WO2016011940A1 - Indole-amide derivative, preparation method therefor and application thereof in medicine - Google Patents

Abstract

The present invention relates to an indole-amide derivative, a preparation method therefor and an application thereof in medicine. Specifically, the present invention relates to an indole-amide derivative represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, a use thereof as a therapeutic agent, especially as an XIa factor inhibitor, and a use thereof in the preparation of drugs for treating and/or preventing diseases such as thromboembolism, wherein the definition of the substituents in general formula (I) is the same as that in the specification.

Description

Nitrogen-amide derivative, preparation method thereof and application thereof in medicine Technical field

The present invention relates to a novel class of nitrogen hydrazine-amide derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same, and their use as therapeutic agents, in particular as XIa factor inhibitors, and in the preparation of treatment and/or prevention Use in drugs for diseases such as thromboembolism.

Background technique

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

According to data from independent market analyst firm Datamonitor in 2011, with the production of generic drugs, the share of cardiovascular and metabolic diseases in the seven major markets will peak in 2011 and then gradually decrease, and its sales will be from 1090 in 2010. The billion dollars will reach $101 billion in 2019. The thrombus market remained basically stable, from $19.5 billion in 2010 to $18.9 billion in 2019 (Datamonitor: HC00034-001, HC00139-001). The survey report of Guangzhou Punctuation in 2011 also showed that the scale of China's antithrombotic drug market reached 8.135 billion yuan in 2011, an increase of 20.52% over the same period, with huge market potential (anti-thrombotic drug market research report: Guangzhou punctuation (2011)).

The human coagulation system contains two processes: the intrinsic pathway and the extrinsic pathway and a common pathway (Annu. Rev. Med. 2011. 62: 41-57). The exogenous pathway, also known as the tissue factor pathway, acts as a foreign pathway, and under the injury and various external stimuli, the tissue activator and activated factor VIIa (FVIIa) constitute a complex of activator X (FX), forming factor Xa. (FXa), activated FXa can convert prothrombin (PT) into thrombin, which acts as a central catalytic enzyme in the coagulation process, catalyzing the formation of fibrin by fibrinogen and acting as a coagulation. The process involves fewer enzymes and is quicker. The endogenous pathway belongs to the body's intrinsic pathway, and all the factors involved in blood coagulation come from the blood. The cascade activates factor XII (FXII), factor XI (FXI), and factor IX (FIX), which in turn activates FXa to downstream prothrombin ( PT) is converted to thrombin, which in turn activates FXI. This process involves a large number of enzymes and is slower to respond (Arterioscler Thromb Vasc Biol. 2010; 30: 388-392).

FXI and FXIa play an extremely important role throughout the coagulation process. As a co-regulator of exogenous and endogenous coagulation pathways, antagonists have been widely developed for the treatment of various thrombi. A variety of FXa antagonists have been marketed, and their significant effectiveness has occupied the majority of cardiovascular and cerebrovascular markets. However, their side effects have become more and more significant. Among them, "bleeding risk" is the most serious problem (N Engl J Med 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).

In order to solve this problem, the recent target FXIa has become a hot research topic among major companies and research institutions. Studies have found that severe FXI deficiency can cause hemophilia C, which occurs mostly in Jewish people (1:450). The symptoms of hemophilia C are milder than those of hemophilia A and B, and spontaneous bleeding occurs a little. Even if the hemostatic function of the body is not affected during injury or surgery, patients with hemophilia C can be pregnant normally (Arterioscler Thromb) Vasc Biol. 2010; 30: 388-392). Therefore FXIa security is significantly better than FXa. In the thrombus model, inhibition of FXIa factor can effectively inhibit thrombus formation, but in the case of more severe thrombosis, FXIa has little effect (Blood. 2010; 116 (19): 3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of VTE (Blood 2009; 114: 2878-2883), while those with severe FXIa have a reduced risk of developing DVT (Thromb Haemost 2011; 105: 269–273) .

As an emerging target, FXIa has not yet announced its entry into the clinical stage, but Bristol-Myers Squibb's BMS-654457 and BMS-262084 may have started clinical research, and the clinical results have not been published. Preclinical studies have shown that BMS-654457 shows a significant dose-dependent potential efficacy in a rabbit model of experimental arterial thrombosis induced by direct current stimulation, with no bleeding side effects (22nd Int Symp Med Chem (Sept 2-6, Berlin) 2012, Abst L63). The pharmacokinetic data of BMS-262084 showed that the compound as a FXIa inhibitor significantly improved the experimental model of thrombosis, and its side effects were extremely small (J Thromb Thrombolysis (2011) 32: 129-137).

Compounds having factor XIa inhibitory activity are disclosed in the patent applications WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, and US20050171148. The present invention has devised a novel compound small molecule FXIa antagonist, which has higher activity and exhibits excellent effects and effects. It can be used to effectively treat cardiovascular and cerebrovascular diseases and thrombotic symptoms.

Summary of the invention

The object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof. Form, or a pharmaceutically acceptable salt thereof:

among them:

Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl;

Ring B is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;

R ¹ each being the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -C(O)R ⁴ , wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkane. Substituted by a substituent of the group;

R ^{2 is} selected from a hydrogen atom, a halogen or an alkyl group;

R ^{3 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Base, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O NHR ⁴ or -NHC(O)NHOR ⁴ ;

R ^{4 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, Substituted by a hydroxyalkyl group, a cycloalkyl group, a substituent of -OC(O)OR ⁵ or -NR ⁵ R ⁶ ;

R ⁵ or R ⁶ are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group;

m is 0, 1, 2 or 3;

n is 0, 1, or 2.

In a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a fused aryl group, preferably a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl ring fused to a benzene ring.

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of:

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ^{1 is the} same or different and each independently selected from halogen, heteroaryl or -C(O)R ⁴ , wherein R ⁴ is as defined (I) stated.

In another preferred embodiment of the invention, a compound of the formula (I) or tautomerized thereof a form, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

R ² is a hydrogen atom;

R ^{3 is} selected from a hydrogen atom, an aryl group, -C(O)OR ⁴ or -NHC(O)OR ⁴ ;

R ^{4 is} selected from a hydrogen atom or an alkyl group, and the alkyl group is optionally further substituted with one or more -OC(O)OR ⁵ ;

R ^{5 is} selected from a hydrogen atom, an alkyl group or a cycloalkyl group.

