TW201910333A - Piperazine-heteroaryl derivative, preparation method thereof and application thereof in medicine - Google Patents

Abstract

The present invention relates to piperazine fused heteroaryl derivatives, a preparation method thereof and pharmaceutical use thereof. Specifically, The present invention relates to piperazine fused heteroaryl derivatives represented by general formula (I), a preparation method thereof, pharmaceutical compositions containing the derivatives and use as capsid protein inhibitors, particularly use in the prevention and/or treatment of diseases such as hepatitis B, influenza, herpes and AIDS. The definition of each substituent group in general formula (I) is the same as the definition in the description.

Description

   Piperazinoheteroaryl derivatives, preparation method and application thereof in medicine   

The invention belongs to the field of medicine and relates to piperazinoheteroaryl derivatives, a preparation method thereof and its application in medicine. In particular, the present invention relates to a piperazinoheteroaryl derivative represented by the general formula (I), a method for preparing the same, a pharmaceutical composition containing the derivative, and a capsid protein inhibitor thereof, particularly for prevention. And / or use in the treatment of diseases such as hepatitis B, influenza, herpes and AIDS.

Chronic hepatitis B virus (HBV) infection is already a global health problem. According to the World Health Organization, about 2 billion people have been infected with HBV, 240 million of whom are chronic HBV infections, and about 650,000 people die each year from HBV infection. Caused liver failure, cirrhosis and hepatocellular carcinoma (HCC). Among patients with cirrhosis and HCC worldwide, HBV infection is responsible for 30% and 45%, respectively. Although prophylactic HBV vaccines can be used, chronic HBV infection has become a medical problem worldwide due to the lack of effective treatments.

At present, there are two main types of drugs for treating chronic HBV: α-interferon preparations (such as pegylated α-interferon) and nucleoside analogs that inhibit HBV DNA polymerase (such as lamivudine, adefovir). Wait). However, interferon preparations have severe side effects, are poorly tolerated, and only a small proportion of patients may have a sustained clinical response to interferon therapy ( Lancet. 2005 Jan 8-14; 365 (9454): 123-9 .; N Engl J Med. 2005 Jun 30; 352 (26): 2682-95 .; Hepatology. 2009 May; 49 (5 Suppl): S103-11). As a competitive inhibitor of reverse transcriptase, nucleoside analog drugs exert antiviral effects by blocking the synthesis of HBV DNA strands. However, the existing nucleoside analog drugs also have the problems of inducing resistance mutations in reverse transcriptase and poor efficacy on drug-resistant strains. In addition, these drugs are often difficult to completely clear HBV infection, even if they are taken for a long time, they cannot be cured; once the drug is discontinued, it may cause a serious withdrawal of the drug, so it is often necessary to take the drug for life ( Hepatology. 2009 May; 49 (5 Suppl) : S112-21). Therefore, there is an urgent need to develop new, safe and effective drugs for chronic hepatitis B.

The reason for the low cure rate of chronic HBV infection is closely related to the characteristics of hepatitis B virus (HBV). HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family. The outermost layer of mature HBV virus particles is an envelope protein, which encapsulates the HBV Nucleocapsid. The nucleocapsid is also called a core particle, and is composed of a capsid protein, HBV Relaxed circular DNA (rcDNA), and a HBV reverse transcriptase that binds to the 5 'end of the negative strand of rcDNA. Upon infection, rcDNA is transformed into covalent closed-loop DNA (cccDNA) in the host cell nucleus as a model of HBV replication. An important step in HBV replication is Encapsidation. Pregenomic RNA (pgRNA) transcribed from cccDNA needs to be encapsulated in the capsid protein together with HBV reverse transcriptase to complete the assembly step in order to initiate subsequent reverse transcription. Before reverse transcription, HBV reverse transcriptase and pgRNA need to be properly enveloped by capsid proteins. Therefore, blocking capsid protein assembly, or accelerating degradation of capsid protein, will block capsid assembly process and affect virus replication. In addition, the N-terminal 149 amino acid residues (Cp149) constituting the core protein dimerization motif and the assembly domain have no human protein homology sequence. Therefore, capsid protein assembly inhibitors are considered as new targets for the development of anti-HBV drugs. Due to the different mechanism of action from traditional antiviral drugs, the combination therapy of capsid protein inhibitors and DNA polymerase inhibitors should synergistically curb HBV replication and prevent drug resistance, providing a safer and more effective treatment for chronic hepatitis B infection Effective treatment.

At present, there are two main classes of drugs for capsid protein inhibitors: heteroaryldihydropyrimidines (HAPs) and phenylacrylamidines, such as GLS-4, NVR-3778, and so on. Relevant patents such as: WO2001068642, WO2014029193, WO2015011281, WO2016016196, WO2017076791, and WO2016113273, etc., but most of the compounds targeted at this target are in the clinical research stage, and no marketed drugs have appeared. Therefore, it is necessary to continue to develop drugs targeting capsid protein inhibitors in order to improve the safety and effectiveness of the drugs and overcome the problems of chronic HBV infection as soon as possible.

Capsid protein inhibitors interfere with the normal assembly of capsid proteins by binding to the assembly domain of the core protein dimerization motif, thereby affecting HBV replication. Therefore, good drug metabolism and high bioavailability (which can make the body have a higher concentration of compounds) can more effectively block HBV replication.

The present invention provides a capsid protein inhibitor with a novel structure represented by the general formula (I). The substituent on the heteroaryl group is amidine, and preferably the amine group in the amidine group is a secondary amine. The comparative example (Example 59) was designed to correspond to the NR ¹ R ² part in the general formula (1). R ¹ R ² forms a tertiary amine with a nitrogen atom, and the heteroaryl group is verified by the comparative example. When the amine group in the amine group is a secondary amine, the biological activity is significantly improved, it has a significant inhibitory effect on the normal assembly of HBV capsid protein, and its drug metabolism is well absorbed and its bioavailability is high. At the same time, the compounds of the new structure represented by the general formula (I) have no effect on the proliferation inhibition of HepG2 cells in vitro or have a small effect, and show good safety.

The object of the present invention is to provide a compound represented by the general formula (I): Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A is an aryl group and Heteroaryl; Y is N or CR ⁵ ; Q is N or CH; R ^{1 is} selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkane Group, haloalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently further selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, Amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S ( O) _m R ⁶ is substituted by one or more substituents; R ^{2 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently further selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano Base, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl ^{, -OR 6, -C (O)} R 6, in a ⁶ -C (O) OR ⁶ and -S (O) _m R or more substituents; R ³ are the same or different and are each independently Selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{4 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkane Base, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ ,- C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{5 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyanide Group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; R ^{6 is} selected from hydrogen atom, alkyl group, haloalkyl group, amino group, hydroxyl group, hydroxyalkane Group, cycloalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention is a compound represented by the general formula (II): Wherein: the rings A, Y, Q, R ¹ , R ³ , R ⁴ , s and n are as defined in the general formula (I).

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention is the general formula (III), the general formula (IV), the general formula (V), and the general formula (VI) Compound shown: Wherein: Ring A, R ¹ , R ³ , R ⁴ , s and n are as defined in the general formula (I).

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein ring A is phenyl or pyridyl.

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention is the general formula (VII), the general formula (VIII), the general formula (IX), and the general formula (X ) Compounds shown: Wherein: G is C or N; R ¹ , R ³ , R ⁴ , s, and n are as defined in the general formula (I).

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein R ^{1 is} selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclic and aryl. Wherein the alkyl, cycloalkyl, heterocyclyl and aryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy and hydroxyl.

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention is a general formula (VII-A), a general formula (VIII-A), a general formula (IX -A) and a compound represented by the general formula (XA): Wherein: G is C or N; R ⁸ is an alkyl group, preferably a methyl group; R ⁹ is an alkyl group, wherein the alkyl group is further substituted with one or more halogens if necessary; R ³ , R ⁴ , s, and n is as defined in the general formula (I).

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein R ³ is a hydrogen atom or an alkyl group.

In another preferred embodiment of the present invention, the compound represented by the general formula (I) according to the present invention, wherein R ^{4 is} selected from a hydrogen atom, a halogen, a haloalkyl group or a cyano group.

Typical compounds of general formula (I), including but not limited to:

Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a compound represented by the general formula (IA), Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ^a is a hydrogen atom or an alkane Ring A is aryl and heteroaryl; Y is N or CR ⁵ ; Q is N or CH; R ^{3 is the} same or different and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkyl Oxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; R ^{4 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, Alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{5 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitrate Group, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ^{6 is} selected from hydrogen atom, alkyl, haloalkyl, amino, hydroxy, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4; In another aspect, the present invention provides a compound represented by the general formula (IC): Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A is an aryl group and a hetero group Aryl; Y is N or CR ⁵ ; Q is N or CH; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano Group, amino group, nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and- S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; R ^{4 is the} same or different and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, Cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{5 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl, and heteroaryl; R ^{6 is} selected from hydrogen atom, alkyl, haloalkyl, amino, hydroxyl, hydroxyalkyl, cycloalkyl, hetero Cyclic, aryl and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4.

It is for preparing a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Intermediate of pharmaceutically acceptable salts.

Typical compounds of general formula (IA), including but not limited to:

In another aspect, the present invention provides a compound of the formula (IIIA): Or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: M is trifluoroacetic acid or hydrochloric acid ; R ^{1 is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are each independently further optionally selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ are substituted with one or more substituents; R ^{3 is the} same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, and cycloalkane Group, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group T is 0 or 1; and n is 0, 1, 2 or 3; it is the preparation of a compound according to formula (III) or a tautomer, meso Isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or intermediates of pharmaceutically acceptable salts thereof.

Typical intermediate compounds, including but not limited to:

In another aspect, the present invention provides a method for preparing a compound represented by the general formula (I) according to the present invention. The method includes the following steps:

The compound of the general formula (IA) is reacted with the compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (I); wherein: R ^a is a hydrogen atom or an alkyl group; R ^{3 is the} same or different, and each is independently selected from Hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, Y, Q, R ¹ , R ² , R ⁴ , s and n are as defined in the general formula (I).

In another aspect, the present invention provides a method for preparing a compound represented by the general formula (I) according to the present invention. The method includes the following steps:

A compound of the general formula (IC) is reacted with a compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (I); wherein: R ^{3 is the} same or different and each is independently selected from a hydrogen atom, a halogen, an alkyl group, and a halogen Alkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O ) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, Y, Q, R ¹ , R ² , R ⁴ , s and n such as As defined in general formula (I).

In another aspect, the present invention provides a method for preparing a compound represented by the general formula (II) according to the present invention. The method includes the following steps:

A compound of the general formula (IA) is reacted with a compound of the general formula (IIB) or a salt thereof to obtain a compound of the general formula (II); wherein: R ^a is a hydrogen atom or an alkyl group; R ^{3 is the} same or different, and is independently selected from Hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, Y, Q, R ¹ , R ⁴ , s and n are as defined in the general formula (II).

In another aspect, the present invention provides a method for preparing a compound represented by the general formula (II) according to the present invention. The method includes the following steps:

A compound of the general formula (IC) is reacted with a compound of the general formula (IIB) or a salt thereof to obtain a compound of the general formula (II); wherein: R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, and a halogen Alkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O ) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, Y, Q, R ¹ , R ⁴ , s, and n are as general formula ( II).

In another aspect, the present invention provides a method for preparing a compound represented by the general formula (III), the general formula (IV)), the general formula (V), and the general formula (VI) according to the present invention. The method includes the following: step:

Reacting a compound of general formula (III-a) with a compound of general formula (IIB) or a salt thereof to obtain a compound of general formula (III); or

Reacting a compound of general formula (IV-a) with a compound of general formula (IIB) or a salt thereof to obtain a compound of general formula (IV);

Reacting a compound of general formula (Va) with a compound of general formula (IIB) or a salt thereof to obtain a compound of general formula (V); or

The compound of the general formula (VI-a) is reacted with the compound of the general formula (IIB) or a salt thereof to obtain a compound of the general formula (VI); wherein: wherein: R ^a is a hydrogen atom or an alkyl group; R ^{3 is the} same or different, and each Independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl , Heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; ring A, R ¹ , R ⁴ , s and n are as defined in the general formula (I).

In another aspect, the present invention provides a method for preparing the compound represented by the general formula (III), which method includes the following:

Reacting a compound of the general formula (IIIA) or a salt thereof with a compound of the general formula (IIB ') or a salt thereof and a bis (trifluoromethyl) carbonate to obtain a compound of the general formula (III); wherein R ^{3 is the} same or different, and Each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aromatic Group, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; M is trifluoroacetic acid or Hydrochloric acid; t is 0 or 1; rings A, R ¹ , R ⁴ , s and n are as defined in general formula (III).

Another aspect of the present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, Diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention also relates to a method for preparing the above composition, which comprises converting a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer The isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier, diluent, or excipient.

The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a compound thereof Use of a pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a capsid protein inhibitor.

The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a compound thereof Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention and / or treatment of a viral infection disease. The virus can be hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the disease can be hepatitis B virus, influenza, herpes and AIDS.

The present invention further relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, which is used as a medicament. The medicament is preferably a medicament for preventing and / or treating a viral infection disease. The virus can be hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the disease can be hepatitis B virus, influenza, herpes and AIDS.

The present invention also relates to a compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, which is used as a capsid protein inhibitor.

The present invention also relates to a method for preventing and / or treating a viral infection disease, which comprises administering to a patient in need thereof a therapeutically effective dose of a compound represented by the general formula (I) as a capsid protein inhibitor or a tautomer thereof Isomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them. The virus can be hepatitis B virus, influenza virus, herpes virus and AIDS virus, and the disease can be hepatitis B virus, influenza, herpes and AIDS.

The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide pleasing and Delicious medicinal preparation. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or they may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained release over a longer period.

Oral formulations may also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspensions, dispersants or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection solution or microemulsion may be injected into the bloodstream of the patient by local mass injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable water or oil suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blending fixing oil can be used. In addition, fatty acids can also be prepared for injection.

The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus will dissolve in the rectum to release the drug.

As known to those skilled in the art, the dosage of a drug depends on a number of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, the patient's behavior, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc. In addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound of the present invention or the type of pharmaceutically acceptable salt can be based on traditional To verify the treatment options.

    [Detailed description of the invention]    

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 Carbon atom alkyl. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, second 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-dimethylbutyl, 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-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl , 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third butyl, Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Methyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Pentyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxygen, carboxyl, carboxylate, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ .

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl, carboxylate, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ .

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably contains 3 to 12 carbon atoms, and more preferably contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members of a single ring sharing a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated Π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bispirocycloalkyl . More preferably, it is 4/4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members, or 5 members / 6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "fused cycloalkyl" refers to a 5 to 20 member, each ring in the system and the other rings in the system share a pair of full carbon polycyclic groups adjacent to each other, where one or more rings may contain one or Multiple double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

The term "bridged cycloalkyl" refers to a full-carbon polycyclic group of 5 to 20 members in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate π electron system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptyl and the like. A cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxy, carboxyl, carboxylate, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ .

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of _m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 3 to 6 ring atoms, of which 1 to 2 is a hetero atom. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and preferably piperidinyl, piperazinyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which 5 to 20 members of a single ring share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a completely conjugated π-electron system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. Spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bispiroheterocyclyl . More preferred are 3 member / 6 member, 4 member / 4 member, 4 member / 5 member, 4 member / 6 member, 5 member / 5 member or 5 member / 6 member monospirocyclic group. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, but none of the rings have a completely conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) _m (where m is an integer from 0 to 2), and the remaining rings Atoms are carbon. It is preferably 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5 member / 5 member or 5 member / 6 member bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclyl include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete A y-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include: with Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxy, carboxyl, carboxylate, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ .

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., ring sharing a pair of adjacent carbon atom pairs) group, preferably 6 to 10 members, having a conjugated pi-electron system, such as Phenyl and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazole , Pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazole Or pyrimidinyl, thiazolyl; more preferably pyridyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl, carboxylate, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ .

The term "amino-protecting group" is to protect the amine group with an easily removable group in order to keep the amine group unchanged during the reaction of other parts of the molecule. Non-limiting examples include tertiary butoxycarbonyl, ethenyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups are optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amine-protecting group is preferably p-methoxybenzyl.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group is as defined above.

The term "hydroxy" refers to the -OH group.

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

The term "amino" refers to -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO _2.

The term "lateral oxygen" refers to = O.

The term "carbonyl" refers to C = O.

The term "carboxy" refers to -C (O) OH.

The term "carboxylate" refers to -C (O) O (alkyl) or -C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "halogen halide" refers to a compound containing a -C (O) -halogen group.

"As needed" or "as needed" means that the event or environment described later can, but does not have to occur, and the description includes situations where the event or environment occurs or does not occur. For example, "heterocyclic group substituted with an alkyl group as necessary" means that the alkyl group may but need not exist, and the description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.

R ⁶ and m are as defined in the general formula (I).

Method for synthesizing compounds of the present invention

In order to achieve the object of the present invention, the present invention adopts the following technical solutions:

    Option One    

The compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (IIB ' ) reacts with a compound of the general formula (I-2) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (I-3); In the step, the compound of the general formula (I-3) and carbon monoxide are reacted under basic conditions in the presence of a catalyst to obtain the compound of the general formula (IA); in the third step, the compound of the general formula (IA) and the compound of the general formula (IB) Or a salt thereof to obtain a compound of general formula (I); reagents for providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilylamine lithium Tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to Sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; catalysts include, but are not limited to, palladium / carbon, Raney nickel, platinum dioxide, tetra-triphenylphosphine palladium, dichloride Palladium, palladium acetate, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, 1 1'-double (two Benzyl phosphorus) dichlorodipentylpalladium, tris (dibenzylideneacetone) dipalladium or 2-biscyclohexylphosphine-2 ', 6'-dimethoxybiphenyl, preferably [1,1'- Bis (diphenylphosphino) ferrocene] palladium dichloride or 2-biscyclohexylphosphine-2 ', 6'-dimethoxybiphenyl.

Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -di Isopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azo Benzotriazole, O -benzotriazole- N , N , N ' , N' -tetramethylurea hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -N, N , N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' - tetramethyluronium hexafluorophosphate, benzotriazole Azole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably 2- (7- Benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, Tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfinium, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; of which: R ^a Is a hydrogen atom or an alkyl group, preferably a hydrogen atom Methyl or ethyl; X is a halogen, preferably bromo; R ³ are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano , Amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, Y, Q, R ¹ , R ² , R ⁴ , s, and n are as defined in the general formula (I).

    Option II    

The compound represented by the general formula (I) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (IIB ' ) reacts with a compound of the general formula (I-4) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (IA); in the second step, Under basic conditions, a compound of the general formula (IA) undergoes a hydrolysis reaction to obtain a compound of the general formula (IC); in the third step, a compound of the general formula (IC) and a compound of the general formula (IB) or a salt thereof undergo a condensation reaction to obtain Compounds of formula (I); reagents for providing basic conditions include organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilylamino lithium tetrahydrofuran solution, N , N -di Isopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, phosphoric acid Potassium, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N ' -Dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1 -Hydroxybenzotriazole, 1- Azo-7-benzotriazole, O - benzotriazol - N, N, N ', N' - tetramethyl uronium hexafluorophosphate, O- (7- azabenzotriazol-1 yl) -N, N, N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' - tetramethyluronium hexafluorophosphate Phosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably It is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to, acetic acid, Methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfinium, 1,4-dioxane, water, N , N -dimethylformamide and its A mixture; wherein: R ^a is alkyl, preferably methyl or ethyl; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy Group, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ Is preferably a hydrogen atom or an alkyl group; the rings A, Y, Q, R ¹ , R ² , R ⁴ , s and n are as defined in the general formula (I).

    third solution    

The compound represented by the general formula (II) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

A compound of the general formula (IA) reacts with a compound of the general formula (IIB) or a salt thereof under basic conditions to obtain a compound of the general formula (II); reagents for providing basic conditions include organic bases and inorganic bases. Bases include, but are not limited to, triethylamine, 1M bistrimethylsilyl lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, The third sodium butoxide or the third potassium butoxide, the inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensing agents include, but not Limited to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide Imine, O -benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O -benzotriazole- N , N , N ' , N' -tetramethylurea hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -N, N, N ' , N '- tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N' , N '- tetramethyluronium hexafluorophosphate, Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably 2- ( 7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to, acetic acid, methanol, ethanol, Toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfine, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; of which: R ^a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group, or an ethyl group; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, and halogen Alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, Q, Y, R ¹ , R ⁴ , s and n are as defined in the general formula (II).

    Option four    

The compound represented by the general formula (II) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

A compound of the general formula (IC) reacts with a compound of the general formula (IIB) or a salt thereof under basic conditions to obtain a compound of the general formula (II); reagents providing basic conditions include organic bases and inorganic bases, and the organic bases Including but not limited to triethylamine, 1M bistrimethylsilyl lithium lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, potassium acetate, third Sodium butoxide or potassium third butoxide, the inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensing agents include, but are not limited to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O -benzene benzotriazole - N, N, N ', N' - tetramethyl uronium hexafluorophosphate, O- (7- aza-benzotriazol-1-yl) -N, N, N ', N' - four Methyl urea hexafluorophosphate, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazole- 1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably 2- (7-benzene oxide Benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, Dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; wherein: R ^{3 is the} same or Different and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic Group, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; ring A, Q, Y, R ¹ , R ⁴ , s and n are as defined in the general formula (II).

    Option five    

The compound represented by the general formula (III) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (IIB ' ) reacts with a compound of the general formula (III-1) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (III-a); Step, the compound of the general formula (III-a) undergoes a hydrolysis reaction under basic conditions to obtain a compound of the general formula (III-b); in the third step, the compound of the general formula (III-b) and the compound of the general formula (IIB) or The salt reacts to obtain the compound of general formula (III); reagents for providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilylamino lithium tetrahydrofuran solution , N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride , Sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Salt, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetramethylurea Tetrafluoroborate, 1-hydroxybenzotris 1-hydroxy-7-azo-benzotriazole, O - benzotriazol - N, N, N ', N' - tetramethyl uronium hexafluorophosphate, O- (7- azabenzotriazole 1-yl) -N, N, N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' - tetramethyl Urea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate , Preferably 2- (7-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to : Acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfine, 1,4-dioxane, water, N , N -dimethylformamidine Amines and mixtures thereof; wherein: R ^a is alkyl, preferably methyl or ethyl; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, Haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C ( O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, R ¹ , R ⁴ , s and n are as defined in the general formula (III).

    Option six    

The compound represented by the general formula (IV) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (IIB ' ) reacts with a compound of the general formula (IV-1) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (IV-a); Step, the compound of the general formula (IV-a) undergoes a hydrolysis reaction under basic conditions to obtain a compound of the general formula (IV-b); in the third step, the compound of the general formula (IV-b) and the compound of the general formula (IIB) or The salt reacts to obtain the compound of general formula (IV); reagents for providing basic conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, 1M bistrimethylsilylamino lithium tetrahydrofuran solution. , N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride , Sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; catalysts include but are not limited to palladium / carbon, Raney nickel, platinum dioxide, tetra-triphenylphosphine palladium, palladium dichloride , Palladium acetate, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride, 1,1 '-Bis (dibenzyl phosphorus) dichlorodipentyl Palladium, tris (dibenzylideneacetone) dipalladium or 2-biscyclohexylphosphine-2 ', 6'-dimethoxybiphenyl, preferably [1,1'-bis (diphenylphosphino) di Ferrocene] palladium dichloride or 2-dicyclohexylphosphine-2 ', 6'-dimethoxybiphenyl.

Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -di Isopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azo Benzotriazole, O -benzotriazole- N , N , N ' , N' -tetramethylurea hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -N, N , N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' - tetramethyluronium hexafluorophosphate, benzotriazole Azole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably 2- (7- Benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, Tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfinium, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; wherein: R ^a It is alkyl, preferably methyl or ethyl; R ³ Are the same or different, and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; a ring A, R ¹ , R ⁴ , s and n are as defined in the general formula (I).

    Option seven    

The compound represented by the general formula (III) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (III-3) and a compound of the general formula (IIB) or a salt thereof are reacted under basic conditions in the presence of a condensing agent to obtain the general formula (III-4); The compound of the general formula (III-4) is deprotected under acidic conditions to obtain the compound of the general formula (IIIA) or a salt thereof; in the third step, the compound of the general formula (IIIA) or a salt thereof and the compound of the general formula (IIB ' ) or A salt reacts with a bis (trichloromethyl) carbonate to obtain a compound of the general formula (III); reagents providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bis Trimethylsilyl lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium third butoxide or potassium third butoxide, The inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate; reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, and acetic acid. , hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, toluenesulfonic acid, Me ₃ SiCl and TMSOT _f; above reaction is preferably It is carried out in a solvent, including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfine, 1,4-dioxane, and water. , N , N -dimethylformamide and mixtures thereof; wherein: M is trifluoroacetic acid or hydrochloric acid; Ra is ^a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group; ^Rb is an amine A protecting group, preferably a third butoxycarbonyl group; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and amine Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O _m R ⁶ ; preferably a hydrogen atom or an alkyl group; t is 0 or 1; rings A, R ¹ , R ⁴ , s and n are as defined in the general formula (III).

    Option eight    

The compound represented by the general formula (V) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (IIB ' ) and a compound of the general formula (V-1) react under basic conditions to obtain a compound of the general formula (V-2); in a second step, a compound of the general formula (V-2) In the presence of a reducing agent, a reduction reaction occurs to obtain a compound of general formula (V-3); in a third step, an oxidation reaction of a compound of general formula (V-3) and an oxidant occurs to obtain a compound of general formula (V-4); fourth In step 5, a compound of the general formula (V-4) undergoes an oxidation reaction in the presence of an oxidant to obtain a compound of the general formula (Va); in a fifth step, a compound of the general formula (Va) undergoes a condensation reaction with a compound of the general formula (IIB) or a salt thereof To obtain a compound of general formula (V); reagents for providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilylamino lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include, but are not limited to, sodium hydride, hydrogen Sodium oxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; reducing agents include, but are not limited to, lithium aluminum hydride, NaBH ₄ , NaBH ₄ -ZnCl ₂ and Diisobutylaluminum hydride (DIBAL-H).

Oxidants include, but are not limited to, pyridinium chlorochromate (PCC), Jones reagent, Collins reagent, pyridinium dichromate (PDC), chloramphochloride (Swern oxidation), carbodiimide, sodium chlorite, and permanganate Potassium.

Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -di Isopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azo Benzotriazole, O -benzotriazole- N , N , N ' , N' -tetramethylurea hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -N, N , N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' - tetramethyluronium hexafluorophosphate, benzotriazole Azole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably 2- (7- Benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, Tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylmethane, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; of which: R ³ The same or different and each independently selected from hydrogen Atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, R ¹ , R ⁴ , s and n As defined in general formula (V).

    Option nine    

The compound represented by the general formula (VI) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (IIB ' ) reacts with a compound of the general formula (VI-1) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (VI-2); Step: A compound of the general formula (VI-a) reacts with a compound of the general formula (IIB) or a salt thereof to obtain a compound of the general formula (VI); reagents for providing basic conditions include organic bases and inorganic bases, and the organic bases include But not limited to triethylamine, 1M bistrimethylsilyllithium lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamine, potassium acetate, tert-butyl Sodium alkoxide or potassium third butoxide, the inorganic bases include, but are not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensing agents include, but are not limited to 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O- Benzotriazole- N , N , N ' , N' -tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O -benzotriazole N - N , N , N ' , N' -tetramethylurea hexafluorophosphate, O- (7-nitrogen Heteroaryl benzotriazol-1-yl) -N, N, N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N ' -Tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or hexafluorophosphate benzotriazol-1-yl-oxy Tripyrrolidinyl phosphorus, preferably 2- (7-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably carried out in a solvent and used Solvents include, but are not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfene, 1,4-dioxane, water, N , N- Dimethylformamide and mixtures thereof; wherein: R ^a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group, or an ethyl group; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, Alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; rings A, R ¹ , R ⁴ , s, and n are as general formula ( I) Medium Definitions.

    Scheme ten    

The compound represented by the general formula (VII) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable form thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (VII-1) reacts with a compound of the general formula (III-1) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (VII-a); In the second step, the compound of the general formula (IV-a) undergoes a hydrolysis reaction under basic conditions to obtain a compound of the general formula (VII-b); in the third step, the compound of the general formula (VII-b) and the compound of the general formula (IIB) or Its salt undergoes a condensation reaction to obtain a compound of the general formula (VII); reagents providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilylamino Lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but not Limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensation agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Amine hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetra Methyl urea tetrafluoroborate, 1-hydroxybenzene Benzotriazole, 1-hydroxy-7-azobenzotriazole, O -benzotriazole- N , N , N ' , N' -tetramethylurea hexafluorophosphate, O- (7-azabenzene and triazol-1-yl) -N, N, N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' - Tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or hexafluorophosphate benzotriazol-1-yl-oxytripyrrole Alkyl phosphorus, preferably 2- (7-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used includes But not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethylsulfine, 1,4-dioxane, water, N , N -dimethyl Methylformamide and mixtures thereof; wherein: R ^a is alkyl, preferably methyl or ethyl; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkyl Oxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ -S (O) _m R ^6; preferably a hydrogen atom or an alkyl group; R ^1, R ^4, s and n are as in formula (I) as defined above.

    Option 11    

The compound represented by the general formula (VIII) of the present invention or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof The preparation method of salt includes the following steps:

In the first step, a compound of the general formula (VII-1) reacts with a compound of the general formula (IV-1) and a bis (trichloromethyl) carbonate under basic conditions to obtain a compound of the general formula (VIII-a); In the second step, the compound of the general formula (VIII-a) undergoes a hydrolysis reaction under basic conditions to obtain a compound of the general formula (VIII-b); in the third step, the compound of the general formula (VIII-b) and the compound of the general formula (IIB) or Its salt undergoes a condensation reaction to obtain a compound of the general formula (VIII); reagents providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilylamino Lithium tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but not Limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensation agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Amine hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -tetra Methyl urea tetrafluoroborate, 1-hydroxyl Benzotriazole, 1-hydroxy-7-azo-benzotriazole, O - benzotriazol - N, N, N ', N' - tetramethyl uronium hexafluorophosphate, O- (7- aza- benzotriazol-1-yl) -N, N, N ', N' - tetramethyluronium hexafluorophosphate, 2- (7-benzotriazole-oxide) - N, N, N ' , N' -Tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or hexafluorophosphate benzotriazol-1-yl-oxytri Pyrrolidyl phosphorus, preferably 2- (7-benzobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate; the above reaction is preferably performed in a solvent, and the solvent used Including but not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfene, 1,4-dioxane, water, N , N -di Methylformamide and mixtures thereof; wherein: R ^a is alkyl, preferably methyl or ethyl; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, Alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O OR ⁶ and -S (O) _m R ⁶ ; preferably a hydrogen atom or an alkyl group; R ¹ , R ⁴ , s and n are as defined in the general formula (I).

    Option 12    

The compound represented by the general formula (VII-A) or the general formula (VIII-A) of the present invention or a tautomer, meso, racemate, enantiomer, diastereomer A method for preparing the same or a mixture thereof or a pharmaceutically acceptable salt thereof includes the following steps:

A compound of general formula (VII-a) reacts with a compound of general formula (VII-B) or a salt thereof to obtain a compound of general formula (VII-A); or a compound of general formula (VIII-a) and general formula (VII-B) A compound or a salt thereof reacts to obtain a compound of the general formula (VIII-A); reagents providing basic conditions include organic bases and inorganic bases, and the organic bases include, but are not limited to, triethylamine, 1M bistrimethylsilyl Lithium amino tetrahydrofuran solution, N , N -diisopropylethylamine, n-butyllithium, lithium diisopropylamino, potassium acetate, sodium third butoxide or potassium third butoxide, the inorganic bases include But not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate or cesium carbonate; condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbon Diimine hydrochloride, N , N' -dicyclohexylcarbodiimide, N , N' -diisopropylcarbodiimide, O -benzotriazole- N , N , N ' , N' -Tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O -benzotriazole- N , N , N ' , N' -tetramethyl hexafluorophosphate, O- (7- aza-benzotriazol-1-yl) - N, N, N ' , N' - tetramethyluroniumhexafluorophosphate Phosphonium salt, 2- (7-benzotriazol-oxide) - N, N, N ' , N' - tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino Amino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, preferably 2- (7-benzotriazole) -N, N, N ', N' -Tetramethylurea hexafluorophosphate; the above reaction is preferably carried out in a solvent, including but not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate , N-hexane, dimethylsulfinium, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof; wherein: G is C or N; R ^a is a hydrogen atom or an alkyl group , Preferably a hydrogen atom, methyl or ethyl; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and amine Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O _m R ⁶ ; preferably a hydrogen atom or an alkyl group; R ⁸ is an alkyl group, preferably a methyl group; R ⁹ is an alkyl group, wherein the alkyl group is further One or more halogens are substituted; R ⁴ and s are as defined in general formula (I).

The present invention is further described below with reference to examples, but these examples do not limit the scope of the present invention.

    [Example]    

The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethylsulfine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was four. Methylsilane (TMS).

MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatography.

HPLC preparation was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatography.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses a Combiflash Rf200 (TELEDYNE ISCO). The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone plate. The thin-layer chromatography (TLC) silicon plate uses a size of 0.15mm ~ 0.2mm. The thin-layer chromatography separation and purification product uses a size of 0.4mm. ~ 0.5mm.

Silicone column chromatography generally uses Yantai Huanghai Silicone 200 ~ 300 mesh silica gel as the carrier.

The average inhibition rate of the kinase and the IC ₅₀ value were measured using a NovoStar microplate reader (BMG, Germany).

The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemicals and other companies.

There is no special description in the examples, and the reaction can be performed under an argon atmosphere or a nitrogen atmosphere.

An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

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

Pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

There is no special description in the examples, and the solution means an aqueous solution.

There is no special description in the examples, and the reaction temperature is room temperature, which is 20 ° C to 30 ° C.

The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin layer chromatography developing system including: A : Dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.

    Example 1     ( R ) -N ^7- (3,4,5-trifluorophenyl) -N ^1- (1,1,1-trifluoroprop-2-yl) -5,6-dihydroimidazo [1, 5- a] pyrazine -1,7 (8 H) - dimethyl Amides

    First step     1-bromo - N - (3,4,5- trifluorophenyl) -5,6-dihydro-imidazo [1,5- a] pyrazin -7 (8 H) - A Amides 1c

3,4,5-trifluoroaniline 1a (0.365 g, 2.48 mmol, prepared by a known method " Tetrahedron Letters , 51 (17), 2010, 2265-2268") and 1-bromo-5,6, 7,8-tetrahydroimidazo [1,5- a ] pyrazine 1b (501.36mg, 2.48mmol, Shanghai Shuya Pharmaceutical Co., Ltd.) was dissolved in 30mL of dichloromethane, and triethylamine (753.26mg, 7.44) was added. mmol) and bis (trichloromethyl) carbonate (294.53 mg, 992.54 μmol), and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography in developing system A to obtain the title compound 1c (300 mg, yield: 32.2%). MS m / z (ESI): 376.1 [M + 1].

