CN105658641B - Benzazole amide derivatives, its preparation method and its application in medicine - Google Patents

Benzazole amide derivatives, its preparation method and its application in medicine Download PDF

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CN105658641B
CN105658641B CN201580002260.5A CN201580002260A CN105658641B CN 105658641 B CN105658641 B CN 105658641B CN 201580002260 A CN201580002260 A CN 201580002260A CN 105658641 B CN105658641 B CN 105658641B
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compound
alkyl
mixtures
mesomer
diastereoisomer
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CN105658641A (en
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杨方龙
瞿健
王春飞
董庆
孙飘扬
应永铖
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

The present invention relates to benzazole amide derivatives, its preparation method and its application in medicine.Specifically, the present invention relates to the benzazole amide derivatives shown in a kind of logical formula (I), its preparation method and pharmaceutical composition as well as therapeutic agent containing the derivative, purposes especially as XIa factor inhibitors and the purposes in the medicine for preparing the disease such as treatment and/or prevention thromboembolism, each substituent in its formula of (I) it is defined as the description.

Description

Benzazole-amide derivatives, its preparation method and its application in medicine
Technical field
The present invention relates to a new class of benzazole-amide derivatives, its preparation method and medicine group containing the derivative Compound as well as therapeutic agent, purposes especially as XIa factor inhibitors and are preparing treatment and/or pre- preventing thrombosis bolt Purposes in the medicines of disease such as plug.
Background technology
The cardiovascular and cerebrovascular diseases such as the global annual cerebrovascular, cerebral infarction, miocardial infarction, coronary heart disease, artery sclerosis seize closely The life of 12000000 people, close to the 1/4 of the total death toll in the world, becomes the No.1 formidable enemy of human health.China dies of the heart every year The number of vascular diseases reaches more than 2,600,000 people, and the patient 75% of survival is disabled, wherein more than 40% weight is residual.By cardiovascular and cerebrovascular Thrombus problem caused by disease and diabetes and its complication, become to be solved now it is very urgent the problem of.
It is cardiovascular according to independent 2011 annual datas of market analysis mechanism Datamonitor, it is expected that with the production of imitation medicine And share of the metabolic disease in seven big staple markets will reach peak in 2011, gradually reduce afterwards, its sales volume will be from 109,000,000,000 dollars of 101,000,000,000 dollars of near 2019 of 2010.Wherein thrombus market was kept basicly stable, by 2010 19500000000 dollars of 18,900,000,000 dollars of (Datamonitor for slightly falling to 2019：HC00034-001、HC00139-001).Mark in Guangzhou The point investigation report of 2011 displays that Chinese antithrombotic reagent market scale increased by a year-on-year basis up to 81.35 hundred million yuan in 2011 20.52%, there is huge market potential (antithrombotic reagent market intelligence：Guangzhou punctuate (2011)).
Human body blood coagulation system includes two processes：Intrinsic pathway (intrinsic pathway) and extrinsic pathway (extrinsic pathway) and common pathway (Annu.Rev.Med.2011.62：41-57).Extrinsic pathway is also referred to as For tissue factor approach, as exogenous route, damage and various external irritants under, tissue factor and the factor VIIa being activated (FVIIa) the compound activity factor X (FX) of composition, forms factor Xa (FXa), the FXa of activation can be by factor (prothrombin, PT) is converted into fibrin ferment (thrombin), center catalyzing enzyme of the fibrin ferment as coagulation process, catalysis fibre Fibrillarin proenzyme forms fibrin, plays hemoglutination.The enzyme quantity that the process participates in is few, quick.Intrinsic pathway category In the intrinsic approach of body, the factor for participating in blood coagulation all is from blood, passes through cascade reaction activity factor XII (FXII), the factor XI (FXI), factors IX (FIX), and then activate FXa and the factor (PT) in downstream is converted into fibrin ferment, fibrin ferment again can be with FXI is activated in turn.The enzyme quantity that the process participates in is more, and take effect relatively slow (Arterioscler Thromb Vasc Biol.2010；30：388-392).
In whole coagulation process, FXI and FXIa play extremely important role, it is coagulated as exogenous and endogenous The share regulatory factors of blood approach, its antagonist are widely deployed the treatment for various thrombus.On existing a variety of FXa antagonists City, vast cardiovascular and cerebrovascular market is occupied with its notable validity, but its side effect is also more and more significant, wherein " bleeding risk (bleeding risk) " is the problem of the severeest (N Engl J Med 1991 that stand in the breach；325：153-8、 Blood.2003；101：4783-4788).
To solve the problems, such as this, recent target spot FXIa becomes the research hot topic of each major company and research institution.There is research to send out Existing serious FXI deficiencies can cause congenital XI factor deficiency, which mostly occurs with Jew (1: 450).The symptom ratio of congenital XI factor deficiency Hemophilia A and B are more gentle, and hematostaxis occurs a little, in injured or operation the hemostatic function of body also from Influence, congenital XI factor deficiency patient can be given a birth (Arterioscler Thromb Vasc Biol.2010 with normal pregnancy；30：388- 392).Therefore FXIa securities are significantly better than FXa.Research is found, in thrombus model, suppressing the FXIa factors can effectively suppress The formation of thrombus, but in the case of even more serious thrombus, the very little (Blood.2010 of effect of FXIa；116(19)： 3981-3989).Clinical statistics show that the illness rate (Blood 2009 of VTE can be increased by improving the amount of FXIa；114：2878- 2883), its reduction of risk with DVT of FXIa wretched insufficiencies person (Thromb Haemost 2011；105：269-273).
FXIa not yet announces it and enters the medicine of clinical stage, but Bristol-Myers Squibb as emerging target spot BMS-654457 and BMS-262084 be possible to that clinical research has been unfolded, its clinical effectiveness not yet discloses.Preclinical study knot Fruit shows that in the experimental rabbit arterial thrombus model of galvanic current stimulation induction, BMS-654457 shows significant dose-dependant Property likely effectiveness, while without hemorrhage side effect exist (22nd Int Symp Med Chem (Sept 2-6, Berlin) 2012, Abst L63).And the medicine codes or data of BMS-262084 shows that the compound significantly improves experiment as FXIa inhibitor Model thrombus symptom, while extremely small (the J Thromb Thrombolysis (2011) 32 of its side effect：129-137).
Patent application WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060 and US20050171148 discloses the compound with factor XI, plasma thromboplastin antecedent a inhibitory activity.The present invention devises new compound small molecule FXIa antagonists, have the activity of higher, and show excellent effect and effect.Available for effective treatment cardiovascular and cerebrovascular disease And thrombus symptom.
The content of the invention
It is an object of the invention to provide the compound shown in a kind of logical formula (I) or its dynamic isomer, mesomer, outer Raceme, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt：
Wherein：
Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclic radical, annelated heterocycles base, aryl, fused-aryl, heteroaryl or thick Close heteroaryl；
Ring B is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl；
R1It is each identical or different, it is each independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl, heterocycle Base, aryl, heteroaryl or-C (O) R4, wherein the alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optionally further by Substituent of the one or more selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkyl is substituted；
R2Selected from hydrogen atom, halogen or alkyl；
R3It is each identical or different, it is each independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyl Alkyl, oxo base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O) R4、-NHC(O)OR4、-NHC(O)NHR4Or-NHC (O) NHOR4；
R4Selected from hydrogen atom, halogen, cyano group, nitro, alkyl or haloalkyl, the alkyl is optionally further by one It is or multiple selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl ,-OC (O) OR5Or-NR5R6Substituent Substituted；
R5Or R6Hydrogen atom, alkyl or cycloalkyl are each independently selected from, wherein the alkyl or cycloalkyl is optionally into one Step is selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic by one or more The substituent of perester radical is substituted；
M is 0,1,2 or 3；And
N is 0,1 or 2.
