Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention belongs to the medical field, more specifically it relates to novel oxazolidinone compounds and pharmaceutical compositions thereof, and their uses in the manufacture of medicaments for inhibiting factor Xa or treating thromboembolic disorders.
• Pro-coagulation hemostasis
• anti-coagulation antithrombus
• Pro-coagulation fibrinolytic system function in vivo gradually declines, and the balance between coagulation and anti-coagulation is disrupted, blood clotting occurs, thereby thrombosis or embolism occurs, which leading to a series of thromboembolic disorders, such as myocardial infarct, stroke, deep venous thromboses or pulmonary embolisms, and the like.
• thromboembolic disorder is one of the most serious cardiovascular diseases, which is also known as the number one killer of human health.
• thrombus thrombotic diseases
• antithrombus anti-coagulation
• anti-platelet drugs anti-platelet drugs
• thrombolytic drugs mainly inhibit the formation and growth of thrombus
• the latter are mainly used to disslove the existing thrombi, thereby eliminating the hazards caused by thrombotic diseases to human beings.
• Coagulation factor Xa is a serine protease that can convert prothrombin to thrombin, and a target for anticoagulation which has a great clinical value, and plays an important role in controlling the formation of thrombin and activating coagulation cascade.
• Factor Xa located in the joint of the internal and extrinsic coagulation pathway mainly catalyzes the the conversion of Factor II to Factor IIa. Because of biological signal amplification in the coagulation process, one blood coagulation factor Xa inhibitor can inhibit the physiological effects of 138 prothrombin molecules.
• the International patent application WO 2001047919 disclosed coagulation factor Xa inhibitors having the structure shown below, which highly inhibit the free factor Xa or combined factor Xa, and can interrupt the internal and external pathway of the coagulation cascade, thereby inhibiting the generation of thrombin and thrombosis. Its representative compound
• the International patent application WO 2003026652 disclosed a compound having anti-coagulation action named 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4, 5-dihydropyrazolo [5, 4-c] pyridine-3-carboxamide, which has been launched in European in 2011. It is used for treating thromboembolisms and acute coronary artery syndromes, and it is commonly named Apixaban.
• the International patent application WO 2004058715 disclosed a compound used for treating venous thromboses named N' - (5-chloropyridin-2-yl) -N- [ (1S, 2R, 4S) -4- (dimethylcarbamoyl) -2- [ (5-methyl-6, 7-dihydro-4H-[1, 3] thiazolo [5, 4-c] pyridine-2-carbonyl) amino] cyclohexyl] oxamide, which has been launched in Japan in 2011, and it is commonly named Edoxaban.
• Effective and specific Factor Xa inhibitors can be used as potential valuable therapeutic agents for the treatment of thromboembolic disorders.
• the present invention provides novel factor Xa inhibitors—oxazolidinone compounds, a pharmaceutically acceptable salt or prodrug thereof, which can effectively treat thromboembolic disorders.
• the invention provides a compound or a pharmaceutical composition thereof used for effectively treating thromboembolic disorders associated with factor Xa.
• provided herein are compounds having Formula (I) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
• Z 2 is - (CR 9 R 10 ) m -;
• R 1 is aryl or heteroaryl
• R 2 is aryl, heteroaryl, cycloalkyl or heterocyclyl
• each R 3 is independently hydrogen, deuterium, halogen, amino, hydroxy, nitro, cyano, alkyl, haloalkyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylsulfonyl, aminosulfonyl, carboxy, alkylacyloxy, aminocarbonyl or alkanoyl;
• each of R 4 and R 5 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, carboxy, hydroxy or amino;
• R 6 is hydrogen, deuterium, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
• R 7 is hydrogen, deuterium, alkyl or haloalkyl
• R 8 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
• each R 9 and R 10 is independently hydrogen, halogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, alkanoyl, alkylsulfonyl, aminosulfonyl, carboxy, hydroxy or amino;
• n 2 or 3;
• n 0, 1, 2 or 3;
• q 1 or 2;
• each R 11 is independently hydrogen, amino, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• each R 12 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, alkylsulfonyl, hydroxyalkyl, aminoalkyl or alkanoyl;
• each R 13 is independently hydrogen, alkyl, cycloalkyl, alkanoyl, haloalkyl, aryl or heteroaryl;
• each R 14 is independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl or heteroaryl;
• each of R 15 and R 16 is independently hydrogen, alkyl, cycloalkyl, alkylsulfonyl or alkanoyl;
• each R 17 , R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, alkanoyl, aminocarbonyl, haloalkyl, aryl or heteroaryl;
• each R 20 is independently hydrogen, cyano, alkyl, aryl or heteroaryl.
