WO2016011940A1 - 氮茚-酰胺类衍生物、其制备方法及其在医药上的应用 - Google Patents

氮茚-酰胺类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2016011940A1
WO2016011940A1 PCT/CN2015/084751 CN2015084751W WO2016011940A1 WO 2016011940 A1 WO2016011940 A1 WO 2016011940A1 CN 2015084751 W CN2015084751 W CN 2015084751W WO 2016011940 A1 WO2016011940 A1 WO 2016011940A1
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group
compound
cycloalkyl
enantiomer
formula
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English (en)
French (fr)
Inventor
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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Priority to CN201580002260.5A priority Critical patent/CN105658641B/zh
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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

Definitions

  • the present invention relates to a novel class of nitrogen hydrazine-amide derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same, and their use as therapeutic agents, in particular as XIa factor inhibitors, and in the preparation of treatment and/or prevention Use in drugs for diseases such as thromboembolism.
  • cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease and arteriosclerosis take nearly 12 million lives, which is close to 1/4 of the world's total death toll, becoming the number one enemy of human health.
  • the number of people dying from cardiovascular disease in China each year is more than 2.6 million, and 75% of surviving patients are disabled, and more than 40% of them are severely disabled.
  • the problem of thrombosis caused by cardiovascular and cerebrovascular diseases and diabetes and its complications has become an urgent problem to be solved today.
  • the human coagulation system contains two processes: the intrinsic pathway and the extrinsic pathway and a common pathway (Annu. Rev. Med. 2011. 62: 41-57).
  • the exogenous pathway also known as the tissue factor pathway, acts as a foreign pathway, and under the injury and various external stimuli, the tissue activator and activated factor VIIa (FVIIa) constitute a complex of activator X (FX), forming factor Xa.
  • FXa tissue activator and activated factor VIIa
  • activated FXa can convert prothrombin (PT) into thrombin, which acts as a central catalytic enzyme in the coagulation process, catalyzing the formation of fibrin by fibrinogen and acting as a coagulation.
  • the process involves fewer enzymes and is quicker.
  • the endogenous pathway belongs to the body's intrinsic pathway, and all the factors involved in blood coagulation come from the blood.
  • the cascade activates factor XII (FXII), factor XI (FXI), and factor IX (FIX), which in turn activates FXa to downstream prothrombin ( PT) is converted to thrombin, which in turn activates FXI.
  • FXII factor XII
  • FXI factor XI
  • FIX factor IX
  • FXI and FXIa play an extremely important role throughout the coagulation process.
  • antagonists As a co-regulator of exogenous and endogenous coagulation pathways, antagonists have been widely developed for the treatment of various thrombi.
  • a variety of FXa antagonists have been marketed, and their significant effectiveness has occupied the majority of cardiovascular and cerebrovascular markets. However, their side effects have become more and more significant. Among them, "bleeding risk" is the most serious problem (N Engl J Med 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).
  • BMS-654457 shows a significant dose-dependent potential efficacy in a rabbit model of experimental arterial thrombosis induced by direct current stimulation, with no bleeding side effects (22nd Int Symp Med Chem (Sept 2-6, Berlin) 2012, Abst L63).
  • the pharmacokinetic data of BMS-262084 showed that the compound as a FXIa inhibitor significantly improved the experimental model of thrombosis, and its side effects were extremely small (J Thromb Thrombolysis (2011) 32: 129-137).
  • the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof.
  • Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl;
  • Ring B is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • R 1 each being the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -C(O)R 4 , wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl or cycloalkane. Substituted by a substituent of the group;
  • R 2 is selected from a hydrogen atom, a halogen or an alkyl group
  • R 3 is each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • Base -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O NHR 4 or -NHC(O)NHOR 4 ;
  • R 4 is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, Substituted by a hydroxyalkyl group, a cycloalkyl group, a substituent of -OC(O)OR 5 or -NR 5 R 6 ;
  • R 5 or R 6 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group;
  • n 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein ring A is selected from the group consisting of:
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein each R 1 is the same or different and each independently selected from halogen, heteroaryl or -C(O)R 4 , wherein R 4 is as defined (I) stated.
  • a compound of the formula (I) or tautomerized thereof a form, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 is a hydrogen atom
  • R 3 is selected from a hydrogen atom, an aryl group, -C(O)OR 4 or -NHC(O)OR 4 ;
  • R 4 is selected from a hydrogen atom or an alkyl group, and the alkyl group is optionally further substituted with one or more -OC(O)OR 5 ;
  • R 5 is selected from a hydrogen atom, an alkyl group or a cycloalkyl group.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A, R 1 , R 2 , R 3 , m and n are as defined in formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 are each the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • q 0, 1 or 2;
  • Rings A, R 2 , R 3 and n are as defined in formula (I).
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 are the same or different and are each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • R 8 or R 9 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O)NHR 4 or -NHC (O) NHOR 4 ;
  • R 4 is as defined in the general formula (I);
  • q 0, 1, or 2.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof a form or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 is each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • Ring C is selected from heteroaryl, aryl, heterocycloalkyl or cycloalkyl, preferably 5- or 6-membered heteroaryl, aryl, heterocycloalkyl or cycloalkyl, more preferably 5 or 6 Heterocycloalkyl;
  • R 10 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O)NHR 4 or -NHC (O) NHOR 4 ; preferably halogen, oxo, -C(O)OR 4 , -C(O)R 4 , -NHC(O
  • R 4 is as defined in the general formula (I);
  • Each of p and q is independently selected from 0, 1, or 2.
  • a typical compound of the formula (I) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Medicinal salts including but not limited to:
  • Another aspect of the invention provides a compound of the formula (IIIC) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or a mixture, or a pharmaceutically acceptable salt thereof, which can be used to prepare a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer An intermediate of the isomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, fused cycloalkyl, heterocyclyl, fused heterocyclyl, aryl, fused aryl, heteroaryl, or fused heteroaryl;
  • R 2 is selected from a hydrogen atom, a halogen or an alkyl group
  • R 3 is each the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an oxo group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • R 4 is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group or a halogenated alkyl group, and the alkyl group is further selected from one or more selected from the group consisting of halogen, cyano, nitro, alkyl, haloalkyl, hydroxyalkane. Substituted by a substituent of a cycloalkyl group, -OC(O)OR 5 or -NR 5 R 6 ;
  • R 5 or R 6 are each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein the alkyl group or cycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, alkoxy. Substituted with a substituent of a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid group or a carboxylate group;
  • R 7 is each the same or different and each independently selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a cycloalkyl group or a heterocyclic group;
  • q 0, 1, or 2
  • n 0, 1, or 2.
  • Another aspect of the invention provides a compound of the formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof or a method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the first step is a condensation reaction of a compound of the formula (IIIA) with a compound of the formula (IIIB) to obtain a compound of the formula (IIIC), and a second step of the compound of the formula (IIIC) obtained by a ring-forming reaction to obtain a formula ( III) a compound;
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a prophylactic and/or therapeutic cardio-cerebral vascular disease, preferably a thromboembolic disease, more preferably an acute heart attack, angina pectoris, angioplasty Re-occlusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis after surgery or aortic coronary shunt.
  • a prophylactic and/or therapeutic cardio-cerebral vascular disease preferably a thromboembolic disease, more preferably an acute heart attack, angina pectoris, angioplasty Re-occlusion and restenosis, stroke, transient ischemic attack, peripheral arterial
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for preventing and/or treating a disease which is positively affected by inhibition of factor XIa; for use in the preparation of a medicament for treating disseminated intravascular coagulation And the use in the preparation of a medicament for inhibiting factor XIa.