    Second step     7-((3,4,5-trifluorophenyl) aminomethylamido) -5,6,7,8-tetrahydroimidazo [1,5- a ] pyrazine-1-carboxylic acid methyl ester 1d

In a carbon monoxide atmosphere, dicobalt octacarbonyl (525.03 mg, 1.54 mmol) and potassium carbonate (1.06 g, 7.68 mmol) were dissolved in 20 mL of methanol, and the reaction was stirred at 60 ° C for 15 minutes. Compound 1c (300 mg, 767.71 μmol) and methyl 2-chloroacetate (499.88 mg, 4.61 mmol) were further added, and the reaction was stirred for 8 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system A to obtain the title compound 1d (70 mg, yield: 21.8%).

MS m / z (ESI): 355.3 [M + 1].

    third step     ( R ) -N ^7- (3,4,5-trifluorophenyl) -N ^1- (1,1,1-trifluoroprop-2-yl) -5,6-dihydroimidazo [1, 5- a] pyrazine -1,7 (8 H) - dimethyl Amides

Compound 1d (70 mg, 197.58 μmol) and (2 R ) -1,1,1-trifluoropropyl-2-amine hydrochloride 1e (59.09 mg, 395.16 μmol) were prepared by the method disclosed in the patent application “CN102875270A” The obtained solution was dissolved in 10 mL of tetrahydrofuran, and 0.988 μL of a 1 M solution of bistrimethylsilylaminolithium tetrahydrofuran was added dropwise at 0 ° C. After the addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure, 15 mL of water was added to the obtained residue, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system A to obtain the title. Compound 1 (15 mg, yield: 17.4%).

MS m / z (ESI): 436.2 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.31 (s, 1H), 8.30 (d, 1H), 7.70 (s, 1H), 7.25-7.31 (m, 2H), 5.05 (s, 2H), 4.78 -4.86 (m, 1H), 4.21-4.24 (m, 2H), 3.94-3.96 (m, 2H), 1.31-1.44 (dd, 3H).

    Example 2     ( R ) -N ^5- (3,4-difluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazolo [1,5 -a ] Pyrazine-3,5 (4 H ) -dimethylformamide

    First step     6,7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dicarboxylic acid 5-third butyl ester 3-methyl ester 2b

In a carbon monoxide atmosphere, dicobalt octacarbonyl (2.26 g, 6.62 mmol) and potassium carbonate (4.57 g, 33.09 mmol) were dissolved in 20 mL of methanol, and the reaction was stirred at 60 ° C. for 15 minutes. Then add 3-bromo-6,7-dihydropyrazolo [1,5- a ] pyrazine-5 ( 4H ) -carboxylic acid third butyl ester 2a (1g, 3.31mmol, using the known method " ACS Medicinal Chemistry Letters , 2015, 6 (1), 37-41 ") and methyl 2-chloroacetate (2.15 g, 19.86 mmol). The reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, 100 mL of ethyl acetate was added, filtered, washed with 100 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography using developing system A to obtain the title compound 2b (0.5 g, product Rate: 53%).

MS m / z (ESI): 282.1 [M + 1].

    Second step     4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester trifluoroacetate 2c

Compound 2b (600 mg, 2.13 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (2.43 g, 21.33 mmol) was added. After the addition, the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2c (250 mg). The product was directly used in the next reaction without purification.

MS m / z (ESI): 182.0 [M + 1].

    third step     5-((3,4-difluorophenyl) aminomethylamidino) -4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester 2e

The crude compound 2c (200 mg, 1.10 mmol), 3,4-difluoroaniline 2d (142.51 mg, 1.10 mmol) and triethylamine (335.08 mg, 3.31 mmol) were dissolved in 10 mL of tetrahydrofuran, and at 0 ° C, biscarbonate was added. (Trichloromethyl) ester (114.64 mg, 386.33 μmol), slowly raised to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography to obtain the title compound 2e (100 mg, yield: 26.9%).

MS m / z (ESI): 337.4 [M + 1].

    the fourth step     ( R ) -N ^5- (3,4-difluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazolo [1,5 -a ] Pyrazine-3,5 (4 H ) -dimethylformamide 2

Compound 2e (100 mg, 297.36 μmol) and compound 1e (133.40 mg, 892.08 μmol) were dissolved in 20 mL of tetrahydrofuran, and 4.46 mL of a 1 M solution of bistrimethylsilyl lithium lithium tetrahydrofuran was added dropwise at 0 ° C. , Slowly raised to room temperature, and stirred for 3 hours. 2 mL of saturated ammonium chloride and 10 mL of water were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography using developing system A, and the obtained crude product was used High-performance liquid preparation (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) was purified to obtain the title compound 2 (15 mg, yield: 12.1%).

MS m / z (ESI): 418.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.07 (s, 1H), 7.51-7.46 (m, 1H), 7.22-7.16 (m, 2H), 5.05 (s, 2H), 4.88-4.82 (m, 1H ), 4.29-4.26 (m, 2H), 4.05-4.02 (m, 2H), 1.42-1.40 (m, 3H).

    Example 3     ^{(R) - N 7 - (} 3- cyano-4-fluorophenyl) - N ¹ - (1,1,1- trifluoro-2-yl) -5,6-dihydro-imidazo [1, 5- a] pyrazine -1,7 (8 H) - dimethyl Amides 3

    First step     ( R ) -1-((1,1,1-trifluoroprop-2-yl) aminomethylmethyl) -5,6-dihydroimidazo [1,5- a ] pyrazine-7 (8 H ) -tert-butyl carboxylic acid 3b

Under argon atmosphere, 5,6-dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dicarboxylic acid 7-tert-butyl ester 1-methyl ester 3a (469.78mg , 1.67 mmol, prepared by the method disclosed in the patent application "US20110034443A1") and compound 1e (249.74 mg, 1.67 mmol) were dissolved in 20 mL of tetrahydrofuran, and 3.3 mL of 1 M bistrimethylsilyl was added dropwise under an ice water bath. The lithium amine tetrahydrofuran solution was heated to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography to obtain the title compound 3b (130 mg, yield: 21.5%).

MS m / z (ESI): 363.2 [M + 1].

    Second step     (R) - N - (1,1,1- trifluoro-2-yl) -5,6,7,8-tetrahydro-imidazo [1,5- a] pyrazine-1-Amides three Fluoroacetate 3c

Compound 3b (130 mg, 358.77 μmol) and trifluoroacetic acid (204.54 mg, 1.79 mmol) were sequentially dissolved in 2 mL of dichloromethane, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 3c (135 mg). The product was directly used in the next reaction without purification.

    third step     ^{(R) - N 7 - (} 3- cyano-4-fluorophenyl) - N ¹ - (1,1,1- trifluoro-2-yl) -5,6-dihydro-imidazo [1, 5- a] pyrazine -1,7 (8 H) - dimethyl Amides 3

The crude compound 3c (50 mg, 190.67 μmol) and 5-amino-2-fluorobenzonitrile 3d (25.96 mg, 190.67 μmol) were prepared by a known method " Bioorganic & Medicinal Chemistry Letters , 2006, 16 (19), 5176- 5182 ") and triethylamine (28.94 mg, 286.01 μmol) were dissolved in 10 mL of tetrahydrofuran. In an ice water bath, bis (trichloromethyl) carbonate (28.29 mg, 95.34 μmol) was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 3 (2 mg, yield: 2.5%).

MS m / z (ESI): 425.1 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.22 (s, 1H), 8.32 (d, 1H), 7.95 (d, 1H), 7.81-7.77 (m, 2H), 7.47-7.43 (m, 1H) , 4.96 (s, 2H), 4.81-4.74 (m, 1H), 4.17-4.10 (m, 2H), 3.89-3.86 (m, 2H), 1.39-1.35 (dd, 3H).

    Example 4     ( R ) -N ^5- (3,4,5-trifluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazolo [1 , 5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 4

    First step     5-((3,4,5-trifluorophenyl) aminomethylamidino) -4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester Ester 4a

Compound 2c (100 mg, 338.74 μmol), compound 1a (49.83 mg, 338.74 μmol), and trifluoroacetic acid (342.77 mg, 3.39 mmol) were dissolved in 10 mL of tetrahydrofuran, and bis (trichloromethyl) carbonate was added at 0 ° C. (35.18 mg, 118.563 μmol), slowly raised to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography to obtain the title compound 4a (50 mg, yield: 25.0%).

MS m / z (ESI): 355.1 [M + 1].

    Second step     ( R ) -N ^5- (3,4,5-trifluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazolo [1 , 5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 4

Compound 4a (50 mg, 141.13 μmol) and 1e (63.31 mg, 423.39 μmol) were dissolved in 20 mL of tetrahydrofuran, and 2.12 mL of a 1 M solution of bistrimethylsilyl lithium lithium tetrahydrofuran was added dropwise at 0 ° C. The temperature was slowly raised to room temperature, and the reaction was stirred for 3 hours. 2 mL of saturated ammonium chloride and 10 mL of water were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography using developing system A, and the obtained crude product was used High-performance liquid preparation (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) was purified to obtain the title compound 4 (5 mg, yield: 4%).

MS m / z (ESI): 436.0 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.07 (s, 1H), 7.30-7.26 (m, 2H), 5.04 (s, 2H), 4.88-4.82 (m, 1H), 4.28-4.26 (m, 2H ), 4.04-4.01 (m, 2H), 1.42-1.40 (m, 3H).

    Example 5     ( R ) -N ^7- (3,4-difluorophenyl) -N ^1- (1,1,1-trifluoroprop-2-yl) -5,6-dihydroimidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl 5 Amides

    First step     7-((3,4-difluorophenyl) aminomethylmethyl) -5,6,7,8-tetrahydroimidazo [1,5- a ] pyrazine-1-carboxylic acid ethyl ester 5b

5,5,7,8-tetrahydroimidazo [1,5- a ] pyrazine-1-carboxylic acid ethyl ester 5a (100 mg, 512.25 μmol, prepared by the method disclosed in the patent application "CN102464661A") and Compound 2d (79.36 mg, 614.70 μmol) was added to 20 mL of tetrahydrofuran, and bis (trichloromethyl) carbonate (76.01 mg, 256.13 μmol) was added under ice-water bath conditions, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin-layer chromatography to obtain the title compound 5b (110 mg, yield: 61.3%).

MS m / z (ESI): 351.1 [M + 1].

    Second step     ( R ) -N ^7- (3,4-difluorophenyl) -N ^1- (1,1,1-trifluoroprop-2-yl) -5,6-dihydroimidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl 5 Amides

Compound 5b (75 mg, 214.009 μmol) and compound 1e (48.02 mg, 321.14 μmol) were added to 20 mL of tetrahydrofuran. Under ice-water bath conditions, lithium bistrimethylsilylamino group (107.47 mg, 642.27 μmol) was added and the reaction was stirred. 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography with developing agent system A. The obtained crude product was prepared by high-performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain The title compound 5 (20 mg, yield: 30.4%).

MS m / z (ESI): 418.2 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.09 (s, 1H), 8.31 (d, 1H), 7.76 (s, 1H), 7.64-7.60 (m, 1H), 7.34-7.23 (m, 2H) , 4.94 (s, 2H), 4.79-4.77 (m, 1H), 4.16-4.14 (m, 2H), 3.88-3.85 (m, 2H), 1.37-1.35 (dd, 3H).

    Example 6     ^{(S) - N 7 - (} 3,4- difluorophenyl) -6-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5,6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 6

    First step     (S) -5 - ((( 1- hydroxypropyl-2-yl) (4-methoxybenzyl) amino) methyl) -1 H - imidazole-4-carboxylic acid methyl ester 6c

( S ) -2-((4-methoxybenzyl) amino) propan-1-ol 6a (34.92 g, 179.08 mmol, using a well-known method " Bioorganic & Medicinal Chemistry Letters , 2015, 25 (5) , 1086-1091 ") was dissolved in 600 mL of tetrahydrofuran, and 5-aldehyde imidazole-4-carboxylic acid methyl ester 6b (23 g, 149.23 mmol, prepared by the method disclosed in the patent application" US2008 / 318935 ") was added) , Sodium triacetoxyborohydride (47.44 g, 223.85 mmol) was added in portions, and the reaction was stirred for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. 600 mL of ethyl acetate was added to the obtained residue, washed with water (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 6c (40 g). Purified and used directly in the next reaction.

MS m / z (ESI): 334.2 [M + 1].

    Second step     ( S ) -7- (4-methoxybenzyl) -6-methyl-5,6,7,8-tetrahydroimidazo [1,5- a ] pyrazine-1-carboxylic acid methyl ester 6d

The crude compound 6c (11 g, 33.03 mmol) and triphenylphosphine (12.98 g, 49.49 mmol) (Sinopec Reagent) were dissolved in 400 mL of tetrahydrofuran, and diisopropyl azodicarboxylate (10 g, 49.45) was slowly added dropwise under ice bath. mmol, Shanghai Shaoyuan Reagent Co., Ltd.), slowly raised to room temperature, and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, 400 mL of ethyl acetate was added to the obtained residue, washed with water (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to elute A was purified to obtain the title compound 6d (4.5 g, yield: 43.2%).

MS m / z (ESI): 315.9 [M + 1].

    third step     ( S ) -6-methyl-5,6,7,8-tetrahydroimidazo [1,5- a ] pyrazine-1-carboxylic acid methyl ester trifluoroacetate 6e

Compound 6d (0.6 g, 2.33 mmol) was dissolved in 2 mL of trifluoroacetic acid, heated to 100 ° C. in a microwave, and reacted for 5 minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain the crude title compound 6e (0.6 g). The product was used in the next reaction without purification.

MS m / z (ESI): 196.1 [M + 1].

    the fourth step     ( S ) -7-((3,4-difluorophenyl) aminomethylamidino) -6-methyl-5,6,7,8-tetrahydroimidazo [1,5- a ] pyrazine Methyl-1-carboxylic acid 6f

The crude compound 6e (240 mg, 776.09 μmol) was dissolved in 15 mL of tetrahydrofuran, compound 2d (150.3 mg, 1.16 mmol) and triethylamine (314.13 mg, 3.10 mmol) were added, and bis (trichloromethyl) carbonate was added in an ice bath. The ester (92.12 mg, 310.44 μmol) was warmed to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by developing solvent system A using thin layer chromatography to obtain the title compound 6f (0.19 g, yield: 69.9%).

MS m / z (ESI): 351.1 [M + 1].

    the fifth step     ^{(S) - N 7 - (} 3,4- difluorophenyl) -6-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5,6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 6

Compound 6f (190 mg, 542.36 μmol) was dissolved in 20 mL of tetrahydrofuran, compound 1e (121.66 mg, 813.54 μmol) was added, and 4 mL of a 1 M solution of bistrimethylsilyl lithium lithium tetrahydrofuran was added dropwise under an ice bath. The reaction was stirred for 2 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and concentrated under reduced pressure. The resulting residue was prepared by high-performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water , Acetonitrile) to obtain the title compound 6 (25 mg, yield: 10.6%).

MS m / z (ESI): 432.1 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 9.28 (s, 1H), 8.25 (d, 1H), 7.73 (s, 1H), 7.54-7.45 (m, 1H), 7.21-7.15 (m, 2H) , 5.27 (s, 1H), 4.95-4.92 (m, 1H), 4.86-4.80 (m, 2H), 4.28-4.22 (m, 2H), 1.50-1.45 (m, 3H), 1.20 (d, 3H) .

    Example 7     ^{(S) - N 5 - (} 3,4- difluorophenyl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6,7 Dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 7

    First step     ( S ) -5-Third-butyl 3-methyl 6-methyl-6,7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dicarboxylic acid ester 7b

In a carbon monoxide atmosphere, ( S ) -3-iodo-6-methyl-6,7-dihydropyrazolo [1,5- a ] pyrazine-5 ( 4H ) -carboxylic acid third butyl ester 7a (8.3g, 22.85mmol, prepared by the method disclosed in the patent application "WO2016113273A1"), palladium acetate (1.03g, 4.57mmol), 1,1'-bis (diphenylphosphine) ferrocene (2.53g, 4.57mmol ) And triethylamine (9.64 mL, 68.56 mmol) were dissolved in 150 mL of methanol, and the reaction was stirred at 55 ° C for 15 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system C to obtain the title compound 7b (6.3 g, yield: 93.34%).

    Second step     ( S ) -6-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester trifluoroacetate 7c

Compound 7b (6.3 g, 21.33 mmol) was dissolved in 20 mL of dichloromethane, trifluoroacetic acid (14.1 mL, 199.91 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 7c (14 g). The product was directly used in the next reaction without purification.

MS m / z (ESI): 196.1 [M + 1].

    third step     ( S ) -5-((3,4-difluorophenyl) aminomethylamidino) -6-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyridine Azine-3-carboxylic acid methyl ester 7e

The crude compound 7c (2 g, 3.23 mmol) and triethylamine (1.64 g, 16.17 mmol) were dissolved in 20 mL of dichloromethane and stirred for 10 minutes. Under ice-bath conditions, 1,2-difluoro-4-phenyl isocyanate (601.87 mg, 3.88 mmol, prepared by the well-known method " European Journal of Medicinal Chemistry, 2016 , 115 , 1-13") was added and reacted for 20 minutes. The reaction temperature was raised to room temperature, and the reaction was stirred for 20 minutes. The reaction solution was sequentially purified by silica gel column chromatography with eluent systems C and A to obtain the title compound 7e (1 g, yield: 88.27%).