It is compound or its dynamic isomer shown in a kind of logical formula (I), interior in yet other embodiments Raceme, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, its middle ring A Selected from fused-aryl, preferably 5~6 circle heterocycles or 5~6 yuan of hetero-aromatic rings and the fused-aryl of phenyl ring fusion.
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, its middle ring A is selected from：
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, wherein R1 It is each identical or different, it is each independently selected from halogen, heteroaryl or-C (O) R4, wherein R4Definition as described in logical formula (I).
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, wherein：
R2For hydrogen atom；
R3Selected from hydrogen atom, aryl ,-C (O) OR4Or-NHC (O) OR4；
R4Selected from hydrogen atom or alkyl, the alkyl is optionally further by one or more-OC (O) OR5Substitution；
R5Selected from hydrogen atom, alkyl or cycloalkyl.
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, it is logical Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer shown in formula (II) or Its form of mixtures, or its pharmaceutically useful salt：
Wherein：
Ring A, R1、R2、R3, m and n be as defined in logical formula (I).
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, it is logical Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer shown in formula (III) or Its form of mixtures, or its pharmaceutically useful salt：
Wherein：
R7It is each identical or different, it is each independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl or miscellaneous Ring group；
Q is 0,1 or 2；
Ring A, R2、R3With n as defined in logical formula (I).
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, it is logical Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer shown in formula (IV) or Its form of mixtures, or its pharmaceutically useful salt：
Wherein：
R7It is identical or different, it is each independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl or heterocyclic radical；
R8Or R9Be each independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, oxo base, Cycloalkyl, heterocyclic radical, aryl ,-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O) NHR4Or-NHC (O) NHOR4；
R4As defined in logical formula (I)；And
Q is 0,1 or 2.
In presently preferred embodiment, compound or its dynamic isomer shown in a kind of logical formula (I), Mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, it is logical Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer shown in formula (V) or its Form of mixtures, or its pharmaceutically useful salt：
Wherein：
R7It is each identical or different, it is independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl or miscellaneous Ring group；
Ring C is selected from heteroaryl, aryl, Heterocyclylalkyl or cycloalkyl, preferably 5 yuan or 6 yuan of heteroaryl, aryl, heterocycle alkane Base or cycloalkyl, more preferably 5 yuan or 6 yuan of Heterocyclylalkyl；R10Selected from hydrogen atom, halogen, cyano group, nitro, alkyl, alkyl halide Base, hydroxyalkyl, oxo base, cycloalkyl, heterocyclic radical, aryl ,-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、- NHC(O)OR4、-NHC(O)NHR4Or-NHC (O) NHOR4；It is preferred that halogen, oxo base ,-C (O) OR4、-C(O)R4、-NHC(O)R4 Or-NHC (O) OR4；More preferably-C (O) OR4；
R4As defined in logical formula (I)；And
P and q is independently selected from 0,1 or 2.
Typical compound or its dynamic isomer shown in the logical formula (I) of the present invention, mesomer, racemic modification, mapping are different Structure body, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, include but not limited to：
Table 1
Another aspect of the present invention provides the compound or its dynamic isomer, meso shown in a kind of general formula (IIIC) Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, it can be used for preparing logical Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer shown in formula (III) or Its form of mixtures, or the intermediate of its officinal salt：
Wherein：
Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclic radical, annelated heterocycles base, aryl, fused-aryl, heteroaryl or thick Close heteroaryl；
R2Selected from hydrogen atom, halogen or alkyl；
R3It is each identical or different, it is each independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyl Alkyl, oxo base, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O) R4、-NHC(O)OR4、-NHC(O)NHR4Or-NHC (O) NHOR4Substituent substituted；
R4Selected from hydrogen atom, halogen, cyano group, nitro, alkyl or haloalkyl, the alkyl is further by one or more It is a to be selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl ,-OC (O) OR5Or-NR5R6Substituent taken Generation；
R5Or R6Hydrogen atom, alkyl or cycloalkyl are each independently selected from, wherein the alkyl or cycloalkyl is optionally into one Step is selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic by one or more The substituent of perester radical is substituted；
R7It is each identical or different, it is independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl or miscellaneous Ring group；
Q is 0,1 or 2, and
N is 0,1 or 2.
Another aspect of the present invention provides one kind and prepares compound shown in logical formula (III) or its dynamic isomer, meso Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or the method for its officinal salt, this method bag Include：
First step reaction carries out condensation reaction and obtains general formula for general formula (IIIA) compound and general formula (IIIB) compound (IIIC) compound, general formula (IIIC) compound that second step is carry out annulation, obtain logical formula (III) compound；
Wherein：Ring A, n, q, R2、R3And R7Definition as defined in logical formula (III).
Another aspect of the present invention is related to a kind of pharmaceutical composition, it contains shown in the logical formula (I) for the treatment of effective dose Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, Or its officinal salt and pharmaceutically acceptable carrier, diluent and excipient.
Another aspect of the present invention is related to compound or its dynamic isomer, mesomer, racemic shown in logical formula (I) Body, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or exist comprising its pharmaceutical composition The purposes in prevention and/or treatment cardiovascular and cerebrovascular disease is prepared, the disease is preferably thrombotic disease, more preferably the heart It is blocking again after anxious infraction, angina pectoris, angioplasty or aortocoronary bypass and restenosis, apoplexy, of short duration Ischaemic breaking-out, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis are formed.
Another aspect of the present invention is related to compound or its dynamic isomer, mesomer, racemic shown in logical formula (I) Body, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or exist comprising its pharmaceutical composition Prepare the purposes in the medicine that prevention and/or treatment pass through the disease of inhibiting factor XIa positive influences；Dispersivity is treated preparing Purposes in the medicine of intravascular coagulation；And the purposes in the medicine for preparing inhibiting factor XIa.
Another aspect of the present invention is related to a kind of regulatory factor XIa activity, the preferably method of inhibiting factor XIa activity, should Method include giving needed for bacterium logical formula (I) shown in compound or its dynamic isomer, mesomer, outer Raceme, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or include its drug regimen Thing.
Another aspect of the present invention is related to a kind of method treated and/or prevent cardiovascular and cerebrovascular disease, and this method includes giving It is compound or its dynamic isomer, mesomer, racemic modification shown in the logical formula (I) of bacterium needed for giving, right Isomers, diastereoisomer or its form of mixtures, or its officinal salt are reflected, or includes its pharmaceutical composition.Wherein institute The disease stated is preferably thrombotic disease, more preferably myocardial infarction, angina pectoris, angioplasty or aortocoronary After bypass block again with restenosis, apoplexy, the breaking-out of of short duration ischaemic, peripheral arterial occlusive disease, pulmonary embolism or Deep vein thrombosis is formed.
Another aspect of the present invention is related to a kind of disease for preventing and/or treating to pass through inhibiting factor XIa positive influences Method, this method include giving needed for bacterium logical formula (I) shown in compound or its dynamic isomer, interior disappear Body, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt are revolved, or includes its medicine Compositions.
Another aspect of the present invention is related to a kind of method for treating disseminated intravascular coagulation disease, and this method includes giving Compound or its dynamic isomer, mesomer, racemic modification, mapping shown in the logical formula (I) of required bacterium Isomers, diastereoisomer or its form of mixtures, or its officinal salt, or include its pharmaceutical composition.
Another aspect of the present invention is related to compound or its dynamic isomer, mesomer, racemic shown in logical formula (I) Body, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or its pharmaceutical composition is included, its For preventing and/or treating cardiovascular and cerebrovascular disease, preferably thrombotic disease, more preferably myocardial infarction, angina pectoris, blood vessel into Blocking again and restenosis, apoplexy, the breaking-out of of short duration ischaemic, peripheral arterial after type art or aortocoronary bypass Obliteran, pulmonary embolism or deep vein thrombosis are formed.
