CN105658641A - Indole-amide derivative, preparation method therefor and application thereof in medicine - Google Patents
Indole-amide derivative, preparation method therefor and application thereof in medicine Download PDFInfo
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- CN105658641A CN105658641A CN201580002260.5A CN201580002260A CN105658641A CN 105658641 A CN105658641 A CN 105658641A CN 201580002260 A CN201580002260 A CN 201580002260A CN 105658641 A CN105658641 A CN 105658641A
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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
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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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- 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
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- 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
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- 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
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
The present invention relates to the new benzazole-amide derivatives of a class, its preparation method and contain the derivative pharmaceutical composition and its as therapeutic agent, the purposes especially as XIa factor inhibitors and the purposes in the medicine for preparing the disease such as treatment and/or prevention thromboembolism.
The cardiovascular and cerebrovascular diseases such as the global annual cerebrovascular, cerebral infarction, miocardial infarction, coronary heart disease, artery sclerosis seize the life of nearly 12,000,000 people, close to the 1/4 of the total death toll in the world, the No.1 formidable enemy as human health.The Chinese annual number for dying from angiocardiopathy reaches more than 2,600,000 people that the patient 75% of survival is disabled, wherein more than 40% weight is residual.The thrombus problem as caused by cardiovascular and cerebrovascular disease and diabetes and its complication, as to be solved now it is very urgent the problem of.
According to the independent years of market analysis mechanism Datamonitor 2011 it is expected that, with the production of imitation medicine, share of the cardiovascular and metabolic disease in seven big staple markets will reach peak in 2011, gradually reduce afterwards, its sales volume is by from 109,000,000,000 in 2010 dollars of 101,000,000,000 dollars of near 2019.Wherein thrombus market keeps basicly stable, and 18,900,000,000 dollars of (Datamonitor of 2019 are slightly fallen to by 19,500,000,000 dollars in 2010:HC00034-001、HC00139-001).The punctuate investigation report of 2011 in Guangzhou displays that Chinese antithrombotic reagent market scale increased by 20.52% on a year-on-year basis, with huge market potential (antithrombotic reagent market intelligence up to 81.35 hundred million yuan in 2011：Guangzhou punctuate (2011)).
Human body blood coagulation system includes two processes：Intrinsic pathway (intrinsic pathway) and extrinsic pathway (extrinsic pathway) and a common pathway (Annu.Rev.Med.2011.62:41–57).Extrinsic pathway is also referred to as tissue factor approach, it is used as exogenous route, under damage and various external irritants, the compound activity factor X (FX) of tissue factor and factor VIIa (FVIIa) composition being activated, form factor Xa (FXa), the FXa of activation can be by factor (prothrombin, PT) it is converted into fibrin ferment (thrombin), fibrin ferment as coagulation process center catalyzing enzyme, catalysis fibre pepsinogen formation fibrin, plays hemoglutination.The enzyme quantity that the process is participated in is few, instant effect.Intrinsic pathway belongs to the intrinsic approach of body, the factor for participating in blood coagulation all is from blood, pass through cascade reaction activity factor XII (FXII), factor XI, plasma thromboplastin antecedent (FXI), factors IX (FIX), and then the factor (PT) in downstream is converted into fibrin ferment by activation FXa, fibrin ferment can activate FXI in turn again.The enzyme quantity that the process is participated 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, and it is widely deployed the treatment for various thrombus as exogenous and intrinsic coagulation pathway share regulatory factors, its antagonist.Existing a variety of FXa antagonists listings, 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 (N Engl J Med 1991 the problem of standing in the breach the severeest；325:153-8、Blood.2003；101:4783-4788).
To solve this problem, recent target spot FXIa turns into the research hot topic of each major company and research institution.Studies have found that serious FXI deficiencies can cause congenital XI factor deficiency, the illness mostly occurs with Jew (1:450).The symptom of congenital XI factor deficiency is more gentleer than hemophilia A and B; it is a little to occur hematostaxis; the hemostatic function of body is also unaffected in injured or operation, and 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, and the formation of thrombus can effectively be suppressed by suppressing the FXIa factors, but in the case of even more serious thrombus, the FXIa very little (Blood.2010 of effect；116(19):3981-3989).Clinical statisticses show that VTE illness rate (Blood 2009 can be increased by improving FXIa amount；114:2878-2883), and FXIa wretched insufficiencies person its with DVT risk reduce (Thromb Haemost 2011；105:269–273).
FXIa not yet announces its medicine for entering clinical stage as emerging target spot, but Bristol-Myers Squibb BMS-654457 and BMS-262084 are possible to deploy clinical research, and its clinical effectiveness is not yet disclosed.Preclinical study result is shown, in the experimental rabbit arterial thrombus model that galvanic current stimulation is induced, BMS-654457 shows the likely effectiveness of significant dose dependent, there is (22nd Int Symp Med Chem (Sept 2-6 without hemorrhage side effect simultaneously, Berlin) 2012, Abst L63).And BMS-262084 medicine codes or data shows the compound as FXIa inhibitor and significantly improves experimental 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 disclose the compound with factor XI, plasma thromboplastin antecedent a inhibitory activity.The present invention devises new compound small molecule FXIa antagonists, with higher activity, and shows 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, racemic modification, 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 condensed 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, heterocyclic radical, aryl, heteroaryl or-C (O) R4, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkyl；
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, hydroxyalkyl, 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, described alkyl is optionally further selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl ,-OC (O) OR by one or more5Or-NR5R6Substituent replaced；
R5Or R6Hydrogen atom, alkyl or cycloalkyl are each independently selected from, wherein described alkyl or cycloalkyl is optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic acid ester groups；
M is 0,1,2 or 3；And
N is 0,1 or 2.