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

Ring A, R ¹ , R ² , R ³ , m and n are as defined in formula (I).

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

R ⁷ are each the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;

q is 0, 1 or 2;

Rings A, R ² , R ³ and n are as defined in formula (I).

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

R ^{7 are the} same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;

R ⁸ or R ⁹ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NHR ⁴ or -NHC (O) NHOR ⁴ ;

R ^{4 is} as defined in the general formula (I);

q is 0, 1, or 2.

In another preferred embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

R ^{7 is} each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;

Ring C is selected from heteroaryl, aryl, heterocycloalkyl or cycloalkyl, preferably 5- or 6-membered heteroaryl, aryl, heterocycloalkyl or cycloalkyl, more preferably 5 or 6 Heterocycloalkyl; R ^{10 is} selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NHR ⁴ or -NHC (O) NHOR ⁴ ; preferably halogen, oxo, -C(O)OR ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ or -NHC(O)OR ⁴ ; more preferably -C( O) OR ⁴ ;

R ^{4 is} as defined in the general formula (I);

Each of p and q is independently selected from 0, 1, or 2.

A typical compound of the formula (I) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Medicinal salts, including but not limited to:

Table 1

Another aspect of the invention provides a compound of the formula (IIIC) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or a mixture, or a pharmaceutically acceptable salt thereof, which can be used to prepare a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer An intermediate of the isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl;

R ^{2 is} selected from a hydrogen atom, a halogen or an alkyl group;

R ^{3 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Base, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O Substituting a substituent of NHR ⁴ or -NHC(O)NHOR ⁴ ;

R ^{4 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkane. Substituted by a substituent of a cycloalkyl group, -OC(O)OR ⁵ or -NR ⁵ R ⁶ ;

R ⁵ or R ⁶ are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group;

R ^{7 is} each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;

q is 0, 1, or 2, and

n is 0, 1, or 2.

Another aspect of the invention provides a compound of the formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or a method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising:

The first step is a condensation reaction of a compound of the formula (IIIA) with a compound of the formula (IIIB) to obtain a compound of the formula (IIIC), and a second step of the compound of the formula (IIIC) obtained by a ring-forming reaction to obtain a formula ( III) a compound;

Wherein: the rings A, n, q, R ² , R ³ and R ⁷ are as defined in the formula (III).

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a prophylactic and/or therapeutic cardio-cerebral vascular disease, preferably a thromboembolic disease, more preferably an acute heart attack, angina pectoris, angioplasty Re-occlusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis after surgery or aortic coronary shunt.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for preventing and/or treating a disease which is positively affected by inhibition of factor XIa; for use in the preparation of a medicament for treating disseminated intravascular coagulation And the use in the preparation of a medicament for inhibiting factor XIa.

Another aspect of the invention relates to a method of modulating factor XIa activity, preferably inhibiting factor XIa, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

Another aspect of the invention relates to a method of treating and/or preventing cardiovascular and cerebrovascular diseases, the method comprising A therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, administered to a subject in need thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The disease described therein is preferably a thromboembolic disease, more preferably re-occlusion and restenosis after arrhythmia, angina pectoris, or aortic coronary artery bypass, stroke, transient ischemic attack, peripheral arterial occlusion Disease, pulmonary embolism or deep vein thrombosis.

Another aspect of the invention relates to a method of preventing and/or treating a disease which is positively affected by inhibition of factor XIa, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof. An isomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

Another aspect of the invention relates to a method of treating a disseminated intravascular coagulopathy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, mesogenic a form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of cardiovascular and cerebrovascular diseases, preferably thromboembolic diseases, more preferably cardiac arrest, angina pectoris, angioplasty or aortic coronary artery shunt Postoperative reocclusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for preventing and/or treating a disease which is positively affected by inhibition of factor XIa; for treating disseminated intravascular coagulation; and for inhibiting factor XIa activity.

Detailed description of the invention

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

"Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-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-dimethyl Lymeyl, 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-decyl, 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 having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene The alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

The cycloalkyl ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring to form a "fused cycloalkyl" wherein the ring to which the parent structure is attached is a cycloalkyl group. Non-limiting examples include tetrahydronaphthyl, benzocycloheptyl,

等。

Wait.

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _m ( Wherein m is a hetero atom of 0 to 2, but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms; more preferably, the heterocyclic ring contains 3 to 10 ring atoms, of which 1 to 3 are hetero atoms; more preferably, the heterocyclic ring contains 5 to 6 ring atoms, of which 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The heterocyclyl ring may be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring to form a "fused heterocyclic group" wherein the ring to which the parent structure is attached is a heterocyclic group. Non-limiting examples include:

等。

Wait.

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, more preferably benzene. The base and naphthyl are most preferably phenyl. The aryl ring may be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring to form a "fused aryl" wherein the ring to which the parent structure is attached is an aryl ring, unrestricted The sexual embodiment includes:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane. Base amino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkyl sulfur Base, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NHR ⁴ or -NHC(O)NHOR ⁴ ; wherein R ^{4 is} as defined in the compound of formula (I).

"Heteroaryl" refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan. The heteroaryl group is preferably 5 or 6 members, and preferred examples include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl , pyridazinyl and the like. The heteroaryl ring may be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring to form a "fused heteroaryl" wherein the ring to which the parent structure is attached is a heteroaryl ring Non-limiting examples include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O) R ⁴ , —NHC(O)R ⁴ , —NHC(O)OR ⁴ , —NHC(O)NHR ⁴ or —NHC(O)NHOR ⁴ ; wherein R ^{4 is} as defined in the compound of formula (I) .

"Haloalkyl" means that the alkyl group is substituted by one or more halogens, wherein the alkyl group is as defined above.

"Hydroxy" refers to an -OH group.

"Hydroxyalkyl" means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH ₂ .

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Oxo group" means =0.

"Carboxylic acid group" means -C(O)OH.

"Carboxylic acid ester group" means -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted 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 will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

Method for synthesizing the compound of the present invention

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

Option One

In the first step, the compound of the formula (IIIA) and the compound of the formula (IIIB) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (IIIC), and the second step is a compound of the formula (IIIC). And a sodium azide, trimethyl orthoformate is subjected to a ring-forming reaction under glacial acetic acid to obtain a compound of the formula (III);

Wherein: the ring A, n, q, R ² , R ³ or R ^{7 is} as defined in the formula (III).