Another aspect of the present invention is related to compound or its dynamic isomer, mesomer, racemic shown in logical formula (I) Body, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or its pharmaceutical composition is included, its For preventing and/or treating the disease by inhibiting factor XIa positive influences；For treating disseminated intravascular coagulation；And For inhibiting factor XIa activity.
Detailed description of the invention
Unless stated to the contrary, it is otherwise following that there are following implications with term in the specification and in the claims.
" alkyl " refers to the aliphatic hydrocarbon groups of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.Preferably comprise The alkyl of 1 to 10 carbon atom, the alkyl of further preferably 1 to 6 carbon atom.Non-limiting example include methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propylenes Base, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyl, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl-pentens Base, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethyls Hexyl, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and its respectively Kind branched chain isomer etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example include methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl Propyl group, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls third Base, 1,1,2- thmethylpropyl, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethyl butyrates Base, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be taken Generation or unsubstituted, when substituted, substituent can be substituted on any workable tie point, be preferably one or Multiple following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur Base, oxo base.
" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, it includes 3 to 20 carbon atoms, 3 to 12 carbon atoms are preferably included, more preferably cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 A carbon atom.The non-limiting example of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, Cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.Polycyclic naphthene base Include the cycloalkyl of loop coil, condensed ring and bridged ring.
The cycloalkyl ring can be condensed on aryl, heteroaryl, cycloalkyl or heterocyclic ring, formed and " condensed cycloalkanes Base ", wherein being cycloalkyl with the ring that precursor structure links together, non-limiting example includes tetralyl, benzocyclohepta Alkyl,
Deng.
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, it includes 3 to 20 annular atoms, Wherein one or more annular atoms are selected from the hetero atom of nitrogen, oxygen or S (O) m (wherein m is 0 to 2 integer), but do not include-O- The loop section of O- ,-O-S- or-S-S-, remaining annular atom are carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is miscellaneous original Son；More preferably heterocyclic ring includes 3 to 10 annular atoms, wherein 1~3 is hetero atom；More preferably heterocyclic ring includes 5 to 6 A annular atom, wherein 1~2 is hetero atom.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazine Piperazine base, morpholinyl, thio-morpholinyl, homopiperazine base, pyranose, tetrahydrofuran base etc..Multiring heterocyclic include loop coil, condensed ring and The heterocyclic radical of bridged ring.
The heterocyclic ring can be condensed on aryl, heteroaryl, heterocyclic radical or cycloalkyl ring, form " annelated heterocycles Base ", wherein the ring to link together with precursor structure is heterocyclic radical, non-limiting example includes：
Deng.
" aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle is (namely shared to adjoin The ring of carbon atom pair) group is preferably 6 to 10 yuan, more preferably phenyl and naphthyl, most preferably phenyl.The aryl rings can be thick Together on aryl, heteroaryl, heterocyclic radical or cycloalkyl ring, formed " fused-aryl ", wherein link together with precursor structure Ring is aryl rings, and non-limiting example includes：
Aryl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkanes Base, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, haloalkyl, Hydroxyalkyl, carboxyl, carboxylic acid ester groups, oxo base ,-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O) OR4、-NHC(O)NHR4Or-NHC (O) NHOR4；Wherein R4Definition as described in logical formula (I) compound.
" heteroaryl " refers to 1 to 4 hetero atom as annular atom, remaining annular atom is 5 to 14 yuan of aryl of carbon, its Middle hetero atom includes oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl, which is preferably, and preference includes but not limited to Furyl, thienyl, pyridine radicals, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, pyridazinyl Deng.The heteroaryl ring can be condensed on aryl, heteroaryl, heterocyclic radical or cycloalkyl ring, formed " condensed heteroaryl ", wherein The ring to link together with precursor structure is heteroaryl ring, and non-limiting example includes：
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyanogen Base, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, amino, halogen Substituted alkyl, hydroxyalkyl, carboxyl, carboxylic acid ester groups, oxo base ,-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、- NHC(O)OR4、-NHC(O)NHR4Or-NHC (O) NHOR4；Wherein R4Definition as described in logical formula (I) compound.
" haloalkyl " refers to alkyl and is substituted by one or more halogens, and wherein alkyl is as defined above.
" hydroxyl " refers to-OH groups.
" hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH2。
" cyano group " refers to-CN.
" nitro " refers to-NO2。
" benzyl " refers to-CH2- phenyl.
" oxo base " refers to=O.
" carboxylic acid group " refers to-C (O) OH.
" carboxylic acid ester groups " refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above institute State.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, mean that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, which includes heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more of group hydrogen atom, preferably at most 5, more preferably 1~3 hydrogen atom Substituted independently of one another by the substituent of respective number.Self-evident, substituent is only in their possible chemical position, Those skilled in the art can determine and (pass through experiment or theoretical) possible or impossible in the case where not paying excessively effort Substitution.For example, amino or hydroxyl with free hydrogen are probably not when being combined with the carbon atom with unsaturated (such as olefinic) key Stable.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is the administration promoted to organism, the absorption beneficial to active ingredient and then performance bioactivity.
The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention adopts the following technical scheme that：
Scheme one
First step reaction is deposited in condensing agent in alkaline conditions for general formula (IIIA) compound and general formula (IIIB) compound General formula (IIIC) compound is obtained in lower progress condensation reaction, second step reaction is general formula (IIIC) compound and sodium azide, Trimethyl orthoformate carries out annulation under the conditions of glacial acetic acid, obtains logical formula (III) compound；
Wherein：Ring A, n, q, R2、R3Or R7Definition as defined in logical formula (III).
Scheme two
First step reaction exists in condensing agent in alkaline conditions for general formula (IVA) compound and general formula (IVB) compound Lower progress condensation reaction obtains general formula (IVC) compound, and second step reaction is general formula (IVC) compound and sodium azide, primitive nail Sour trimethyl carries out annulation under the conditions of glacial acetic acid, obtains logical formula (IV) compound；
Wherein：R2、q、R7~R10Definition as defined in logical formula (IV).
Scheme three
First step reaction is general formula (VA) compound and general formula (VB) compound in alkaline conditions in the presence of condensing agent Carry out condensation reaction and obtain general formula (VC) compound, second step reaction is general formula (VC) compound and sodium azide, orthoformic acid three For methyl esters under the conditions of glacial acetic acid, step carries out annulation, obtains logical formula (V) compound；
Wherein：Ring C, p, q, R7、R10Definition as defined in logical formula (V).
In above-mentioned synthetic technology scheme, there is provided the reagent of alkaline condition includes organic base and inorganic base, and described is organic Bases include but not limited to I-hydroxybenzotriazole, triethylamine, n,N-diisopropylethylamine, n,N-Dimethylformamide, pyridine, Sodium hexamethyldisilazide, n-BuLi, potassium tert-butoxide or tetrabutylammonium bromide, are preferably n,N-Dimethylformamide；Institute The inorganic base stated includes but not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium acid carbonate, carbon Sour potassium, saleratus or cesium carbonate.
Condensing agent includes but not limited to dicyclohexylcarbodiimide, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides Hydrochloride, N, N '-dicyclohexyl carbodiimide, N, N '-diisopropylcarbodiimide, O- benzotriazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester, I-hydroxybenzotriazole, 1- hydroxyl -7- azos benzotriazole, O- benzotriazole-N, N, N ', N '-tetramethylurea (TMU) hexafluorophosphoric acid ester, 2- (7- azos benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, Three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- bases epoxide or hexafluorophosphoric acid benzotriazole -1- bases-epoxide three Pyrrolidinyl phosphorus, is preferably dicyclohexylcarbodiimide.