  • Another aspect of the invention relates to a method of modulating factor XIa activity, preferably inhibiting factor XIa, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • a compound of formula (I) or a tautomer thereof A meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a method of treating and/or preventing cardiovascular and cerebrovascular diseases, the method comprising A therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, administered to a subject in need thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the disease described therein is preferably a thromboembolic disease, more preferably re-occlusion and restenosis after arrhythmia, angina pectoris, or aortic coronary artery bypass, stroke, transient ischemic attack, peripheral arterial occlusion Disease, pulmonary embolism or deep vein thrombosis.
  • Another aspect of the invention relates to a method of preventing and/or treating a disease which is positively affected by inhibition of factor XIa, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof.
  • a compound of formula (I) or a tautomer thereof An isomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a method of treating a disseminated intravascular coagulopathy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, mesogenic a form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of cardiovascular and cerebrovascular diseases, preferably thromboembolic diseases, more preferably cardiac arrest, angina pectoris, angioplasty or aortic coronary artery shunt Postoperative reocclusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.
  • cardiovascular and cerebrovascular diseases preferably thromboembolic diseases, more preferably cardiac arrest, angina pectoris, angioplasty or aortic coronary artery shunt Postoperative reocclusion and restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for preventing and/or treating a disease which is positively affected by inhibition of factor XIa; for treating disseminated intravascular coagulation; and for inhibiting factor XIa activity.
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl, cycloalkyl or heterocyclyl ring to form a "fused cycloalkyl" wherein the ring to which the parent structure is attached is a cycloalkyl group.
  • Non-limiting examples include tetrahydronaphthyl, benzocycloheptyl,
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) m ( Wherein m is a hetero atom of 0 to 2, but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the heterocyclic ring comprises 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms; more preferably, the heterocyclic ring contains 3 to 10 ring atoms, of which 1 to 3 are hetero atoms; more preferably, the heterocyclic ring contains 5 to 6 ring atoms, of which 1 to 2 are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring to form a "fused heterocyclic group" wherein the ring to which the parent structure is attached is a heterocyclic group.
  • Non-limiting examples include:
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
  • the base and naphthyl are most preferably phenyl.
  • the aryl ring may be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring to form a "fused aryl" wherein the ring to which the parent structure is attached is an aryl ring, unrestricted
  • the sexual embodiment includes:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane.
  • Base amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)R 4 , -NHC(O)R 4 , -NHC(O)OR 4 , -NHC(O)NHR 4 or -NHC(O)NHOR 4 ; wherein R 4 is as defined in the compound of formula (I).
  • Heteroaryl refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
  • the heteroaryl group is preferably 5 or 6 members, and preferred examples include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl , pyridazinyl and the like.
  • the heteroaryl ring may be fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring to form a "fused heteroaryl" wherein the ring to which the parent structure is attached is a heteroaryl ring
  • Non-limiting examples include:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, oxo, -OR 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O) R 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 or —NHC(O)NHOR
  • Haloalkyl means that the alkyl group is substituted by one or more halogens, wherein the alkyl group is as defined above.
  • Hydrophilicity refers to an -OH group.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxylic acid group means -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the compound of the formula (IIIA) and the compound of the formula (IIIB) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (IIIC), and the second step is a compound of the formula (IIIC).
  • a sodium azide, trimethyl orthoformate is subjected to a ring-forming reaction under glacial acetic acid to obtain a compound of the formula (III);
  • the ring A, n, q, R 2 , R 3 or R 7 is as defined in the formula (III).
  • the compound of the formula (IVA) and the compound of the formula (IVB) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (IVC), and the second step is a compound of the formula (IVC).
  • the ring-forming reaction is carried out with sodium azide and trimethyl orthoformate under glacial acetic acid to obtain a compound of the formula (IV);
  • R 2 , q, R 7 to R 10 are as defined in the formula (IV).
  • the first step reaction is a compound of the formula (VA) and a compound of the formula (VB) which are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (VC), and the second step is a compound of the formula (VC).
  • the ring-forming reaction is carried out with sodium azide and trimethyl orthoformate under glacial acetic acid to obtain a compound of the formula (V);
  • the reagent for providing basic conditions includes an organic base and an inorganic base, and the organic base includes, but not limited to, 1-hydroxybenzotriazole, triethylamine, N,N-diisopropyl.
  • the inorganic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
  • Condensing agents include, but are not limited to, bicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide Amine, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzoate Triazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azo Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate Or
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR chemical shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone System, D: ethyl acetate and dichloromethane system, E: ethyl acetate and dichloromethane and n-hexane, F: ethyl acetate and dichloromethane and acetone, the volume ratio of the solvent is different depending on the polarity of the compound Adjustment, can also be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.
  • Methyl 6-amino-1H-indole-2-carboxylate 200 mg, 1 mmol, prepared by the method disclosed in the patent application "WO 2012101013"
  • (S)-7-(2-amino-5-chloro Phenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid 1b 304 mg, 1 mmol
  • 1-hydroxybenzotriazole 150 mg, 1.1 mmol
  • bicyclo Hexylcarbodiimide 220 mg, 1.1 mmol was dissolved in 3 mL of N,N-dimethylformamide and stirred at room temperature for 4 hours.
  • the obtained residue was purified by silica gel column chromatography elutd elut elut elut elut elut elut elut elut elut elut elut elut elut 1,2,3,4-tetrahydroquinolin-6-yl)-1,2,3,5-tetrahydroindolizine-3-carboxamide 7b (100 mg, pale yellow solid), yield: 55.0% .
  • Tetramethylethylenediamine (12.5 mL, 82.8 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -78 °C with argon.
  • n-Butyllithium (33.4 mL, 82.8 mmol, 2.5 M in tetrahydrofuran) was added dropwise to the above reaction mixture. After the completion of the dropwise addition, stirring was continued at 78 ° C for 1 hour.
  • Methyl 5-amino-1H-indole-2-carboxylate 1a (76 mg, 0.4 mmol), (S)-7-(2-acetyl-5-chlorophenyl)-5-oxo-1, 2,3,5-tetrahydroindolizine-3-carboxylic acid 10b (132 mg, 0.4 mmol), 1-hydroxybenzotriazole (65 mg, 0.48 mmol), dicyclohexylcarbodiimide (99 mg, 0.48 mmol) Dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours.
  • Examples 11-26 were synthesized according to the synthesis method of Examples 1-10 of the present invention using different starting materials.
  • the spectral parameters of Examples 11-26 are shown in Table 2 below:
  • the experimental method in which the specific conditions are not indicated in the test examples of the present invention is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer of the product.
  • Reagents without specific source are routine reagents purchased from the market.
  • Test Example 1 Fluorometric detection of biological activity of factor XIa inhibitor
  • Buffer 100 mM tris-HCl, 200 mM NaCl, 0.02% tween 20, pH 7.4.
  • Example 27 Compound number IC 50 (factor XIa) / (nM) Example 2 6.4 Example 3 284.5 Example 4 17.2 Example 5 20.1 Example 7 60.6 Example 8 25.3 Example 9 12.5 Example 11 57.2 Example 15 96.6 Example 18 214.0 Example 20 290.4 Example 21 34.3 Example 24 70.7 Example 25 132.9 Example 27 132.7
  • the compounds of the present invention have significant inhibitory activity against factor XIa.