In yet other embodiments, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, its middle ring A is selected from fused-aryl, the fused-aryl that preferably 5~6 circle heterocycles or 5~6 yuan of hetero-aromatic rings are condensed with phenyl ring.
In presently preferred embodiment, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, its middle ring A is selected from：
In presently preferred embodiment, compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, wherein R1It 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 tautomerism shown in a kind of logical formula (I)
Body, 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, described 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, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (II), 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, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (III), 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 heterocyclic radical；
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, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (IV), 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 R9It is 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, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (V), 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 heterocyclic radical；
Ring C is selected from heteroaryl, aryl, Heterocyclylalkyl or cycloalkyl, preferably 5 yuan or 6 yuan of heteroaryl, aryl, Heterocyclylalkyl or cycloalkyl, more preferably 5 yuan or 6 yuan of Heterocyclylalkyl；R10Selected 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；It is preferred that halogen, oxo base ,-C (O) OR4、-C(O)R4、-NHC(O)R4Or-NHC (O) OR4；More preferably-C (O) OR4；
R4As defined in logical formula (I)；And
P and q are independently selected from 0,1 or 2.
Typical compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of the present invention, or its pharmaceutically useful salt, include but is not limited to：
Table 1
Another aspect of the present invention provides the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of formula (IIIC), or its officinal salt, it can be used for preparing the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (III), or its officinal salt intermediate：
Wherein：
Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclic radical, annelated heterocycles base, aryl, fused-aryl, heteroaryl or condensed 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, hydroxyalkyl, 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 replaced；
R4Selected from hydrogen atom, halogen, cyano group, nitro, alkyl or haloalkyl, described alkyl is further selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl ,-OC (O) OR by one or more5Or-NR5R6Substituent replaced；
R5Or R6Hydrogen atom, alkyl or cycloalkyl are each independently selected from, wherein described alkyl or cycloalkyl is optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic acid ester groups；
R7It is each identical or different, it is independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl or heterocyclic radical；
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, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or the method for its officinal salt, this method includes：
First step reaction is that formula (IIIA) compound and formula (IIIB) compound carry out condensation reaction and obtain formula (IIIC) compound, second step is that obtained formula (IIIC) compound carries out annulation, obtains 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 compound or its dynamic isomer shown in the logical formula (I) for the treatment of effective dose, 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 shown in logical formula (I), mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or purposes of the pharmaceutical composition comprising it in prevention and/or treatment cardiovascular and cerebrovascular disease is prepared, the disease is preferably thrombotic disease, more preferably myocardial infarction, angina pectoris, blocking again and ISR after angioplasty or aortocoronary bypass, apoplexy, of short duration ischaemic breaking-out, peripheral arterial occlusive disease, pulmonary embolism or dvt are formed.
Another aspect of the present invention is related to compound or its dynamic isomer shown in logical formula (I), mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or purposes of the pharmaceutical composition comprising it in the medicine that prevention and/or treatment pass through the disease of inhibiting factor XIa positive influences is prepared；Purposes in the medicine for preparing treatment disseminated 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, it is preferred that the method for inhibiting factor XIa activity, this method includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of bacterium needed for giving, or its officinal salt, or the pharmaceutical composition comprising it.
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
Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures needed for giving shown in the logical formula (I) of bacterium, or its officinal salt, or the pharmaceutical composition comprising it.Wherein described disease is preferably thrombotic disease, and more preferably blocking again after myocardial infarction, angina pectoris, angioplasty or aortocoronary bypass and ISR, apoplexy, of short duration ischaemic breaking-out, peripheral arterial occlusive disease, pulmonary embolism or dvt is formed.
Another aspect of the present invention is related to a kind of method prevented and/or treat the disease by inhibiting factor XIa positive influences, this method includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of bacterium needed for giving, or its officinal salt, or the pharmaceutical composition comprising it.
Another aspect of the present invention is related to a kind of method for treating disseminated intravascular coagulation disease, this method includes the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in the logical formula (I) of bacterium needed for giving, or its officinal salt, or the pharmaceutical composition comprising it.
Another aspect of the present invention is related to compound or its dynamic isomer shown in logical formula (I), mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or the pharmaceutical composition comprising it, it is used to preventing and/or treating cardiovascular and cerebrovascular disease, it is preferred that thrombotic disease, more preferably myocardial infarction, angina pectoris, blocking again and ISR after angioplasty or aortocoronary bypass, apoplexy, of short duration ischaemic breaking-out, peripheral arterial occlusive disease, pulmonary embolism or dvt are formed.
Another aspect of the present invention is related to compound or its dynamic isomer shown in logical formula (I), mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its officinal salt, or the pharmaceutical composition comprising it, it is used to prevent and/or treats 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 includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, 2, 2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1, 1, 2- thmethylpropyls, 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 amyl groups, 3, 3-
Dimethyl amyl group, 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- ethylhexyls, 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 various branched chain isomers etc..Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, 2, 2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyl propyl group, 1, 1, 2- thmethylpropyls, 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 etc..Alkyl can be substituted or unsubstituted, when substituted, substituent can be substituted on any workable tie point, preferably one or more 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 alkylthio group, oxo base.
" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring includes 3 to 10 carbon atoms, and most preferably cycloalkyl ring includes 3 to 6 carbon atoms.The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc., preferably cyclopropyl, cyclohexenyl group.Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.