Option II

In the first step, the compound of the formula (IVA) and the compound of the formula (IVB) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (IVC), and the second step is a compound of the formula (IVC). The ring-forming reaction is carried out with sodium azide and trimethyl orthoformate under glacial acetic acid to obtain a compound of the formula (IV);

Wherein: R ² , q, R ⁷ to R ¹⁰ are as defined in the formula (IV).

third solution

The first step reaction is a compound of the formula (VA) and a compound of the formula (VB) which are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (VC), and the second step is a compound of the formula (VC). The ring-forming reaction is carried out with sodium azide and trimethyl orthoformate under glacial acetic acid to obtain a compound of the formula (V);

Wherein: the definition of the ring C, p, q, R ⁷ , R ^{10 is} as defined in the formula (V).

In the above synthetic technical scheme, the reagent for providing basic conditions includes an organic base and an inorganic base, and the organic base includes, but not limited to, 1-hydroxybenzotriazole, triethylamine, N,N-diisopropyl. Ethylamine, N,N-dimethylformamide, pyridine, sodium hexamethyldisilazide, n-butyllithium, potassium t-butoxide or tetrabutylammonium bromide, preferably N,N-dimethyl Carboxamide; the inorganic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.

Condensing agents include, but are not limited to, bicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide Amine, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzoate Triazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azo Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Or benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate, preferably dicyclohexylcarbodiimide.

detailed description

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the raw material or the manufacturer of the commodity. Reagents without specific source are routine reagents purchased from the market.

Example

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

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

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

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

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

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

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.

Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

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

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

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

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone System, D: ethyl acetate and dichloromethane system, E: ethyl acetate and dichloromethane and n-hexane, F: ethyl acetate and dichloromethane and acetone, the volume ratio of the solvent is different depending on the polarity of the compound Adjustment, can also be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.

Example 1

(S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- Methyl 3-amido)-1H-indole-2-carboxylate

first step

(S)-5-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole Methyl 2-carboxylate

Methyl 5-amino-1H-indole-2-carboxylate 1a (124 mg, 0.64 mmol, obtained by a known method "Journal of the American Chemical Society, 2007, 129 (35), 10858-10869") (S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (200 mg, 0.64 mmol, Prepared by the method disclosed in the patent application "WO2013093484", 1-hydroxybenzotriazole (104 mg, 0.77 mmol), dicyclohexylcarbodiimide (160 mg, 0.77 mmol) dissolved in 10 mL of N,N-dimethyl The carboxamide was stirred at room temperature for 16 hours. Filter and filter cake was washed with 20 mL of N,N-dimethylformamide. The mother liquors were combined and concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography elutd elut elut elut elut eluting , 5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid methyl ester 1c (240 mg, brown oil), yield: 78.0%.

MS m/z (ESI): 477.1 [M+1]

Second step

(S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- Methyl 3-amido)-1H-indole-2-carboxylate

(S)-5-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole Methyl hydrazine-2-carboxylate 1c (120 mg, 0.25 mmol), sodium azide (56 mg, 0.87 mmol) was dispersed in trimethyl orthoformate (0.98 mL, 8.82 mmol), then 2 mL glacial acetic acid was added dropwise, 70 ° C The reaction was stirred for 16 hours. The organic layer was concentrated under reduced pressure. The mixture was washed with a saturated aqueous solution of sodium chloride (20 mL? The residue obtained by purification (HPLC) was purified by preparative elution to afford the title product (S)-5-(7-(5-chloro-2-(1H-tetraazol-1-yl)phenyl)-5-oxo Methyl-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylate 1 (50 mg, white solid), yield: 38.0%.

MSm/z (ESI): 530.2 [M+1]

¹ H NMR (400 MHz, CD ₃ OD): δ 9.24 (s, 1H), 7.92 (s, 1H), 7.74-7.67 (m, 3H), 7.39-7.38 (m, 2H), 7.11 (s, 1H) ), 6.18 (s, 1H), 6.04 (s, 1H), 5.26-5.23 (m, 1H), 3.91 (s, 3H), 3.13 - 3.03 (m, 1H), 3.29 - 3.21 (m, 1H), 2.64-2.53(m,1H),2.42-2.34(m,1H)

Example 2

(S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)-1H-indole-2-carboxylic acid

first step

(S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine Methyl 3-amido)-1H-indole-2-carboxylate 1 (23 mg, 0.043 mmol) was added to a mixture of 2 mL of methanol and tetrahydrofuran (V/V = 1:1). The lithium solution was stirred at room temperature for 2 hours. Concentrate under reduced pressure, add 10 mL of water, add 2M hydrochloric acid to adjust the pH to 2 to 3, extract with dichloromethane and methanol (V/V = 5:1, 30mL × 3), and combine the organic phase with anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The residue obtained by purification (HPLC) was purified by preparative elution to afford the title product (S)-5-(7-(5-chloro-2-(1H-tetraazol-1-yl)phenyl)-5-oxo -1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid 2 (10 mg, white solid), yield: 45%.

MS m/z (ESI): 516.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ11.7 (s, 1H), 10.32 (s, 1H), 9.70 (s, 1H), 8.0 (s, 1H), 7.81-7.79 (m, 3H) , 7.36-7.35 (m, 2H), 7.03 (s, 1H), 5.98-5.93 (m, 2H), 5.14-5.08 (m, 1H), 3.10-2.98 (m, 2H), 2.52-2.48 (m, 1H), 2.24 - 2.12 (m, 1H)

Example 3

(S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N-(1H-indol-5-yl)-5-oxo-1,2, 3,5-tetrahydroindolizine-3-carboxamide

first step

(S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-carboxylate Acid (S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (60 mg, 0.2 mmol) Sodium azide (13 mg, 0.2 mmol) was dispersed in 0.3 mL of trimethyl orthoformate, and 2 mL of glacial acetic acid was added dropwise thereto, and the reaction was stirred at 65 ° C for 16 hours. The residue was purified by silica gel column chromatography eluting -Oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 3a (73 mg, m.p.).

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

Second step

(S)-7-(5-Chloro-2-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N-(1H-indol-5-yl)-5- Oxo-1,2,3,5-tetrahydroindolizin-3-carboxamide

(S)-7-(5-Chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3- Carboxylic acid 3a (73 mg, 0.2 mmol), 5-aminoindole (39 mg, 0.3 mmol, prepared by a known method "Electrochimica Acta, 2013, 107, 292-300"), 1-hydroxybenzotriazole (40 mg, 0.3 mmol), dicyclohexylcarbodiimide (60 mg, 0.3 mmol) was dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 72 hours. Filter and filter cake was washed with 20 mL of N,N-dimethylformamide. The mother liquors were combined, concentrated under reduced pressure and purified (mjjjjjjj N-(1H-Indol-5-yl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxamide 3 (20 mg, m.p.).