• R 8 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or phenyl
• each R 9 and R 10 is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 haloalkyl, C 6-10 aryl, C 1-5 heteroaryl, C 3-6 cycloalkyl or C 2-7 heterocyclyl.
• each R 3 is independently hydrogen, fluorine, chlorine, bromine, amino, hydroxy, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkanoyl;
• each of R 4 and R 5 is independently hydrogen, deuterium, fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy or amino;
• R 6 is hydrogen, deuterium or C 1-4 alkyl
• R 7 is hydrogen, deuterium or C 1-4 alkyl.
• R 1 is one of the following Formulae:
• each X 1 , X 2 and X 3 is independently N or CH;
• each X 4 is independently -CH 2 -, -O-, -NH-or -S-;
• R 2 is one of the following Formulae:
• each Y 1 , Y 2 , Y 3 and Y 8 is independently N or CH;
• each Y 4 is independently -CH 2 -, -O-, -NH-or -S-;
• each q is independently 1 or 2;
• each t, r and p is independently 0, 1, 2, 3 or 4;
• R 2 is one of the following Formulae:
• each Y 1 , Y 3 and Y 8a is independently N or CH;
• each Y 5a and Y 6b is independently -CH-or -N-;
• Y 7b is -CH 2 -, -O-, -S-or -NH-;
• each t is independently 0, 1, 2 or 3;
• each R 11 is independently hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 12 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 alkanoyl;
• each R 13 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkanoyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 14 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each of R 15 and R 16 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl or C 1-6 alkanoyl;
• each R 17 , R 18 and R 19 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl; and
• each R 20 is independently hydrogen, cyano or C 1-6 alkyl.
• each R 11 is independently hydrogen, amino, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl, phenyl or pyridyl;
• each R 12 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methanesulfonyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl or acetyl;
• each R 13 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, acetyl, trifluoromethyl, phenyl or pyridyl;
• each R 14 is hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, trifluoromethyl, phenyl or pyridyl;
• each of R 15 and R 16 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methanesulfonyl or acetyl;
• each R 17 , R 18 and R 19 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, acetyl, aminocarbonyl, trifluoromethyl, phenyl or pyridyl; and
• each R 20 is independently hydrogen, cyano, methyl, ethyl, propyl, i-propyl, n-butyl or t-butyl.
• the compound disclosed herein having Formula (IV) or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
• each of Z 1 , Z 2 , R 1 and R 2 is as defined herein.
• the compound disclosed herein having Formula (V) or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
• each of R 1 and R 2 is as defined herein.
• R 1 is one of the following Formulae:
• R 2 is one of the following Formulae:
• a pharmaceutical composition comprising any one of the compounds disclosed herein.
• the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.
• provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening a thromboembolic disorder in a subject.
• the thromboembolic disorder is a myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aorto-coronary bypass, stroke, a transitory ischaemic attack, a peripheral arterial occlusive disease, a pulmonary embolism or a deep venous thrombosis.
• DIC disseminated intravascular coagulation
• provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting factor Xa.
• provided herein is a method for preventing, managing, treating or lessening a thromboembolic disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
• the thromboembolic disorder is a myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aorto-coronary bypass, stroke, a transitory ischaemic attack, a peripheral arterial occlusive disease, a pulmonary embolism or a deep venous thrombosis.
• DIC disseminated intravascular coagulation
• provided herein is a method for inhibiting factor Xa, comprising administering to a subject a therapeutically effective amount of the compound or the pharmaceutical composition disclosed herein.
• provided herein is the compound or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening a thromboembolic disorder in a subject.
• the thromboembolic disorder is a myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aorto-coronary bypass, stroke, a transitory ischaemic attack, a peripheral arterial occlusive disease, a pulmonary embolism or a deep venous thrombosis.
• DIC disseminated intravascular coagulation
• provided herein is the compound or the pharmaceutical composition disclosed herein for use in inhibiting factor Xa.
• the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
• primates e.g., humans, male or female
• the subject is a primate.
• the subject is a human.
• patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
• Stereoisomers refers to compounds which have identical chemical constituton, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
• Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
• Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
• Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
• optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
• the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
• the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
• a compound prefixed with (+) or d is dextrorotatory.
• a specific stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is called an enantiomeric mixture.
• a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur when there has been no stereoselection or stereospecificity in a chemical reaction or process.