Embodiment
The present invention is further described with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
The experimental method of actual conditions is not specified in the embodiment of the present invention, usually according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Embodiment
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).Nmr chemical displacement (δ) with 10-6(ppm) unit provides.The measure of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl Sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
The measure of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model：Finnigan LCQ advantage MAX)。
The measure of HPLC uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18 150 × 4.6mm chromatographies Column) and Waters 2695-2996 high pressure liquid chromatographs (Gimini 150 × 4.6mm of C18 chromatographic columns).
Kinases average inhibition and IC50The measure of value is with NovoStar microplate reader (German BMG companies).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.2mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。
Column chromatography is carrier generally using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
The known starting material of the present invention can be used or synthesized according to methods known in the art, or can purchase certainly ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemical science and technology (Accela ChemBio Inc), up to companies such as auspicious chemicals.
It can be carried out in embodiment without specified otherwise, reaction under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Refer to aqueous solution without specified otherwise, solution in embodiment.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), the system of solvent used in reaction Have：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C：Petroleum ether and ethyl acetate system, D：Acetone, The volume ratio of solvent is different according to the polarity of compound and is adjusted.
The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound uses include：A：Two Chloromethanes and methanol system, B：N-hexane and ethyl acetate system, C：Dichloromethane and acetone system, D：Ethyl acetate and dichloro Methane system, E：Ethyl acetate and dichloromethane and n-hexane, F：Ethyl acetate and dichloromethane and acetone, the volume ratio of solvent It is different according to the polarity of compound and be adjusted, can also add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent into Row is adjusted.
Embodiment 1
(S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) -1H- indole -2-carboxylic methyl esters
The first step
(S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Yin Diindyl -2- carboxylate methyl esters
By 5- amino -1H- indole -2-carboxylic methyl esters 1a (124mg, 0.64mmol, using known method " Journal Of the American Chemical Society, 2007,129 (35), 10858-10869 " are prepared), (S) -7- (2- Amido -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (200mg, 0.64mmol, using patent application Method disclosed in " WO2013093484 " is prepared), I-hydroxybenzotriazole (104mg, 0.77mmol), dicyclohexyl carbon two Imines (160mg, 0.77mmol) is dissolved in 10mL n,N-Dimethylformamide, be stirred at room temperature 16 it is small when.Filtering, filter cake are used 20mL n,N-Dimethylformamide is washed.Merge mother liquor, be concentrated under reduced pressure.Institute is purified with eluant, eluent system A with silica gel column chromatography Residue is obtained, obtains title product (S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- Amide groups) -1H- indole -2-carboxylic methyl esters 1c (240mg, brown oil), yield：78.0%.
MS m/z(ESI)：477.1[M+1]
Second step
(S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) -1H- indole -2-carboxylic methyl esters
By (S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Indole -2-carboxylic methyl ester 1c (120mg, 0.25mmol), sodium azide (56mg, 0.87mmol) are dispersed in trimethyl orthoformate In (0.98mL, 8.82mmol), then 2mL glacial acetic acid is added dropwise, when stirring reaction 16 is small at 70 DEG C.It is concentrated under reduced pressure, adds 60mL second Acetoacetic ester stirring and dissolving, it is in mutually alkalescent to be washed with saturated sodium bicarbonate solution to water, separates organic phase, water mutually uses ethyl acetate Extract (30mL × 2), merge organic phase, washed with saturated nacl aqueous solution (20mL × 2), anhydrous sodium sulfate drying, is filtered, filter Liquid is concentrated under reduced pressure.Purify residue obtained by (HPLC) with preparative separation method, obtain title product (S) -5- (7- (chloro- 2- (1H- of 5- Tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters 1 (50mg, white solid), yield：38.0%.MS m/z(ESI)：530.2[M+1]
1H NMR (400MHz, CD3OD)：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)
Embodiment 2
(S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) -1H- indole-2-carboxylic acids
The first step
By (S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- Amide groups) -1H- indole -2-carboxylic methyl esters 1 (23mg, 0.043mmol) add 2mL methanol and tetrahydrofuran (V/V=1: 1) is mixed In bonding solvent, add the lithium hydroxide solution of 0.2mL 2N, be stirred at room temperature 2 it is small when.It is concentrated under reduced pressure, adds 10mL water, be added dropwise 2M's Salt acid for adjusting pH is 2~3, is extracted with dichloromethane and methanol (V/V=5: 1,30mL × 3), merges organic phase, uses anhydrous slufuric acid Sodium is dried, filtering, filtrate decompression concentration.Purify residue obtained by (HPLC) with preparative separation method, obtain title product (S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indoles - 2- carboxylic acids 2 (10mg, white solid), yield：45%.
MS m/z(ESI)：516.1[M+1]
1H NMR (400MHz, DMSO-d6)：δ 11.7 (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)
Embodiment 3
(S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl)-N- (1H- indoles -5- bases) -5- oxos -1,2,3,5- Indolizine -3- formamides
The first step
(S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (60mg, 0.2mmol), sodium azide (13mg, 0.2mmol) is dispersed in 0.3mL trimethyl orthoformates, then 2mL glacial acetic acid is added dropwise, 65 DEG C It is lower stirring reaction 16 it is small when.It is concentrated under reduced pressure, silica gel column chromatography purifies gained residue with eluant, eluent system, obtains title product (S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 3a (73mg, Gray solid), yield：98.0%.
MS m/z(ESI)：358.1[M+1]
Second step
(S) -7- (the chloro- 2- of 5- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl)-N- (1H- indoles -5- bases) -5- oxos - 1,2,3,5- indolizine -3- formamides
By (S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- carboxylics Sour 3a (73mg, 0.2mmol), 5- amino indoles (39mg, 0.3mmol, using known method " Electrochimica Acta, 2013,107,292-300 " is prepared), I-hydroxybenzotriazole (40mg, 0.3mmol), dicyclohexylcarbodiimide (60mg, 0.3mmol) is dissolved in 5mL n,N-Dimethylformamide, be stirred at room temperature 72 it is small when.Filtering, filter cake 20mL N, Dinethylformamide washs.Merge mother liquor, be concentrated under reduced pressure, with preparative separation method purify (HPLC) gained residue, marked Topic product (S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl)-N- (1H- indoles -5- bases) -5- oxos -1,2,3,5- tetra- Hydrogen indolizine -3- formamides 3 (20mg, gray solid), yield：24.1%.
MS m/z(ESI)：472.2[M+1]
1H NMR (400MHz, DMSO-d6)：δ 10.03 (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)
Embodiment 4
(S) -6- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) -1H- indole-2-carboxylic acids
The first step
(S) -6- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Yin Diindyl -2- carboxylate methyl esters
By 6- amino -1H- indole -2-carboxylic methyl esters (200mg, 1mmol, using patent application " WO2012101013 " public affairs The method opened is prepared), (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (304mg, 1mmol), I-hydroxybenzotriazole (150mg, 1.1mmol), dicyclohexylcarbodiimide (220mg, 11mmol) are molten Solution in 3mL n,N-Dimethylformamide, be stirred at room temperature 4 it is small when.Filtering, filter cake are washed with 20mL n,N-Dimethylformamide Wash.Merge mother liquor, be concentrated under reduced pressure.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (S) -6- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids Methyl esters 4a (203mg, brown solid), yield：42.8%.
Second step
(S) -6- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Yin Diindyl -2- carboxylic acids
By (S) -6- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Indole -2-carboxylic methyl ester 4a (203mg, 0.43mmol) is dissolved in 10mL methanol, adds the sodium hydroxide solution of 3mL 2N, room temperature React 4 it is small when.It is concentrated under reduced pressure, adds 10mL water, it is 2~3 that the hydrochloric acid of 2M, which is added dropwise, to pH, is extracted, closed with ethyl acetate (30mL × 3) And organic phase, dried with anhydrous sodium sulfate, filter, filtrate decompression concentration, obtain crude product (S) -6- (7- (2- amino -5- chlorphenyls) - 5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids 4b (200mg, gray solid).