  • Test Example 2 Determination of anticoagulant effect in human blood in vitro
  • Plasma human blood was collected in a blood collection tube containing no anticoagulant, adding 3.8% sodium citrate (volume ratio 1:9), centrifuged at 2500 rpm for 10 min at room temperature, and the plasma was collected and stored at -80 ° C;
  • APTT reagent activated partial thromboplastin time assay kit, SIEMENS, item number B4218-1
  • PT reagent prothrombin time assay kit, SIEMENS, item number OUHP29
  • calcium chloride solution calcium chloride solution
  • the divided plasma was melted at room temperature and mixed evenly. 10000 uM test compound dissolved in 100% DMSO was diluted to 3000, 300, 200, 150, 75, 30, 10, 3, 0.3 uM with 100% DMSO and the blank was 100% DMSO. The reagent, plasma, and compound are placed in the corresponding positions in the coagulation instrument, and the APTT and PT of the compound are detected.
  • Example 2 Compound number Inhibition of platelet aggregation CT 2 ( ⁇ M) Example 2 1.83 Example 5 36.58 Example 8 21.71 Example 9 3.84 Example 24 10.74
  • the compounds of the present invention have significant inhibitory activity against human blood agglutination.
  • Test Example 3 Pharmacokinetic Testing of Compounds of the Inventive Examples
  • SD rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compounds of Examples 1 and 2 by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • PEG polyethylene glycol
  • CMC-Na sodium carboxymethyl cellulose
  • the rats in the gavage administration group collected blood at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h before and after the administration.
  • 0.2 ml was placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 min, and stored at -20 °C.
  • the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.

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Abstract

本发明涉及氮茚-酰胺类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式（I）所示的氮茚-酰胺类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为XIa因子抑制剂的用途和在制备治疗和/或预防血栓栓塞等疾病的药物中的用途，其中通式（I）中的各取代基的定义与说明书中的定义相同。

Description

氮茚-酰胺类衍生物、其制备方法及其在医药上的应用 技术领域
本发明涉及一类新的氮茚-酰胺类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为XIa因子抑制剂的用途和在制备治疗和/或预防血栓栓塞等疾病的药物中的用途。
背景技术
全球每年脑血管、脑梗塞、心肌梗塞、冠心病、动脉硬化等心脑血管疾病夺走近1200万人的生命，接近世界总死亡人数的1/4，成为人类健康的头号大敌。中国每年死于心血管疾病的人数达到260万人以上，存活的患者75％致残，其中40％以上重残。由心脑血管疾病和糖尿病及其并发症引起的血栓问题，成为当今要解决的刻不容缓的问题。
据独立市场分析机构Datamonitor 2011年数据预计，随着仿制药的生产，心血管及代谢疾病在七大主要市场的份额将在2011年达到顶峰，之后逐渐降低，其销售额将从2010年的1090亿美元将至2019年的1010亿美元。其中血栓市场保持基本稳定，由2010年的195亿美元微降至2019年的189亿美元(Datamonitor:HC00034-001、HC00139-001)。广州标点2011年的调研报告也显示，2011年中国抗血栓药物市场规模可达81.35亿元，同比增长20.52％，具有巨大的市场潜力(抗血栓药物市场研究报告：广州标点(2011))。
人体凝血系统包含两个过程：内源性途径(intrinsic pathway)及外源性途径(extrinsic pathway)及一个共同途径(Annu.Rev.Med.2011.62:41–57)。外源性途径也称为组织因子途径，作为外源途径，在损伤和各种外来刺激下，组织因子和被激活的因子VIIa(FVIIa)组成的复合物激活因子X(FX)，形成因子Xa(FXa)，激活的FXa可以将凝血酶原(prothrombin,PT)转化为凝血酶(thrombin)，凝血酶作为凝血过程的中心催化酶，催化纤维蛋白酶原形成纤维蛋白，起到凝血作用。该过程参与的酶数量少，见效快。内源性途径属于机体固有途径，参与凝血的因子全部来自血液，通过级联反应激活因子XII(FXII)、因子XI(FXI)、因子IX(FIX)，进而激活FXa将下游的凝血酶原(PT)转化为凝血酶，凝血酶又可以反过来激活FXI。该过程参与的酶数量多，见效较慢(Arterioscler Thromb Vasc Biol.2010；30:388-392)。
在整个凝血过程中，FXI和FXIa扮演着极其重要的角色，其作为外源性和内源性凝血途径的共同调节因子，其拮抗剂被广泛开发用于各种血栓的治疗。现有多种FXa拮抗剂上市，以其显著有效性占据广大心脑血管市场，然而其副作用也越来越显著，其中“出血风险(bleeding risk)”是首当其冲最为严峻的问题(N Engl J Med 1991；325:153-8、Blood.2003；101:4783-4788)。
为解决这个问题，近期靶点FXIa成为各大公司及研究机构的研究热门。有研究发现严重的FXI不足会引起血友病C，该病症多发生在犹太人身上(1:450)。血友病C的症状比血友病A和B更为温和，少许发生自发性出血，即使在受伤或手术中机体的止血功能也不受影响，血友病C患者可以正常怀孕分娩(Arterioscler Thromb Vasc Biol.2010；30:388-392)。因此FXIa安全性显著优于FXa。研究发现，在血栓模型中，抑制FXIa因子可以有效抑制血栓的形成，但在更为严重的血栓情况下，FXIa的作用微乎其微(Blood.2010；116(19):3981-3989)。临床统计显示，提高FXIa的量会增加VTE的患病率(Blood 2009；114:2878-2883)，而FXIa严重不足者其患有DVT的风险性减少(Thromb Haemost 2011；105:269–273)。
FXIa作为新兴靶点，尚未公布其进入临床阶段的药物，但Bristol-Myers Squibb的BMS-654457及BMS-262084有可能已展开临床研究，其临床结果尚未公开。临床前研究结果显示，在直流电刺激诱导的实验兔动脉血栓模型中，BMS-654457显示了显著的剂量依赖性的潜在有效性，同时无出血副作用存在(22nd Int Symp Med Chem(Sept 2-6,Berlin)2012,Abst L63)。而BMS-262084的药代数据显示了该化合物作为FXIa抑制剂显著改善实验模型血栓症状，同时其副作用极其微小(J Thromb Thrombolysis(2011)32:129–137)。
专利申请WO9630396、WO9941276、WO2013093484、WO2004002405、WO2013056060和US20050171148公开了具有因子XIa抑制活性的化合物。本发明设计了新的化合物小分子FXIa拮抗剂，具有更高的活性，并表现出优异的效果和作用。可用于有效治疗心脑血管疾病及血栓症状。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
Figure PCTCN2015084751-appb-000001
其中：
环A选自环烷基、稠合环烷基、杂环基、稠合杂环基、芳基、稠合芳基、杂芳基、或稠合杂芳基；
环B选自环烷基、杂环基、芳基或杂芳基；
R1各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基或-C(O)R4，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基或环烷基的取代基所取代；
R2选自氢原子、卤素或烷基；
R3各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；
R4选自氢原子、卤素、氰基、硝基、烷基或卤代烷基，所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、-OC(O)OR5或-NR5R6的取代基所取代；
R5或R6各自独立地选自氢原子、烷基或环烷基，其中所述的烷基或环烷基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸基或羧酸酯基的取代基所取代；
m为0、1、2或3；且
n为0、1或2。
在本发明一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中环A选自稠合芳基，优选5～6元杂环或5～6元杂芳环与苯环稠合的稠合芳基。
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中环A选自：
Figure PCTCN2015084751-appb-000002
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中R1各自相同或不同，各自独立地选自卤素、杂芳基或-C(O)R4，其中R4的定义如通式(I)所述。
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构 体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中：
R2为氢原子；
R3选自氢原子、芳基、-C(O)OR4或-NHC(O)OR4；
R4选自氢原子或烷基，所述的烷基任选进一步被一个或多个-OC(O)OR5取代；
R5选自氢原子、烷基或环烷基。
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
其中：