• any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
• each asymmetric atom has at least 50%enantiomeric excess, at least 60%enantiomeric excess, at least 70%enantiomeric excess, at least 80%enantiomeric excess, at least 90%enantiomeric excess, at least 95%enantiomeric excess, or at least 99%enantiomeric excess in the (R) -or (S) -configuration.
• the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
• Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
• Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
• racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
• Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
• HPLC high performance liquid chromatography
• Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
• tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
• proton tautomers also known as prototropic tautomers
• Valence tautomers include interconversions by reorganization of some of the bonding electrons.
• keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
• tautomerization is phenol-keto tautomerization.
• a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (lH) -one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
• compounds disclosed herein may optionally be substituted with one or more substituents, such as the compound (s) illustrated by general formula above, or as exemplified by particular classes, subclasses, and species of the invention.
• substituents such as the compound (s) illustrated by general formula above, or as exemplified by particular classes, subclasses, and species of the invention.
• the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
• substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
• an optionally substituted group may have a substituent at each substitutable position of the group.
• substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
• C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
• linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
• alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In still other embodiments, the alkyl group contains 1-4 carbon atoms, and in yet other embodiments, the alkyl group contains 1-3 carbon atoms.
• alkyl group examples include, methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) , 2-propyl (i-Pr, i-propyl, -CH (CH 3 ) 2 ) , 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-l-propyl (i-Bu, i-butyl, -CH 2 CH (CH 3 ) 2 ) , 2-butyl (s-Bu, s-butyl, -CH(CH 3 ) CH 2 CH 3 ) , 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH 3 ) 3 ) , 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 )
• alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms. In other embodiments, the alkylene group contains 1-4 carbon atoms. In other embodiments, the alkylene group contains 1-3 carbon atoms. In still other embodiments, the alkylene group contains 1-2 carbon atoms. And the alkylene group is exemplified by methylene (-CH 2 -) , ethylene (-CH 2 CH 2 -) , isopropylene (-CH (CH 3 ) CH 2 -) , and the like.
• alkoxy refers to an alkyl group, as previously defined, attached to the the rest of molecule via an oxygen atom.
• the alkoxy group contains 1-6 carbon atoms.
• the alkoxy group contains 1-4 carbon atoms.
• the alkoxy group contains 1-3 carbon atoms.
• the alkoxy radical is optionally substituted with one or more substituents described herein.
• Some non-limiting examples of alkoxy group include, methoxy (MeO, -OCH 3 ) , ethoxy (EtO, -OCH 2 CH 3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ) , and the like.
• sulfonyl refers to respectively divalent radicals -SO 2 -.
• alkylsulfonyl refers to an alkyl group, as previously defined, attached to the rest group of molecule via sulfonyl (-SO 2 -) . Wherein the alkylsulfonyl group may be optionally substituted with one or more substituents described herein. Examples of the alkylsulfonyl group include, but are not limited to, methylsulfonyl (-SO 2 CH 3 ) , ethylsulfonyl (-SO 2 CH 2 CH 3 ) , and the like.
• sulfamyl refers to a sulfonyl radical substituted with an amine radical, forming an aminosulfonyl (-SO 2 NH 2 ) .
• haloalkyl , “haloalkenyl” and “haloalkoxy” respectively refer to an alkyl, alkenyl or alkoxy substituted with one or more halogen atoms. Examples of such groups include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
• cycloalkyl refers to a monovalent or multivalent, nonaromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, the cycloalkyl contains 3 to 8 carbon atoms, and in still other embodiments, the cycloalkyl contains 3 to 6 carbon atoms.
• cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohex-dienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
• the cycloalkyl radical may be optionally substituted with one or more substituents described herein.
• Ring sulfur atoms may be optionally oxidized to form S-oxides.
• Ring nitrogen atoms may be optionally oxidized to form N-oxides.
• heterocyclyl examples include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1, 2-dihydropyridyl, morpholinyl, thiomorpholinyl, hexahydropyrimidyl, 1, 6-dihydropyrimidyl, 1, 2-dihydropyrimidyl, 1, 2-dihydropyrazinyl, 1, 3-oxazinyl, piperazinyl, oxazolidinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, indolin
• heterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl, 1, 1-dioxo-thiomorpholinyl, 1, 2-thiazinanyl-1, 1-dioxide.
• heterocyclyl may be a 5-to 6-membered heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring containing 5 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
• Non-liminting examples of 5-to 6-membered heterocyclyl include, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinyl, pyperidinyl, 1, 2-dihydropyridyl, morpholinyl, thiomorpholinyl, hexahydropyrimidyl, 1, 6-dihydropyrimidyl, 1, 2-dihydropyrimidyl, 1, 2-dihydropyrazinyl, 1, 3-oxazinyl, piperazinyl, and the like.