MS m / z (ESI): 351.1 [M + 1].

    the fourth step     ( S ) -5-((3,4-difluorophenyl) aminomethylamidino) -6-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyridine Azine-3-carboxylic acid 7f

Compound 7e (500 mg, 1.43 mmol) and sodium hydroxide (285.45 mg, 7.14 mmol) were dissolved in 5 mL of a mixed solvent of methanol, tetrahydrofuran, and water (V: V: V = 2: 2: 1). The reaction was stirred at 40 ° C for 1 hour. The reaction was stirred at 35 ° C for 15 hours. The reaction solution was concentrated under reduced pressure, 10 mL of water was added, 6 M hydrochloric acid was added dropwise to the above solution to pH 2, and the filter cake was collected to obtain the crude title compound 7f (450 mg). The product was directly used in the next reaction without purification.

MS m / z (ESI): 337.4 [M + 1].

    the fifth step     ^{(S) - N 5 - (} 3,4- difluorophenyl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6,7 Dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 7

The crude compound 7f (80 mg, 237.89 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (67.16 mg, 285.47 μmol), N, N -diisopropylethylamine (122.98 mg, 951.55 μmol) were dissolved in 3 mL of N, N -dimethylformamide, reacted for 10 minutes, and compound 1e (53.36 mg, 356.83 μmol) was added. The reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography in developing system C. The obtained crude product was prepared by high-performance liquid phase (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound. 7 (70 mg, yield: 68.22%).

MS m / z (ESI): 432.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.09 (m, 1H), 7.49-7.47 (m, 1H), 7.16-7.13 (m, 2H), 5.32 (d, 1H), 5.01-4.99 (m, 1H ), 4.84-4.80 (m, 1H), 4.66 (d, 1H), 4.32-4.29 (m, 1H), 4.17 (d, 1H), 1.40 (d, 3H), 1.21 (d, 3H).

    Example 8     (S) - N ³ - (tert-butyl) - N ⁵ - (3,4- difluorophenyl) -6-methyl-6,7-dihydro-pyrazolo [1,5- a] pyridine Pyrazine-3,5 ( 4H ) -dimethylformamide 8

The crude compound 7f (150 mg, 446.04 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (157.41 mg, 669.06 μmol), N, N -diisopropylethylamine (230.58 mg, 1.78 mmol) was dissolved in 3 mL of N, N -dimethylformamide, and reacted for 10 minutes. A third butylamine (48.93 mg, 669.06) was added. μmol), and the reaction was stirred for 3 hours. The reaction solution was added with 30 mL of water, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, and the organic phases were concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography using developing system C, and the obtained crude product was prepared by high performance liquid phase (Waters -2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 8 (30 mg, yield: 17.18%).

MS m / z (ESI): 392.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.02 (s, 1H), 7.53-7.50 (m, 1H), 7.20-7.17 (m, 2H), 5.31 (d, 1H), 5.01-4.98 (m, 1H ), 4.68 (d, 1H), 4.33-4.29 (m, 1H), 4.18 (d, 1H), 1.46 (s, 9H), 1.23 (d, 3H).

    Example 9     ( R ) -N ^5- (3-cyano-4-fluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazolo [1 , 5- a ] pyrazine-3,5 ( 4H ) -dimethyl etheramine 9

    First step     5- (3-cyano-4-fluorophenyl) aminomethylfluorenyl) -4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester 9a

Compound 2c (50 mg, 275.95 μmol), compound 3d (38.56 mg, 275.95 μmol) and triethylamine (279.23 mg, 2.76 mmol) were dissolved in 10 mL of tetrahydrofuran, and at 0 ° C, bis (trichloromethyl) carbonate was added (32.76 mg, 110.38 μmol), slowly raised to room temperature, and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin-layer chromatography to obtain the title compound 9a (20 mg, yield: 21.1%).

MS m / z (ESI): 344.2 [M + 1].

    Second step     5- (3-cyano-4-fluorophenyl) aminomethylfluorenyl) -4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid 9b

Compound 9a (100 mg, 291.28 μmol) was dissolved in 10 mL of methanol, lithium hydroxide (139.52 mg, 5.83 mmol) and 2 mL of water were added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, 10 mL of water was added, and 6 M hydrochloric acid was added dropwise to the above solution to pH 2. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 9b (95.91 mg). The product was directly used in the next reaction without purification.

MS m / z (ESI): 330.1 [M + 1].

    third step     ( R ) -N ^5- (3-cyano-4-fluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazolo [1 , 5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 9

The crude compound 9b (95.91 mg, 291.28 μmol) was dissolved in 10 mL of N , N -dimethylformamide, compound 1e (34.34 mg, 303.69 μmol), and triethylamine (92.19 mg, 911.06 μmol) were added at 0 ° C. O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (85.74 mg, 364.43 μmol) was added and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 9 (5 mg, yield: 3.88%).

MS m / z (ESI): 425.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.07 (s, 1H), 7.87-7.85 (m, 2H), 7.32-7.27 (m, 1H), 5.06 (s, 2H), 4.86-4.84 (m, 1H ), 4.29-4.27 (m, 2H), 4.06-4.03 (m, 2H), 1.42 (d, 3H).

    Example 10     ( S ) -N ^3- (third butyl) -6-methyl- N ⁵ -((3,4,5-trifluorophenyl) -6,7-dihydropyrazolo [1,5- a ) Pyrazine-3,5 ( 4H ) -dimethylformamide 10

    First step     ( S ) -6-methyl-5-((3,4,5-trifluorophenyl) aminomethylfluorenyl) -4,5,6,7-tetrahydropyrazolo [1,5- a ] Pyrazine-3-carboxylic acid methyl ester 10a

Compound 1a (1.17 g, 7.92 mmol) and compound 7c (1.63 g, 5.28 mmol) were dissolved in 30 mL of dichloromethane, and triethylamine (2.14 g, 21.22 mmol) and bis (trichloromethyl) carbonate were added. (626.8 mg, 2.11 mmol) and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by developing solvent system A using thin-layer chromatography to obtain the title compound 10a (730 mg, yield: 37.5%).

MS m / z (ESI): 369.1 [M + 1].

    Second step     ( S ) -6-methyl-5-((3,4,5-trifluorophenyl) aminomethylfluorenyl) -4,5,6,7-tetrahydropyrazolo [1,5- a ] Pyrazine-3-carboxylic acid 10b

Compound 10a (730 mg, 1.98 mmol) and sodium hydroxide (396.45 mg, 9.91 mmol) were dissolved in 10 mL of a mixed solvent of methanol, tetrahydrofuran, and water (V: V: V = 2: 2: 1), and the reaction was stirred at 40 ° C. After 1 hour, the reaction was stirred at 35 ° C for 15 hours. The reaction solution was concentrated under reduced pressure, 10 mL of water was added, 6 M hydrochloric acid was added dropwise to the above solution to pH 2, and the filter cake was collected to obtain a crude title compound 10b (702 mg, 1.98 mmol). The product was directly used in the next step without purification. reaction.

MS m / z (ESI): 355.4 [M + 1].

    third step     ( S ) -N ^3- (third butyl) -6-methyl- N ^5- (3,4,5-trifluorophenyl) -6,7-dihydropyrazolo [1,5- a ] Pyrazine-3,5 (4 H ) -dimethylformamide 10

The crude compound 10b (85 mg, 239.92 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (67.74 mg, 287.91 μmol) and N, N -diisopropylethylamine (129.21 mg, 719.76 μmol) were dissolved in 3 mL of N, N -dimethylformamide, reacted for 10 minutes, and tert-butylamine (35.09 mg, 479.84) was added. μmol), and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography in developing system C. The obtained crude product was prepared by high-performance liquid phase (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound. 10 (50 mg, yield: 50.90%).

MS m / z (ESI): 410.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.00 (s, 1H), 7.30-7.28 (m, 2H), 5.31 (d, 1H), 4.98-4.96 (m, 1H), 4.69 (d, 1H), 4.31-4.27 (m, 1H), 4.17 (d, 1H), 1.44 (s, 9H), 1.22 (d, 3H).

    Example 11     ^{(S) - N 7 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7- (8 H) - dimethyl Amides 11

    First step     ( S ) -7-((3-cyano-4-fluorophenyl) aminomethylamidino) -6-methyl-5,6,7,8-tetrahydroimidazo [1,5- a ] Pyrazine-1-carboxylic acid methyl ester 11a

The crude compound 6e (9.2 g, 47.13 mmol) was dissolved in 50 mL of tetrahydrofuran, and compound 3d (6.5 g, 47.13 mmol) and triethylamine (5.82 g, 56.55 mmol) were added. At 0 ° C, bis (trichloromethyl carbonate) was added. Alkyl ester (4.9 g, 16.49 mmol), slowly raised to room temperature, and stirred for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 11a (16.84 g). The product was used in the next reaction without purification.

MS m / z (ESI): 358.1 [M + 1].

    Second step     ( S ) -7-((3-cyano-4-fluorophenyl) aminomethylamidino) -6-methyl-5,6,7,8-tetrahydroimidazo [1,5- a ] Pyrazine-1-carboxylic acid 11b

The crude compound 11a (16.84 g, 47.13 mmol) was dissolved in 50 mL of methanol, and a pre-formed sodium hydroxide solution (sodium hydroxide (12 g, 282.76 mmol) in 60 mL of water) was added dropwise at 0 ° C, and the mixture was slowly raised to room Warm and stir for 4 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The obtained residue was washed with dichloromethane, the aqueous phase was adjusted to pH 1 to 2 with 6 M hydrochloric acid, and concentrated under reduced pressure to obtain the crude title compound 11b (16.18 g). The product was directly purified without purification. Used for the next reaction.

MS m / z (ESI): 344.1 [M + 1].

    third step     ^{(S) - N 7 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7- (8 H) - dimethyl Amides 11

The crude compound 11b (13 g, 37.87 mmol), compound 1e (7.4 g, 49.23 mmol) and triethylamine (11.6 g, 113.6 mmol) were dissolved in 200 mL of N , N -dimethylformamide, and cooled to 0 ° C Add O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (29g, 75.73mmol), and slowly raise to room temperature, The reaction was stirred for 12 hours. The reaction solution was added with 300 mL of ethyl acetate, washed with water (100 mL × 3), and the organic phase was concentrated under reduced pressure. The obtained residue was prepared by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile), The title compound 11 was obtained (1.8 g, yield: 10.8%).

MS m / z (ESI): 439.0 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.87-7.85 (m, 1H), 7.73-7.70 (m, 2H), 7.69-7.27 (m, 1H), 5.30-5.26 (d, 1H), 4.83-4.82 (m, 1H), 4.85-4.72 (m, 2H), 4.23-4.21 (m, 2H), 1.43 (d, 3H), 1.20 (d, 3H).

    Example 12     (S) - N ¹ - (tert-butyl) - N ⁷ - (3,4- difluorophenyl) -6-methyl-5,6-dihydro-imidazo [1,5- a] pyrazine -1,7- (8 H ) -dimethylformamide 12

Compound 6f (2.11 g, 6.27 mmol) was dissolved in 15 mL of tetrahydrofuran, and tert-butylamine (600 mg, 8.16 mmol) was added. At 0 ° C, a 1 M solution of bistrimethylsilyl lithium lithium tetrahydrofuran (5 g, 31.37 mmol), and the reaction was stirred for 2 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 12 (120 mg, yield: 4.9%).

MS m / z (ESI): 392.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.65 (s, 1H), 7.50-7.49 (m, 1H), 7.19-7.17 (m, 2H), 5.25-5.21 (d, 1H), 4.92-4.90 (m , 1H), 4.77-4.73 (m, 1H), 4.20-4.18 (m, 2H), 1.46 (s, 9H), 1.19-1.17 (d, 3H).

    Example 13     (S) -6- methyl - N ¹ - (3- methyl-oxetan-3-yl) - N ⁷ - (3,4,5- trifluorophenyl) -5,6-dihydro imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 13

    First step     ( S ) -6-methyl-7-((3,4,5-trifluorophenyl) aminomethylamidino) -5,6,7,8-tetrahydroimidazo [1,5- a ] Pyrazine-1-carboxylic acid methyl ester 13a

The crude compound 6e (140.00 mg, 452.72 μmol) was dissolved in 15 mL of tetrahydrofuran, and compound 1a (99.89 mg, 679.08 μmol) and triethylamine (183.24 mg, 1.81 mmol) were added. At 0 ° C, bis (trichloromethyl carbonate) was added. Ester) (53.74 mg, 181.09 μmol), slowly raised to room temperature, and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by developing solvent system A using thin layer chromatography to obtain the title compound 13a (88 mg, yield: 52.8%).

MS m / z (ESI): 369.1 [M + 1].

    Second step     ( S ) -6-methyl-7-((3,4,5-trifluorophenyl) aminomethylamidino) -5,6,7,8-tetrahydroimidazo [1,5- a ] Pyrazine-1-carboxylic acid 13b

Compound 13a (75 mg, 203.63 mol) was dissolved in 10 mL of methanol, sodium hydroxide (81.45 mg, 2.04 mmol) and 2 mL of water were added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 13b (75 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 355.0 [M + 1].

    third step     (S) -6- methyl - N ¹ - (3- methyl-oxetan-3-yl) - N ⁷ - (3,4,5- trifluorophenyl) -5,6-dihydro imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 13

The crude compound 13b (75 mg, 211.69 μmol) was dissolved in 10 mL of N, N -dimethylformamide, and 3-methyl-3-aminooxetane 13c (27.66 mg, 317.53 μmol, Shanghai Book Asia Medical Technology Co., Ltd.) and triethylamine (64.26mg, 635.07 μmol), at 0 ° C, O- (7-azabenzotriazol-1-yl) -N , N , N ' , N'- Tetramethylurea hexafluorophosphate (99.61 mg, 423.38 μmol) was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 13 (16 mg, yield: 17.9%).

MS m / z (ESI): 424.0 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.87 (s, 1H), 8.36 (s, 1H), 7.68 (s, 1H), 7.33-7.27 (m, 2H), 5.27-5.20 (m, 1H) , 4.92 (d, 2H), 4.73 (d, 2H), 4.78-4.73 (m, 1H), 4.52 (d, 2H), 4.26-4.20 (m, 2H), 1.73 (s, 3H), 1.20 (d , 3H).

    Example 14     (S) -6- methyl - N ³ - (3- methyl-oxetan-3-yl) - N ⁵ - (3,4,5- trifluorophenyl) -6,7-dihydro- Pyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 14

The crude compound 10b (100 mg, 282.26 μmol), compound 13c (36.89 mg, 423.39 μmol), and N, N -diisopropylethylamine (42.84 mg, 423.39 μmol) were dissolved in 10 mL of N, N -dimethylformamidine To the amine, add O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (79.69 mg, 338.71 μmol), and stir the reaction 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography. The obtained crude product was purified by high performance liquid phase (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound. 14 (80 mg, yield: 66.94%).

MS m / z (ESI): 424.5 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.89 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.33-7.17 (m, 2H), 5.33 (d, 1H), 5.00 -4.98 (m, 1H), 4.88 (d, 2H), 4.71 (d, 1H), 4.52 (d, 2H), 4.34-4.31 (m, 1H), 4.21-4.18 (m, 1H), 1.72 (s 3H), 1.25 (d, 3H).

    Example 15     ^{(S) - N 5 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6, 7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 15

    First step     ( S ) -5- (Third-butoxycarbonyl) -6-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid 15a

Compound 7b (525 mg, 1.78 mmol) and lithium hydroxide monohydrate (373 mg, 8.9 mmol) were dissolved in 10 mL of a mixed solvent of methanol, tetrahydrofuran, and water (V: V: V = 2: 2: 1), and the reaction was stirred for 16 hours. . The reaction solution was concentrated under reduced pressure, 10 mL of water was added, 6 M hydrochloric acid was added dropwise to the above solution to pH 2, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 15a (500 mg). The product was used directly in the next reaction without purification.

MS m / z (ESI): 282.2 [M + 1].

    Second step     ( S ) -6-methyl-3-((( R ) -1,1,1-trifluoroprop-2-yl) aminomethylmethyl) -6,7-dihydropyrazolo [1, 5- a ] pyrazine-5 ( 4H ) -carboxylic acid third butyl ester 15b

The crude compound 15a (500 mg, 1.78 mmol), compound 1e (479 mg, 3.2 mmol) and N, N -diisopropylethylamine (360 mg, 3.56 mmol) were dissolved in 20 mL of N, N -dimethylformamide. O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (628 mg, 2.67 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography to obtain the title compound 15b (600 mg, yield: 89.56%).

MS m / z (ESI): 377.2 [M + 1]

    third step     ( S ) -6-methyl- N -(( R ) -1,1,1-trifluoroprop-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5- a ] Piperazine-3-carboxamide trifluoroacetate 15c

Compound 15b (500 mg, 1.33 mmol) was dissolved in 20 mL of dichloromethane, trifluoroacetic acid (758 mg, 6.65 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 15c (500 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 277.2 [M + 1].

    the fourth step     ^{(S) - N 5 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6, 7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 15

The crude compound 15c (50 mg, 128 μmol) was dissolved in 10 mL of tetrahydrofuran, compound 3d (26 mg, 192 μmol) and triethylamine (26 mg, 256 μmol) were added, and at 0 ° C, bis (trichloromethyl) carbonate (13 mg, 45 μmol), warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography. The obtained crude product was purified by high performance liquid phase (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound. 15 (20 mg, yield: 35.61%).