环A、R1、R2、R3、m和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
Figure PCTCN2015084751-appb-000004
其中：
R7各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
q为0、1或2；
环A、R2、R3和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
Figure PCTCN2015084751-appb-000005
其中：
R7相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
R8或R9各自独立地选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；
R4如通式(I)中所定义；且
q为0、1或2。
在本发明另一个优选的实施方案中，一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(V)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
Figure PCTCN2015084751-appb-000006
其中：
R7各自相同或不同，各自独立的选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
环C选自杂芳基、芳基、杂环烷基或环烷基，优选5元或6元的杂芳基、芳基、杂环烷基或环烷基，更优选5元或6元的杂环烷基；R10选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；优选卤素、氧代基、-C(O)OR4、-C(O)R4、-NHC(O)R4或-NHC(O)OR4；更优选-C(O)OR4；
R4如通式(I)中所定义；且
p和q各自独立的选自0、1或2。
本发明通式(I)所示的典型化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，包括但不限于：
表1
Figure PCTCN2015084751-appb-000007
Figure PCTCN2015084751-appb-000008
Figure PCTCN2015084751-appb-000009
Figure PCTCN2015084751-appb-000010
Figure PCTCN2015084751-appb-000011
Figure PCTCN2015084751-appb-000012
本发明的另一方面提供一种通式(IIIC)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，其可用于制备通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐的中间体：
Figure PCTCN2015084751-appb-000013
其中：
环A选自环烷基、稠合环烷基、杂环基、稠合杂环基、芳基、稠合芳基、杂芳基、或稠合杂芳基；
R2选自氢原子、卤素或烷基；
R3各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4的取代基所取代；
R4选自氢原子、卤素、氰基、硝基、烷基或卤代烷基，所述的烷基进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、-OC(O)OR5或-NR5R6的取代基所取代；
R5或R6各自独立地选自氢原子、烷基或环烷基，其中所述的烷基或环烷基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸基或羧酸酯基的取代基所取代；
R7各自相同或不同，各自独立的选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
q为0、1或2，且
n为0、1或2。
本发明的另一方面提供一种制备通式(III)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐的方法，该方法包括：
Figure PCTCN2015084751-appb-000014
第一步反应为通式(IIIA)化合物和通式(IIIB)化合物进行缩合反应得到通式(IIIC)化合物，第二步为得到的通式(IIIC)化合物进行成环反应，得到通式(III)化合物；
其中：环A、n、q、R2、R3和R7的定义如通式(III)中所定义。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐以及药学上可接受的载体、稀释剂和赋形剂。
本发明的另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备预防和/或治疗心脑血管疾病中的用途，所述疾病优选为血栓栓塞性疾病，更优选为心急梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
本发明的另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物在制备预防和/或治疗通过抑制因子XIa正性影响的疾病的药物中的用途；在制备治疗弥散性血管内凝血的药物中的用途；以及在制备抑制因子XIa的药物中的用途。
本发明的另一方面涉及一种调控因子XIa活性，优选抑制因子XIa活性的方法，该方法包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本发明的另一方面涉及一种治疗和/或预防心脑血管疾病的方法，该方法包括 给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。其中所述的疾病优选为血栓栓塞性疾病，更优选心急梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
本发明的另一方面涉及一种预防和/或治疗通过抑制因子XIa正性影响的疾病的方法，该方法包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本发明的另一方面涉及一种治疗弥散性血管内凝血疾病的方法，该方法包括给予所需患者治疗有效量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。
本发明另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于预防和/或治疗心脑血管疾病，优选血栓栓塞性疾病，更优选心急梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
本发明另一方面涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用于预防和/或治疗通过抑制因子XIa正性影响的疾病；用于治疗弥散性血管内凝血；以及用于抑制因子XIa活性。
发明的详细说明
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指饱和的脂肪族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3- 二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优选环烷基环包含3至6个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基环可以稠合于芳基、杂芳基、环烷基或杂环基环上，形成“稠合环烷基”，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括四氢萘基、苯并环庚烷基、
Figure PCTCN2015084751-appb-000015
等。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0至2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子；更优选杂环基环包含3至10个环原子，其中1～3个是杂原子；更优选杂环基环包含5至6个环原子，其中1～2个是杂原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基、杂环基或环烷基环上，形成“稠合杂环基”，其中与母体结构连接在一起的环为杂环基，非限制性实施例包含：
Figure PCTCN2015084751-appb-000016
等。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选苯基和萘基，最优选苯基。所述芳基环可以稠合于芳基、杂芳基、杂环基或环烷基环上，形成“稠合芳基”，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2015084751-appb-000017
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、氧代基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；其中R4的定义如通式(I)化合物中所述。
“杂芳基”指具有1至4个杂原子作为环原子，其余的环原子为碳的5至14元芳基，其中杂原子包括氧、硫和氮。优选为5至10元。杂芳基优选为是5元或6元，优选例包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、哒嗪基等。所述杂芳基环可以稠合于芳基、杂芳基、杂环基或环烷基环上，形成“稠合杂芳基”，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2015084751-appb-000018
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷 氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、氧代基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；其中R4的定义如通式(I)化合物中所述。
“卤代烷基”指烷基被一个或多个卤素取代，其中烷基的定义如上所述。
“羟基”指-OH基团。
“羟烷基”指被羟基取代的烷基，其中烷基的定义如上所述。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“氧代基”指＝O。
“羧酸基”指-C(O)OH。
“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基的定义如上所述。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基所取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
方案一
Figure PCTCN2015084751-appb-000019
第一步反应为通式(IIIA)化合物和通式(IIIB)化合物在碱性条件下在缩合剂存在下进行缩合反应得到通式(IIIC)化合物，第二步反应为通式(IIIC)化合物与叠氮化钠，原甲酸三甲酯在冰醋酸条件下，进行成环反应，得到通式(III)化合物；
其中：环A、n、q、R2、R3或R7的定义如通式(III)中所定义。
方案二
Figure PCTCN2015084751-appb-000020
第一步反应为通式(IVA)化合物和通式(IVB)化合物在碱性条件下在缩合剂存在下进行缩合反应得到通式(IVC)化合物，第二步反应为通式(IVC)化合物与叠氮化钠，原甲酸三甲酯在冰醋酸条件下，进行成环反应，得到通式(IV)化合物；
其中：R2、q、R7～R10的定义如通式(IV)中所定义。
方案三
Figure PCTCN2015084751-appb-000021
第一步反应为通式(VA)化合物和通式(VB)化合物在碱性条件下在缩合剂存在下进行缩合反应得到通式(VC)化合物，第二步反应为通式(VC)化合物与叠氮化钠，原甲酸三甲酯在冰醋酸条件下，步进行成环反应，得到通式(V)化合物；
其中：环C、p、q、R7、R10的定义如通式(V)中所定义。