MS m/z(ESI)：463.0[M+1]
3rd step
(S) -6- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) -1H- indole-2-carboxylic acids
By crude product (S) -6- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) - 1H- indole-2-carboxylic acids 4b (200mg, 0.43mmol), sodium azide (30mg, 0.43mmol) are dispersed in 2mL trimethyl orthoformates In, then 5mL glacial acetic acid is added dropwise, when stirring reaction 5 is small at 70 DEG C.It is concentrated under reduced pressure, adds 10mL water, (30mL is extracted with ethyl acetate × 3), merge organic phase, washed with saturated sodium bicarbonate solution (20mL × 1), saturated nacl aqueous solution (20mL × 2), it is anhydrous Sodium sulphate is dried, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, marked Inscribe product (S) -6- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acid amides Base) -1H- indole-2-carboxylic acids 4 (15mg, faint yellow solid), yield：6.8%.
MS m/z(ESI)：516.0[M+1]
Embodiment 5
(S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) benzofuran -2- carboxylic acids
The first step
(S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzo furan Mutter -2- carboxylic acid, ethyl esters
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (305mg, 1mmol), 5- aminobenzofurs -2- carboxylic acid, ethyl esters (205mg, 1mmol, using known method " Journal of Medicinal Chemistry, 2008,51 (11), 3133-3144 " are prepared), I-hydroxybenzotriazole (163mg, 1.2mmol), dicyclohexylcarbodiimide (247mg, 1.2mmol) is dissolved in 5mL n,N-Dimethylformamide, is stirred at room temperature 16 it is small when.Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (N-5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acid, ethyl esters 5a (600mg, yellow solid), yield：100%.
MS m/z(ESI)：492.2[M+1]
Second step
(S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzo furan Mutter -2- carboxylic acids
By (S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzo Furans -2- carboxylic acid, ethyl esters 5a (600mg, 1.22mmol) is dissolved in the mixed solvent of 12mL methanol and tetrahydrofuran (V/V=1: 1) In, add the sodium hydroxide solution of 6.1mL 2N, when room temperature reaction 16 is small.It is concentrated under reduced pressure, adds 10mL water, the hydrochloric acid of 6M is added dropwise to pH For 2~3, extracted with ethyl acetate (30mL × 3), merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression concentration. Crude product (S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzofuran - 2- carboxylic acids 5b (150mg, yellow solid), yield：26.5%.
MS m/z(ESI)：464.2[M+1]
3rd step
(S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) benzofuran -2- carboxylic acids
By crude product (S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) Benzofuran -2- carboxylic acids 5b (150mg, 0.32mmol), sodium azide (105mg, 1.62mmol) are dispersed in 3mL orthoformic acid front threes In ester, then 3mL glacial acetic acid is added dropwise, when stirring reaction 16 is small at 70 DEG C.It is concentrated under reduced pressure, preparative separation purifying gained residue, obtains To title product (S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- Amide groups) benzofuran -2- carboxylic acids 5 (20mg, yellow solid), yield：12.1%.MS m/z(ESI)：517.1[M+1]
1H NMR (400MHz, DMSO-d6)：δ 13.50 (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)
Embodiment 6
(S) -4- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) benzoic acid
The first step
(S) -4- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzoic acid Methyl esters
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (150mg, 0.5mmol), methyl p-aminobenzoate (76mg, 0.5mmol), I-hydroxybenzotriazole (81mg, 0.6mmol), dicyclohexyl Carbodiimide (124mg, 0.6mmol) is dissolved in 5mL n,N-Dimethylformamide, be stirred at room temperature 16 it is small when.It is concentrated under reduced pressure, With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (S) -4- (7- (2- amino -5- chlorobenzenes Base) -5- oxos -1,2,3,5- indolizine -3- amide groups) methyl benzoate 6a (120mg, yellow solid), yield： 55%.
MS m/z(ESI)：438.2[M+1]
Second step
(S) -4- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzoic acid
By (S) -4- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzene first Sour methyl esters 6a (600mg, 1.22mmol) is dissolved in 8mL methanol, adds the sodium hydroxide solution of 1.9mL 2N, and room temperature reaction 16 is small When.It is concentrated under reduced pressure, adds 10mL water, it is 2~3 that the hydrochloric acid of 6M, which is added dropwise, to pH, is extracted, merged organic with ethyl acetate (30mL × 3) Phase, is dried with anhydrous sodium sulfate, filtering, filtrate decompression concentration.Obtain crude product (S) -4- (7- (2- amino -5- chlorphenyls) -5- oxygen - 1,2,3,5- indolizine -3- amide groups of generation) benzoic acid 6b (60mg, yellow solid), yield：51.7%.
MS m/z(ESI)：424.0[M+1]
3rd step
(S) -4- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) benzoic acid
By crude product (S) -4- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) Benzoic acid 6b (60mg, 0.14mmol), sodium azide (46mg, 0.71mmol) is dispersed in 2mL trimethyl orthoformates, then is added dropwise 2mL glacial acetic acid, when stirring reaction 16 is small at 70 DEG C.It is concentrated under reduced pressure, preparative separation purifying gained residue, obtains title product (S) -4- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzene Formic acid 6 (30mg, faint yellow solid), yield：45.0%.
MS m/z(ESI)：475.1[M-1]
1H NMR (400MHz, DMSO-d6)：δ 13.50 (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)
Embodiment 7
(S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydrochysene quinolines Quinoline -6- bases) -1,2,3,5- indolizine -3- formamides
The first step
(S) -7- (2- amino -5- chlorphenyls) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydroquinoline -6- bases) -1,2, 3,5- indolizine -3- formamides
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (122mg, 0.4mmol), (1H) -one of 6- amino -3,4- dihydroquinoline -2 7a (65mg, 0.4mmol), I-hydroxybenzotriazole (65mg, 0.48mmol), dicyclohexylcarbodiimide (99mg, 0.48mmol) is dissolved in 5mL n,N-Dimethylformamide, and room temperature is stirred Mix 16 it is small when.Add 20mL water, extracted with ethyl acetate (30mL × 3), merge organic phase, dried with anhydrous sodium sulfate, filter, filter Liquid is concentrated under reduced pressure.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (S) -7- (2- ammonia Base -5- chlorphenyls) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydroquinoline -6- bases) -1,2,3,5- indolizine -3- first Acid amides 7b (100mg, faint yellow solid), yield：55.0%.MS m/z(ESI)：449.3[M+1]
Second step
(S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydrochysene quinolines Quinoline -6- bases) -1,2,3,5- indolizine -3- formamides
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydroquinoline -6- bases) -1, 2,3,5- indolizine -3- formamides 7b (100mg, 0.22mmol), sodium azide (44mg, 0.66mmol) are dispersed in 1mL In trimethyl orthoformate, then 2mL glacial acetic acid is added dropwise, when stirring reaction 16 is small at 60 DEG C.Vacuum distillation, adds 60mL ethyl acetate Stirring and dissolving, it is in mutually alkalescent to be washed with saturated sodium bicarbonate solution to water, separates and collects organic phase, is done with anhydrous sodium sulfate It is dry, filtering, filtrate decompression concentration.With preparative separation purify gained residue, obtain title product (S) -7- (chloro- 2- (1H- of 5- Tetrazole -1- bases) phenyl) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydroquinoline -6- bases) -1,2,3,5- indolizines - 3- formamides 7 (90mg, faint yellow solid), yield：81.8%.MS m/z(ESI)：502.1[M+1]
1H NMR (400MHz, DMSO-d6)：δ 10.30 (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)
Embodiment 8
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- amide groups) benzofuran -2- carboxylic acids
The first step
N- (the chloro- 3- of 4- fluoro- 2- (tributyl tin) phenyl) -2,2,2- trifluoroacetamides
Tetramethylethylenediamine (12.5mL, 82.8mmol) is dissolved in 100mL tetrahydrofurans, argon gas protection is cooled to -78 ℃.N-BuLi (tetrahydrofuran solution of 33.4mL, 82.8mmol, 2.5M) is added dropwise in above-mentioned reaction solution.Be added dropwise- Continue at 78 DEG C stirring 1 it is small when.By N- (the chloro- 3- fluorophenyls of 4-) -2,2,2- trifluoroacetamide 8a, (10g, 41.4mmol, use Method disclosed in patent application " WO2009114677 " is prepared) 50mL tetrahydrofuran solutions be added dropwise to above-mentioned reaction solution In.Be added dropwise at -78 DEG C continue stirring 2 it is small when.Finally by the 50mL tetrahydrochysenes of tributyltin chloride (13.4mL, 49.6mmol) Tetrahydrofuran solution is added dropwise in above-mentioned reaction solution, drop finish be slowly increased to room temperature the reaction was continued 2 it is small when.100mL water quenchings are added under ice bath Go out reaction, ethyl acetate (200mL × 3) extraction, merges organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression concentration. With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain target product N- (the fluoro- 2- of the chloro- 3- of 4- (tributyl tin) Phenyl) -2,2,2- trifluoroacetamide 8b (11.1g, brown oil), yield：50.5%.