MS m / z (ESI): 439.2 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 7.87-7.86 (m, 1H), 7.83 (s, 1H), 7.70-7.68 (m, 1H), 7.42 (s, 1H), 7.20-7.16 (m, 1H) , 6.01 (d, 1H), 5.34-5.23 (m, 2H), 4.2-4.89 (m, 1H), 4.84 (d, 1H), 4.38-4.34 (m, 1H), 4.25 (d, 1H), 1.49 (d, 3H), 1.27 (d, 3H).

    Example 16     ^{(S) - N 5 - (} 2,6- difluoro-4-yl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6 , 7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 16

    First step         2,6-difluoro-4-pyridine isocyanate 16b    

2,6-Difluoro-4-aminopyridine 16a (500 mg, 3.84 mmol) and N, N -diisopropylethylamine (583 mg, 5.76 mmol) were dissolved in 25 mL of toluene, and bis (trichloromethyl carbonate) was added. ) Ester (297 mg, 4.61 mmol) and stirred at 110 ° C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 16b (1 g), which was used in the next reaction without purification.

    Second step         (S) -N5- (2,6-difluoropyridin-4-yl) -6-methyl-N3-((R) -1,1,1- trifluoropropan-2-yl) -6,7-dihydropyrazolo [1, 5-a] pyrazine-3,5 (4H) -dicarboxamide     ^{(S) - N 5 - (} 2,6- difluoro-4-yl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6 , 7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 16

The crude compound 15c (100 mg, 256 μmol) was dissolved in 10 mL of dichloromethane, the crude compound 16b (80 mg) and triethylamine (78 mg, 769 μmol) were added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system A using thin layer chromatography. The obtained crude product was purified by high performance liquid phase (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound. 16 (20 mg, yield: 18.05%).

MS m / z (ESI): 433.5 [M + 1]

¹ H NMR (400MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 7.10 (s, 1H), 6.05 (d, 1H), 5.34 (d, 1H ), 5.27-5.25 (m, 1H), 4.90-4.88 (m, 1H), 4.84 (d, 1H), 4.38-4.34 (m, 1H), 4.28 (d, 1H), 1.48 (d, 3H), 1.29 (d, 3H).

    Example 17     ( R ) -N ^5- (3,4,5-trifluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydro- [1,2 , 3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 17

    First step     (5-((3,4,5-trifluorophenyl) aminomethylfluorenyl) -4,5,6,7-tetrahydro- [1,2,3] triazolo [1,5- a ] Pyrazin-3-yl) methyl acetate 17b

Acetate (4,5,6,7-tetrahydro- [1,2,3] triazolo [1,5- a ] pyrazin-3-yl) methyl ester 17a (350 mg, 2 mmol) (using a well-known (Prepared by " Journal of Medicine Chemistry , 2014, 57 (9), 3687-3706") and diisopropylethylamine (790 mg, 6 mmol) were dissolved in 20 mL of dichloromethane and stirred for 10 minutes. In an ice bath, 1,2,3-trifluoro-5-benzene isocyanate 17f (400 mg, 2 mmol, Braunwell Technology Co., Ltd.) was added, the reaction was carried out for 20 minutes, the temperature was raised to room temperature, and the reaction was stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent systems C and A to obtain the title compound 17b (190 mg, yield: 25.24%).

MS m / z (ESI): 370.1 [M + 1].

    Second step     3- (hydroxymethyl) - N - (3,4,5- trifluorophenyl) -6,7-dihydro - [1,2,3] triazolo [1,5- a] pyrazin - 5 (4 H ) -formamidine 17c

Compound 17b (190 mg, 0.51 mmol) was dissolved in 5 mL of a mixed solvent of methanol and water (V: V = 4: 1), lithium hydroxide (108 mg, 2.57 mmol) was added, and the mixture was stirred for 2 hours. 20 mL of water was added to the reaction solution, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 17c (65 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 328.1 [M + 1].

    third step     3-methylfluorenyl- N- (3,4,5-trifluorophenyl) -6,7-dihydro- [1,2,3] triazolo [1,5- a ] pyrazine-5 ( 4 H ) -formamidine 17d

The crude compound 17c (65 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane, and pyridinium chlorochromate (138 mg, 0.64 mmol) and silica gel (140 mg, 100-200 mesh) were added, followed by stirring for 3 hours. Filtration and concentration under reduced pressure, the obtained residue was purified by thin layer chromatography with developing system A to obtain the title compound 17d (30 mg, yield: 43.12%).

MS m / z (ESI): 326.1 [M + 1].

    the fourth step     (5-((3,4,5-trifluorophenyl) aminomethylfluorenyl) -4,5,6,7-tetrahydro- [1,2,3] triazolo [1,5- a ] Pyrazine-3-carboxylic acid 17e

Compound 17d (30 mg, 0.1 mmol) was dissolved in 5 mL of a mixed solvent of acetonitrile and water (V: V = 3: 2), aminosulfonic acid (20 mg, 0.2 mmol) was added, stirred for 10 minutes, and sodium chlorite ( 20 mg, 0.2 mmol), and stirred for 2 hours. 0.5 mL of saturated sodium sulfite solution and 10 mL of water were added sequentially, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude compound 17e (25 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 342.1 [M + 1].

    the fifth step     ( R ) -N ^5- (3,4,5-trifluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydro- [1,2 , 3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 17

The crude compound 17e (25 mg, 73.2 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (35 mg, 146.5 μmol), N, N -diisopropylethylamine (47mg, 366.2μmol) was dissolved in 3mL N, N -dimethylformamide, and reacted for 10 minutes. Compound 1e (33mg, 220μmol) was added, and the reaction was stirred for 3 minutes. hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography in developing system C to obtain the title compound 17 (5 mg, yield: 15.6%).

MS m / z (ESI): 437.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.29-7.27 (m, 2H), 4.60 (br, 1H), 4.54 (t, 2H), 4.04 (t, 2H), 2.80 (s, 2H), 1.45 ( d, 3H).

    Example 18     (S) -6- methyl - N ⁷ - (3,4,5- ^{trifluorophenyl) - N 1 - ((R} ) -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 18

Using the synthetic route of Example 6, the raw material compound 2d in the fourth step was replaced with the raw material compound 1a to obtain the title compound 18 (2.8 mg).

MS m / z (ESI): 450.2 [M + 1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.86 (s, 1H), 8.33 (d, 1H), 7.73 (s, 1H), 7.33-7.28 (m, 2H), 5.29 (d, 1H), 4.92 (d, 1H), 4.85-4.76 (m, 2H), 4.28-4.22 (m, 2H), 1.44 (d, 3H), 1.34 (d, 3H).

    Example 19     N ³ - (3- methyl-oxetan-3-yl) - N ⁵ - (3,4,5- trifluorophenyl) -6,7-dihydro-pyrazolo [1,5- a ] Pyrazine-3,5 ( 4H ) -dimethylformamide 19

    First step     5-((3,4,5-trifluorophenyl) aminomethylamidino) -4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid 19a

Compound 4a (3 g, 8.74 mmol) was dissolved in 20 mL of methanol and 20 mL of tetrahydrofuran, sodium hydroxide (3.39 g, 84.67 mmol) and 10 mL of water were added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, 20 mL of water was added, and 6 M hydrochloric acid was added dropwise to the above solution to pH 2. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 19a (100 mg). The product was directly used in the next reaction without purification.

MS m / z (ESI): 341.1 [M + 1].

    Second step     (N ³ - (3- methyl-oxetan-3-yl) - N ⁵ - (3,4,5- trifluorophenyl) -6,7-dihydro-pyrazolo [1,5- a ) Pyrazine-3,5 ( 4H ) -dimethylformamide 19

The crude compound 19a (100 mg, 293.90 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (69.14 mg, 293.90 μmol) and triethylamine (29.74 mg, 293.90 μmol) were dissolved in 5 mL of N, N -dimethylformamide, reacted for 10 minutes, compound 13c (108.96 mg, 881.69 μmol) was added, and the reaction was stirred for 3 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (20 mL × 2). The organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system C. The obtained crude product was prepared by high performance liquid phase (Waters-2767 , Elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 19 (20 mg, yield: 16.62%).

MS m / z (ESI): 410.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.95 (s, 1H), 7.30-7.26 (m, 2H), 5.01 (s, 2H), 4.88 (d, 2H), 4.50 (d, 2H), 4.28- 4.25 (m, 2H), 4.04-4.01 (m, 2H), 1.71 (s, 3H).

    Example 20     ^{(S) - N 7 - (} 2,6- difluoro-4-yl) -6-methyl-N ¹ - ((R) -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7- (8 H) - dimethyl Amides 20

Using the synthetic route of Example 6, the raw material compound 2d in the fourth step was replaced with the raw material 2,6-difluoro-4-pyridylamine (Shanghai Biode Medical Technology Co., Ltd.) to obtain the title compound 20 (10 mg).

MS m / z (ESI): 433.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.69 (s, 1H), 7.11-7.09 (d, 2H), 5.33-5.29 (m, 1H), 4.97-4.77 (m, 1H), 4.56-4.41 (m , 1H), 4.27-4.21 (m, 1H), 3.80-3.45 (m, 2H), 1.38 (d, 3H), 1.15 (d, 3H).

    Example 21     ( R ) -N ^3- (second butyl) -N ^5- (3,4,5-trifluorophenyl) -6,7-dihydropyrazolo [1,5- a ] pyrazine-3 , 5 (4 H ) -dimethylformamide 21

Compound 19a (96 mg, 282.26 μmol) was dissolved in 10 mL of N, N -dimethylformamide, and ( R ) -butan-2-amine (20.64 mg, 282.26 μmol, Tishini (Shanghai) Chemical Industry Development) Co., Ltd.) and triethylamine (85.69mg, 846.78μmol), at 0 ° C, O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethyl Urea hexafluorophosphate (79.69 mg, 338.71 μmol) was warmed to room temperature and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 21 (10 mg, yield: 8.96%).

MS m / z (ESI): 396.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.00 (s, IH), 7.30-7.26 (m, 2H), 5.04 (s, 2H), 4.27-4.25 (m, 2H), 4.04-4.00 (m, 3H ), 1.60-1.56 (m, 2H), 1.22 (d, 3H), 0.96 (t, 3H).

    Example 22     ^{(S) - N 3 - (} (R - second - butyl)) - N ⁵ - (3,4- difluorophenyl) -6-methyl-6,7-dihydro-pyrazolo [1, 5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 22

Using the synthetic route of Example 7, the starting compound 1e was replaced with the starting compound ( R ) -but-2-amine to obtain the title compound 22 (20 mg).

MS m / z (ESI): 392.1 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.53-7.50 (m, 1H), 7.23 (s, 1H), 7.06-7.02 (m, 2H), 5.62 (d, 1H), 5.23 (d, 2H), 4.82 (d, 1H), 4.31-4.28 (m, 1H), 4.28 (d, 1H), 4.07 (d, 1H), 1.60-1.57 (m, 2H), 1.22 (d, 6H ), 0.99 (t, 3H).

    Example 23     ^{(S) - N 5 - (} 3,4- difluorophenyl) - N ³ - isopropyl-6-methyl-6,7-dihydro-pyrazolo [1,5- a] pyrazin-3 , 5 (4 H ) -dimethylformamide 23

Using the synthetic route of Example 7, the raw material compound 1e in the fifth step was replaced with the isopropylamine raw material to obtain the title compound 23 (25 mg).

MS m / z (ESI): 378.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.00 (s, 1H), 7.50-7.45 (m, 1H), 7.18-7.14 (m, 2H), 5.35-5.30 (m, 1H), 4.99-4.95 (m , 1H), 4.69-4.62 (m, 1H), 4.32-4.22 (m, 1H), 4.22-4.12 (m, 2H), 1.23-1.16 (m, 9H).

    Example 24     ( S ) -N ^5- (3,4-difluorophenyl) -N ^3- (1-methoxy-2-methylpropane-2-yl) -6-methyl-6,7-dihydro Pyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 24

Using the synthetic route of Example 7, the raw material compound 1e in the fifth step was replaced with the raw material 1-methoxy-2-methylpropane-2-amine (Sinochemical Shanghai Chemical Reagent) to obtain the title compound 24 (15 mg).

MS m / z (ESI): 422.1 [M + 1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.56-7.51 (m, 1H), 7.15-7.09 (m, 3H), 6.13 (s, 1H), 5.26-5.22 (m, 1H) , 5.20 (d, 1H), 4.85 (d, 1H), 4.36-4.32 (m, 1H), 4.22 (d, 1H), 3.47 (s, 3H), 3.44 (s, 2H), 1.50 (s, 6H ), 1.25 (d, 3H).

    Example 25     ^{(S) - N 5 - (} 3- chloro-2-fluoro-4-yl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) - 6,7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 25

Using the synthetic route of Example 3, the raw material compound 3a in the first step was replaced with the raw material compound 7b, and the raw material compound 3d in the third step was replaced with the raw material compound 2-chloro-3-fluoropyridine-4-amine Company) to give the title compound 25 (20 mg).

MS m / z (ESI): 449.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.09 (s, 1H), 8.04 (d, 1H), 7.87 (t, 1H), 5.42 (d, 1H), 5.02 (t, 1H), 4.84 (t, 1H), 4.77 (d, 1H), 4.38-4.35 (m, 1H), 4.21 (d, 1H), 1.41 (d, 3H), 1.29 (d, 3H).

    Example 26     (R) - N ¹ - (sec-butyl) - N ⁷ - (3,4,5- trifluorophenyl) -5,6-dihydro-imidazo [1,5- a] pyrazine-1, 7 (8 H ) -dimethylformamide 26

Using the synthetic route of Example 1, the starting compound 1e in the third step was replaced with the starting compound ( R ) -but-2-amine to obtain the title compound 26 (4 mg).

MS m / z (ESI): 396.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.68 (s, 1H), 7.31-7.29 (m, 2H), 5.05 (s, 2H), 4.23-4.21 (m, 2H), 4.01-3.95 (m, 3H ), 1.61-1.58 (m, 2H), 1.24-1.23 (m, 3H), 0.96 (t, 3H).

    Example 27     (S) - N ³ - (tetrahydrofuran-3-yl) - N ⁵ - (3,4,5- trifluorophenyl) -6,7-dihydro-pyrazolo [1,5- a] pyrazin - 3,5 ( 4H ) -dimethylformamide 27

The crude compound 19a (100 mg, 293.90 μmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (138.29 mg, 587.79 μmol) and triethylamine (148.70 mg, 1.47 mmol) were dissolved in 3 mL of N, N -dimethylformamide, reacted for 10 minutes, and ( S ) -tetrahydrofuran-3-amine hydrochloride 27a (72.64 mg) was added. , 587.79 μmol, Shanghai Beide Pharmaceutical Technology Co., Ltd.), and stirred for 3 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, and the organic phases were concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography using developing system C, and the obtained crude product was prepared by high-performance liquid phase -2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 27 (20 mg, yield: 16.62%).

MS m / z (ESI): 410.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.02 (s, 1H), 7.30-7.26 (m, 2H), 5.03 (s, 2H), 4.56-4.55 (m, 1H), 4.27-4.25 (m, 2H ), 4.04-3.95 (m, 4H), 3.85-3.84 (m, 1H), 3.72-3.71 (m, 1H), 2.32-2.27 (m, 1H), 2.02-1.96 (m, 1H).

    Example 28     ^{(S) - N 5 - (} 3,4- difluorophenyl) - N ³ - (1- hydroxy-2-methylpropan-2-yl) -6-methyl-6,7-dihydro-pyrazolo Benzo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 28

Using the synthetic route of Example 7, the raw material compound 1e in the fifth step was replaced with the raw material 2-amino-2-methylpropane-1-ol (Shaoyuan Chemical Reagent Co., Ltd.) to obtain the title compound 28 (10 mg).

MS m / z (ESI): 408.1 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.57-7.52 (m, 1H), 7.16-7.10 (m, 3H), 5.94 (s, 1H), 5.25-5.23 (m, 1H) , 5.22 (d, 1H), 4.83 (d, 1H), 4.59-4.58 (m, 1H), 4.37-4.32 (m, 1H), 4.21 (d, 1H), 3.77-3.69 (m, 2H), 1.45 (s, 6H), 1.25 (d, 3H).

    Example 29     ( R ) -N ^5- (3,4-difluorophenyl) -2-methyl- N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydropyrazole Benzo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 29

    First step     2- (benzyl ((3-methyl- 1H -pyrazol-5-yl) methyl) amino) ethan-1-ol 29b

Dissolve 3-methyl- 1H -pyrazole-5-carboxaldehyde 29a (5.1g, 45.41mmol, Shanghai Biod Medical Technology Co., Ltd.) in 100mL of dichloromethane, and add 2- (benzylamino) ethanol (6.87 g, 45.41 mmol), and the reaction was stirred for 1 hour. Sodium borohydride acetate (9.62 g, 45.41 mmol) was added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using eluent systems C and A to obtain the title compound 29b (11 g, yield: 98.75%).

MS m / z (ESI): 246.1 [M + 1].