上述合成技术方案中，提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于1-羟基苯并三唑、三乙胺、N,N-二异丙基乙胺、N,N-二甲基甲酰胺、吡啶、六甲基二硅基胺基钠，正丁基锂、叔丁醇钾或四丁基溴化铵，优选为N,N-二甲基甲酰胺；所述的无机碱类包括但不限于氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸铯。
缩合剂包括但不限于二环已基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为二环已基碳二亚胺。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR化学位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan  LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)，达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和丙酮体系，D：乙酸乙酯和二氯甲烷体系，E：乙酸乙酯和二氯甲烷和正己烷，F：乙酸乙酯和二氯甲烷和丙酮，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯
Figure PCTCN2015084751-appb-000022
Figure PCTCN2015084751-appb-000023
第一步
(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯
将5-氨基-1H-吲哚-2-羧酸甲酯1a(124mg，0.64mmol，采用公知的方法“Journal of the American Chemical Society,2007,129(35),10858-10869”制备而得)，(S)-7-(2-胺基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸1b(200mg，0.64mmol，采用专利申请“WO2013093484”公开的方法制备而得)，1-羟基苯并三唑(104mg，0.77mmol)，二环己基碳二亚胺(160mg，0.77mmol)溶解于10mL N,N-二甲基甲酰胺中，室温搅拌16小时。过滤，滤饼用20mL N,N-二甲基甲酰胺洗涤。合并母液，减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯1c(240mg，棕色油状物)，产率：78.0％。
MS m/z(ESI):477.1[M+1]
第二步
(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯
将(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯1c(120mg，0.25mmol)，叠氮化钠(56mg，0.87mmol)分散在原甲酸三甲酯(0.98mL，8.82mmol)中，再滴加2mL冰醋酸，70℃下搅拌反应16小时。减压浓缩，加入60mL乙酸乙酯搅拌溶解，用饱和碳酸氢钠溶液洗涤至水相呈弱碱性，分出有机相，水相用乙酸乙酯萃取(30mL×2)，合并有机相，用饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用制备分离法纯化(HPLC)所得残余物，得到标题产物(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯1(50mg，白色固体)，产率：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)
实施例2
(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
Figure PCTCN2015084751-appb-000024
第一步
将(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯1(23mg，0.043mmol)加入2mL甲醇和四氢呋喃(V/V＝1:1)混合溶剂中，加入0.2mL 2N的氢氧化锂溶液，室温搅拌2小时。减压浓缩，加10mL水，滴加2M的盐酸调节pH为2～3，用二氯甲烷和甲醇(V/V＝5:1,30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。用制备分离法纯化(HPLC)所得残余物，得到标题产物(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸2(10mg，白色固体)，产率：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)
实施例3
(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-N-(1H-吲哚-5-基)-5-氧代-1,2,3,5-四氢中氮茚-3-甲酰胺
Figure PCTCN2015084751-appb-000025
Figure PCTCN2015084751-appb-000026
第一步
(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸将(S)-7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸1b(60mg，0.2mmol)，叠氮化钠(13mg，0.2mmol)分散在0.3mL原甲酸三甲酯中，再滴加2mL冰醋酸，65℃下搅拌反应16小时。减压浓缩，硅胶柱色谱法以洗脱剂体系纯化所得残余物，得到标题产物(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸3a(73mg，灰色固体)，产率：98.0％。
MS m/z(ESI):358.1[M+1]
第二步
(S)-7-(5-氯-2-(5-氯-2-(1H-四氮唑-1-基)苯基)-N-(1H-吲哚-5-基)-5-氧代-1,2,3,5-四氢中氮茚-3-甲酰胺
将(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸3a(73mg，0.2mmol)，5-氨基吲哚(39mg，0.3mmol，采用公知的方法“Electrochimica Acta,2013,107,292-300”制备而得)，1-羟基苯并三唑(40mg，0.3mmol)，二环己基碳二亚胺(60mg，0.3mmol)溶解于5mL N,N-二甲基甲酰胺中，室温搅拌72小时。过滤，滤饼用20mL N,N-二甲基甲酰胺洗涤。合并母液，减压浓缩，用制备分离法纯化(HPLC)所得残余物，得到标题产物(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-N-(1H-吲哚-5-基)-5-氧代-1,2,3,5-四氢中氮茚-3-甲酰胺3(20mg，灰色固体)，产率：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)
实施例4
(S)-6-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
Figure PCTCN2015084751-appb-000027
第一步
(S)-6-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯
将6-氨基-1H-吲哚-2-羧酸甲酯(200mg，1mmol，采用专利申请“WO 2012101013”公开的方法制备而得)，(S)-7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸1b(304mg，1mmol)，1-羟基苯并三唑(150mg，1.1mmol)，二环己基碳二亚胺(220mg，1.1mmol)溶解于3mL N,N-二甲基甲酰胺中，室温搅拌4小时。过滤，滤饼用20mL N,N-二甲基甲酰胺洗涤。合并母液，减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-6-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯4a(203mg，棕色固体)，产率：42.8％。
第二步
(S)-6-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
将(S)-6-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯4a(203mg，0.43mmol)溶解于10mL甲醇中，加3mL 2N的氢氧化钠溶液，室温反应4小时。减压浓缩，加10mL水，滴加2M的盐酸至pH为2～3，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品(S)-6-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2- 羧酸4b(200mg，灰色固体)。
MS m/z(ESI):463.0[M+1]
第三步
(S)-6-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
将粗品(S)-6-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸4b(200mg，0.43mmol)，叠氮化钠(30mg，0.43mmol)分散在2mL原甲酸三甲酯中，再滴加5mL冰醋酸，70℃下搅拌反应5小时。减压浓缩，加10mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和碳酸氢钠溶液(20mL×1)、饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-6-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸4(15mg，淡黄色固体)，产率：6.8％。
MS m/z(ESI):516.0[M+1]
实施例5
(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸
Figure PCTCN2015084751-appb-000028
第一步
(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸乙酯
将(S)-7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸1b(305mg，1 mmol)，5-氨基苯并呋喃-2-羧酸乙酯(205mg，1mmol，采用公知的方法“Journal of Medicinal Chemistry,2008,51(11),3133-3144”制备而得)，1-羟基苯并三唑(163mg，1.2mmol)，二环己基碳二亚胺(247mg，1.2mmol)溶解于5mL N,N-二甲基甲酰胺中，室温搅拌16小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸乙酯5a(600mg，黄色固体)，产率：100％。
MS m/z(ESI):492.2[M+1]
第二步
(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸
将(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸乙酯5a(600mg，1.22mmol)溶解于12mL甲醇和四氢呋喃(V/V＝1:1)的混合溶剂中，加6.1mL 2N的氢氧化钠溶液，室温反应16小时。减压浓缩，加10mL水，滴加6M的盐酸至pH为2～3，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。得粗品(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸5b(150mg，黄色固体)，产率：26.5％。
MS m/z(ESI):464.2[M+1]