• the 5-to 6-membered heterocyclyl group is optionally substituted with one or more substituents described herein.
• n membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
• piperidinyl is an example of a 6 membered heterocycloalkyl
• 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10 membered cycloalkyl group.
• unsaturated refers to a moiety having one or more units of unsaturation.
• heteroatom refers to oxygen (O) , sulfur (S) , nitrogen (N) , phosphorus (P) and silicon (Si) , including any oxidized form of nitrogen, sulfur, and phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) .
• halogen refers to fluorine (F) , chlorine (Cl) , bromine (Br) , or iodine (I) .
• aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
• aryl may be used interchangeably with the term “aryl ring” or “aromatic. ” Examples of aryl ring would include phenyl, naphthyl, and anthracene.
• heteroaryl refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5 to 12 ring members, preferably, 5 to 10 ring members, and more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
• heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
• a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
• heteroaryl examples include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl) , thiazolyl, 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl) , pyrazinyl, 1, 3, 5-triazinyl; and the following non-limiting bicycles: benzimidazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl, indolyl (e.g., 2-indolyl) , isoindolinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinol
• alkylamino embraces “N-alkylamino” and “N, N-dialkylamino” , wherein amino groups are independently substituted with one or two alkyl radicals, respectively. And wherein the alkyl radical is as defined herein. Suitable alkylamino radical may be mono or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.
• arylamino refers to an amino group substituted with one or two aryl radicals.
• Non-limiting examples of arylamino include, N-phenylamino.
• aryloxy refers to an optionally substituted aryl, as described herein, attached to the rest of the molecule via an oxygen atom, wherein the aryl group is as defined herein.
• aryloxy refers to an optionally substituted aryl, as described herein, attached to the rest of the molecule via an oxygen atom, wherein the aryl group is as defined herein.
• Such examples include, but are not limited to, phenyloxy, tolyloxy, ethylphenyloxy and the like.
• aminoalkyl refers to a linear or branched alkyl radical having one to ten carbon atoms substituted with one or more amino radicals. More preferred aminoalkyl radical is a “lower aminoalkyl” radical having 1-6 carbon atoms and one or more amino substitutents. Examples of such radical include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
• hydroxyalkyl refers to a linear or branched alkyl radical having one to ten carbon atoms substituted with one or more hydroxy radicals. More preferred hydroxyalkyl radical is a “lower hydroxyalkyl” radical having 1-6 carbon atoms and one or more hydroxy substitutents. Examples of such radical include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
• a bond drawn from substituents (R e ) n to the center of one ring within a ring system represents substitution of n membered substituents R e at any substitutable position on the rings.
• Figure a represents possible substitution of n membered R e in any of the positions on the A ring and B ring.
• points of attachment to the rest of the molecule can be in any connectable position of the rings.
• Figure b represents any connectable position on the A ring and B ring can independently be an attachment point.
• protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
• an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
• Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc) .
• hydroxy-protecting group refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality
• suitable protecting groups include acetyl and silyl
• a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
• Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl and the like.
• protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
• prodrug refers to a compound that is transformed in vivo into a compound disoclosed herein. Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.
• Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position in its prodrug form.
• prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of a hydroxy group on the parent compound.
• phosphates such as, for example those phosphates resulting from the phosphonation of a hydroxy group on the parent compound.
• a thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, each of which is incorporated herein by reference.
• a “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities are determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including compounds produced by a process comprising contacting a compound disclosed herein with a mammal for a period of time sufficiently to yield a metabolic product thereof.
• a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
• solvents that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and ethanolamine.
• hydrate refers to the complex where the solvent molecule is water.
• Room temperature in the invention refers a temperature range of 10°Cto 40°C. In some embodiments, “room temperature” or “rt” refers a temperature range of 20°Cto 30°C; in other embodiments, “room temperature” or “rt” refers a temperature of 25°C.
• the term “treat” , “treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
• “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
• “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
• Thromboembolic disorders used in the invention are disorders caused by two pathological processes of thrombogenesis and thromboembolism, which are also known as thrombotic diseases.
• Thrombogenesis is a pathological process of partial or completed blockage of the blood vessels and the corresponding blood supply obstacle, which is caused by the formation of a blood clot (thrombus) in vessel or local cardiac intima under certain conditions.