    Second step     N -benzyl-2-chloro- N -((3-methyl- 1H -pyrazol-5-yl) methyl) ethyl-1-amine 29c

Compound 29b (11 g, 44.84 mmol) was dissolved in 200 mL of dichloromethane, cooled to 0 ° C, dichloromethylene dichloride (16.00 g, 134.52 mmol) was added dropwise, and reacted at 40 ° C for 16 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain the crude title compound 29c (11.8 g). The product was used in the next reaction without purification.

MS m / z (ESI): 264.1 [M + 1].

    third step     5-benzyl-2-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine 29d

The crude compound 29c (11.8 g, 44.74 mmol) was dissolved in 200 mL of acetonitrile, cooled to 0 ° C, and triethylamine (46 g, 447.37 mmol) was added, and reacted at 80 ° C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 100 mL of water was added, and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, and the organic phases were concentrated under reduced pressure to obtain the crude title compound 29d (10.17 g). The product was used in the next reaction without purification.

MS m / z (ESI): 228.1 [M + 1].

    the fourth step     5-benzyl-3-bromo-2-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine 29e

The crude compound 29d (228 mg, 1.0 mmol) was dissolved in 10 mL of acetonitrile. At 0 ° C., N -bromosuccinimide (180 mg, 1.0 mmol) was added, the temperature was slowly raised to room temperature, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography in developing system A to obtain the title compound 29e (185 mg, yield: 60.6%).

MS m / z (ESI): 306.1 [M + 1].

    Second step     5-Benzyl-2-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester 29f

In a carbon monoxide atmosphere, biscarbonyl octacarbonyl (226 mg, 662 μmol) and potassium carbonate (457 mg, 3.31 mmol) were added to 10 mL of methanol, and the reaction was stirred at 60 ° C. for 45 minutes. Compound 29e (100 mg, 327 μmol) and methyl 2-chloroacetate (215 mg, 1.98 mmol) were further added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, 100 mL of ethyl acetate was added, filtered, washed with 100 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography using developing system A to obtain the title compound 29f (60 mg, yield : 64.39%).

MS m / z (ESI): 286.2 [M + 1].

    third step     2-methyl-4,5,6,7-tetrahydropyrazolo [1,5- a ] pyrazine-3-carboxylic acid methyl ester 29g

Under a hydrogen atmosphere, compound 29f (60 mg, 210.28 µmol) was dissolved in 10 mL of methanol, and a palladium-carbon hydrogenation catalyst (wet) (22.38 mg, 210.28 µmol) was added, and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 29 g (30 mg) of the crude title compound. The product was used in the next reaction without purification.

MS m / z (ESI): 196.2 [M + 1].

Using the synthetic route in Example 2, the raw material compound 2c in the third step was replaced with the crude material compound 29g to obtain the title compound 29 (10 mg).

MS m / z (ESI): 432.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.49-7.44 (m, 1H), 7.19-7.14 (m, 2H), 4.96 (s, 2H), 4.87-4.83 (m, 1H), 4.20-4.17 (m , 2H), 4.01-3.96 (m, 2H), 2.40 (s, 3H), 1.42-1.39 (m, 3H).

    Example 30     N ¹ -((3-methyloxetane-3-yl) -N ^7- (3,4,5-trifluorophenyl) -5,6-dihydroimidazo [1,5- a ] Pyrazine-1,7 (8 H ) -dimethylformamide 30

Using the synthetic route of Example 1, the raw material compound 1e in the fifth step was replaced with the raw material compound 13c to obtain the title compound 30 (5 mg).

MS m / z (ESI): 410.0 [M + 1]

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.39 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.31-7.26 (m, 2H), 5.02 (s, 2H), 4.54 -4.51 (d, 2H), 4.23-4.20 (m, 2H), 3.96-3.93 (m, 2H), 3.57-3.53 (m, 2H), 1.72 (s, 3H).

    Example 31     ( R ) -N ^5- (3,4-difluorophenyl) -N ^3- (1,1,1-trifluoroprop-2-yl) -6,7-dihydro- [1,2,3 ] Triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 31

Using the synthetic route of Example 17, the first step starting compound 17f was replaced with the starting compound 7d to obtain the title compound 31 (20 mg).

MS m / z (ESI): 419.1 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 8.11 (s, 1H), 8.09 (s, 1H), 7.56-7.52 (m, 1H), 7.13-7.08 (m, 1H), 7.06 (br, 1H), 5.35 -5.32 (m, 1H), 4.99 (s, 1H), 4.94 (s, 1H), 4.68 (s, 2H), 2.26 (t, 2H), 1.42 (d, 3H).

    Example 32     ^{(R) - N 7 - (} 2,6- difluoro-4-yl) - N ¹ - (1,1,1- trifluoro-2-yl) -5,6-dihydro-imidazo [1 , 5- a] pyrazine -1,7 (8 H) - dimethyl Amides 32

Using the synthetic route of Example 16, the starting compound 15c in the second step was replaced with the starting compound 3c to obtain the title compound 32 (25 mg).

MS m / z (ESI): 419.1 [M + 1]

¹ H NMR (400MHz, DMSO- d ₆ ) δ 8.79 (s, 1H), 8.33 (s, 1H), 7.70 (s, 1H), 7.10 (s, 2H), 5.08 (s, 2H), 4.84-4.80 (m, 1H), 4.26-4.23 (m, 2H), 3.99-3.96 (m, 2H), 1.44 (d, 3H).

    Example 33     (S) -6- methyl - N ⁵ - (3,4,5- ^{trifluorophenyl) - N 3 - ((R} ) -1,1,1- trifluoro-2-yl) -6, 7-dihydropyrazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 33

Using the synthetic route of Example 7, substituting the starting compound 7d for the third step with compound 17f, the title compound 33 (20 mg) was obtained.

MS m / z (ESI): 450.0 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.09 (s, 1H), 7.30-7.27 (m, 2H), 5.36 (d, 1H), 4.98-4.95 (m, 1H), 4.83-4.80 (m, 1H ), 4.70 (d, 1H), 4.31-4.27 (m, 1H), 4.20 (d, 1H), 1.41 (d, 3H), 1.22 (d, 3H).

    Example 34     ^{(S) - N 5 - (} 3,4- difluorophenyl) -6-methyl ^{- N 3 - ((S)} - tetrahydrofuran-3-yl) -6,7-dihydro-pyrazolo [1, 5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 34

The crude compound 7f (150 mg, 446.04 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (157.41 mg, 669.06 μmol), N , N -diisopropylethylamine (230.58 mg, 1.78 mmol) were dissolved in 3 mL of N, N -dimethylformamide, reacted for 10 minutes, and compound 27a (82.3 mg, 669.06 μmol) was added. The reaction was stirred for 3 hours. The reaction solution was added with 30 mL of water, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system C. The obtained crude product was prepared by high-performance liquid phase (Waters-2767 , Elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 34 (30 mg, yield: 16.54%).

MS m / z (ESI): 406.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.05 (s, 1H), 7.52-7.47 (m, 1H), 7.20-7.17 (m, 2H), 5.33 (d, 1H), 5.00-4.99 (m, 1H ), 4.70 (d, 1H), 4.56-4.54 (m, 1H), 4.34-4.32 (m, 1H), 4.21-4.20 (m, 1H), 4.04-3.95 (m, 2H), 3.85-3.83 (m , 1H), 3.73-3.72 (m, 1H), 2.32-2.27 (m, 1H), 2.01-1.94 (m, 3H), 1.24 (d, 1H).

    Example 35     N ^1- (3-methyltetrahydrofuran-3-yl) -N ^7- (3,4,5-trifluorophenyl) -5,6-dihydroimidazo [1,5- a ] pyrazine-1 , 7- (8 H ) -dimethylformamide 35

Using the synthetic route of Example 1, the raw material compound 1e in the fifth step was replaced with the raw material 3-methyltetrahydrofuran-3-amine (Shanghai Biode Medical Technology Co., Ltd.) to obtain the title compound 35 (16 mg).

MS m / z (ESI): 424.1 [M + 1].

1H NMR (400MHz, DMSO- d ₆ ) δ 8.87 (s, 1H), 8.35 (s, 1H), 7.67 (s, 1H), 7.31-7.27 (m, 2H), 5.03 (s, 2H), 4.21 ( t, 2H), 4.10 (d, 1H), 3.96-3.92 (m, 4H), 3.75 (d, 1H), 2.46-2.41 (m, 1H), 2.09-2.01 (m, 1H), 1.59 (s, 3H).

    Example 36     ^{(R) - N 2 - (} 3,4- difluorophenyl) - N ⁸ - (1,1,1- trifluoro-2-yl) -3,4-dihydro-pyrrolo [1,2- a ) Pyrazine-2,8 ( 1H ) -dimethylformamide 36

Under a hydrogen atmosphere, pyrrolo [1,2- a ] pyrazine-8-carboxylic acid methyl ester 36a (500 mg, 2.84 mmol, prepared by the method disclosed in the patent application "US2015 / 51189 A1") and palladium carbon ( 698.38 mg, 2.84 mmol) in 10 mL of methanol and stirred for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain crude 1,2,3,4-tetrahydropyrrolo [1,2- a ] pyrazine-8-carboxylic acid methyl ester 36b (511 mg, yield: 100%).

MS m / z (ESI): 181.2 [M + 1].

Using the synthetic route of Example 2, the raw material compound 2c in the third step was replaced with the crude material compound 36b to obtain the title compound 36 (10 mg).

MS m / z (ESI): 417.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.51-7.46 (m, 1H), 7.19-7.15 (m, 2H), 6.71-6.70 (m, 2H), 5.00 (s, 2H), 4.85-4.82 (m , 1H), 4.11-4.09 (m, 2H), 3.94-3.91 (m, 2H), 1.39 (d, 3H).

    Example 37     ( R ) -N ^7- (2- (difluoromethyl) pyridin-4-yl) -N ^1- (1,1,1-trifluoroprop-2-yl) -5,6-dihydroimidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 37

    First step     7-((2- (difluoromethyl) pyridin-4-yl) aminomethylamidino) -5,6,7,8-tetrahydroimidazo [1,5- a ] pyrazine-1-carboxyl Ethyl Ester 37c

2- (difluoromethyl) pyridine-4-amine 37a (73.83 mg, 512.25 μmol, prepared by the method disclosed in the patent application "WO2015 / 118057A1"), 5,6,7,8-tetrahydroimidazo [1,5- a ] Pyrazine-1-carboxylic acid ethyl ester 37b (100 mg, 512.25 μmol, Shanghai Beide Pharmaceutical Technology Co., Ltd.) and triethylamine (103.67 mg, 1.02 mmol) were dissolved in 10 mL of tetrahydrofuran at 0 Add bis (trichloromethyl) carbonate (60.80 mg, 204.09 μmol) at ℃, slowly raise to room temperature, and stir the reaction for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography in developing system A to obtain the title compound 37c (120 mg, yield: 64.2%).

MS m / z (ESI): 366.2 [M + 1].

    Second step     ( R ) -N ^7- (2- (difluoromethyl) pyridin-4-yl) -N ^1- (1,1,1-trifluoroprop-2-yl) -5,6-dihydroimidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 37

Compound 37c (100 mg, 273.72 μmol) and compound 1e (30.95 mg, 273.72 μmol) were dissolved in 10 mL of tetrahydrofuran, and 1 mL of a 1 M solution of bistrimethylsilyl lithium lithium tetrahydrofuran was added dropwise at 0 ° C. The temperature was slowly raised to room temperature, and the reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 37 (20 mg, yield: 16.9%).

MS m / z (ESI): 433.2 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.42 (d, 1H), 7.88-7.87 (m, 1H), 7.70-7.66 (m, 2H), 6.80-6.53 (m, 1H), 5.10 (s, 2H ), 4.83-4.81 (m, 1H), 4.26-4.24 (m, 2H), 4.00-3.98 (m, 2H), 1.44 (d, 3H).

    Example 38     ^{(S) - N 3, N} 5 - bis (3,4-difluorophenyl) -6-methyl-6,7-dihydro-pyrazolo [1,5- a] pyrazine-3,5 ( 4 H ) -dimethylformamide 38

The crude compound 7f (80 mg, 237.89 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (83.95 mg, 356.83 μmol) and N, N -diisopropylethylamine (92.23 mg, 713.66 μmol) were dissolved in 3 mL of N, N -dimethylformamide, reacted for 10 minutes, and compound 2d (46.07 mg, 356.83 μmol) was added. And stir for 16 hours. The reaction solution was added with 10 mL of water, and extracted with ethyl acetate (40 mL × 2). The organic phases were combined, and the organic phases were concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography using developing system C, and the obtained crude product was prepared by high performance liquid -2767, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 38 (10 mg, yield: 9.4%).

MS m / z (ESI): 448.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 8.18 (s, 1H), 7.83-7.81 (m, 1H), 7.52-7.50 (m, 1H), 7.41-7.39 (m, 1H), 7.24-7.17 (m 3H), 5.39 (d, 1H), 5.04-5.01 (m, 1H), 4.75 (d, 1H), 4.38-4.36 (m, 1H), 4.22 (d, 1H), 1.26 (d, 3H).

    Example 39     ^{(S) - N 5 - (} 3,4- difluorophenyl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6,7 Dihydro- [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 39

    First step     ( S ) -4-((1-hydroxypropyl-2-yl) (4-methoxybenzyl) amino)) butyl-2yn-1-ylacetate 39b

Compound 6a (3.00 g, 15.00 mmol) was dissolved in 60 mL of dioxane, and 4-chlorobutyl-2-yn-1-yl acetate 39a (5.73 g, 39.00 mmol, using a known method " Journal of Medicine Chemistry , 2014, 57 (9), 3687-3706 "), triethylamine (4.7 g, 46.00 mmol) was added, and the reaction was stirred at 60 ° C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using eluent system A to obtain the title compound 39b (2.20 g, yield: 42.2%).

MS m / z (ESI): 306.2 [M + 1].

    Second step     ( S ) -4-((1-chloropropyl-2-yl) (4-methoxybenzyl) amino) butyl-2yn-1-ylacetate 39c

Compound 39b (2.20 g, 7.20 mmol) and pyridine (854 mg, 10.08 mmol) were dissolved in 30 mL of dichloromethane, and thallium chloride (1.50 g, 12.60 mmol) was slowly added dropwise under an ice bath, and the temperature was slowly raised to room temperature. The reaction was stirred for 2 hours. 100 mL of dichloromethane was added to the reaction solution, washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 39c (2.20 g). The product was used in the next reaction without purification.

    third step     ( S )-(5- (4-methoxybenzyl) -6-methyl-4,5,6,7-tetrahydro- [1,2,3] triazolo [1,5- a ] Pyrazin-3-yl) methyl acetate 39d

The crude compound 39c (2.20 g, 6.79 mmol) was dissolved in 20 mL of N, N -dimethylformamide, sodium azide (574 mg, 8.83 mmol,) was added, and the mixture was reacted at 80 ° C for 12 hours. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate was added, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to obtain The title compound 39d (1.30 g, yield: 57.9%).

MS m / z (ESI): 331.1 [M + 1].

    the fourth step     ( S )-(6-methyl-4,5,6,7-tetrahydro- [1,2,3] triazolo [1,5- a ] piperazin-3-yl) methyl acetate Trifluoroacetate 39e

Compound 39d (1.30 g, 2.33 mmol) was dissolved in 5 mL of trifluoroacetic acid, heated to 100 ° C. in a microwave, and reacted for 5 minutes. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain the crude title compound 39e (1.28 g). The product was used in the next reaction without purification.

    the fifth step     ( S )-(5-((3,4-difluorophenyl) aminomethylamido) -6-methyl-4,5,6,7-tetrahydro- [1,2,3] triazole Benzo [1,5- a ] pyrazin-3-yl) methyl acetate 39f

The crude compound 39e (200 mg, 0.62 mmol), compound 2d (228 mg, 1.90 mmol) and triethylamine (290 mg, 2.86 mmol) were dissolved in 10 mL of tetrahydrofuran. In an ice-water bath, bis (trichloromethyl) carbonate ( 87 mg, 0.3 mmol), and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system C to obtain the title compound 39f (90 mg, yield: 40.1%).

MS m / z (ESI): 366.1 [M + 1].

Using the synthetic route of Example 17, replacing the starting compound 17b with the compound 39f in the second step, the title compound 39 (20 mg) was obtained.

MS m / z (ESI): 433.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.50-7.48 (m, 1H), 7.18-7.16 (m, 2H), 5.43 (d, 1H), 5.08-5.06 (m, 1H), 4.89-4.87 (m , 1H), 4.74 (d, 1H), 4.60 (d, 1H), 4.49-4.46 (m, 1H), 1.49 (d, 3H), 1.21 (d, 3H).

    Example 40     ^{(S) - N 5 - (} 4- fluoro-3-methylphenyl -) - 6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6 , 7-dihydro- [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 40

Using the synthetic route of Example 39 and replacing the starting compound 2d with 3-methyl-4fluoroaniline 40a in the fifth step, the title compound 40 (25 mg) was obtained.

MS m / z (ESI): 429.1 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.29-7.26 (m, 1H), 7.21-7.20 (m, 1H), 6.99-6.94 (m, 1H), 5.45-5.41 (d, 1H), 5.09-5.08 (m, 2H), 4.76-4.71 (d, 1H), 4.63-4.59 (m, 1H), 4.52-4.51 (d, 1H), 2.27-2.26 (d, 3H), 1.48-1.46 (d, 3H) , 1.23-1.22 (d, 3H).