The cycloalkyl ring can be condensed on aryl, heteroaryl, cycloalkyl or heterocyclic ring, formed " fused cycloalkyl ", wherein be cycloalkyl with the ring that precursor structure links together, non-limiting example include tetralyl, benzocyclohepta alkyl,
Deng.
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is 0 to 2 integer), but do not include-O-O- ,-O-S- or-S-S- loop section, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 1~4 is hetero atom；More preferably heterocyclic ring includes 3 to 10 annular atoms, wherein 1~3 is hetero atom；More preferably heterocyclic ring includes 5 to 6 annular atoms, wherein 1~2 is hetero atom.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base, pyranose, tetrahydrofuran base etc..Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring.
The heterocyclic ring can be condensed on aryl, heteroaryl, heterocyclic radical or cycloalkyl ring, formed " annelated heterocycles base ", wherein the ring linked together with precursor structure is heterocyclic radical, non-limiting example is included：
Deng.
" aryl ", which refers to, has 6 to 14 yuan of full carbon of the pi-electron system being conjugated monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, more preferably preferably 6 to 10 yuan, most preferably phenyl and naphthyl, phenyl.The aryl rings can be condensed on aryl, heteroaryl, heterocyclic radical or cycloalkyl ring, formed " fused-aryl ", wherein the ring linked together with precursor structure is aryl rings, non-limiting example is included：
Aryl can be substituted or unsubstituted, 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, cycloalkyl, 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, and remaining annular atom is 5 to 14 yuan of aryl of carbon, and wherein 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 is not limited to furyl, thienyl, pyridine radicals, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical, pyridazinyl etc..The heteroaryl ring can be condensed on aryl, heteroaryl, heterocyclic radical or cycloalkyl ring, formed " condensed heteroaryl ", wherein the ring linked together with precursor structure is heteroaryl ring, non-limiting example is included：
Heteroaryl can be optionally substituted or unsubstituted, 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, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocycle alkane
Epoxide, 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.
" haloalkyl " refers to alkyl and replaced 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), and wherein alkyl and cycloalkyl is as defined above.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes the event or environment occurs or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " mean alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more of group hydrogen atom, and preferably at most 5, more preferably 1~3 hydrogen atom is replaced by the substituent of respective number independently of one another.Self-evident, substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theoretical) possible or impossible substitution in the case where not paying excessively effort.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key.
" pharmaceutical composition " is represented 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.The purpose of pharmaceutical composition is to promote the administration to organism, the absorption beneficial to active component 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 is adopted the following technical scheme that：
Scheme one
First step reaction is that formula (IIIA) compound and formula (IIIB) compound carry out condensation reaction in the basic conditions in the presence of condensing agent and obtain formula (IIIC) compound, second step reaction is formula (IIIC) compound and sodium azide, trimethyl orthoformate is under the conditions of glacial acetic acid, annulation is carried out, logical formula (III) compound is obtained；
Wherein：Ring A, n, q, R2、R3Or R7Definition as defined in logical formula (III).
Scheme two
First step reaction is that formula (IVA) compound and formula (IVB) compound carry out condensation reaction in the basic conditions in the presence of condensing agent and obtain formula (IVC) compound, second step reaction is formula (IVC) compound and sodium azide, trimethyl orthoformate is under the conditions of glacial acetic acid, annulation is carried out, logical formula (IV) compound is obtained；
Wherein：R2、q、R7~R10Definition as defined in logical formula (IV).
Scheme three
First step reaction is that formula (VA) compound and formula (VB) compound carry out condensation reaction in the basic conditions in the presence of condensing agent and obtain formula (VC) compound, second step reaction is formula (VC) compound and sodium azide, trimethyl orthoformate is 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 alkalescence condition includes organic base and inorganic base, described organic bases include but is not limited to I-hydroxybenzotriazole, triethylamine, N, N- diisopropylethylamine, N, dinethylformamide, pyridine, sodium hexamethyldisilazide, n-BuLi, potassium tert-butoxide or TBAB, preferably DMF；Described inorganic base includes but is not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus or cesium carbonate.
Condensing agent includes but is not limited to dicyclohexylcarbodiimide, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, N, N'- dicyclohexyl carbodiimides, N, N'- diisopropylcarbodiimides, O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters, I-hydroxybenzotriazole, 1- hydroxyl -7- azo BTAs, O- BTAs-N, N, N', N'- tetramethylurea (TMU) hexafluorophosphoric acid esters, 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters, (dimethylamino) the phosphorus hexafluorophosphate of BTA -1- bases epoxide three or hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus, preferably dicyclohexylcarbodiimide.
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 unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to the condition proposed by raw material or commodity manufacturer.The unreceipted reagent specifically originated, is 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) is with 10-6(ppm) unit is provided.NMR measure 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).
MS measure is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model：Finnigan
LCQ advantage MAX)。
HPLC measure uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire 150 × 4.6mm of C18 chromatographic columns) 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 ELIASAs (German BMG companies).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.2mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or it is commercially available from ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry is scientific and technological (Accela ChemBio Inc), up to companies such as auspicious chemicals.
Without specified otherwise in embodiment, reaction can be carried out 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.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
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), there is the system of solvent used in reaction：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 adjusted according to the polarity difference of compound.
The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound is used include：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, 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 solvent are different and be adjusted according to the polarity of compound, can also add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent is adjusted.