• Thromboembolism is a pathological process that blood clots (thrombuses) break loose from the formation location and are carried by the blood stream to plug partially or completely the blood vessels, which causes the ischemia, hypoxia, necrosis, congestion or edema of vessels or systems.
• thromboembolic disorders include, but are not limited to, arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart. More specific examples of such disorders include, but are not limited to, myocardial infarct, angina pectoris (including unstable angina) , acute coronary syndrome, reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusion disorders, arterial thrombosis, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, thrombophlebitis, venous thrombosis or deep vein thrombosis, and the like.
• myocardial infarct angina pectoris (including unstable angina) , acute coronary syndrome, reocclusions and restenoses after angioplasty or aor
• DIC Disseminated intravascular coagulation
• blood clotting a clinical syndrome of activation of coagulation (blood clotting) that happens in response to a variety of diseases, which leads to the formation of small blood clots inside the blood vessels throughout the body, and consumes a large amounts of coagulation factors to cause secondary fibrinolytic hyperfunction, thus leading to systemic bleeding and microcirculation failure.
• a wide range formation of micro-thrombosis can lead to multiple organs failure, activate the fibrinolytic system and lead to depletion of coagulation factors, thereby leading to secondary bleeding. Therefore, disseminated intravascular coagulation is a syndrome that clotting and hemorrhage occur at the same time.
• the main method of treatment is anticoagulation, alternative, antiplatelet aggregation and symptomatic and supportive treatment, which is based on the active control of the primary disease.
• the compounds disclosed herein can be used in the treatment of disseminated intravascular coagulation.
• the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
• such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like) , or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
• a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
• Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
• use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
• the pharmaceutically acceptable salts can be pharmaceutically acceptable acid addition salts, which can be formed with inorganic or organic acids.
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, trifluoroacetic acid, propionic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, stearic acid, succinic acid, sulfosalicylic acid, lactic acid, benzoic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, and the like.
• the pharmaceutically acceptable salts can be pharmaceutically acceptable base addition salts, which can be formed with inorganic or organic bases.
• Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
• the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
• Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
• the compounds disclosed herein, including their salts can also be obtained in the form of their hydrates, or include other solvents such as ethanol, dimethylsulfoxide, and the like, used for their crystallization.
• the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
• any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds.
• Isotopically enriched compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H (deuterium, D) , 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I, respectively.
• the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
• isotopically enriched compounds are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F-enriched compound may be particularly desirable for PET or SPECT studies.
• Isotopically-enriched compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
• isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
• a substituent in a compound of this invention is denoted deuterium
• such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
• Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, acetone-d 6 , DMSO-d
• the inventors of this application have extensively studied and synthesized a series of compounds, and firstly found these compounds having the following Formula (I) have potent FXa inhibition activities, excellent metablic properties and physicochemical properties demonstrated by series of tests, such as FXa inhibition activity screening, metabolic screening, anticoagulant test and the like. Especially these compounds are suitable for using as anticoagulants drugs to treat thromboembolic disorders.
• the invention provides a compound, which has a tricyclic structure (such as Formula (Ia) ) in its core, and the middle E ring can be 5-, 6-, 7-or 8-memembered ring, especially the compound, E ring of which is a 7-membered ring, have not been disclosed by related literatures so far.
• provided herein are compounds having Formula (I) , or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
• Z 2 is - (CR 9 R 10 ) m -;
• R 1 is aryl or heteroaryl
• R 2 is aryl, heteroaryl, cycloalkyl or heterocyclyl
• each R 3 is independently hydrogen, deuterium, halogen, amino, hydroxy, nitro, cyano, alkyl, haloalkyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylsulfonyl, aminosulfonyl, carboxy, alkylacyloxy, aminocarbonyl or alkanoyl;
• each of R 4 and R 5 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, aryloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, carboxy, hydroxy or amino;
• R 6 is hydrogen, deuterium, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
• R 7 is hydrogen, deuterium, alkyl or haloalkyl
• R 8 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
• each R 9 and R 10 is independently hydrogen, halogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, alkanoyl, alkylsulfonyl, aminosulfonyl, carboxy, hydroxy or amino;
• n 2 or 3;
• n 0, 1, 2 or 3;
• q 1 or 2;
• each R 11 is independently hydrogen, amino, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• each R 12 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, alkylsulfonyl, hydroxyalkyl, aminoalkyl or alkanoyl;
• each R 13 is independently hydrogen, alkyl, cycloalkyl, alkanoyl, haloalkyl, aryl or heteroaryl;
• each R 14 is independently hydrogen, alkyl, cycloalkyl, haloalkyl, aryl or heteroaryl;
• each of R 15 and R 16 is independently hydrogen, alkyl, cycloalkyl, alkylsulfonyl or alkanoyl;
• each R 17 , R 18 and R 19 is independently hydrogen, alkyl, cycloalkyl, alkanoyl, aminocarbonyl, haloalkyl, aryl or heteroaryl;
• each R 20 is independently hydrogen, cyano, alkyl, aryl or heteroaryl.