Second step
(S) -7- (the fluoro- 6- of the chloro- 2- of 3- (2,2,2- trifluoroacetyl group) phenyl) -5- oxos -1,2,3,5- indolizines - 3- carboxylic acid, ethyl esters
By N- (the chloro- 3- of 4- fluoro- 2- (tributyl tin) phenyl) -2,2,2- trifluoroacetamide 8b (1.5g, 2.8mmol), (S) -5- oxos -7- (((trifluoromethyl) sulfonyl) epoxide) -1,2,3,5- indolizine -3- carboxylic acid, ethyl esters 8c (1g, 2.8mmol, is prepared using method disclosed in patent application " WO2013093484 "), it is dissolved in 10mL dioxane, argon Gas is replaced, and adds [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (41mg, 0.06mmol), argon gas displacement protection, 100 DEG C When stirring reaction 16 is small.Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain target product (S) -7- (the fluoro- 6- of the chloro- 2- of 3- (2,2,2- trifluoroacetyl group) phenyl) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid second Ester 8d (1.2g, yellow solid), yield：96.0%.
MS m/z(ESI)：447.0[M+1]
3rd step
(S) -7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids
By (S) -7- (the fluoro- 6- of the chloro- 2- of 3- (2,2,2- trifluoroacetyl group) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- carboxylic acid, ethyl esters 8d (1.2g, 2.7mmol) is dissolved in 10mL ethanol, is added 7.3mL 1N sodium hydroxide solutions, is heated back Flow 4 it is small when.It is concentrated under reduced pressure, it is 2~3 that the hydrochloric acid of 2M, which is added dropwise, to pH, is extracted with ethyl acetate (50mL × 3), merges organic phase, used Anhydrous sodium sulfate is dried, filtering, and filtrate decompression concentration, obtains crude product (S) -7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxo -1, 2,3,5- indolizine -3- carboxylic acids 8e (700mg, yellow solid), yield：80.4%.
MS m/z(ESI)：323.0[M+1]
4th step
(S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzene And furans -2- carboxylic acid, ethyl esters
By (S) -7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 8e (162mg, 0.5mmol), 5- aminobenzofur -2- carboxylic acid, ethyl esters (103mg, 0.5mmol, using known method " Journal of Medicinal Chemistry, 2008,51 (11), 3133-3144 " are prepared), 1- hydroxy benzos three Azoles (135mg, 1mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (192mg, 1mmol), N, N- bis- Wopropyl ethyl amine (322mg, 2.5mmol) is dissolved in 6mL n,N-Dimethylformamide, be stirred at room temperature 16 it is small when.Depressurize dense Contracting, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product (S) -5- (7- (6- amino -3- Chloro- 2- fluorophenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acid, ethyl esters 8f (40mg, in vain Color solid), yield：16%.
MS m/z(ESI)：510.1[M+1]
5th step
(S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzene And furans -2- carboxylic acids
By (S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- amide groups) Benzofuran -2- carboxylic acid, ethyl esters 8f (40mg, 0.078mmol) is dissolved in 6mL methanol, and the sodium hydroxide for adding 3mL 2N is molten Liquid, be stirred at room temperature 16 it is small when.It is concentrated under reduced pressure, it is 2~3 that the hydrochloric acid of 2M, which is added dropwise, to pH, is extracted, closed with ethyl acetate (50mL × 3) And organic phase, dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, obtains crude product (S) -5- (7- (chloro- 2- fluorine of 6- amino -3- Phenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acids 8h (51mg, yellow solid), production Rate：100%.
MS m/z(ESI)：482.0[M+1]
6th step
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- amide groups) benzofuran -2- carboxylic acids
By crude product (S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- acyls Amido) benzofuran -2- carboxylic acids 8h (51mg, 0.11mmol), sodium azide (36mg, 0.55mmol) is dispersed in 2mL orthoformic acid In trimethyl, then 3mL glacial acetic acid is added dropwise, when stirring reaction 16 is small at 70 DEG C.It is concentrated under reduced pressure, preparative separation purifying gained is remaining Thing, obtain title product (S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- tetra- Hydrogen indolizine -3- amide groups) benzofuran -2- carboxylic acids 8 (24mg, yellow solid), yield：41.4%.
MS m/z(ESI)：534.5[M+1]
1H NMR (400MHz, DMSO-d6)：δ 13.50 (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)
Embodiment 9
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- amide groups) -1H- indole-2-carboxylic acids
The first step
(S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- amide groups) - The 1H- indole-2-carboxylic acid tert-butyl esters
By (S) -7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 8e (250mg, 0.77mmol), 5- amino -1H- indole-2-carboxylic acid tert-butyl esters 9a (180mg, 0.77mmol, using known method " Journal of Medicinal Chemistry, 2012,55 (2), 766-782 " are prepared), 2- (7- azos benzos three Nitrogen azoles)-N, N, N ', N- tetramethylurea hexafluorophosphoric acid esters (354mg, 0.95mmol), n,N-diisopropylethylamine (0.3g, 2.3mmol) it is dissolved in 6mL n,N-Dimethylformamide, when 50 DEG C of stirring reactions 4 are small.Reaction solution adds 10mL water, there is solid Separate out, filtering.Filter cake 100mL ethyl acetate dissolves, and is dried with anhydrous sodium sulfate, filters, and filtrate concentration, uses thin-layered chromatography Gained residue is purified with eluant, eluent system A, obtains title product (S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxygen - 1,2,3,5- indolizine -3- amide groups of generation) -1H- indole-2-carboxylic acid tert-butyl esters 9b (50mg, faint yellow color solid), production Rate：12.1%.
MS m/z(ESI)：537.2[M+1]
Second step
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- amide groups) -1H- indole-2-carboxylic acid the tert-butyl esters
By (S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- acid amides Base) -1H- indole-2-carboxylic acid tert-butyl ester 9b (50mg, 0.1mmol), trimethyl orthoformate (160mg, 1.5mmol) addition 6mL ice In acetic acid, react at room temperature 30 minutes, add sodium azide (20mg, 0.3mmol), when stirring reaction 16 is small at 60 DEG C.Obtain (S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- acid amides Base) -1H- indole-2-carboxylic acid tert-butyl esters 9c solution.
MS m/z(ESI)：560.1[M+1]
3rd step
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- amide groups) -1H- indole-2-carboxylic acids
In (S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2, nitrogen in 3,5- tetrahydrochysenes Indenes -3- amide groups) -1H- indole-2-carboxylic acid tert-butyl esters 9c solution in add 1mL trifluoroacetic acids, be stirred at room temperature reaction 2 it is small when. It is concentrated under reduced pressure, the residue of preparative separation purifying gained, obtains title product (S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (tetra- nitrogen of 1H- Azoles -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids 9 (20mg, it is faint yellow Solid), yield：37.7%.