    Example 41     ^{(S) - N 7 - (} 3,4- difluorophenyl) -6-methyl ^{- N 1 - ((S)} -1,1,1- trifluoro-2-yl) -5,6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 41

Using the synthetic route of Example 6, the raw material compound 1e was replaced with the raw material compound (2 S ) -1,1,1-trifluoropropyl-2-amine hydrochloride (Shanghai Biode Medical Technology Co., Ltd.) to obtain The title compound 41 (110 mg).

MS m / z (ESI): 432.1 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 7.54-7.51 (m, 1H), 7.50 (s, 1H), 7.21-7.02 (m, 3H), 6.83 (s, 1H), 5.26-5.16 (m, 1H) , 5.15-5.04 (m, 1H), 4.95-4.92 (m, 1H), 4.86-4.80 (m, 1H), 4.28-4.22 (m, 1H), 4.01-4.05 (m, 1H), 1.48 (d, 3H), 1.20 (d, 3H).

    Example 42     ( R ) -N ^5- (3,4-difluorophenyl) -7-methyl- N ³ -(( R ) -1,1,1-trifluoroprop-2-yl) -6,7- Dihydro [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 42

Using the synthetic route of Example 39, the first starting material compound 6a was replaced with the compound (2 R ) -1-((4-methoxybenzyl) amino) propan-1-ol (using a well-known method " Organic and Biomolecular Chemistry, 2014 , 12 , 16 , 2584-2591 "), to give the title compound 42 (20 mg).

MS m / z (ESI): 433.1 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.50-7.48 (m, 1H), 7.15-7.12 (m, 2H), 5.16 (d, 1H), 5.02 (d, 1H), 4.77-4.75 (m, 1H ), 4.13-4.10 (m, 1H), 3.77 (m, 1H), 3.06-3.03 (m, 1H), 1.67 (d, 3H), 1.44 (d, 3H).

    Example 43     ^{(S) - N 5 - (} 3,4- difluorophenyl) -6-methyl ^{- N 3 - ((S)} -1,1,1- trifluoro-2-yl) -6,7 Dihydro [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 43

Using the synthetic route of Example 17, replacing the starting compound 17b with compound 39f and the starting compound 1e with the starting compound ( 2S ) -1,1,1-trifluoropropyl-2-amine hydrochloride, The title compound 43 (30 mg) was obtained.

MS m / z (ESI): 433.3 [M + 1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.53-7.50 (m, 1H), 7.30 (d, 1H), 7.15 (dd, 1H), 7.06-7.04 (m, 1H), 6.84 (s, 1H), 5.37 -5.32 (m, 1H), 5.27 (d, 1H), 4.89-4.85 (m, 2H), 4.61 (d, 1H), 4.52-4.48 (m, 1H), 1.50 (d, 3H), 1.26 (d , 3H).

    Example 44     ( R ) -N ^5- (3-cyano-4-fluorophenyl) -7-methyl- N ³ -(( R ) -1,1,1-trifluoroprop-2-yl) -6, 7-dihydro [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 44

Using the synthetic route of Example 39, replacing the starting material compound 6a with the compound (2 R ) -1-((4-methoxybenzyl) amino) propan-1-ol in the first step and the starting material compound 2d in the fifth step Substitution with compound 3d gave the title compound 44 (15 mg).

MS m / z (ESI): 440.3 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.86-7.84 (m, 1H), 7.73-7.70 (m, 1H), 7.29 (t, 1H), 5.19 (d, 1H), 5.05 (d, 1H), 4.85-4.82 (m, 1H), 4.12 (d, 1H), 3.77-3.73 (m, 1H), 3.64-3.62 (m, 1H), 1.69 (d, 3H), 1.46 (d, 3H).

    Example 45     ^{(S) - N 5 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 3 - ((R)} -1,1,1- trifluoro-2-yl) -6, 7-Dihydro [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 45

    First step     ( S )-(5-((3-cyano-4-fluorophenyl) aminomethylmethyl) -6-methyl-4,5,6,7-tetrahydro- [1,2,3] Triazolo [1,5- a ] pyrazin-3-yl) methyl acetate 45a

The crude compound 39e (400 mg, 1.24 mmol), compound 3d (450 mg, 3.80 mmol) and triethylamine (580 mg, 5.80 mmol) were dissolved in 20 mL of tetrahydrofuran. In an ice-water bath, bis (trichloromethyl) carbonate ( 180 mg, 0.6 mmol) and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system C to obtain the title compound 45a (195 mg, yield: 40.1%).

MS m / z (ESI): 373.1 [M + 1].

    Second step     ( S ) -N- (3-cyano-4-fluorophenyl) -3- (hydroxymethyl) -6-methyl-6,7-dihydro- [1,2,3] triazolo [ 1,5- a ] pyrazine-5 ( 4H ) -formamidine 45b

Compound 45a (190 mg, 0.51 mmol) was dissolved in 5 mL of a mixed solvent of methanol and water (V: V = 4: 1), lithium hydroxide (108 mg, 2.57 mmol) was added, and the mixture was stirred for 2 hours. 20 mL of water was added to the reaction solution, and extracted with ethyl acetate (15 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 45b (120 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 331.2 [M + 1].

    third step     (S) - N - (3- cyano-4-fluorophenyl) -3-acyl-6,7-dihydro-6-methyl - [1,2,3] triazolo [1, 5- a ] pyrazine-5 ( 4H ) -methanamine 45c

The crude compound 45b (100 mg, 0.3 mmol) was dissolved in 5 mL of dichloromethane, and pyridinium chlorochromate (138 mg, 0.64 mmol) and silica gel (140 mg, 100-200 mesh) were added, followed by stirring for 3 hours. Filtration and concentration under reduced pressure, and the resulting residue was purified by thin layer chromatography using developing system A to obtain the title compound 45c (60 mg, yield: 43.1%).

MS m / z (ESI): 329.5 [M + 1].

    the fourth step     ( S )-(5-((3-cyano-4-fluorophenyl) aminomethylmethyl) -6-methyl-4,5,6,7-tetrahydro- [1,2,3] Triazolo [1,5- a ] pyrazine-3-carboxylic acid 45d

Compound 45c (30 mg, 0.1 mmol) was dissolved in 5 mL of a mixed solvent of acetonitrile and water (V: V = 3: 2), aminosulfonic acid (20 mg, 0.2 mmol) was added, stirred for 10 minutes, and sodium chlorite ( 20 mg, 0.2 mmol), and stirred for 2 hours. 0.5 mL of saturated sodium sulfite solution and 10 mL of water were added sequentially, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude compound 45d (25 mg). The product was used in the next reaction without purification.

MS m / z (ESI): 345.2 [M + 1].

    the fifth step     S ) -N ^5- (3-cyano-4-fluorophenyl) -6-methyl- N ³ -(( R ) -1,1,1-trifluoroprop-2-yl) -6,7 -Dihydro [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 45

The crude compound 45d (20 mg, 58.0 μmol), O- (7-azabenzotriazol-1-yl) -N , N , N ' , N' -tetramethylurea hexafluorophosphate (105 mg, 146.5 μmol), N, N -diisopropylethylamine (150mg, 366.2μmol) was dissolved in 3mL N, N -dimethylformamide, and reacted for 10 minutes. Compound 1e (50mg, 110μmol) was added, and the reaction was stirred for 3 minutes. hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by developing solvent system C using thin layer chromatography to obtain the title compound 45 (8 mg, yield: 31.3%).

MS m / z (ESI): 440.3 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.87-7.84 (m, 1H), 7.73-7.70 (m, 1H), 7.29 (t, 1H), 5.45 (t, 1H), 5.08-5.06 (m, 1H ), 4.92-4.89 (m, 1H), 4.77 (d, 1H), 4.62 (d, 1H), 4.50 (d, 1H), 1.46 (d, 3H), 1.21 (d, 3H).

    Example 46     ^{(S) - N 7 - (} 3- cyano-4-fluorophenyl) -6-methyl - N ¹ - (1- methyl-cyclobutyl) -5,6-dihydro-imidazo [1,5- -a ] pyrazine-1,7 (8 H ) -dimethylformamide 46

Using the synthetic route of Example 11, the raw material compound 1e in the third step was replaced with the compound 1-methylcyclobutyl 1-amine (Shanghai Biode Medical Technology Co., Ltd.) to obtain the title compound 46 (20 mg).

MS m / z (ESI): 411.4 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.86-7.84 (m, 1H), 7.72-7.70 (m, 1H), 7.65 (s, 1H), 7.28 (t, 1H), 5.26 (d, 1H), 4.92-4.89 (m, 1H), 4.78 (d, 1H), 4.20-4.17 (m, 2H), 2.45-2.43 (m, 2H), 2.10-2.07 (m, 2H), 1.92-1.90 (m, 2H ), 1.55 (s, 3H), 1.20 (d, 3H).

    Example 47     ^{(R) - N 7 - (} 3- cyano-4-fluorophenyl) -5-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 47

Using the synthetic route of Example 6, the first step starting compound 6a was replaced with the starting compound ( 2S ) -1-((4-methoxybenzyl) amino) propan-1-ol, and the fourth step starting compound 2d was replaced with the starting compound 3d to obtain the title compound 47 (12 mg).

MS m / z (ESI): 439.2 [M + 1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.88 (dd, 1H), 7.62-7.61 (m, 1H), 7.57 (s, 1H), 7.22-7.17 (m, 3H), 5.20 (d, 1H), 5.03 (d, 1H), 4.84-4.80 (m, 1H), 4.42-4.40 (m, 1H), 4.25-4.21 (dd, 1H), 3.58-3.53 (dd, 1H), 1.64 (d, 3H), 1.47 (d, 3H).

    Example 48     ^{(S) - N 7 - (} 3- cyano-4-fluorophenyl) -6-methyl - N ¹ - (1- methyl-cyclopropyl) -5,6-dihydro-imidazo [1,5- - a] pyrazine -1,7 (8 H) - dimethyl Amides 48

Using the synthetic route of Example 11 and replacing the raw material compound 1e in the third step with the compound 1-methylcyclopropyl 1-amine (Shanghai Biode Medical Technology Co., Ltd.), the title compound 48 (20 mg) was obtained.

MS m / z (ESI): 397.3 [M + 1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.86-7.84 (m, 1H), 7.72-7.70 (m, 1H), 7.63 (s, 1H), 7.29 (t, 1H), 5.28 (d, 1H), 4.91-4.89 (m, 1H), 4.80 (d, 1H), 4.20-4.17 (m, 2H), 1.44 (s, 3H), 1.20 (d, 3H), 0.71-0.68 (m, 2H), 0.68- 0.66 (m, 2H).

    Example 49     ( R ) -N ^5- (3-4-Difluorophenyl-)-6-methyl- N ³ -(( R ) -1,1,1-trifluoroprop-2-yl) -6,7 -Dihydroimidazo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 49

Using the synthetic route of Example 7, the first step starting compound 7a was replaced with the starting compound ( R ) -3-iodo-6-methyl-6,7-dihydropyrazolo [1,5- a ] pyrazine -5 ( 4H ) -carboxylic acid third butyl ester (prepared by the method disclosed in patent application "WO2017198744A1") to obtain the title compound 49 (20 mg)

MS m / z (ESI): 432.2 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ 8.11 (m, 1H), 7.52-7.47 (m, 1H), 7.21-7.16 (m, 2H), 5.38-5.33 (d, 2H), 5.02-4.99 (m , 1H), 4.74-4.69 (d, 1H), 4.36-4.33 (m, 1H), 4.23-4.19 (d, 1H), 1.43-1.42 (d, 3H), 1.27-1.25 (d, 3H).

    Example 50     (S) - N ¹ - (tert-butyl) - N ⁷ - (3- cyano-4-fluorophenyl -) - 6-methyl-5,6-dihydro-imidazo [1,5- a ] Pyrazine-1,7 (8 H ) -dimethylformamide 50

Using the synthetic route of Example 11, the third step starting material compound 1e was replaced with the starting compound tert-butylamine (Sinopec Group Chemical Reagent Co., Ltd.) to obtain the title compound 50 (180 mg).

MS m / z (ESI): 399.2 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.90-7.88 (m, 1H), 7.75-7.67 (m, 1H), 7.33 (s, 1H), 7.31-7.29 (m, 1H), 5.28-5.24 (d , 1H), 4.94 (m, 1H), 4.81-4.77 (m, 1H), 4.26-4.20 (m, 2H), 1.48 (d, 9H), 1.22-1.20 (d, 3H).

    Example 51     ^{(S) - N 7 - (} 3- ^{cyano-4-fluorophenyl) - N 1 - ((R} ) -1- fluoro-2-yl) -6-methyl-5,6-dihydro-imidazole and [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 51

Using the synthetic route of Example 11, the raw material compound 1e in the third step was replaced with the raw material compound ( S ) -2-fluoro-1-methyl-ethylamine hydrochloride (Shanghai Biode Medical Technology Co., Ltd.) to obtain the title compound. 51 (20 mg).

MS m / z (ESI): 403.2 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.89-7.87 (m, 1H), 7.77-7.74 (m, 1H), 7.73 (s, 1H), 7.31-7.29 (m, 1H), 5.31-5.27 (d , 1H), 4.94-4.92 (m, 1H), 4.83-4.78 (d, 1H), 4.52-4.50 (d, 1H), 4.40-4.39 (m, 2H), 4.25-4.22 (m, 2H), 1.32 -1.30 (d, 3H), 1.22-1.20 (d, 3H).

    Example 52     ^{(S) - N 7 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 1 - ((S)} -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 52

Using the synthetic route of Example 11, the raw material compound 1e in the third step was replaced with the raw material compound ( 2S ) -1,1,1-trifluoropropyl-2-amine hydrochloride to obtain the title compound 52 (20 mg) .

MS m / z (ESI): 439.2 [M + 1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.91 (dd, 1H), 7.63-7.62 (m, 1H), 7.50 (s, 1H), 7.20-7.14 (m, 3H), 5.22-5.16 (m, 2H) , 4.95 (d, 1H), 4.85-4.83 (m, 1H), 4.26-4.23 (m, 1H), 4.11-4.08 (dd, 1H), 1.48 (d, 3H), 1.26 (d, 3H).

    Example 53     ^{(R) - N 7 - (} 3,4- difluorophenyl -) - 6-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5,6 - dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 53

Using the synthetic route of Example 6, the first step starting material 6a was replaced with the starting material ( R ) -2-((4-methoxybenzyl) amino) propan-1-ol (using the well-known method " Bioorganic & Medicinal Chemistry Letters , 2015, 25 (5), 1086-1091 "), to give the title compound 53 (90 mg)

MS m / z (ESI): 432.2 [M + 1]

¹ H NMR (400MHz, CD3OD) δ 7.71 (s, 1H), 7.52-7.47 (m, 1H), 7.21-7.17 (m, 2H), 5.31-5.27 (d, 1H), 4.94-4.92 (m, 1H ), 4.76-4.84 (m, 2H), 4.24-4.22 (m, 2H), 1.45-1.43 (d, 3H), 1.23-1.21 (d, 3H).

    Example 54     ( R ) -N ^7- (3-cyano-4-fluorophenyl-)-6-methyl- N ¹ -(( R ) -1,1,1-trifluoroprop-2-yl) -5 1,6-dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 54

Using the synthetic route of Example 6, the first step raw material compound 6a was replaced with the raw material ( R ) -2-((4-methoxybenzyl) amino) propan-1-ol, and the fourth step raw material compound 2d Replace with 3d to give the title compound 54 (88 mg).

MS m / z (ESI): 439.2 [M + 1]

1H NMR (400MHz, CD3OD) δ 7.89-7.87 (m, 1H), 7.75-7.73 (m, 1H), 7.71 (s, 1H), 7.33-7.29 (m, 1H), 5.32-5.28 (d, 1H) , 4.95-4.93 (m, 1H), 4.85-4.82 (m, 2H), 4.25-4.22 (m, 2H), 1.45-1.43 (d, 3H), 1.23-1.22 (d, 3H).

    Example 55     ^{(R) - N 7 - (} 3- cyano-4-fluorophenyl) -6-methyl ^{- N 1 - ((S)} -1,1,1- trifluoro-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 55

Using the synthetic route of Example 6, the first step raw material compound 6a was replaced with the raw material ( R ) -2-((4-methoxybenzyl) amino) propan-1-ol, and the fourth step raw material compound 2d Replace it with 3d and replace the starting compound 1e in the fifth step with the starting compound (2 S ) -1,1,1-trifluoropropyl-2-amine hydrochloride to obtain the title compound 55 (20 mg).

MS m / z (ESI): 439.2 [M + 1]

¹ H NMR (400MHz, CDCl ₃ ) δ 7.86 (dd, 1H), 7.70-7.65 (m, 2H), 7.30-7.26 (m, 3H), 5.30 (d, 1H), 4.94-4.93 (m, 1H) , 4.81-4.76 (m, 2H), 4.26-4.17 (m, 2H), 1.43 (d, 3H), 1.20 (d, 3H).

    Example 56     (S) -N ^7- (3-cyano-4-fluorophenyl) -5-methyl- N ¹ -(( R ) -1,1,1-trifluoroprop-2-yl) -5, 6- dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 56

Using the synthetic route of Example 6, the first step starting compound 6a was replaced with the starting compound ( S ) -1-((4-methoxybenzyl) amino) propan-2-ol (using the well-known method " Organic and Biomolecular Chemistry, 2014 , 12 , 16 , 2584-2591 "), the fourth step of the starting compound 2d was replaced with the starting compound 3d to obtain the title compound 56 (10mg).