第三步
(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸
将粗品(S)-5-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸5b(150mg，0.32mmol)，叠氮化钠(105mg，1.62mmol)分散在3mL原甲酸三甲酯中，再滴加3mL冰醋酸，70℃下搅拌反应16小时。减压浓缩，制备分离纯化所得残余物，得到标题产物(S)-5-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸5(20mg，黄色固体)，产率：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)
实施例6
(S)-4-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸
Figure PCTCN2015084751-appb-000029
Figure PCTCN2015084751-appb-000030
第一步
(S)-4-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸甲酯
将(S)-7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸1b(150mg，0.5mmol)，对氨基苯甲酸甲酯(76mg，0.5mmol)，1-羟基苯并三唑(81mg，0.6mmol)，二环己基碳二亚胺(124mg，0.6mmol)溶解于5mL N,N-二甲基甲酰胺中，室温搅拌16小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-4-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸甲酯6a(120mg，黄色固体)，产率：55％。
MS m/z(ESI):438.2[M+1]
第二步
(S)-4-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸
将(S)-4-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸甲酯6a(600mg，1.22mmol)溶解于8mL甲醇中，加1.9mL 2N的氢氧化钠溶液，室温反应16小时。减压浓缩，加10mL水，滴加6M的盐酸至pH为2～3，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。得粗品(S)-4-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸6b(60mg，黄色固体)，产率：51.7％。
MS m/z(ESI):424.0[M+1]
第三步
(S)-4-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸
将粗品(S)-4-(7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯甲酸6b(60mg，0.14mmol)，叠氮化钠(46mg，0.71mmol)分散在2mL原甲酸三甲酯中，再滴加2mL冰醋酸，70℃下搅拌反应16小时。减压浓缩，制备分离纯化所得残余物，得到标题产物(S)-4-(7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四 氢中氮茚-3-酰胺基)苯甲酸6(30mg，淡黄色固体)，产率：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)
实施例7
(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-N-(2-氧代-1,2,3,4-四氢喹啉-6-基)-1,2,3,5-四氢中氮茚-3-甲酰胺
Figure PCTCN2015084751-appb-000031
第一步
(S)-7-(2-氨基-5-氯苯基)-5-氧代-N-(2-氧代-1,2,3,4-四氢喹啉-6-基)-1,2,3,5-四氢中氮茚-3-甲酰胺
将(S)-7-(2-氨基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸1b(122mg，0.4mmol)，6-氨基-3,4-二氢喹啉-2(1H)-酮7a(65mg，0.4mmol)，1-羟基苯并三唑(65mg，0.48mmol)，二环己基碳二亚胺(99mg，0.48mmol)溶解于5mL N,N-二甲基甲酰胺中，室温搅拌16小时。加20mL水，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-7-(2-氨基-5-氯苯基)-5-氧代-N-(2-氧代-1,2,3,4-四氢喹啉-6-基)-1,2,3,5-四氢中氮茚-3-甲酰胺7b(100mg，淡黄色固体)，产率：55.0％。
MS m/z(ESI):449.3[M+1]
第二步
(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-N-(2-氧代-1,2,3,4-四氢喹啉-6- 基)-1,2,3,5-四氢中氮茚-3-甲酰胺
将(S)-7-(2-氨基-5-氯苯基)-5-氧代-N-(2-氧代-1,2,3,4-四氢喹啉-6-基)-1,2,3,5-四氢中氮茚-3-甲酰胺7b(100mg，0.22mmol)，叠氮化钠(44mg，0.66mmol)分散在1mL原甲酸三甲酯中，再滴加2mL冰醋酸，60℃下搅拌反应16小时。减压蒸馏，加入60mL乙酸乙酯搅拌溶解，用饱和碳酸氢钠溶液洗涤至水相呈弱碱性，分离收集有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。用制备分离纯化所得残余物，得到标题产物(S)-7-(5-氯-2-(1H-四氮唑-1-基)苯基)-5-氧代-N-(2-氧代-1,2,3,4-四氢喹啉-6-基)-1,2,3,5-四氢中氮茚-3-甲酰胺7(90mg，淡黄色固体)，产率：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)
实施例8
(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸
Figure PCTCN2015084751-appb-000032
Figure PCTCN2015084751-appb-000033
第一步
N-(4-氯-3-氟-2-(三丁基锡)苯基)-2,2,2-三氟乙酰胺
将四甲基乙二胺(12.5mL，82.8mmol)溶于100mL四氢呋喃中，氩气保护冷却至-78℃。将正丁基锂(33.4mL，82.8mmol，2.5M的四氢呋喃溶液)滴加入上述反应液中。滴加完毕-78℃下继续搅拌1小时。将N-(4-氯-3-氟苯基)-2,2,2-三氟乙酰胺8a(10g，41.4mmol，采用专利申请“WO2009114677”公开的方法制备而得)的50mL四氢呋喃溶液滴加入上述反应液中。滴加完毕-78℃下继续搅拌2小时。最后将三丁基氯化锡(13.4mL，49.6mmol)的50mL四氢呋喃溶液滴加入上述反应液中，滴毕缓慢升至室温继续反应2小时。冰浴下加入100mL水淬灭反应，乙酸乙酯(200mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得目标产物N-(4-氯-3-氟-2-(三丁基锡)苯基)-2,2,2-三氟乙酰胺8b(11.1g，褐色油状物)，产率：50.5％。
第二步
(S)-7-(3-氯-2-氟-6-(2,2,2-三氟乙酰基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸乙酯
将N-(4-氯-3-氟-2-(三丁基锡)苯基)-2,2,2-三氟乙酰胺8b(1.5g，2.8mmol)，(S)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-1,2,3,5-四氢中氮茚-3-羧酸乙酯8c(1g，2.8mmol，采用专利申请“WO2013093484”公开的方法制备而得)，溶解于10mL二氧六环中，氩气置换，加[1,1'-双(二苯基磷)二茂铁]二氯化钯(41mg，0.06mmol)，氩气置换保护，100℃搅拌反应16小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得目标产物(S)-7-(3-氯-2-氟-6-(2,2,2-三氟乙酰基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸乙酯8d(1.2g，黄色固体)，产率：96.0％。
MS m/z(ESI):447.0[M+1]
第三步
(S)-7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸
将(S)-7-(3-氯-2-氟-6-(2,2,2-三氟乙酰基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧 酸乙酯8d(1.2g，2.7mmol)溶解于10mL乙醇中，加入7.3mL 1N氢氧化钠溶液，加热回流4小时。减压浓缩，滴加2M的盐酸至pH为2～3，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品(S)-7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸8e(700mg，黄色固体)，产率：80.4％。
MS m/z(ESI):323.0[M+1]
第四步
(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸乙酯
将(S)-7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸8e(162mg，0.5mmol)，5-氨基苯并呋喃-2-羧酸乙酯(103mg，0.5mmol，采用公知的方法“Journal of Medicinal Chemistry,2008,51(11),3133-3144”制备而得)，1-羟基苯并三唑(135mg，1mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(192mg，1mmol)，N,N-二异丙基乙胺(322mg，2.5mmol)溶解于6mL N,N-二甲基甲酰胺中，室温搅拌16小时。减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸乙酯8f(40mg，白色固体)，产率：16％。
MS m/z(ESI):510.1[M+1]
第五步
(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸
将(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸乙酯8f(40mg，0.078mmol)溶解于6mL甲醇中，加入3mL 2N的氢氧化钠溶液，室温搅拌16小时。减压浓缩，滴加2M的盐酸至pH为2～3，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸8h(51mg，黄色固体)，产率：100％。
MS m/z(ESI):482.0[M+1]
第六步
(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸
将粗品(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸8h(51mg，0.11mmol)，叠氮化钠(36mg，0.55mmol)分散在2mL原甲酸三甲酯中，再滴加3mL冰醋酸，70℃下搅拌反应16小时。减压浓缩，制备分离纯化所得残余物，得到标题产物(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)苯并呋喃-2-羧酸8(24mg，黄色固体)，产 率：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).