• R 8 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or phenyl
• each R 9 and R 10 is independently hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 haloalkyl, C 6-10 aryl, C 1-5 heteroaryl, C 3-6 cycloalkyl or C 2-7 heterocyclyl.
• each R 3 is independently hydrogen, fluorine, chlorine, bromine, amino, hydroxy, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkanoyl;
• each of R 4 and R 5 is independently hydrogen, deuterium, fluorine, chlorine, bromine, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy or amino;
• R 6 is hydrogen, deuterium or C 1-4 alkyl
• R 7 is hydrogen, deuterium or C 1-4 alkyl.
• R 1 is one of the following Formulae:
• each X 1 , X 2 and X 3 is independently N or CH;
• each X 4 is independently -CH 2 -, -O-, -NH-or -S-;
• R 1 is one of the following Formulae:
• each X 1 , X 2 and X 3 is independently N or CH;
• each X 4 is independently -CH 2 -, -O-, -NH-or -S-;
• R 2 is one of the following Formulae:
• each Y 1 , Y 2 , Y 3 and Y 8 is independently N or CH;
• each Y 4 is independently -CH 2 -, -O-, -NH-or -S-;
• each q is independently 1 or 2;
• each t, r and p is independently 0, 1, 2, 3 or 4;
• R 2 is one of the following Formulae:
• each Y 1 , Y 3 and Y 8a is independently N or CH;
• each Y 5a and Y 6b is independently -CH-or -N-;
• Y 7b is -CH 2 -, -O-, -S-or -NH-;
• each t is independently 0, 1, 2 or 3;
• each R 11 is independently hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 12 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl or C 1-6 alkanoyl;
• each R 13 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkanoyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 14 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each of R 15 and R 16 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl or C 1-6 alkanoyl;
• each R 17 , R 18 and R 19 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl; and
• each R 20 is independently hydrogen, cyano or C 1-6 alkyl.
• each R 11 is independently hydrogen, amino, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, trifluoromethyl, cyclopropyl, cyclopentyl, cyclohexyl, piperidyl, morpholinyl, phenyl or pyridyl;
• each R 12 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methanesulfonyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl or acetyl;
• each R 13 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, acetyl, trifluoromethyl, phenyl or pyridyl;
• each R 14 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, trifluoromethyl, phenyl or pyridyl;
• each of R 15 and R 16 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methanesulfonyl or acetyl;
• each R 17 , R 18 and R 19 is independently hydrogen, methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclopentyl, cyclohexyl, acetyl, aminocarbonyl, trifluoromethyl, phenyl or pyridyl; and
• each R 20 is independently hydrogen, cyano, methyl, ethyl, propyl, i-propyl, n-butyl or t-butyl.
• the compound disclosed herein having Formula (IV) or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
• Z 2 is - (CR 9 R 10 ) m -;
• R 1 is one of the following Formulae:
• each X 1 , X 2 and X 3 is independently N or CH;
• each X 4 is independently -CH 2 -, -O-, -NH-or -S-;
• R 2 is one of the following Formulae:
• each Y 1 , Y 2 , Y 3 and Y 8 is independently N or CH;
• each Y 4 is independently -CH 2 -, -O-, -NH-or-S-;
• each t is independently 0, 1, 2 or 3;
• R 8 is hydrogen or C 1-4 alkyl
• each R 9 and R 10 is independently hydrogen, fluorine, chlorine, bromine or C 1-4 alkyl
• each R 11 is independently hydrogen, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 12 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 alkanoyl;
• each R 13 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkanoyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 14 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each of R 15 and R 16 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl or C 1-6 alkanoyl;
• each R 17 , R 18 and R 19 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 20 is independently hydrogen, cyano or C 1-6 alkyl
• n 2 or 3
• each q is independently 1 or 2.