Embodiment 1
(S) -5- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters
The first step
(S) -5- (7- (2- amino -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters
By 5- amino -1H- indole -2-carboxylic methyl ester 1a (124mg, 0.64mmol, using known method " Journal of the American Chemical Society, 2007, 129 (35), 10858-10869 " is prepared), (S) -7- (2- amido -5- chlorphenyls) -5- oxos -1, 2, 3, 5- indolizine -3- carboxylic acid 1b (200mg, 0.64mmol, it is prepared using method disclosed in patent application " WO2013093484 "), I-hydroxybenzotriazole (104mg, 0.77mmol), dicyclohexylcarbodiimide (160mg, 0.77mmol) it is dissolved in 10mL N, in dinethylformamide, it is stirred at room temperature 16 hours.Filtering, filter cake is washed with 20mL DMFs.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) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl ester 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- oxo -1,2,3,5- indolizine -3- amide groups) -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 esters 1c (120mg, 0.25mmol), sodium azide (56mg, 0.87mmol) it is dispersed in trimethyl orthoformate (0.98mL, in 8.82mmol), then stirring reaction 16 hours at 2mL glacial acetic acid, 70 DEG C are added dropwise.It is concentrated under reduced pressure, add 60mL ethyl acetate stirring and dissolvings, it is in alkalescent to be washed with saturated sodium bicarbonate solution to aqueous phase, organic phase is separated, aqueous phase is extracted with ethyl acetate (30mL × 2), merge organic phase, washed with saturated nacl aqueous solution (20mL × 2), anhydrous sodium sulfate drying, 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) 1 (50mg of -1H- indole -2-carboxylic methyl esters, white solid), yield：38.0%.
MSm/z(ESI):530.2[M+1]
1H NMR(400MHz,CD3OD):δ9.24(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- oxo -1,2,3,5- indolizine -3- amide groups) -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) in the mixed solvent, adds 0.2mL 2N lithium hydroxide solution, is stirred at room temperature 2 hours.It is concentrated under reduced pressure, plus 10mL water, the salt acid for adjusting pH that 2M is added dropwise is 2~3, with dichloromethane and methanol (V/V=5:1,30mL × 3) extract, merge organic phase, with anhydrous sodium sulfate drying, 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) 2 (10mg of -1H- indole-2-carboxylic acids, white solid), yield：45%.
MS m/z(ESI):516.1[M+1]
1H NMR(400MHz,DMSO-d6):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)
Embodiment 3
(S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl)-N- (1H- indoles -5- bases) -5- oxo -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 are 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) it is dispersed in 0.3mL trimethyl orthoformates, then stirring reaction 16 hours at 2mL glacial acetic acid, 65 DEG C is added dropwise.It is concentrated under reduced pressure, silica gel column chromatography purifies gained residue with eluant, eluent system, obtain 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- oxo -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- carboxylic acid 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, in dinethylformamide, it is stirred at room temperature 72 hours.Filtering, filter cake is washed with 20mL DMFs.Merge mother liquor, it is concentrated under reduced pressure, purify residue obtained by (HPLC) with preparative separation method, obtain title product (S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl)-N- (1H- indoles -5- bases) -5- oxos -1, (the 20mg of 2,3,5- indolizine -3- formamides 3, gray solid), yield：24.1%.
MS m/z(ESI):472.2[M+1]
1H NMR(400MHz,DMSO-d6):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)
Embodiment 4
(S) -6- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids
The first step
(S) -6- (7- (2- amino -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters
By 6- amino -1H- indole -2-carboxylic methyl esters (200mg, 1mmol, using patent application " method is prepared disclosed in WO 2012101013 "), (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid 1b (304mg, 1mmol), I-hydroxybenzotriazole (150mg, 1.1mmol), dicyclohexylcarbodiimide (220mg, 1.1mmol) it is dissolved in 3mL DMFs, is stirred at room temperature 4 hours.Filtering, filter cake is washed with 20mL DMFs.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 methyl ester 4a (203mg, brown solid), yield：42.8%.
Second step
(S) -6- (7- (2- amino -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole-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) it is dissolved in 10mL methanol, plus 3mL 2N sodium hydroxide solution, react at room temperature 4 hours.It is concentrated under reduced pressure, plus 10mL water, be added dropwise 2M hydrochloric acid to pH be 2~3, with ethyl acetate (30mL × 3) extract, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude product (S) -6- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indoles -2-
Carboxylic acid 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- oxo -1,2,3,5- indolizine -3- amide groups) -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 acid 4b (200mg, 0.43mmol), sodium azide (30mg, 0.43mmol) is dispersed in 2mL trimethyl orthoformates, stirring reaction 5 hours at 5mL glacial acetic acid, 70 DEG C are added dropwise again.It is concentrated under reduced pressure, plus 10mL water, it is extracted with ethyl acetate (30mL × 3), merge organic phase, washed with saturated sodium bicarbonate solution (20mL × 1), saturated nacl aqueous solution (20mL × 2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (S) -6- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos -1,2,3,5- indolizine -3- amide groups) 4 (15mg of -1H- indole-2-carboxylic acids, 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- oxo -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acids
The first step
(S) -5- (7- (2- amino -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acid, ethyl esters
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acids 1b (305mg, 1
Mmol), 5- aminobenzofurs -2- carboxylic acid, ethyl esters (205mg, 1mmol, using known method " Journal of Medicinal Chemistry; 2008,51 (11), 3133-3144 " is prepared), I-hydroxybenzotriazole (163mg, 1.2mmol), dicyclohexylcarbodiimide (247mg, 1.2mmol) is dissolved in 5mL N, in dinethylformamide, it is stirred at room temperature 16 hours.It is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (S) -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- oxo -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acids
By (S) -5- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) benzofuran -2- carboxylic acid, ethyl esters 5a (600mg, 1.22mmol) is dissolved in 12mL methanol and tetrahydrofuran (V/V=1:1) in the mixed solvent, plus 6.1mL 2N sodium hydroxide solution, react at room temperature 16 hours.It is concentrated under reduced pressure, plus 10mL water, it is 2~3 that 6M hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate (30mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Obtain 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- oxo -1,2,3,5- indolizine -3- amide groups) 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 acid 5b (150mg, 0.32mmol), sodium azide (105mg, 1.62mmol) is dispersed in 3mL trimethyl orthoformates, stirring reaction 16 hours at 3mL glacial acetic acid, 70 DEG C are added dropwise again.It is concentrated under reduced pressure, preparative separation purifying gained residue, 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) benzofuran -2- carboxylic acids 5 (20mg, yellow solid), yield：12.1%.