MS m/z (ESI): 472.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ10.03 (s, 1H), 10.22 (s, 1H), 9.72 (s, 1H), 7.87 (s, 1H), 7.87-7.80 (m, 3H) , 7.33-7.30 (m, 2H), 7.20 (d, 1H), 6.37 (s, 1H), 5.99 (s, 1H), 5.95 (s, 1H), 5.11 (d, 1H), 3.17-3.05 (m , 1H), 3.01-2.95 (m, 1H), 2.48-2.42 (m, 1H), 2.20-2.15 (m, 1H)

Example 4

(S)-6-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)-1H-indole-2-carboxylic acid

first step

(S)-6-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole Methyl 2-carboxylate

Methyl 6-amino-1H-indole-2-carboxylate (200 mg, 1 mmol, prepared by the method disclosed in the patent application "WO 2012101013"), (S)-7-(2-amino-5-chloro Phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (304 mg, 1 mmol), 1-hydroxybenzotriazole (150 mg, 1.1 mmol), bicyclo Hexylcarbodiimide (220 mg, 1.1 mmol) was dissolved in 3 mL of N,N-dimethylformamide and stirred at room temperature for 4 hours. Filter and filter cake was washed with 20 mL of N,N-dimethylformamide. The mother liquors were combined and concentrated under reduced pressure. The obtained residue was purified to silica gel column chromatography eluting elut elut elut elut elut elut elut , 5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid methyl ester 4a (203 mg, brown solid), yield: 42.8%.

Second step

(S)-6-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole 2-carboxylic acid

(S)-6-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amide)-1H-indole Methyl hydrazine-2-carboxylate 4a (203 mg, 0.43 mmol) was dissolved in 10 mL of methanol, and 3 mL of a 2N sodium hydroxide solution was added and allowed to react at room temperature for 4 hours. The organic layer was combined with EtOAc (3 mL). Crude (S)-6-(7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole哚-2- Carboxylic acid 4b (200 mg, grey solid).

MS m/z (ESI): 463.0 [M+1]

third step

(S)-6-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)-1H-indole-2-carboxylic acid

The crude (S)-6-(7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amide)-1H- Indole-2-carboxylic acid 4b (200 mg, 0.43 mmol), sodium azide (30 mg, 0.43 mmol) was dispersed in 2 mL of trimethyl orthoformate, and 5 mL of glacial acetic acid was added dropwise thereto, and the reaction was stirred at 70 ° C for 5 hours. The organic layer was combined with ethyl acetate (30 mL×3), and the organic phase was combined and washed with saturated sodium hydrogen carbonate solution (20 mL×1) and saturated sodium chloride solution (20 mL×2). The sodium was dried, filtered, and the filtrate was concentrated. The obtained residue was purified to silica gel column chromatography elut elut elut elut eluting 5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid 4 (15 mg, pale yellow solid), yield: 6.8%.

MS m/z (ESI): 516.0 [M+1]

Example 5

(S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)benzofuran-2-carboxylic acid

first step

(S)-5-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran-2 -carboxylic acid ethyl ester

(S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (305 mg, 1 Ment), ethyl 5-aminobenzofuran-2-carboxylate (205 mg, 1 mmol, prepared by the known method "Journal of Medicinal Chemistry, 2008, 51 (11), 3133-3144"), 1-hydroxyl Benzotriazole (163 mg, 1.2 mmol), dicyclohexylcarbodiimide (247 mg, 1.2 mmol) was dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours. The residue was purified by silica gel column chromatography elut eluting , 2,3,5-tetrahydroindolizin-3-amido)benzofuran-2-carboxylic acid ethyl ester 5a (600 mg, yellow solid), yield: 100%.

MS m/z (ESI): 492.2 [M+1]

Second step

(S)-5-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran-2 -carboxylic acid

(S)-5-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran- Ethyl 2-carboxylate 5a (600 mg, 1.22 mmol) was dissolved in 12 mL of a mixed solvent of methanol and tetrahydrofuran (V/V = 1:1), and 6.1 mL of 2N sodium hydroxide solution was added thereto, and the mixture was reacted at room temperature for 16 hours. The organic layer was extracted with EtOAc (3 mL, EtOAc). Obtained crude (S)-5-(7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran 2-carboxylic acid 5b (150 mg, yellow solid), yield: 26.5%.

MS m/z (ESI): 464.2 [M+1]

third step

(S)-5-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)benzofuran-2-carboxylic acid

Crude (S)-5-(7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran 2-carboxylic acid 5b (150 mg, 0.32 mmol), sodium azide (105 mg, 1.62 mmol) was dispersed in 3 mL of trimethyl orthoformate, and 3 mL of glacial acetic acid was added dropwise thereto, and the reaction was stirred at 70 ° C for 16 hours. The residue obtained by separation and purification was purified to give the title product (S)-5-(7-(5-chloro-2-(1H-tetraazol-1-yl)phenyl)-5-oxo- 1,2,3,5-tetrahydroindolizin-3-amido)benzofuran-2-carboxylic acid 5 (20 mg, yellow solid), yield: 12.1%.

MS m/z (ESI): 517.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ13.50 (s, 1H), 10.61 (s, 1H), 9.71 (s, 1H), 8.20-8.13 (m, 1H), 7.83-7.79 (s, 3H), 7.62-7.60 (m, 2H), 7.60 (s, 1H), 6.02-5.94 (d, 2H), 5.14-5.08 (m, 1H), 3.14-2.94 (m, 2H), 2.51-2.49 ( m, 1H), 2.24 - 2.14 (m, 1H)

Example 6

(S)-4-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)benzoic acid

first step

(S)-4-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)methyl benzoate

(S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (150 mg, 0.5 mmol), Methyl p-aminobenzoate (76 mg, 0.5 mmol), 1-hydroxybenzotriazole (81 mg, 0.6 mmol), dicyclohexylcarbodiimide (124 mg, 0.6 mmol) dissolved in 5 mL of N,N-dimethyl The formamide was stirred at room temperature for 16 hours. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut , 2,3,5-tetrahydroindolizin-3-amido)methyl benzoate 6a (120 mg, yellow solid), yield: 55%.