MS m/z(ESI)：534.0[M+1]
1H NMR (400MHz, CD3OD)：δ 9.37 (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)
Embodiment 10
(S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Indole-2-carboxylic acid
The first step
(S) -7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid, ethyl esters
By -1,2,3,5- indolizine -3- carboxylic acid, ethyl esters of (S) -5- oxos -7- (((trifluoromethyl) sulfonyl) epoxide) 8c (430mg, 1.21mmol), 2- acetyl group -5- chlorophenylboronic acids pinacol ester (407mg, 1.45mmol, using known method " Chemistry Letters, 2011,40 (9), 1007-1008 " are prepared), the aqueous sodium carbonate of 1.81mL 2N, four Triphenyl phosphorus palladium (70mg, 0.06mmol) is dissolved in the in the mixed solvent of 45mL toluene and ethanol (V/V=2: 1), argon gas displacement Protection, when 70 DEG C of stirring reactions 16 are small.Filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify gained remnants Thing, obtains title product (S) -7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid, ethyl esters 10a (500mg, faint yellow solid), yield：100%.MS m/z(ESI)：360.0[M+1]
Second step
(S) -7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids
By (S) -7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid, ethyl esters 10a (500mg, 1.4mmol) is dissolved in 20mL methanol, adds the sodium hydroxide solution of 2.1mL 2N, and it is small that reaction 48 is stirred at room temperature When.It is concentrated under reduced pressure, adds 20mL water, dichloromethane (20mL × 2) extraction, it is 2~3 that 1N hydrochloric acid, which is added dropwise, to water phase pH, uses dichloromethane Alkane and methanol (V/V=20: Isosorbide-5-Nitrae 0mL × 2) extraction.Extractant after adjusting pH is merged, anhydrous sodium sulfate drying, filtering, Filtrate decompression concentrates, and obtains crude product (S) -7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 10b (390mg, yellow solid), yield：84.2%.MS m/z(ESI)：332.1[M+1]
3rd step
(S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Indole -2-carboxylic methyl ester
By 5- amino -1H- indole -2-carboxylic methyl esters 1a (76mg, 0.4mmol), (S) -7- (2- acetyl group -5- chlorobenzenes Base) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 10b (132mg, 0.4mmol), I-hydroxybenzotriazole (65mg, 0.48mmol), dicyclohexylcarbodiimide (99mg, 0.48mmol) is dissolved in 10mL n,N-Dimethylformamide, and room temperature is stirred Mix 16 it is small when.Add 30mL water, ethyl acetate (40mL × 2) extraction, merges organic phase, anhydrous sodium sulfate drying, is filtered, filtrate subtracts Pressure concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product (S) -5- (7- (2- acetyl Base -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters 10c (200mg, Brown oil), yield：94.3%.
MS m/z(ESI)：504.2[M+1]
4th step
(S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- Indole-2-carboxylic acid is by (S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- acid amides Base) -1H- indole -2-carboxylic methyl esters 10c (200mg, 0.39mmol) is dissolved in 15mL methanol and tetrahydrofuran (V/V=2: 1) is mixed In bonding solvent, be added dropwise to the sodium hydroxide solution of 1mL 2N, be stirred at room temperature reaction 5 it is small when.It is concentrated under reduced pressure, adds water 20mL, is added dropwise The hydrochloric acid of 2M is 2~3 to pH, is extracted with ethyl acetate (50mL × 3), merges organic phase, dried with anhydrous sodium sulfate, filtered, Filtrate decompression concentrates.Purified with silica gel column chromatography with eluant, eluent system A, obtain target product (S) -5- (7- (2- acetyl group -5- Chlorphenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids 10 (100mg, white solid), Yield：52.6%.
MS m/z(ESI)：490.2[M+1]
1H NMR (400MHz, DMSO-d6)：δ 11.70 (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)
Synthetic method synthetic example 11-26 using different raw materials according to 1-10 of the embodiment of the present invention.Embodiment 11- 26 collection of illustrative plates parameter is as shown in table 2 below：
Table 2
Biological assessment
The explanation present invention is further described below in conjunction with test case, but these embodiments are not meant as the limitation present invention's Scope.
The experimental method of actual conditions is not specified in test case of the present invention, usually according to normal condition, or according to commodity system Make the condition proposed by manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
The bioactivity of 1 Fluorometric assay factor XI, plasma thromboplastin antecedent a inhibitor of test case
1st, experiment material
Enzyme：Factor XI, plasma thromboplastin antecedent a protease (Abcam, article No. ab62411),
Substrate：Factor XI, plasma thromboplastin antecedent a specific substrates (DaiPharma, article No. S821090),
Buffer solution：100mM tris-HCl, 200mM NaCl, 0.02%tween20, pH7.4.
2nd, experimental procedure
The 20mM test-compounds for being dissolved in 100%DMSO are diluted to 200 with 100%DMSO, 20,2,0.2,0.02, 0.002uM；1ul compounds are added per hole in 384 orifice plates, blank and control wells are substituted with DMSO, are centrifuged, by compound from extremely Bottom.The FXIa enzyme solutions of 10ul (2.5ug/ml) are added per hole, blank well adds 10ul buffer solutions and substitutes, and centrifugation is molten by enzyme Liquid is to bottom.
It is last to add 2mM substrate 10ul per hole, centrifugation, by substrate solution to bottom.
It is incubated 10 minutes at 37 DEG C；Then its light absorption value is surveyed at 405nm.Light absorption value is carried out curve fitting simultaneously with Prism Obtain IC50。
Compound number IC50(factor XI, plasma thromboplastin antecedent a)/(nM)
Embodiment 2 6.4
Embodiment 3 284.5
Embodiment 4 17.2
Embodiment 5 20.1
Embodiment 7 60.6
Embodiment 8 25.3
Embodiment 9 12.5
Embodiment 11 57.2
Embodiment 15 96.6
Embodiment 18 214.0
Embodiment 20 290.4
Embodiment 21 34.3
Embodiment 24 70.7
Embodiment 25 132.9
Embodiment 27 132.7
Conclusion：The compounds of this invention has obvious inhibitory activity to factor XI, plasma thromboplastin antecedent a.
The measure of the external blood coagulation resisting function of 2 human blood of test case
1st, experiment material
Blood plasma：People's blood is collected in the heparin tube without anti-coagulants, adds 3.8% sodium citrate (volume ratio 1: 9), room temperature 2500rpm centrifuges 10min, collects blood plasma, and packing is stored in -80 DEG C；
Reagent：APTT reagents (activated partial thromboplastin time assay kit, SIEMENS, article No. B4218-1), PT Reagent (prothrombin time determination reagent box, SIEMENS, article No. OUHP29), calcium chloride solution；
Instrument：Blood coagulation instrument (SYSMEX, CA-500).
2nd, experiment detection
Packing blood plasma room temperature is taken to be uniformly mixed after melting.The 10000uM test-compounds for being dissolved in 100%DMSO are used 100%DMSO is diluted to 3000,300,200,150,75,30,10,3,0.3uM, blank 100%DMSO.By reagent, blood plasma, Compound is put into correspondence position in Blood coagulation instrument, carries out the detection of the APTT and PT of compound.
3rd, data processing
Carried out curve fitting by Prism, calculate CT2, i.e., the compound corresponding to APTT, PT of 2 times blank controls Concentration is as a result as follows：
Compound number Suppress platelet aggregation CT2(μM)
Embodiment 2 1.83
Embodiment 5 36.58
Embodiment 8 21.71
Embodiment 9 3.84
Embodiment 24 10.74
Conclusion：The compounds of this invention has obvious inhibitory activity to human blood aggegation.
