic diseases, more preferably myocardial infarction, angina pectoris, angioplasty or aortic coronary artery shunt reocclusion And restenosis, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
A method for preventing and / or treating a factor XIa-mediated disease, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomeric A structuring or solvate, or the pharmaceutical composition according to claim 25.
A method for preventing and / or treating cardiovascular and cerebrovascular diseases, comprising administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or stereoisomer thereof Or a solvate, and optionally another therapeutically active agent.
The method according to claim 32, wherein the cardiovascular and cerebrovascular diseases are preferably thromboembolic diseases, and more preferably myocardial infarction, angina pectoris, angioplasty or aortic coronary artery shunt reocclusion and Restenosis, disseminated intravascular coagulation, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.
A compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

In the formula,

R 3 is -L 1 -R c ; L 1 is a bond, C (O) or (CR 31 R 32 ) q ; R c is a 5 to 6 membered monocyclic heteroaryl ring or a 3 to 6 membered saturated monoheterocyclic ; The 5 to 6 membered monocyclic heteroaromatic ring and the 3 to 6 membered saturated monoheterocyclic ring are unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy, C 1-10 alkyl, halogenated C 1-10 alkyl, -NR 11 R 12 , -COC 1-10 alkyl, -CONR 11 R 12 , -C (O) OC 1-10 alkyl, -SO 2 NR 11 R 12 or -SO 2 C 1-10 alkyl;

The other groups are as defined in claim 8.
The compound according to claim 34, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from Table E.