实施例9
(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
Figure PCTCN2015084751-appb-000034
第一步
(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸叔丁酯
将(S)-7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸8e(250mg，0.77mmol)，5-氨基-1H-吲哚-2-羧酸叔丁酯9a(180mg，0.77mmol，采用公知的方法“Journal of Medicinal Chemistry,2012,55(2),766-782”制备而得)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(354mg，0.95mmol)，N,N-二异丙基乙胺(0.3g，2.3mmol)溶解于6mL N,N-二甲基甲酰胺中，50℃搅拌反应4小时。反应液加10mL水，有固体析出，过滤。滤饼用100mL乙酸乙酯溶解，用无水硫酸钠干燥，过滤，滤液浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸叔丁酯9b(50mg，淡黄色色固体)，产率：12.1％。
MS m/z(ESI):537.2[M+1]
第二步
(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸叔丁酯
将(S)-5-(7-(6-氨基-3-氯-2-氟苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸叔丁酯9b(50mg，0.1mmol)，原甲酸三甲酯(160mg，1.5mmol)加入6mL冰醋酸中，室温反应30分钟，再加入叠氮化钠(20mg，0.3mmol)，60℃下搅拌反应16小时。得到(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸叔丁酯9c的溶液。
MS m/z(ESI):560.1[M+1]
第三步
(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
在(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸叔丁酯9c的溶液中加入1mL三氟乙酸，室温搅拌反应2小时。减压浓缩，制备分离纯化所得的残余物，得到标题产物(S)-5-(7-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸9(20mg，淡黄色固体)，产率：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)
实施例10
(S)-5-(7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸
Figure PCTCN2015084751-appb-000035
Figure PCTCN2015084751-appb-000036
第一步
(S)-7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸乙酯
将(S)-5-氧代-7-(((三氟甲基)磺酰基)氧基)-1,2,3,5-四氢中氮茚-3-羧酸乙酯8c(430mg，1.21mmol)，2-乙酰基-5-氯苯硼酸频哪醇酯(407mg，1.45mmol，采用公知的方法“Chemistry Letters,2011,40(9),1007-1008”制备而得)，1.81mL 2N的碳酸钠水溶液，四三苯基磷钯(70mg，0.06mmol)溶解于45mL甲苯和乙醇(V/V＝2:1)的混合溶剂中，氩气置换保护，70℃搅拌反应16小时。滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸乙酯10a(500mg，淡黄色固体)，产率：100％。
MS m/z(ESI):360.0[M+1]
第二步
(S)-7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸
将(S)-7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸乙酯10a(500mg，1.4mmol)溶解于20mL甲醇中，加入2.1mL 2N的氢氧化钠溶液，室温搅拌反应48小时。减压浓缩，加20mL水，二氯甲烷(20mL×2)萃取，滴加1N盐酸至水相pH为2～3，用二氯甲烷和甲醇(V/V＝20:1，40mL×2)萃取。将调节pH后的萃取溶剂合并，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品(S)-7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸10b(390mg，黄色固体)，产率：84.2％。
MS m/z(ESI):332.1[M+1]
第三步
(S)-5-(7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯
将5-氨基-1H-吲哚-2-羧酸甲酯1a(76mg，0.4mmol)，(S)-7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-羧酸10b(132mg，0.4mmol)，1-羟基苯并三唑(65mg，0.48mmol)，二环己基碳二亚胺(99mg，0.48mmol)溶解于10mL N,N-二甲基甲酰胺中，室温搅拌16小时。加30mL水，乙酸乙酯(40mL×2)萃取，合并有机 相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物(S)-5-(7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯10c(200mg，棕色油状物)，产率：94.3％。
MS m/z(ESI):504.2[M+1]
第四步
(S)-5-(7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸将(S)-5-(7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸甲酯10c(200mg，0.39mmol)溶解于15mL甲醇和四氢呋喃(V/V＝2:1)混合溶剂中，滴加入1mL 2N的氢氧化钠溶液，室温搅拌反应5小时。减压浓缩，加水20mL，滴加2M的盐酸至pH为2～3，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系A纯化，得目标产物(S)-5-(7-(2-乙酰基-5-氯苯基)-5-氧代-1,2,3,5-四氢中氮茚-3-酰胺基)-1H-吲哚-2-羧酸10(100mg，白色固体)，产率：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)
利用不同的原料按照本发明实施例1-10的合成方法合成实施例11-26。实施例11-26的图谱参数如下表2所示：
表2
Figure PCTCN2015084751-appb-000037
Figure PCTCN2015084751-appb-000038
Figure PCTCN2015084751-appb-000039
Figure PCTCN2015084751-appb-000040
生物学评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
本发明测试例中未注明具体条件的实验方法，通常按照常规条件，或按照商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
测试例1 荧光法检测因子XIa抑制剂的生物活性
1、实验材料
酶：因子XIa蛋白酶(Abcam,货号ab62411)，
底物：因子XIa特异性底物(DaiPharma，货号S821090)，
缓冲液：100mM tris-HCl，200mM NaCl，0.02％tween20，pH7.4。
2、实验步骤
将溶于100％DMSO的20mM受试化合物用100％DMSO稀释至200、20、2、0.2、0.02、0.002uM；在384孔板中每孔加入1ul化合物，空白和对照孔用DMSO替代，离心，将化合物离至底部。每孔加入10ul(2.5ug/ml)的FXIa酶溶液，空白孔加入10ul缓冲液替代，离心，将酶溶液离至底部。
最后每孔加入2mM底物10ul，离心，将底物液离至底部。
在37℃孵育10分钟；然后在405nm处测其吸光值。吸光值用Prism进行曲线 拟合并获得IC50。
化合物编号 IC50(因子XIa)/(nM)
实施例2 6.4
实施例3 284.5
实施例4 17.2
实施例5 20.1
实施例7 60.6
实施例8 25.3
实施例9 12.5
实施例11 57.2
实施例15 96.6
实施例18 214.0
实施例20 290.4
实施例21 34.3
实施例24 70.7
实施例25 132.9
实施例27 132.7
结论：本发明化合物对因子XIa具有明显的抑制活性。
测试例2 人血液体外抗凝血作用的测定
1、实验材料
血浆：人血收集于不含抗凝剂的采血管中，加入3.8％柠檬酸钠(体积比1：9)，室温2500rpm离心10min，收集血浆，分装保存于-80℃；
试剂：APTT试剂(活化部分凝血活酶时间测定试剂盒，SIEMENS，货号B4218-1)、PT试剂(凝血酶原时间测定试剂盒，SIEMENS，货号OUHP29)、氯化钙溶液；
仪器：凝血仪(SYSMEX，CA-500)。
2、实验检测
取分装血浆室温融化后混合均匀。将溶于100％DMSO的10000uM受试化合物用100％DMSO稀释至3000、300、200、150、75、30、10、3、0.3uM，空白为100％DMSO。将试剂、血浆、化合物放入凝血仪中对应位置，进行化合物的APTT及PT的检测。
3、数据处理
通过Prism进行曲线拟合，计算CT2，即2倍空白对照的APTT、PT所对应的化合物的浓度，结果如下：
化合物编号 抑制血小板凝集CT2(μM)
实施例2 1.83
实施例5 36.58
实施例8 21.71
实施例9 3.84
实施例24 10.74
结论：本发明化合物对人血液凝集具有明显的抑制活性。
药代动力学评价
测试例3、本发明实施例化合物的药代动力学测试
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例1和2化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例1、2、28和29化合物
2.2试验动物
健康成年SD大鼠16只，雌雄各半，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
2.3药物配制
Figure PCTCN2015084751-appb-000041
注：PEG:聚乙二醇CMC-Na:羧甲基纤维素钠
2.4给药
SD大鼠16只，雌雄各半，平均分成4组；禁食一夜后分别灌胃给药，灌胃给药。
3、操作
灌胃给药组于给药前及给药后0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0h采血 0.2ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。用LC/MS/MS法测定不同化合物灌胃给药后大鼠血浆中的待测化合物含量。
4、药代动力学参数结果
本发明实施例1、2、28和29化合物的药代动力学参数如下：
Figure PCTCN2015084751-appb-000042
结论：本发明化合物1、28和29作为实施例化合物2的前药的药代吸收良好，具有明显的药代吸收效果。

Claims (17)

  1. 一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2015084751-appb-100001