MS m/z (ESI): 438.2 [M+1]

Second step

(S)-4-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzoic acid

(S)-4-(7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzoic acid methyl ester 6a (600 mg, 1.22 mmol) was dissolved in 8 mL of methanol, and 1.9 mL of 2N sodium hydroxide solution was added and allowed to react at room temperature for 16 hours. The organic layer was extracted with EtOAc (3 mL, EtOAc). Obtained crude (S)-4-(7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzoic acid 6b (60 mg, yellow solid), Yield: 51.7%.

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

third step

(S)-4-(7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine- 3-amido)benzoic acid

The crude (S)-4-(7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzoic acid 6b (60 mg, 0.14 mmol), sodium azide (46 mg, 0.71 mmol) was dispersed in 2 mL of trimethyl orthoformate, and 2 mL of glacial acetic acid was added dropwise thereto, and the reaction was stirred at 70 ° C for 16 hours. The residue obtained by separation and purification was purified to give the title product (S)-4-(7-(5-chloro-2-(1H-tetraazol-1-yl)phenyl)-5-oxo- 1,2,3,5-four Hydrogen hydrazin-3-amido)benzoic acid 6 (30 mg, pale yellow solid), yield: 45.0%.

MS m/z (ESI): 475.1 [M-1]

^{1 H NMR (400MHz, DMSO-} d 6): δ13.50 (s, 1H), 10.61 (s, 1H), 9.71 (s, 1H), 8.20-8.13 (m, 1H), 8.04-8.00 (m, 1H), 7.83-7.79(s,3H), 7.62-7.60(m,2H), 6.02-5.94(m,2H),5.14-5.08(m,1H),3.14-2.94(m,2H),2.51- 2.49 (m, 1H), 2.24 - 2.14 (m, 1H)

Example 7

(S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2-oxo-1,2,3,4-tetra Hydroquinolin-6-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide

first step

(S)-7-(2-Amino-5-chlorophenyl)-5-oxo-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1 ,2,3,5-tetrahydroindolizine-3-carboxamide

(S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b (122 mg, 0.4 mmol), 6-Amino-3,4-dihydroquinolin-2(1H)-one 7a (65 mg, 0.4 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol), dicyclohexylcarbodiimide (99 mg) , 0.48 mmol) was dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours. After adding 20 mL of water, the mixture was extracted with ethyl acetate (30 mL? The obtained residue was purified by silica gel column chromatography elutd elut elut elut elut elut elut elut elut 1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide 7b (100 mg, pale yellow solid), yield: 55.0% .

MS m/z (ESI): 449.3 [M+1]

Second step

(S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(2-oxo-1,2,3,4-tetra Hydroquinolin-6- 1,1,2,3,5-tetrahydroindolizine-3-carboxamide

(S)-7-(2-Amino-5-chlorophenyl)-5-oxo-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)- 1,2,3,5-tetrahydroindolizine-3-carboxamide 7b (100 mg, 0.22 mmol), sodium azide (44 mg, 0.66 mmol) was dispersed in 1 mL of trimethyl orthoformate, and 2 mL was added dropwise. The glacial acetic acid was stirred at 60 ° C for 16 hours. Distilled under reduced pressure, and the mixture was stirred and evaporated, evaporated, evaporated, evaporated. The obtained residue was purified by preparative purification to give the title product (S)-7-(5-chloro-2-(1H-tetraazol-1-yl)phenyl)-5-oxo-N-(2-oxo Generation-1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide 7 (90 mg, pale yellow solid), yield: 81.8%.

MS m/z (ESI): 502.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ10.30 (s, 1H), 10.03 (s, 1H), 9.70 (s, 1H), 7.81-7.79 (m, 2H), 7.78-7.77 (m, 1H), 7.46 (m, 1H), 7.29 (s, 1H), 6.78 (d, 1H), 5.93-5.79 (m, 2H), 5.07-5.04 (m, 1H), 3.11-2.94 (m, 2H) , 2.85-2.81(t,2H),2.44-2.41(m,3H),2.16-2.08(m,1H)

Example 8

(S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydro Indolizin-3-amido)benzofuran-2-carboxylic acid

first step

N-(4-chloro-3-fluoro-2-(tributyltin)phenyl)-2,2,2-trifluoroacetamide

Tetramethylethylenediamine (12.5 mL, 82.8 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -78 °C with argon. n-Butyllithium (33.4 mL, 82.8 mmol, 2.5 M in tetrahydrofuran) was added dropwise to the above reaction mixture. After the completion of the dropwise addition, stirring was continued at 78 ° C for 1 hour. 50 mL of tetrahydrofuran solution of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide 8a (10 g, 41.4 mmol, prepared by the method disclosed in the patent application "WO2009114677") It was added to the above reaction solution. After the completion of the dropwise addition, stirring was continued at 78 ° C for 2 hours. Finally, a solution of tributyltin chloride (13.4 mL, 49.6 mmol) in 50 mL of tetrahydrofuran was added dropwise to the above reaction solution, and the mixture was slowly warmed to room temperature and the reaction was continued for 2 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The obtained residue was purified by silica gel column chromatography using eluent system B to give the desired product N-(4-chloro-3-fluoro-2-(t-butyltin)phenyl)-2,2,2-trifluoroacetamide 8b (11.1 g, brown oil), yield: 50.5%.

Second step

(S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetyl)phenyl)-5-oxo-1,2,3,5-tetrahydro-nitrogen Ethyl-3-carboxylate

N-(4-Chloro-3-fluoro-2-(tributyltin)phenyl)-2,2,2-trifluoroacetamide 8b (1.5 g, 2.8 mmol), (S)-5-oxo- 7-(((Trifluoromethyl)sulfonyl)oxy)-1,2,3,5-tetrahydroindolizine-3-carboxylic acid ethyl ester 8c (1 g, 2.8 mmol, using the patent application "WO2013093484" Prepared by the disclosed method, dissolved in 10 mL of dioxane, replaced with argon, and added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (41 mg, 0.06 mmol), The mixture was protected by argon gas, and the reaction was stirred at 100 ° C for 16 hours. The organic layer was concentrated under reduced pressure, and the residue obtained was purified to silica gel column chromatography to eluent to afford the desired product (S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetyl) Ethyl phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid ethyl ester 8d (1.2 g, yellow solid), yield: 96.0%.