MS m/z(ESI):517.1[M+1]
1H NMR(400MHz,DMSO-d6):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)
Embodiment 6
(S) -4- (7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxo -1,2,3,5- indolizine -3- amide groups) benzoic acid
The first step
(S) -4- (7- (2- amino -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- amide groups) methyl benzoate
By (S) -7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid 1b (150mg, 0.5mmol), methyl p-aminobenzoate (76mg, 0.5mmol), I-hydroxybenzotriazole (81mg, 0.6mmol), dicyclohexylcarbodiimide (124mg, 0.6mmol) is dissolved in 5mL N, in dinethylformamide, it is stirred at room temperature 16 hours.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- chlorphenyls) -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- oxo -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) methyl benzoate 6a (600mg, 1.22mmol) it is dissolved in 8mL methanol, plus 1.9mL 2N sodium hydroxide solution, react at room temperature 16 hours.It is concentrated under reduced pressure, plus 10mL water, it is 2~3 that 6M hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate (30mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Obtain crude product (S) -4- (7- (2- amino -5- chlorphenyls) -5- oxos -1,2,3,5- indolizine -3- amide groups) 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- oxo -1,2,3,5- indolizine -3- amide groups) 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, stirring reaction 16 hours at 2mL glacial acetic acid, 70 DEG C are added dropwise again.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- tetra-
Hydrogen indolizine -3- amide groups) benzoic acid 6 (30mg, faint yellow solid), yield：45.0%.
MS m/z(ESI):475.1[M-1]
1H NMR(400MHz,DMSO-d6):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)
Embodiment 7
(S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos-N- (2- oxo -1,2,3,4- tetrahydroquinoline -6- bases) -1,2,3,5- indolizine -3- formamides
The first step
(S) -7- (2- amino -5- chlorphenyls) -5- oxos-N- (2- oxo -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), 6- amino -3,4- EEDQs -2 (1H) -one 7a (65mg, 0.4mmol), I-hydroxybenzotriazole (65mg, 0.48mmol), dicyclohexylcarbodiimide (99mg, 0.48mmol) it is dissolved in 5mL DMFs, is stirred at room temperature 16 hours.Plus 20mL water, extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (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, 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- oxo -1,2,3,4- tetrahydroquinolines -6-
Base) -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) it is dispersed in 1mL trimethyl orthoformates, then stirring reaction 16 hours at 2mL glacial acetic acid, 60 DEG C is added dropwise.Vacuum distillation, adds 60mL ethyl acetate stirring and dissolvings, and it is in alkalescent to be washed with saturated sodium bicarbonate solution to aqueous phase, separates and collects organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.With preparative separation purify gained residue, obtain title product (S) -7- (the chloro- 2- of 5- (1H- tetrazole -1- bases) phenyl) -5- oxos-N- (2- oxos -1,2,3,4- tetrahydroquinoline -6- bases) -1,2,3,5- indolizine -3- formamides 7 (90mg, faint yellow solid), yield：81.8%.