    其中：
    环A选自环烷基、稠合环烷基、杂环基、稠合杂环基、芳基、稠合芳基、杂芳基、或稠合杂芳基；
    环B选自环烷基、杂环基、芳基或杂芳基；
    R1各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基或-C(O)R4，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基或环烷基的取代基所取代；
    R2选自氢原子、卤素或烷基；
    R3各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；
    R4选自氢原子、卤素、氰基、硝基、烷基或卤代烷基，所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、OC(O)OR5或-NR5R6的取代基所取代；
    R5或R6各自独立地选自氢原子、烷基或环烷基，其中所述的烷基或环烷基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸基或羧酸酯基的取代基所取代；
    m为0、1、2或3；且
    n为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中环A选自稠合芳基，优选5～6元杂环或5～6元杂芳环与苯环稠合的稠合芳基。
  3. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中环A选自：
    Figure PCTCN2015084751-appb-100002
  4. 根据权利要求1～3任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中R1各自相同或不同，各自独立地选自卤素、杂芳基或-C(O)R4，其中R4的定义如权利要求1所述。
  5. 根据权利要求1～4任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中：
    R2为氢原子；
    R3各自相同或不同，各自独立的选自氢原子、芳基、-C(O)OR4或-NHC(O)OR4；
    R4选自氢原子或烷基，所述的烷基任选进一步被一个或多个-OC(O)OR5取代；
    R5选自氢原子、烷基或环烷基。
  6. 根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2015084751-appb-100003
    其中：
    环A、R1、R2、R3、m和n如权利要求1所定义。
  7. 根据权利要求6所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2015084751-appb-100004
    其中：
    R7各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
    q为0、1或2；且
    环A、R2、R3和n如权利要求1所定义。
  8. 根据权利要求7所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2015084751-appb-100005
    其中：
    R7相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
    R8或R9各自独立地选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；
    R4如权利要求1中所定义；且
    q为0、1或2。
  9. 根据权利要求7所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其为通式(V)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2015084751-appb-100006
    其中：
    R7各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、环 烷基或杂环基；
    环C选自杂芳基、芳基、杂环基或环烷基，优选5元或6元的杂芳基、芳基、杂环烷基或环烷基，更优选5元或6元的杂环烷基；
    R10选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；优选卤素、氧代基、-C(O)OR4、-C(O)R4、-NHC(O)R4或-NHC(O)OR4；更优选-C(O)OR4；
    R4如权利要求1中所定义；且
    p和q各自独立的选自0、1或2。
  10. 根据权利要求1～9任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，其中所述化合物选自：
    Figure PCTCN2015084751-appb-100007
    Figure PCTCN2015084751-appb-100008
  11. 一种通式(IIIC)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2015084751-appb-100009
    其中：
    环A选自环烷基、稠合环烷基、杂环基、稠合杂环基、芳基、稠合芳基、杂芳基、或稠合杂芳基；
    R2选自氢原子、卤素或烷基；
    R3各自相同或不同，各自独立地选自氢原子、卤素、氰基、硝基、烷基、卤代烷基、羟烷基、氧代基、环烷基、杂环基、芳基、杂芳基、-OR4、-C(O)OR4、-OC(O)R4、-C(O)R4、-NHC(O)R4、-NHC(O)OR4、-NHC(O)NHR4或-NHC(O)NHOR4；
    R4选自氢原子、卤素、氰基、硝基、烷基或卤代烷基，所述的烷基任选进一步被一个或多个选自卤素、氰基、硝基、烷基、卤代烷基、羟烷基、环烷基、OC(O)OR5或-NR5R6的取代基所取代；
    R5或R6各自独立地选自氢原子、烷基或环烷基，其中所述的烷基或环烷基任选进一步被一个或多个选自烷基、卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸基或羧酸酯基的取代基所取代；
    R7各自相同或不同，其各自独立的选自氢原子、卤素、氰基、硝基、烷基、环烷基或杂环基；
    q为0、1或2；且
    n为0、1或2。
  12. 一种制备根据权利要求7所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的方法，该方法包括：
    Figure PCTCN2015084751-appb-100010
    第一步反应为通式(IIIA)化合物和通式(IIIB)化合物进行缩合反应得到通式(IIIC)化合物，第二步反应为得到的通式(IIIC)化合物进行成环反应，得到通式(III)化合物；
    其中：环A、n、q、R2、R3和R7的定义如权利要求7中所定义。
  13. 一种药物组合物，其含有治疗有效量的根据权利要求1-10任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐以及药学上可接受的载体、稀释剂和赋形剂。
  14. 根据权利要求1～10任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物在制备预防和/或治疗心脑血管疾病中的用途，所述心脑血管疾病优选为血栓栓塞性疾病，更优选为心急梗塞、心绞痛、血管成型术或主动脉冠状动脉分流术后的再阻塞和再狭窄、中风、短暂的局部缺血发作、周围动脉闭塞性疾病、肺栓塞或深部静脉血栓形成。
  15. 根据权利要求1～10任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物在制备预防和/或治疗通过抑制因子XIa正性影响 的疾病的药物中的用途。
  16. 根据权利要求1～10任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物在制备治疗弥散性血管内凝血的药物中的用途。
  17. 根据权利要求1～10任一项所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，或根据权利要求13所述的药物组合物在制备抑制因子XIa的药物中的用途。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039094A1 (en) 2016-08-22 2018-03-01 Merck Sharp & Dohme Corp. Pyridine-1-oxide derivatives and their use as factor xia inhibitors
JP2020012004A (ja) * 2014-12-10 2020-01-23 小野薬品工業株式会社 ジヒドロインドリジノン誘導体
JP2021514944A (ja) * 2018-02-27 2021-06-17 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． オキソピコリナミド誘導体の結晶形及びそれらの製造方法
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1222909A (zh) * 1996-04-23 1999-07-14 麦克公司 吡嗪酮凝血酶抑制剂
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
WO2015120777A1 (zh) * 2014-02-14 2015-08-20 四川海思科制药有限公司 一种吡啶酮或嘧啶酮衍生物、及其制备方法和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1222909A (zh) * 1996-04-23 1999-07-14 麦克公司 吡嗪酮凝血酶抑制剂
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
WO2015120777A1 (zh) * 2014-02-14 2015-08-20 四川海思科制药有限公司 一种吡啶酮或嘧啶酮衍生物、及其制备方法和应用

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020012004A (ja) * 2014-12-10 2020-01-23 小野薬品工業株式会社 ジヒドロインドリジノン誘導体
WO2018039094A1 (en) 2016-08-22 2018-03-01 Merck Sharp & Dohme Corp. Pyridine-1-oxide derivatives and their use as factor xia inhibitors
JP2021514944A (ja) * 2018-02-27 2021-06-17 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． オキソピコリナミド誘導体の結晶形及びそれらの製造方法
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
US12221416B2 (en) 2018-04-12 2025-02-11 Morphic Therapeutic, Inc. Antagonists of human integrin α4β7
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11370773B1 (en) 2019-10-16 2022-06-28 Morphic Therapeutic, Inc. Inhibiting human integrin (alpha-4) (beta-7)

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