MS m/z (ESI): 447.0 [M+1]

third step

(S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid

(S)-7-(3-chloro-2-fluoro-6-(2,2,2-trifluoroacetyl)phenyl)-5-oxo-1,2,3,5-tetrahydro Azaindole-3-carboxylate Ethyl acetate 8d (1.2 g, 2.7 mmol) was dissolved in 10 mL of ethanol, and 7.3 mL of 1N sodium hydroxide solution was added, and the mixture was heated to reflux for 4 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) -7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 8e (700 mg, yellow solid) Yield: 80.4%.

MS m/z (ESI): 323.0 [M+1]

the fourth step

(S)-5-(7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzene Ethyl furan-2-carboxylate

(S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 8e (162 mg, 0.5 mmol), ethyl 5-aminobenzofuran-2-carboxylate (103 mg, 0.5 mmol, obtained by a known method "Journal of Medicinal Chemistry, 2008, 51 (11), 3133-3144"), 1 -Hydroxybenzotriazole (135 mg, 1 mmol), 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (192 mg, 1 mmol), N,N-diisopropyl The amine (322 mg, 2.5 mmol) was dissolved in 6 mL of N-N-dimethylformamide and stirred at room temperature for 16 hours. The residue was purified by silica gel column chromatography elut elut elut elut elut elut elut Ethyl-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran-2-carboxylic acid ethyl ester 8f (40 mg, white solid), yield: 16%.

MS m/z (ESI): 510.1 [M+1]

the fifth step

(S)-5-(7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzene Furan-2-carboxylic acid

(S)-5-(7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido) Ethyl benzofuran-2-carboxylate 8f (40 mg, 0.078 mmol) was dissolved in 6 mL of methanol, and 3 mL of 2N sodium hydroxide solution was added and stirred at room temperature for 16 hours. The organic layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) -5-(7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran- 2-carboxylic acid 8 h (51 mg, yellow solid), yield: 100%.

MS m/z (ESI): 482.0 [M+1]

Step 6

(S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydro Indolizin-3-amido)benzofuran-2-carboxylic acid

Crude (S)-5-(7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido Benzylfuran-2-carboxylic acid 8h (51mg, 0.11mmol), sodium azide (36mg, 0.55mmol) was dispersed in 2mL of trimethyl orthoformate, 3mL glacial acetic acid was added dropwise, and the reaction was stirred at 70 °C. hour. The residue obtained by separation and purification was purified to give the title product (S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetraazol-1-yl)phenyl)-5. -oxo-1,2,3,5-tetrahydroindolizin-3-amido)benzofuran-2-carboxylic acid 8 (24 mg, yellow solid) Rate: 41.4%.

MS m/z (ESI): 534.5 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ13.50 (s, 1H), 10.61 (s, 1H), 9.71 (s, 1H), 8.21-8.16 (m, 1H), 8.06-7.99 (m, 1H), 7.75 (dd, 1H), 7.70-7.64 (m, 2H), 7.59-7.53 (m, 1H), 6.10 (s, 2H), 5.17-5.07 (m, 1H), 3.15-3.03 (m, 2H), 2.57-2.53 (m, 1H), 2.25-2.14 (m, 1H) ^.

Example 9

(S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydro Medium azaindole-3-amido)-1H-indole-2-carboxylic acid

first step

(S)-5-(7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)- 1H-indole-2-carboxylic acid tert-butyl ester

(S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 8e (250 mg, 0.77 mmol), 5-amino-1H-indole-2-carboxylic acid tert-butyl ester 9a (180 mg, 0.77 mmol, prepared by a known method "Journal of Medicinal Chemistry, 2012, 55(2), 766-782") (), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (354 mg, 0.95 mmol), N,N-diisopropyl Ethylamine (0.3 g, 2.3 mmol) was dissolved in 6 mL of N,N-dimethylformamide, and the mixture was stirred at 50 ° C for 4 hours. 10 mL of water was added to the reaction mixture, and a solid was precipitated and filtered. The filter cake was dissolved in ethyl acetate (100 mL), dried over anhydrous sodium sulfate 6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid Butyrate 9b (50 mg, pale yellow solid), yield: 12.1%.

MS m/z (ESI): 537.2 [M+1]

Second step

(S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydro N-indole-3-amido)-1H-indole-2-carboxylic acid tert-butyl ester

(S)-5-(7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido) -1H-indole-2-carboxylic acid tert-butyl ester 9b (50 mg, 0.1 mmol), trimethyl orthoformate (160 mg, 1.5 mmol) was added to 6 mL of glacial acetic acid, and reacted at room temperature for 30 minutes, then sodium azide was added ( 20 mg, 0.3 mmol), and the reaction was stirred at 60 ° C for 16 hours. (S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetra A solution of tert-butyl ester 9c of -1H-indole-2-carboxylic acid in hydrogen.

MS m/z (ESI): 560.1 [M+1]

third step

(S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetrahydro Medium azaindole-3-amido)-1H-indole-2-carboxylic acid

(S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5-tetra To a solution of tert-butyl ester 9c of -1H-indole-2-carboxylic acid in hydrogen, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by separation and purification was purified to give the title product (S)-5-(7-(3-chloro-2-fluoro-6-(1H-tetraazol-1-yl)phenyl)- 5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid 9 (20 mg, pale yellow solid), yield: 37.7%.

MS m/z (ESI): 534.0 [M+1]

_{^{1 H NMR (400MHz, CD 3}} OD): δ9.37 (s, 1H), 7.94 (d, 2H), 7.88 (dd, 1H), 7.60 (dd, 1H), 7.45-7.38 (m, 2H), 7.12(s,1H), 6.23(d,1H), 5.28(dd,1H), 3.25-3.10(m,2H),2.56-2.66(m,1H),2.33-2.48(m,1H)

Example 10

(S)-5-(7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole Indole-2-carboxylic acid

first step

(S)-7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid ethyl ester

(S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5-tetrahydroindolizine-3-carboxylic acid ethyl ester 8c (430 mg , 1.21 mmol), 2-acetyl-5-chlorophenylboronic acid pinacol ester (407 mg, 1.45 mmol, prepared by the well-known method "Chemistry Letters, 2011, 40 (9), 1007-1008"), 1.81 A 2N sodium carbonate aqueous solution, tetrakistriphenylphosphorus palladium (70 mg, 0.06 mmol) was dissolved in 45 mL of a mixed solvent of toluene and ethanol (V/V = 2:1), protected by argon gas exchange, and stirred at 70 ° C for 16 hours. . The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl 2,3,5-tetrahydroindolizin-3-carboxylate 10a (500 mg, pale yellow solid), yield: 100%.