MS m/z(ESI):502.1[M+1]
1H NMR(400MHz,DMSO-d6):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)
Embodiment 8
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxo -1,2,3,5- indolizine -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 DEG C.N-BuLi (33.4mL, 82.8mmol, 2.5M tetrahydrofuran solution) is added dropwise in above-mentioned reaction solution.Continue to stir 1 hour at -78 DEG C of completion of dropping.N- (the chloro- 3- fluorophenyls of 4-) -2,2,2- trifluoroacetamide 8a (10g, 41.4mmol are prepared using method disclosed in patent application " WO2009114677 ") 50mL tetrahydrofuran solutions are added dropwise in above-mentioned reaction solution.Continue to stir 2 hours at -78 DEG C of completion of dropping.Finally the 50mL tetrahydrofuran solutions of tributyltin chloride (13.4mL, 49.6mmol) are added dropwise in above-mentioned reaction solution, drop, which finishes, is slowly increased to room temperature continuation reaction 2 hours.Add 100mL water quenchings under ice bath to go out reaction, ethyl acetate (200mL × 3) extraction merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated.With silica gel column chromatography with eluant, eluent system B purify gained residue, obtain target product N- (the chloro- 3- of 4- fluoro- 2- (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 groups) phenyl) -5- oxo -1,2,3,5- indolizine -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 ester 8c (1g, 2.8mmol, it is prepared using method disclosed in patent application " WO2013093484 "), it is dissolved in 10mL dioxane, argon gas is replaced, plus [1, double (diphenylphosphine) ferrocene of 1'-] palladium chloride (41mg, 0.06mmol), argon gas displacement protection, 100 DEG C of stirring reactions 16 hours.It is concentrated under reduced pressure; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain target product (S) -7- (fluoro- 6- (2 of the chloro- 2- of 3-; 2,2- trifluoroacetyl groups) phenyl) -5- oxos -1,2; 3; 5- indolizine -3- carboxylic acid, ethyl esters 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- oxo -1,2,3,5- indolizine -3- carboxylic acids
By (S) -7- (the fluoro- 6- of the chloro- 2- of 3- (2,2,2- trifluoroacetyl groups) phenyl) -5- oxo -1,2,3,5- indolizine -3- carboxylics
Acetoacetic ester 8d (1.2g, 2.7mmol) is dissolved in 10mL ethanol, is added 7.3mL 1N sodium hydroxide solutions, is heated to reflux 4 hours.Be concentrated under reduced pressure, be added dropwise 2M hydrochloric acid to pH be 2~3, with ethyl acetate (50mL × 3) extract, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude product (S) -7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- carboxylic acid 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- oxo -1,2,3,5- indolizine -3- amide groups) benzofuran -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 acid 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 " is prepared), I-hydroxybenzotriazole (135mg, 1mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (192mg, 1mmol), N, N- diisopropylethylamine (322mg, 2.5mmol) it is dissolved in 6mL N, in dinethylformamide, it is stirred at room temperature 16 hours.It is concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (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, white 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- oxo -1,2,3,5- indolizine -3- amide groups) benzofuran -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 ester 8f (40mg, 0.078mmol) it is dissolved in 6mL methanol, 3mL 2N sodium hydroxide solution is added, is stirred at room temperature 16 hours.Be concentrated under reduced pressure, be added dropwise 2M hydrochloric acid to pH be 2~3, with ethyl acetate (50mL × 3) extract, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude product (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 8h (51mg, yellow solid), yield：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- oxo -1,2,3,5- indolizine -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- amide groups) benzofuran -2- carboxylic acid 8h (51mg, 0.11mmol), sodium azide (36mg, 0.55mmol) is dispersed in 2mL trimethyl orthoformates, stirring reaction 16 hours at 3mL glacial acetic acid, 70 DEG C are added dropwise again.It is concentrated under reduced pressure, preparative separation purifying gained residue, 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- indolizine -3- amide groups) benzofuran -2- carboxylic acids 8 (24mg, yellow solid), production
Rate：41.4%.
MS m/z(ESI):534.5[M+1]
1H NMR(400MHz,DMSO-d6):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).
Embodiment 9
(S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids
The first step
(S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxo -1,2,3,5- indolizine -3- the amide groups) -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 acid 8e (250mg, 0.77mmol), 5- amino -1H- indole-2-carboxylic acid tert-butyl ester 9a (180mg, 0.77mmol, using known method " Journal of Medicinal Chemistry, 2012, 55 (2), 766-782 " is prepared), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (354mg, 0.95mmol), N, N- diisopropylethylamine (0.3g, 2.3mmol) it is dissolved in 6mL N, in dinethylformamide, 50 DEG C of stirring reactions 4 hours.Reaction solution adds 10mL water, there is solid precipitation, filtering.Filter cake 100mL ethyl acetate dissolves, with anhydrous sodium sulfate drying, filtering, filtrate concentration, with thin-layered chromatography with eluant, eluent system A purify obtained by residue, obtain title product (S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acid tert-butyl ester 9b (50mg, faint yellow color solid), yield：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- oxo -1,2,3,5- indolizine -3- the amide groups) -1H- indole-2-carboxylic acid tert-butyl esters
By (S) -5- (7- (the chloro- 2- fluorophenyls of 6- amino -3-) -5- oxos -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acid tert-butyl ester 9b (50mg, 0.1mmol), trimethyl orthoformate (160mg, 1.5mmol) add in 6mL glacial acetic acid, react at room temperature 30 minutes, add sodium azide (20mg, 0.3mmol), stirring reaction 16 hours at 60 DEG C.Obtain (S) -5- (7- (the fluoro- 6- of the chloro- 2- of 3- (1H- tetrazole -1- bases) phenyl) -5- oxo -1,2,3,5- indolizine -3- amide groups) -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- oxo -1,2,3,5- indolizine -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 -1,2,3,5- indolizine -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 hours.It is concentrated under reduced pressure, residue obtained by preparative separation purifying, 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- indolizine -3- amide groups) -1H- indole-2-carboxylic acids 9 (20mg, faint yellow solid), yield：37.7%.