MS m / z (ESI): 439.2 [M + 1]

1H NMR (400MHz, CD ₃ OD) δ 7.88-7.86 (m, 1H), 7.83 (s, 1H), 7.76-7.72 (m, 1H), 7.33-7.28 (m, 1H), 5.16-5.11 (d, 1H), 5.03-4.98 (m, 1H), 4.85-4.81 (m, 2H), 4.04-4.00 (m, 1H), 3.72-3.66 (m, 1H), 1.60-1.56 (d, 3H), 1.44- 1.42 (d, 3H).

    Example 57     N ^5- (3-cyano-4-fluorophenyl-)-7-methyl- N ³ -(( R ) -1,1,1-trifluoroprop-2-yl) -6,7-di Hydrogen- [1,2,3] triazolo [1,5- a ] pyrazine-3,5 ( 4H ) -dimethylformamide 57

Using the synthetic route of Example 39, the first step starting compound 6a was replaced with the starting compound 1-((4-methoxybenzyl) amino) propan-2-ol (using a known method " Organic and Biomolecular Chemistry, 2014,12, 16,2584-2591 "), the fifth step of the raw material compound 2d was replaced with the raw material compound 3d, to obtain the title compound 57 (220mg).

MS m / z (ESI): 440.2 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) δ 7.85-7.87 (m, 1H), 7.72-7.75 (m, 1H), 7.28-7.33 (m, 1H), 5.01-5.06 (d, 1H), 5.16-5.21 (d, 1H), 4.80-4.81 (m, 2H), 4.13-4.17 (m, 1H), 3.75-3.80 (m, 1H), 1.69-1.70 (d, 3H), 1.18-1.21 (d, 3H) .

    Example 58     ^{(S) - N 7 - (} 4- fluoro-3-methylphenyl -) - 6-methyl ^{- N 1 - ((R)} -1,1,1- trifluoro-2-yl) -5 1,6-dihydro-imidazo [1,5- a] pyrazine -1,7 (8 H) - dimethyl Amides 58

Using the synthetic route of Example 6, the raw material compound 2d in the fourth step was replaced with the raw material compound 4-fluoro-3-methylaniline (Shanghai Biode Medical Technology Co., Ltd.) to obtain the title compound 58 (14 mg).

MS m / z (ESI): 427.9 [M + 1]

¹ H NMR (400MHz, CD ₃ OD) 7.71 (s, 1H), 7.29-7.27 (m, 1H), 7.22-7.20 (m, 1H), 6.99-6.94 (m, 1H), 5.30-5.25 (d, 1H), 4.94-4.92 (m, 1H), 4.81-4.75 (m, 2H), 4.24-4.21 (m, 2H), 2.27-2.26 (d, 3H), 1.45-1.43 (d, 3H), 1.20- 1.19 (d, 3H).

    Example 59     (S) - N - (3,4- difluorophenyl) -6-methyl-1- (pyrrolidine-1-carbonyl) -5,6-dihydro-imidazo [1,5- a] pyrazine -7 (8 H ) -formamidine 59

Using the synthetic route of Example 11, the first step raw material compound 3d was replaced with compound 2d, and the third step raw material compound 1e was replaced with the raw material compound pyrrolidine (Sinopec Group Chemical Reagent Co., Ltd.) to obtain the title compound 59 (10 mg).

MS m / z (ESI): 389.8 [M + 1].

¹ H NMR (400MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.52-7.47 (m, 1H), 7.20-7.16 (m, 3H), 5.26 (d, 1H), 4.93-4.90 (m, 1H) , 4.77 (d, 1H), 4.23-4.21 (m, 2H), 4.04-4.01 (m, 2H), 3.63-3.60 (m, 2H), 2.01-1.93 (m, 4H), 1.22 (d, 3H) .

    Biological evaluation         Test Example 1. In vitro anti-HBV activity test of the compound of the present invention (quantitative analysis of intracellular HBV DNA)         I. Experimental materials and instruments    

1.QIAamp 96 DNA QIAcube HT Kit (Qiagen)

2.QIAcube HT plasticware (Qiagen)

3. Hepatitis B virus nucleic acid quantitative detection kit (Taip Bio)

4.DNA extraction equipment (QIAcube) (Qiagen)

5.QuantStudio 6 Fiex (ABI, ThermFisher)

6. Microplate reader (BMG)

7.HepG2.2.15 cells (Shanghai Ruilu Biotechnology Co., Ltd.)

    Experimental steps    

HepG2.2.15 cells are stable expression cell lines that integrate the HBV genome, and can be secreted outside the cell by replication, transcription, translation, and packaging into virus particles with HBV DNA. This study used quantitative PCR to quantitatively analyze HBV DNA produced by HepG2.2.15 in vitro proliferation, and screened the compounds of the present invention for inhibiting HBV DNA replication activity by inhibiting HBV capsid protein assembly inhibition.

HepG2.2.15 cells were cultured in DMEM / high glucose medium (10% FBS, 400 μg / ml G418) and passaged every 3 days. On the day of the experiment, a cell suspension was prepared in fresh cell culture medium, and cultured at 37 ° C in a 40,000 cells / well 96-well plate (Corning, # 3599) with 5% carbon dioxide. The next day, the compound was dissolved in pure DMSO at a concentration of 20 mM, and then the first concentration was made up to 2 mM with DMSO, and then diluted 4 times to 8 concentrations, and 90 μl of DMSO was added to the control wells. Dilute 200-fold with DMEM / high glucose medium. Take out the cell culture plate inoculated on the first day, use a negative pressure suction device to suck out the culture medium in the well plate, and then add the prepared compound culture medium containing each concentration to each well, 200 μl / well, and culture at 37 ° C for 72 hours. . On the fifth day, the cultured cells were exchanged with fresh medium containing the same compound, the same method as the second day, and then cultured at 37 ° C for 72 hours. On the eighth day, the cell culture plate was taken out, centrifuged at 300 g for 3 minutes, and the culture supernatant was collected at 200 μl / well. Qiagen automatic DNA extraction equipment was used to extract HBV DNA from the cell culture supernatant. For specific methods, refer to the reagent and instrument instructions. Finally, the extracted DNA was eluted with DNA elution buffer at 100 μl / well. The HBV DNA quantitative PCR analysis of the extracted DNA was performed by using the ATP HBV nucleic acid quantitative detection kit from Taipu Biological. For specific methods, refer to the kit description. The quantitative standard curve uses the standard sample provided in the kit, and experiments are performed in parallel. Quantitative conversion of each sample according to the standard curve. EC ₅₀ values of the compound calculated using Graphpad Prism software final compound according to the respective concentration values corresponding DNA. Emax is the effect value of the compound to maximally inhibit HBV DNA replication.

The compound of the present invention inhibits the in vitro activity of HBV DNA replication by inhibiting the assembly of HBV capsid protein, and the in vitro activity of HBV DNA replication is determined by the above test. The measured EC ₅₀ values are shown in Table 1.

Conclusion: The compound of the present invention has a significant inhibitory effect on HBV DNA replication, and has significant advantages compared with Comparative Example 59. The structural difference between Comparative Example 59 and the compound of the present application is that the amine group in the amidine group is a tertiary amine, and it can be seen that the secondary amine in the amidine group in the compound of the present application has a significant improvement in biological activity.

    Test Example 2. Effect of the compound of the present invention on HepG2 cell proliferation in vitro         I. Experimental materials and instruments    

1. HepG2 cells (ATCC)

2.CellTiter-Glo ^TM Cell Proliferation Kit (Promega)

3. Automatic Pipetting Workstation (Bravo): Agilent Technologies

4. Microplate reader (VICTOR 3): PerkinElmer

5.CO ₂ incubator (Fisher Scientific)

6.Centrifuge (Fisher Scientific)

    Experimental steps    

HepG2 cells in logarithmic growth phase were taken and trypsinized to prepare cell suspensions. The cells were cultured at 6,000 cells / well in a 96-well plate (bottom-through white 96-well plate, PerkinElmer), 5% carbon dioxide, and incubated at 37 ° C for 16-20 hours. The next day, the compound was dissolved in pure DMSO at a concentration of 20 mM. The compound was diluted by gradient using an automatic pipetting station (Bravo), and diluted three-fold. Each compound was provided with 8 concentration points. The control well was DMSO. (Containing 10% FBS) medium was diluted 200-fold at each concentration point compound formulated in DMSO. Take out the cell culture plate inoculated on the first day, use a negative pressure suction device to suck out the culture medium in the well plate, and then add the prepared compound culture medium with each concentration to each well, and incubate at 100 μl / well for 72 hours at 37 ° C. . On the fifth day, take out a 96-well cell culture plate, add freshly prepared CellTiter Glo to each well, leave it at 100 μl / well for 5-10 minutes, seal the bottom of the 96-well plate with a white backing film (PerkinElmer), place Luminescence signal was measured in a microplate reader using a microplate reader. CC ₅₀ values _are calculated values based on the compound to inhibit signal corresponding to each concentration of compound proliferation with Graphpad Prism software.

The effect of the compound of the present invention on the proliferation inhibition of HepG2 cells in vitro was determined by the above test. The measured CC ₅₀ values are shown in Table 2.

Conclusion: The compound of the present invention has no effect on the proliferation inhibition of HepG2 cells in vitro or has a small effect, and shows high safety.

    Pharmacokinetic evaluation         Test example 3, pharmacokinetic test of the compound of the present invention         1.Abstract    

Using rats as test animals, LC / MS / MS method was used to measure the administration of the compound of Example 1, compound of Example 2, compound of Example 4, compound of Example 6, compound of Example 7, compound of Example 11 The drug concentration in the plasma at different times after the compound, the compound of Example 39, the compound of Example 42, the compound of Example 44, the compound of Example 45, and the compound of Example 47. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

    2. Test plan         2.1 Test drugs    

Example 1 compound, Example 2 compound, Example 4 compound, Example 6 compound, Example 7 compound, Example 11 compound, Example 39 compound, Example 42 compound, Example 44 compound, Example 45 compound, and Example 47 Compound.

    2.2 Test animals    

Forty-four healthy adult SD rats, half male and four female, were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.

    2.3 Drug Formulation    

Weigh a certain amount of drug, add 5% volume of DMSO, 5% volume of Tween 80, and 90% volume of normal saline to prepare a 0.2 mg / mL colorless, clear liquid.

    2.4 Administration    

SD rats were fasted orally after fasting overnight. The doses were all 2.0 mg / kg, and the volumes were 10.0 mL / kg.

    3. operation    

The compound of Example 1, the compound of Example 2, the compound of Example 4, the compound of Example 6, the compound of Example 7, the compound of Example 11, the compound of Example 39, the compound of Example 42, and the compound of Example 44 1. The compound of Example 45 and the compound of Example 47. Before and after administration, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours, 0.1 mL of blood was collected from the orbit and placed in a heparinized test tube, 3500 rpm The plasma was separated by centrifugation for 10 minutes per minute, stored at -20 ° C, and eaten 2 hours after administration.

Determining the content of test compound in rat plasma after oral administration of drugs with different concentrations: Take 25 μL of rat plasma at various times after administration, add 40 μL of internal standard solution camptothecin (100 ng / mL), 200 μL of acetonitrile, and vortex Spin-mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 0.2 μL of the supernatant from the plasma sample for LC / MS / MS analysis.

    4. Results of pharmacokinetic parameters    

The pharmacokinetic parameters of the compounds of the invention are as follows:

Conclusion: The compound of the present invention has good drug metabolism and absorption, high bioavailability, and has pharmacokinetic advantages.

Claims (26)

A compound represented by the general formula (I) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof salt, Wherein: ring A is aryl and heteroaryl; Y is N or CR ⁵ ; Q is N or CH; R ^{1 is} selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently further selected from halogen, alkyl, haloalkyl, alkoxy, Haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C ( O) OR ⁶ and -S (O) _m R ⁶ are substituted with one or more substituents; R ^{2 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently further selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy Group, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ ,- one of the ⁶ C (O) oR ⁶ and -S (O) _m R or more substituents; R ³ are the same or different and are each independently selected from Atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{4 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, halogen Alkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{5 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, and amino , Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ^{6 is} selected from hydrogen atom, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, naphthenic Aryl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, or 3; m is 0, 1, or 2; and s is 0, 1, 2, 3, or 4. The compound represented by the general formula (I) or the tautomer, meso, racemate, enantiomer, diastereomer or the A mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof Among them: the rings A, Y, Q, R ¹ , R ³ , R ⁴ , s and n are as defined in the first scope of the patent application. The compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), the general formula (IV), the general formula (V) and the general formula (VI) or a tautomer, Racemates, racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, Wherein: Ring A, R ¹ , R ³ , R ⁴ , s and n are as defined in the first scope of the patent application.     The compound represented by the general formula (I) as described in any one of claims 1 to 3 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridyl.     The compound represented by the general formula (I) as described in any one of claims 1 to 4 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (VII), general formula (VIII), general formula (IX) and general formula (X) or mutual variation thereof Structure, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, Wherein: G is C or N; R ¹ , R ³ , R ⁴ , s and n are as defined in item 1 of the scope of patent application. The compound represented by the general formula (I) according to any one of claims 1 to 5 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and aryl, wherein the alkyl, cycloalkyl, hetero The cyclic group and the aryl group are further optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, and hydroxyl. The compound represented by the general formula (I) as described in any one of claims 1 to 6 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, are represented by the general formula (VII-A), the general formula (VIII-A), the general formula (IX-A), and the general formula (XA) Compounds or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, Wherein: G is C or N; R ⁸ is an alkyl group; R ⁹ is an alkyl group, wherein the alkyl group is further substituted with one or more halogens as needed; R ³ , R ⁴ , s, and n are as claimed in the patent application Defined in Scope Item 1. The compound represented by the general formula (I) or the tautomer, meso, racemate, enantiomer, diastereomer, or A mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is methyl. The compound represented by the general formula (I) as described in any one of claims 1 to 8 or a tautomer, meso, racemate, enantiomer, diastereomer An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or an alkyl group. The compound represented by the general formula (I) according to any one of claims 1 to 9 or a tautomer, meso, racemate, enantiomer, diastereomer An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{4 is} selected from a hydrogen atom, halogen, alkyl, haloalkyl, or cyano. The compound represented by the general formula (I) as described in any one of claims 1 to 10 or a tautomer, meso, racemate, enantiomer, diastereomer Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, selected from: A compound represented by the general formula (IA) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof , Wherein: R ^a is a hydrogen atom or an alkyl group; ring A is an aryl group and a heteroaryl group; Y is N or CR ⁵ ; Q is N or CH; R ^{3 is the} same or different and each is independently selected from a hydrogen atom and a halogen , Alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{4 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, Alkoxy, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ -C (O) OR ⁶ and -S (O) _m R ⁶ ; R ^{5 is} selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitrate Group, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R ^{6 is} selected from hydrogen atom, alkyl, haloalkyl, amino, hydroxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2 or 3; m is 0, 1 or 2; and s is 0, 1, 2, 3 or 4. The compound or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof as described in item 12 of the scope of the patent application, or a pharmaceutically acceptable compound thereof A salt wherein R ³ is a hydrogen atom or an alkyl group. The compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer or its A mixture, or a pharmaceutically acceptable salt thereof, selected from: A compound represented by the general formula (IIIA) or a tautomer, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof , Wherein: M is trifluoroacetic acid or hydrochloric acid; R ^{1 is} selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, haloalkyl, cyclic Alkyl, heterocyclyl, aryl, and heteroaryl are each independently further optionally selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, and hydroxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ Substituted by one or more substituents; R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; T is 0 or 1; and n is 0, 1, 2 or 3. The compound or tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable substance thereof A salt wherein R ³ is a hydrogen atom or an alkyl group. A compound selected from: A compound represented by the general formula (I) or a tautomer, meso, racemate, enantiomer, diastereomer, or A method of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound of the general formula (IA) is reacted with the compound of the general formula (IB) or a salt thereof to obtain a compound of the general formula (I); wherein: R ^a is a hydrogen atom or an alkyl group; R ^{3 is the} same or different, and each is independently selected from Hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; rings A, Y, Q, R ¹ , R ² , R ⁴ , s and n such as As defined in the first patent application scope. The method as described in claim 18, wherein R ³ is a hydrogen atom or an alkyl group. A method for preparing a compound represented by the general formula (II) or the tautomers, mesomers, racemates, enantiomers, diastereomers as described in item 2 of the scope of patent application Or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound of the general formula (IA) is reacted with a compound of the general formula (IIB) or a salt thereof to obtain a compound of the general formula (II); wherein: R ^a is a hydrogen atom or an alkyl group; R ^{3 is the} same or different, and each is independently selected from Hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , -OR ⁶ , -C (O) R ⁶ , -C (O) OR ⁶ and -S (O) _m R ⁶ ; rings A, Y, Q, R ¹ , R ⁴ , s and n are as in the scope of patent application As defined in item 1. The method according to claim 20, wherein R ³ is a hydrogen atom or an alkyl group.     A medicinal composition containing a therapeutically effective amount of a compound represented by the general formula (I) according to any one of claims 1 to 11 or a tautomer, meso, racemic Rotates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.         A use of the compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 22, which is used for preparing a capsid protein inhibitor .         A use of a compound represented by the general formula (I) according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 22, which is used for preparing a viral infection Drugs for the disease.         Use according to item 24 of the scope of patent application, wherein the virus is selected from hepatitis B virus, influenza virus, herpes virus and AIDS virus.         The use according to item 24 of the scope of patent application, wherein the disease is selected from hepatitis B, influenza, herpes and AIDS.