MS m/z (ESI): 360.0 [M+1]

Second step

(S)-7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid

(S)-7-(2-Acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid ethyl ester 10a (500 mg, 1.4 Methyl) was dissolved in 20 mL of methanol, and 2.1 mL of 2N sodium hydroxide solution was added, and the reaction was stirred at room temperature for 48 hours. Concentrate under reduced pressure, add 20 mL of water, extract with dichloromethane (20 mL×2), add 1N hydrochloric acid to the aqueous phase pH 2-3, with dichloromethane and methanol (V/V=20:1, 40mL×2) extraction. The extraction solvent after adjusting the pH was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude (S)-7-(2-acetyl-5-chlorophenyl)-5-oxo-1, 2,3,5-tetrahydroindolizine-3-carboxylic acid 10b (390 mg, yellow solid), yield: 84.2%.

MS m/z (ESI): 332.1 [M+1]

third step

(S)-5-(7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole Methyl hydrazine-2-carboxylate

Methyl 5-amino-1H-indole-2-carboxylate 1a (76 mg, 0.4 mmol), (S)-7-(2-acetyl-5-chlorophenyl)-5-oxo-1, 2,3,5-tetrahydroindolizine-3-carboxylic acid 10b (132 mg, 0.4 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol), dicyclohexylcarbodiimide (99 mg, 0.48 mmol) Dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours. Add 30 mL of water, extract with ethyl acetate (40 mL × 2), and combine organic The residue was dried over anhydrous sodium sulfate (MgSO4) -Chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid methyl ester 10c (200 mg, brown oil) , Yield: 94.3%.

MS m/z (ESI): 504.2 [M+1]

the fourth step

(S)-5-(7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizin-3-amido)-1H-indole (S)-5-(7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizidine-3-carboxylate Methylamide-1H-indole-2-carboxylic acid methyl ester 10c (200 mg, 0.39 mmol) was dissolved in 15 mL of a mixed solvent of methanol and tetrahydrofuran (V/V = 2:1), and 1 mL of 2N sodium hydroxide solution was added dropwise. The reaction was stirred at room temperature for 5 hours. After concentrating under reduced pressure, water (2 mL), EtOAc (EtOAc)EtOAc. Purification by eluent system A using silica gel column chromatography to give the desired product (S)-5-(7-(2-acetyl-5-chlorophenyl)-5-oxo-1,2,3,5 - tetrahydroindolizin-3-amido)-1H-indole-2-carboxylic acid 10 (100 mg, white solid), yield: 52.6%.

MS m/z (ESI): 490.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6): δ11.70 (s, 1H), 10.36 (s, 1H), 8.02 (s, 1H), 7.76 (d, 1H), 7.65-7.61 (m, 1H) , 7.49 (d, 1H), 7.39-7.36 (m, 2H), 7.05-7.02 (m, 1H), 6.19 (s, 1H), 6.11 (s, 1H), 5.19-5.16 (m, 1H), 3.24 -3.11(m,2H), 2.52-2.48(m,1H), 2.45(s,3H), 2.26-2.18(m,1H)

Examples 11-26 were synthesized according to the synthesis method of Examples 1-10 of the present invention using different starting materials. The spectral parameters of Examples 11-26 are shown in Table 2 below:

Table 2

Biological evaluation

The invention is further described below in conjunction with the test examples, but these examples are not intended to limit the scope of the invention.

The experimental method in which the specific conditions are not indicated in the test examples of the present invention is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer of the product. Reagents without specific source are routine reagents purchased from the market.

Test Example 1 Fluorometric detection of biological activity of factor XIa inhibitor

1. Experimental materials

Enzyme: Factor XIa Protease (Abcam, Cat. No. ab62411),

Substrate: Factor XIa specific substrate (DaiPharma, Cat. No. S821090),

Buffer: 100 mM tris-HCl, 200 mM NaCl, 0.02% tween 20, pH 7.4.

2, the experimental steps

20 mM test compound in 100% DMSO was diluted to 200, 20, 2, 0.2, 0.02, 0.002 uM with 100% DMSO; 1 ul of compound was added to each well in a 384-well plate, blank and control wells were replaced with DMSO, centrifuged , leaving the compound to the bottom. Add 10 ul (2.5 ug/ml) of FXIa enzyme solution to each well, add 10 ul of buffer to the blank well, centrifuge, and leave the enzyme solution to the bottom.

Finally, 10 ul of 2 mM substrate was added to each well and centrifuged to remove the substrate solution to the bottom.

Incubate at 37 ° C for 10 minutes; then measure its absorbance at 405 nm. Absorbance values were fitted using Prism curve obtained IC _50.

Compound number IC ₅₀ (factor XIa) / (nM) Example 2 6.4 Example 3 284.5 Example 4 17.2 Example 5 20.1 Example 7 60.6 Example 8 25.3 Example 9 12.5 Example 11 57.2 Example 15 96.6 Example 18 214.0 Example 20 290.4 Example 21 34.3 Example 24 70.7 Example 25 132.9 Example 27 132.7

Conclusion: The compounds of the present invention have significant inhibitory activity against factor XIa.

Test Example 2 Determination of anticoagulant effect in human blood in vitro

1. Experimental materials

Plasma: human blood was collected in a blood collection tube containing no anticoagulant, adding 3.8% sodium citrate (volume ratio 1:9), centrifuged at 2500 rpm for 10 min at room temperature, and the plasma was collected and stored at -80 ° C;

Reagents: APTT reagent (activated partial thromboplastin time assay kit, SIEMENS, item number B4218-1), PT reagent (prothrombin time assay kit, SIEMENS, item number OUHP29), calcium chloride solution;

Instrument: Coagulation instrument (SYSMEX, CA-500).

2, experimental testing

The divided plasma was melted at room temperature and mixed evenly. 10000 uM test compound dissolved in 100% DMSO was diluted to 3000, 300, 200, 150, 75, 30, 10, 3, 0.3 uM with 100% DMSO and the blank was 100% DMSO. The reagent, plasma, and compound are placed in the corresponding positions in the coagulation instrument, and the APTT and PT of the compound are detected.