MS m/z(ESI):534.0[M+1]
1H NMR(400MHz,CD3OD):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)
Embodiment 10
(S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole-2-carboxylic acids
The first step
(S) -7- (2- acetyl group -5- chlorphenyls) -5- oxo -1,2,3,5- indolizine -3- carboxylic acid, ethyl esters
By (S) -5- oxos -7- (((trifluoromethyl) sulfonyl) epoxide) -1; 2; 3; 5- indolizine -3- carboxylic acid, ethyl ester 8c (430mg; 1.21mmol); 2- acetyl group -5- chlorophenylboronic acid pinacol esters (407mg; 1.45mmol; using known method " Chemistry Letters, 2011,40 (9); 1007-1008 " is prepared); 1.81mL 2N aqueous sodium carbonate, four triphenyl phosphorus palladiums (70mg, 0.06mmol) are dissolved in 45mL toluene and ethanol (V/V=2:1) in the mixed solvent, argon gas displacement protection, 70 DEG C of stirring reactions 16 hours.Filtrate decompression is concentrated; with silica gel column chromatography with eluant, eluent system A purify gained residue; obtain 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- oxo -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 ester 10a (500mg; 1.4mmol) it is dissolved in 20mL methanol, adds 2.1mL 2N sodium hydroxide solution, reaction 48 hours is stirred at room temperature.It is concentrated under reduced pressure, plus 20mL water, dichloromethane (20mL × 2) extraction, dropwise addition 1N hydrochloric acid to aqueous phase pH is 2~3, with dichloromethane and methanol (V/V=20:Isosorbide-5-Nitrae 0mL × 2) extract.The extractant after pH will be adjusted to merge, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration; obtain 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- oxo -1,2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters
By 5- amino -1H- indole -2-carboxylic methyl esters 1a (76mg, 0.4mmol), (S) -7- (2- acetyl group -5- chlorphenyls) -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; in dinethylformamide, it is stirred at room temperature 16 hours.Plus 30mL water, ethyl acetate (40mL × 2) extraction, merge organic
Phase; anhydrous sodium sulfate drying; filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue; obtain title product (S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1; 2,3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl ester 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 acids are by (S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1; 2; 3,5- indolizine -3- amide groups) -1H- indole -2-carboxylic methyl esters 10c (200mg, 0.39mmol) is dissolved in 15mL methanol and tetrahydrofuran (V/V=2:1) in the mixed solvent, is added dropwise to 1mL 2N sodium hydroxide solution, and reaction 5 hours is stirred at room temperature.It is concentrated under reduced pressure, add water 20mL, it is 2~3 that 2M hydrochloric acid, which is added dropwise, to pH, is extracted with ethyl acetate (50mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Purified with silica gel column chromatography with eluant, eluent system A; obtain target product (S) -5- (7- (2- acetyl group -5- chlorphenyls) -5- oxos -1; 2; 3; 5- indolizine -3- amide groups) 10 (100mg of -1H- indole-2-carboxylic acids; white solid), yield：52.6%.
MS m/z(ESI):490.2[M+1]
1H NMR(400MHz,DMSO-d6):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)
Utilize synthetic method synthetic example 11-26 of the 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 in no way meant to be limiting for the scope of the invention.
The experimental method of unreceipted actual conditions in test case of the present invention, generally according to normal condition, or according to the condition proposed by commodity manufacturer.The unreceipted reagent specifically originated, is the conventional reagent of market purchase.
The bioactivity of the Fluorometric assay factor XI, plasma thromboplastin antecedent a inhibitor of test case 1
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 substitute with DMSO, centrifuged, by compound to bottom.10ul (2.5ug/ml) FXIa enzyme solutions are added per hole, blank well adds 10ul buffer solutions and substituted, centrifugation, by enzyme solutions 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 carries out curve with Prism
It is fitted and obtains 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 the human blood of test case 2
1st, experiment material
Blood plasma：Human 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 (APTT kit, SIEMENS, article No. B4218-1), PT reagents (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 well mixed after melting.The 10000uM test-compounds for being dissolved in 100%DMSO are diluted to 3000 with 100%DMSO, 300,200,150,75,30,10,3,0.3uM, blank is 100%DMSO.Reagent, blood plasma, compound are put into correspondence position in Blood coagulation instrument, the APTT and PT of compound detection is carried out.
3rd, data processing
Carried out curve fitting by Prism, calculate CT2, i.e., the concentration of the compound corresponding to APTT, PT of 2 times blank controls 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, determine rat oral gavage using LC/MS/MS methods and give after Examples 1 and 2 compound not drug concentration in blood plasma in the same time.Pharmacokinetics behavior of the compounds of this invention in rat body is studied, its characteristics of pharmacokinetics is evaluated.
2nd, testing program
2.1 test drug
Embodiment 1,2,28 and 29 compounds
2.2 experimental animal
Healthy adult SD rat 16, male and female half and half, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2008-0016.
2.3 medicines are prepared
Note：PEG:Polyethylene glycol CMC-Na:Sodium carboxymethylcellulose
2.4 administration
SD rats 16, male and female half and half are divided into 4 groups；Gastric infusion, gastric infusion are distinguished after the night of fasting one.
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.The testing compound content after different compound gastric infusions in rat plasma is determined with LC/MS/MS methods.
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 good as the medicine generation of the prodrug of embodiment compound 2, with obvious medicine for assimilation effect.
Claims (17)
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of logical formula (I), or its pharmaceutically useful salt：Wherein：Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclic radical, annelated heterocycles base, aryl, fused-aryl, heteroaryl or condensed 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, heterocyclic radical, aryl, heteroaryl or-C (O) R4, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkyl；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, hydroxyalkyl, 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, described alkyl is optionally further selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, OC (O) OR by one or more5Or-NR5R6Substituent replaced；R5Or R6Hydrogen atom, alkyl or cycloalkyl are each independently selected from, wherein described alkyl or cycloalkyl is optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic acid ester groups；M is 0,1,2 or 3；AndN is 0,1 or 2.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1, or its pharmaceutically useful salt, its middle ring A is selected from fused-aryl, the fused-aryl that preferably 5~6 circle heterocycles or 5~6 yuan of hetero-aromatic rings are condensed with phenyl ring.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1, or its pharmaceutically useful salt, its middle ring A are selected from：
- The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to any one of claims 1 to 3, or its pharmaceutically useful salt, wherein R1It is each identical or different, it is each independently selected from halogen, heteroaryl or-C (O) R4, wherein R4Definition it is as claimed in claim 1.