Pharmacokinetic Evaluation
The pharmacokinetics test of test case 3, compound of the embodiment of the present invention
1st, make a summary
Using SD rats as animal subject, determined using LC/MS/MS methods after rat oral gavage gives Examples 1 and 2 compound Drug concentration in blood plasma at different moments.Pharmacokinetics behavior of the compounds of this invention in rat body is studied, evaluates its medicine It is dynamic to learn feature.
2nd, testing program
2.1 test drug
Embodiment 1,2,28 and 29 compounds
2.2 experimental animal
Healthy adult SD rat 16, half male and half female, purchased from the western Poole-Bi Kai experimental animals Co., Ltd in Shanghai, animal Production licence number：SCXK (Shanghai) 2008-0016.
2.3 medicines are prepared
Note：PEG：Polyethylene glycol CMC-Na：Sodium carboxymethylcellulose
2.4 administration
SD rats 16, half male and half female, is divided into 4 groups；Gastric infusion, gastric infusion are distinguished after one night of fasting.
3rd, operate
Gastric infusion group in administration before and administration after 0.5,1.0,2.0,4.0,6.0,8.0,11.0,24.0h blood sampling 0.2ml, is placed in heparinised tubes, 3500rpm centrifugation 10min separated plasmas, in -20 DEG C of preservations.Measured with LC/MS/MS methods Testing compound content after different compound gastric infusions in rat plasma.
4th, pharmacokinetic parameter result
The pharmacokinetic parameter of the embodiment of the present invention 1,2,28 and 29 compounds is as follows：
Conclusion：The compounds of this invention 1,28 and 29 absorbs well as the medicine generation of the prodrug of embodiment compound 2, has bright Aobvious medicine is for assimilation effect.

Claims (16)

  1. It is 1. compound or its dynamic isomer, mesomer, racemic modification, enantiomter shown in a kind of logical formula (II), non- Enantiomter or its form of mixtures, or its pharmaceutically useful salt：
    Wherein：
    Ring A is selected from：
    R1It is each identical or different, it is each independently selected from hydrogen atom, halogen, C1-6Alkyl, tetrazole or-C (O) R4；
    R2Selected from hydrogen atom, halogen or C1-6Alkyl；
    R3It is each identical or different, it is each independently selected from hydrogen atom, C1-6Alkyl, oxo base, phenyl or-C (O) OR4；
    R4For C1-6Alkyl, the C1-6Alkyl is optionally further by one or more-OC (O) OR5Substituent substituted；
    R5Selected from hydrogen atom, C1-6Alkyl or C3-6Cycloalkyl；
    M is 0,1,2 or 3；And
    N is 0,1 or 2.
  2. 2. compound or its dynamic isomer, mesomer, racemic shown in logical formula (II) according to claim 1 Body, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, wherein：
    R2For hydrogen atom；
    R3It is each identical or different, it is independently selected from phenyl or-C (O) OR4；
    R4For C1-6Alkyl, the C1-6Alkyl is optionally further by one or more-OC (O) OR5Substitution；
    R5Selected from C1-6Alkyl or C3-6Cycloalkyl.
  3. 3. compound or its dynamic isomer, mesomer, racemic shown in logical formula (II) according to claim 1 Body, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, it is the change shown in logical formula (III) Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its pharmaceutically useful salt：
    Wherein：
    R7It is each identical or different, it is each independently selected from hydrogen atom or halogen；
    Q is 0,1 or 2；And
    Ring A, R2、R3With n as defined in claim 1.
  4. 4. compound or its dynamic isomer, mesomer, racemic shown in logical formula (II) according to claim 1 Body, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, it is the change shown in logical formula (IV) Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or Its pharmaceutically useful salt：
    Wherein：
    R7It is identical or different, it is each independently selected from hydrogen atom or halogen；
    R8Or R9It is each independently selected from hydrogen atom or phenyl；And
    Q is 0,1 or 2.
  5. It is 5. compound or its dynamic isomer, mesomer, racemic modification, enantiomter shown in a kind of logical formula (V), non-right Reflect isomers or its form of mixtures, or its pharmaceutically useful salt：
    Wherein：
    R7It is each identical or different, it is each independently selected from hydrogen atom or halogen；
    Ring C is selected from pyrrolidinyl, furyl or piperidyl；
    R10Selected from oxo base or-C (O) OR4；
    R4As defined in claim 1；And
    P and q is independently selected from 0,1 or 2.
  6. 6. compound or its dynamic isomer, mesomer, racemic modification shown in logical formula (V) according to claim 5, Enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt,
    Wherein, R10For-C (O) OR4；R4It is as defined in claim 5 with p.
  7. 7. compound as described below：
  8. 8. compound or its dynamic isomer, mesomer, racemic modification, enantiomter shown in a kind of general formula (IIIC), Diastereoisomer or its form of mixtures, or its pharmaceutically useful salt：
    Wherein：
    Ring A is selected from：
    R2Selected from hydrogen atom, halogen or C1-6Alkyl；
    R3It is each identical or different, it is each independently selected from C1-6Alkyl, oxo base, phenyl or-C (O) OR4；
    R4For C1-6Alkyl, the C1-6Alkyl is optionally further by one or more OC (O) OR5Substituted；
    R5Selected from hydrogen atom, C1-6Alkyl or C3-6Cycloalkyl；
    R7Each identical or different, it is independently selected from halogen or C1-6Alkyl；
    Q is 0,1 or 2；And
    N is 0,1 or 2.
  9. 9. a kind of compound prepared shown in logical formula (III) or its dynamic isomer, mesomer, racemic modification, enantiomerism Body, diastereoisomer or its form of mixtures, or the method for its pharmaceutically useful salt, this method include：
    First step reaction carries out condensation reaction and obtains general formula (IIIC) for general formula (IIIA) compound and general formula (IIIB) compound Compound, second step reaction carry out annulation for obtained general formula (IIIC) compound, obtain logical formula (III) compound；
    Wherein：Ring A, n, q, R2、R3And R7Definition it is as defined in claim 3.
  10. 10. a kind of pharmaceutical composition, its contain therapeutically effective amount according to claim 1-7 any one of them compound or its Dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its is pharmaceutically acceptable Salt and pharmaceutically acceptable carrier, diluent and excipient.
  11. 11. according to claim 1~7 any one of them compound or its dynamic isomer, mesomer, racemic modification, right Reflect isomers, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, or medicine according to claim 10 Purposes of the composition in the medicine for preparing prevention and/or treatment cardiovascular and cerebrovascular disease.
  12. 12. purposes according to claim 11, the cardiovascular and cerebrovascular disease is thrombotic disease.
  13. 13. purposes according to claim 11, the cardiovascular and cerebrovascular disease is myocardial infarction, angina pectoris, angioplasty Or blocking again and restenosis, apoplexy, the breaking-out of of short duration ischaemic, Peripheral arterial occlusion after aortocoronary bypass Property disease, pulmonary embolism or deep vein thrombosis are formed.
  14. 14. according to claim 1~7 any one of them compound or its dynamic isomer, mesomer, racemic modification, right Reflect isomers, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, or medicine according to claim 10 Purposes of the composition in the medicine for preparing the disease that prevention and/or treatment pass through inhibiting factor XIa positive influences.
  15. 15. according to claim 1~7 any one of them compound or its dynamic isomer, mesomer, racemic modification, right Reflect isomers, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, or medicine according to claim 10 Purposes of the composition in the medicine for preparing treatment disseminated intravascular coagulation.
  16. 16. according to claim 1~7 any one of them compound or its dynamic isomer, mesomer, racemic modification, right Reflect isomers, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, or medicine according to claim 10 Purposes of the composition in the medicine for preparing inhibiting factor XIa.
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