3, data processing

Curve fitting was performed by Prism to calculate the concentration of CT ₂ , which is the compound corresponding to APTT and PT of 2 times the blank control. The results are as follows:

Compound number Inhibition of platelet aggregation CT ₂ (μM) Example 2 1.83 Example 5 36.58 Example 8 21.71 Example 9 3.84 Example 24 10.74

Conclusion: The compounds of the present invention have significant inhibitory activity against human blood agglutination.

Pharmacokinetic evaluation

Test Example 3, Pharmacokinetic Testing of Compounds of the Inventive Examples

1. Summary

SD rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compounds of Examples 1 and 2 by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

2, the test plan

2.1 test drugs

Examples 1, 2, 28 and 29 compounds

2.2 Test animals

Healthy adult SD rats, 16 males and females, were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

2.3 drug preparation

Note: PEG: polyethylene glycol CMC-Na: sodium carboxymethyl cellulose

2.4 administration

Sixteen SD rats, half male and half female, were divided into 4 groups on average. After fasting overnight, they were intragastrically administered and administered intragastrically.

3, operation

The rats in the gavage administration group collected blood at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h before and after the administration. 0.2 ml was placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 min, and stored at -20 °C. The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.

4, pharmacokinetic parameters results

The pharmacokinetic parameters of the compounds of Examples 1, 2, 28 and 29 of the present invention are as follows:

Conclusion: Compounds 1, 28 and 29 of the present invention have good pharmacological absorption as prodrugs of the compound of Example 2, and have obvious pharmacological absorption effects.

Claims (17)

a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable drug thereof Salt used:

among them: Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl; Ring B is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; R ¹ each being the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -C(O)R ⁴ , wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkane. Substituted by a substituent of the group; R ^{2 is} selected from a hydrogen atom, a halogen or an alkyl group; R ^{3 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Base, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O NHR ⁴ or -NHC(O)NHOR ⁴ ; R ^{4 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, Substituted by a substituent of a hydroxyalkyl group, a cycloalkyl group, OC(O)OR ⁵ or -NR ⁵ R ⁶ ; R ⁵ or R ⁶ are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group; m is 0, 1, 2 or 3; n is 0, 1, or 2. A compound of the formula (I) according to claim 1 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a fused aryl group, preferably a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaryl ring fused to a benzene ring. A compound of the formula (I) according to claim 1 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of

The compound of the formula (I) according to any one of claims 1 to 3, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ^{1 is the} same or different, each independently selected from halo, heteroaryl or -C(O)R ⁴ , wherein R ⁴ is as defined in claim 1 Said. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 4; Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ² is a hydrogen atom; R ^{3 is} each the same or different and each independently selected from a hydrogen atom, an aryl group, -C(O)OR ⁴ or -NHC(O)OR ⁴ ; R ^{4 is} selected from a hydrogen atom or an alkyl group, and the alkyl group is optionally further substituted with one or more -OC(O)OR ⁵ ; R ^{5 is} selected from a hydrogen atom, an alkyl group or a cycloalkyl group. A compound of the formula (I) according to claim 1 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them: Rings A, R ¹ , R ² , R ³ , m and n are as defined in claim 1. The compound of the formula (I) according to claim 6, or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them: R ⁷ are each the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group; q is 0, 1, or 2; Rings A, R ² , R ³ and n are as defined in claim 1. The compound of the formula (I) according to claim 7 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them: R ^{7 are the} same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group; R ⁸ or R ⁹ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NHR ⁴ or -NHC (O) NHOR ⁴ ; R ^{4 is} as defined in claim 1; q is 0, 1, or 2. The compound of the formula (I) according to claim 7 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them: R ^{7 is} each the same or different and is each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group; Ring C is selected from heteroaryl, aryl, heterocyclic or cycloalkyl, preferably 5- or 6-membered heteroaryl, aryl, heterocycloalkyl or cycloalkyl, more preferably 5 or 6 Heterocycloalkyl; R ^{10 is} selected from the group consisting of hydrogen atom, halogen, cyano group, nitro group, alkyl group, haloalkyl group, hydroxyalkyl group, oxo group, cycloalkyl group, heterocyclic group, aryl group, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NHR ⁴ or -NHC(O)NHOR ⁴ ; Preferred is halogen, oxo, -C(O)OR ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ or -NHC(O)OR ⁴ ; more preferably -C(O)OR ⁴ ; R ^{4 is} as defined in claim 1; Each of p and q is independently selected from 0, 1, or 2. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 9. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

a compound of the formula (IIIC) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a drug thereof Salt used:

among them: Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl; R ^{2 is} selected from a hydrogen atom, a halogen or an alkyl group; R ^{3 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Base, -OR ⁴ , -C(O)OR ⁴ , -OC(O)R ⁴ , -C(O)R ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O NHR ⁴ or -NHC(O)NHOR ⁴ ; R ^{4 is} selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, Substituted by a substituent of a hydroxyalkyl group, a cycloalkyl group, OC(O)OR ⁵ or -NR ⁵ R ⁶ ; R ⁵ or R ⁶ are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group; R ^{7 is} each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group; q is 0, 1, or 2; n is 0, 1, or 2. A compound of the formula (I) according to claim 7 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising:

The first step is a condensation reaction of a compound of the formula (IIIA) with a compound of the formula (IIIB) to obtain a compound of the formula (IIIC), and a second step of the reaction of the obtained compound of the formula (IIIC) is carried out to form a ring-like reaction. (III) a compound; Wherein: the definition of the rings A, n, q, R ² , R ³ and R ⁷ is as defined in claim 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a tautomer, a mesophil, a racemate, an enantiomer, a non- An enantiomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, and excipient. A compound according to any one of claims 1 to 10, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt or a pharmaceutical composition according to claim 13 for the preparation of a prophylactic and/or therapeutic cardio-cerebral vascular disease, preferably a thromboembolic disease, more preferably a cardiac infarction Re-obstruction and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis after angina pectoris, angioplasty, or aortic coronary shunt. A compound according to any one of claims 1 to 10, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 13, for the prevention and/or treatment of positive effects by inhibitory factor XIa The use of the disease in medicine. A compound according to any one of claims 1 to 10, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of disseminated intravascular coagulation. A compound according to any one of claims 1 to 10, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for inhibiting Factor XIa.