- The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to any one of Claims 1 to 4, or its pharmaceutically useful salt, wherein：R2For hydrogen atom；R3It is each identical or different, it is independently selected from hydrogen atom, aryl ,-C (O) OR4Or-NHC (O) OR4；R4Selected from hydrogen atom or alkyl, described alkyl is optionally further by one or more-OC (O) OR5Substitution；R5Selected from hydrogen atom, alkyl or cycloalkyl.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 1, or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (II), or its pharmaceutically useful salt：Wherein：Ring A, R1、R2、R3, m and n as defined in claim 1.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 6, or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (III), 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 heterocyclic radical；Q is 0,1 or 2；AndRing A, R2、R3With n as defined in claim 1.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 7, or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (IV), 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 R9It is 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 claim 1；AndQ is 0,1 or 2.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to claim 7, or its pharmaceutically useful salt, it is to lead to the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in formula (V), 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, ring Alkyl or heterocyclic radical；Ring C is selected from heteroaryl, aryl, heterocyclic radical or cycloalkyl, preferably 5 yuan or 6 yuan of heteroaryl, aryl, Heterocyclylalkyl or cycloalkyl, more preferably 5 yuan or 6 yuan of Heterocyclylalkyl；R10Selected 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；It is preferred that halogen, oxo base ,-C (O) OR4、-C(O)R4、-NHC(O)R4Or-NHC (O) OR4；More preferably-C (O) OR4；R4As defined in claim 1；AndP and q are independently selected from 0,1 or 2.
- The compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in logical formula (I) according to any one of claim 1~9, or its pharmaceutically useful salt, wherein the compound is selected from：
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures shown in a kind of formula (IIIC), or its pharmaceutically useful salt：Wherein：Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclic radical, annelated heterocycles base, aryl, fused-aryl, heteroaryl or condensed 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, hydroxyalkyl, 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, described alkyl is optionally further selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, OC (O) OR by one or more5Or-NR5R6Substituent replaced；R5Or R6Hydrogen atom, alkyl or cycloalkyl are each independently selected from, wherein described alkyl or cycloalkyl is optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid group or carboxylic acid ester groups；R7Each identical or different, it is independently selected from hydrogen atom, halogen, cyano group, nitro, alkyl, cycloalkyl or heterocyclic radical；Q is 0,1 or 2；AndN is 0,1 or 2.
- A kind of compound or its dynamic isomer prepared shown in logical formula (I) according to claim 7, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or the method for its pharmaceutically useful salt, this method includes：First step reaction is that formula (IIIA) compound and formula (IIIB) compound carry out condensation reaction and obtain formula (IIIC) compound, second step reaction carries out annulation for obtained formula (IIIC) compound, obtains logical formula (III) compound；Wherein：Ring A, n, q, R2、R3And R7Definition it is as defined in claim 7.
- A kind of pharmaceutical composition, it contains the compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures according to claim any one of 1-10 of therapeutically effective amount, or its pharmaceutically useful salt and pharmaceutically acceptable carrier, diluent and excipient.
- Compound or its dynamic isomer according to any one of claim 1~10, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures, or its pharmaceutically useful salt, or purposes of the pharmaceutical composition according to claim 13 in prevention and/or treatment cardiovascular and cerebrovascular disease is prepared, the cardiovascular and cerebrovascular disease is preferably thrombotic disease, more preferably myocardial infarction, angina pectoris, blocking again and ISR after angioplasty or aortocoronary bypass, apoplexy, of short duration ischaemic breaking-out, peripheral arterial occlusive disease, pulmonary embolism or dvt are formed.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures according to any one of claim 1~10, or its pharmaceutically useful salt, or pharmaceutical composition according to claim 13 is in preparation prevention and/or treats by inhibiting factor XIa positive influences Disease medicine in purposes.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures according to any one of claim 1~10, or its pharmaceutically useful salt, or purposes of the pharmaceutical composition according to claim 13 in the medicine for preparing treatment disseminated intravascular coagulation.
- Compound or its dynamic isomer, mesomer, racemic modification, enantiomter, diastereoisomer or its form of mixtures according to any one of claim 1~10, or its pharmaceutically useful salt, or purposes of the pharmaceutical composition according to claim 13 in the medicine for preparing inhibiting factor XIa.
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| CN1222909A (en) * | 1996-04-23 | 1999-07-14 | 麦克公司 | Pyrazinone thrombin inhibitors |
| WO2008079787A2 (en) * | 2006-12-20 | 2008-07-03 | Takeda San Diego, Inc. | Glucokinase activators |
| WO2013093484A1 (en) * | 2011-12-21 | 2013-06-27 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
| CN105829298A (en) * | 2014-02-14 | 2016-08-03 | 四川海思科制药有限公司 | Pyridone or pyrimidone derivative, preparation method therefor and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222909A (en) * | 1996-04-23 | 1999-07-14 | 麦克公司 | Pyrazinone thrombin inhibitors |
| WO2008079787A2 (en) * | 2006-12-20 | 2008-07-03 | Takeda San Diego, Inc. | Glucokinase activators |
| WO2013093484A1 (en) * | 2011-12-21 | 2013-06-27 | Ono Pharmaceutical Co., Ltd. | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
| CN105829298A (en) * | 2014-02-14 | 2016-08-03 | 四川海思科制药有限公司 | Pyridone or pyrimidone derivative, preparation method therefor and application thereof |
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