• the compound disclosed herein having Formula (V) or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
• R 1 is one of the following Formulae:
• each X 1 , X 2 and X 3 is independently N or CH;
• each X 4 is independently -CH 2 -, -O-, -NH-or -S-;
• R 2 is one of the following Formulae:
• each Y 1 , Y 2 , Y 3 and Y 8 is independently N or CH;
• each Y 4 is independently -CH 2 -, -O-, -NH-or-S-;
• each t is independently 0, 1, 2 or 3;
• each q is independently 1 or 2.
• each R 11 is independently hydrogen, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 12 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 alkanoyl;
• each R 13 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkanoyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each R 14 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl;
• each of R 15 and R 16 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylsulfonyl or C 1-6 alkanoyl;
• each R 17 , R 18 and R 19 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 haloalkyl, C 6-10 aryl or C 1-9 heteroaryl; and
• each R 20 is independently hydrogen, cyano or C 1-6 alkyl.
• R 1 is one of the following Formulae:
• R 2 is one of the following Formulae:
• a pharmaceutical composition comprising any one of the compounds disclosed herein.
• the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant or vehicle.
• provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening a thromboembolic disorder in a subject.
• the thromboembolic disorder is a myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aorto-coronary bypass, stroke, a transitory ischaemic attack, a peripheral arterial occlusive disease, a pulmonary embolism or a deep venous thrombosis.
• DIC disseminated intravascular coagulation
• provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting factor Xa.
• a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein in association with at least one pharmaceutically acceptable carrier, exicipient, diulent, adjuvant or vehicle.
• Also provided herein is a method of treating or alleviating thromboembolic disorders in a subject, or a method sensitive to these disorders, comprising administering to the subject an effective therapeutic amount of a compound disclosed herein.
• thromboembolic disorders disclosed herein are myocardial infarct, angina pectoris, reocclusions and restenoses after angioplasty or aorto-coronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses.
• the salt is a pharmaceutically acceptable salt.
• pharmaceutically acceptable refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith
• the compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds disclosed herein and/or for separating enantiomers of compounds disclosed herein.
• the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; a pyranosidyl acid, such as glucuronic acid or galacturonic acid; an alpha hydroxy acid, such as citric acid or tartaric acid; an amino acid, such as aspartic acid or glutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid, ethanesulfonic acid , and the like.
• an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid
• a pyranosidyl acid such as glucuronic acid or galactur
• the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, or an alkaline earth metal hydroxide, and the like.
• an inorganic or organic base such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, or an alkaline earth metal hydroxide, and the like.
• suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia (primary, secondary, and tertiary amines) , and cyclic amines, such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
• amino acids such as glycine and arginine
• ammonia primary, secondary, and tertiary amines
• cyclic amines such as piperidine, morpholine, piperazine and the like
• inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
• the invention features a pharmaceutical composition that includes a compound having formula (I) , (IV) or (V) , a compound listed herein, or a compound named in Examples 1 to 34, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the amount of the compound in the composition disclosed herein is effective for treating or alleviating the thromboembolic disorders in a patient, or inhibiting the acitivity of factor Xa.
• certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
• pharmaceutically acceptable derivative include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
• the pharmaceutically acceptable composition disclosed herein additionally comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• Some non-limiting examples of materials which can serve as pharmaceutically acceptable carriers include ion exchangers, aluminium, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipient
• the compound disclosed herein may be administered in oral dosage forms, such as tablets, capsules (each of which includes the sustained release or timed release formulation) , pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise they may be administered in an intravenous (bolus or infusion) , intraperitoneal, subcutaneous, or intramuscular form. All using forms are well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally administered together with a pharmaceutical carrier which is selected based on the mode of administration and the standard pharmaceutical practices.
• the dosage regimen of the compound disclosed herein is selected in accordance with a variety of known factors, such as pharmacokinetic characteristics and models of a specific reagent, and it’s administering route; race, age, sex, healthy condition, medical condition and weight of the patient; the nature and degree of the symptoms; the parallel types of the treatment; the frequency of the treatment; the route of administration, the renal and hepatic function of the patient and the desired effect.
• a skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, offset or stop the progress of a thromboembolic disorder.
• the range of daily oral dose of an active agent for desired effect is about 0.001 per kg to 1000 mg per kg, preferably, about 0.01 per kg to 100 mg per kg, and most preferably, about 1.0 per kg to 20 mg per kg.
• the most optional dose range administered in intravenous in the process of regular rate of infusion is about 1 mg/kg/min to 10 mg/kg/min.
• the compound in the invention can be administered once daily, or twice daily, three times or four times daily.
• compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• the compound is administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier materials” ) suitably selected with respect to the intended form of administration, such as oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
• carrier materials suitably selected with respect to the intended form of administration, such as oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
• the active ingredient can be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, calcium dihydrogen phosphate, calcium sulfate, mannitol, sorbitol and the like;
• an oral, nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, calcium dihydrogen phosphate, calcium sulfate, mannitol, sorbitol and the like
• the oral drug components can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture of active ingredient (s) and inert carrier materials.
• Suitable binders may include starch, gelatin, natural sugars such as glucose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
• the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
• the compounds of the present invention can also be coupled to soluble polymers as targeted medicament carriers.
• soluble polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidophenol, polyhydroxyethylaspartamidophenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
• the compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
• a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
• Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.
• the active ingredient will ordinarily be present in an amount of about 0.5-95%by weight based on the total weight of the composition.
• Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
• powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
• Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
• water a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
• Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
• Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
• citric acid and its salts and sodium EDTA are also used.
• parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.
• a daily dosage may be about 0.1 to 100 milligrams of the compound disclosed herein and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
• the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.
• the other anticoagulant agents include, but are not limited to, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran, bemiparin, enoxaparin sodium, tinzaparin sodium, danaparoid sodium, fondaparinux sodium, nadroparin calcium, ardeparin sodium, parnaparin sodium, and the like.
• a daily dosage may be about 0.01 to 25 milligrams of the compound disclosed herein and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound disclosed herein and about 1 to 3 milligrams of anti-platelet agents, per kilogram of patient body weight.
• a daily dosage may be about 0.1 to 1 milligrams of the compound disclosed herein, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80%when administered with a compound disclosed herein.
• the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
• one active ingredient may be enteric coated.
• enteric coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
• One of the active ingredients may also be coated with a material which affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
• the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
• Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
• HPMC hydroxypropyl methylcellulose
• the polymer coating serves to form an additional barrier to interaction with the other component.
• the compounds described herein or a pharmaceutical salt or solvate thereof are effective for preventing, managing, treating or lessing thromboembolic disorders in a patient, especially for treating mycocardial infarct, angina pectoris, reocclusions and restenoses after angioplasty or aorto-coronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses.
• the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formulas (I) , (IV) or (V) , above, except where further noted.
• the following non-limiting schemes and examples 1-34 are presented to further exemplify the invention.
• Anhydrous tertrahydrofuran, dioxane, toluene and ethyl ether were obtained by drying independently under the refluxing condition with sodium added.
• Anhydrous dichloromethane and anhydrous chloroform were obtained by drying independently under the refluxing condition equipped with hydride calcium.
• Ethyl acetate, petrol ether, n-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate before use.
• MS mass spectral
• Compound (8) can be prepared by the procedure described in scheme 1, and wherein M is Na, K or Li;W is Cl, Br or I; L is a hydroxy activating group, such as p-tosyl, trifluoromethylsulfonyl, methanesulfonyl, and the like; Y is a hydroxy-protecting group, such as methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl, and the like; each R 3 and n is as defined herein.
• 6-Dihydro-2H-pyran-2-one can react with a base (such as LiOH) to give compound (m1) , and compound (m1) can react with iodomethane in a suitable solvent to give compound (m2) .
• Compound (m2) can react with a suitable reagent to give compound (m3) which has a good leaving group -OL, then compound (m3) can be converted to compound (m4) in the presence of an appropriate reducing agent.
• Compound (m4) can react with a suitable hydroxy-protecting reagent to give compound (m5) , and compound (m5) can react with compound A in the presence of a base (such as cesium carbonate) in a polar solvent (such as acetonitrile) to give compound (m6) .
• the hydroxy-protecting group of compound (m6) can be removed under an appropriate condition to give compound (m7) , followed by Sharpless epoxidation to give the compound (m8) which has a desired configuration.
• Compound (m8) can react with tert-butyldimethylsilyl chloride in the presence of a base (such as imidazole) to give compound (m9) , and compound (m9) can be reduced by an appropriate reducing agent to give compound (m10) .
• Compound (m10) can be cyclized in a polar solvent (such as iso-propanol) at an appropriate temperature to give compound (m11) .
• Compound (m11) can react with a reactive carbonyl compound (such as triphosgene) in an aprotic polar solvent to give compound (8) .
• Compound (7) can be prepared by the procedure described in scheme 1, and wherein W is Cl, Br or I, each Z 1 , Z 2 , R 1 , R 2 , R 3 and n is as defined herein.
• Compound (1) can react with R 2 H in a suitable solvent to give compound (2) , followed by deprotection to give compound (3) in a polar solvent (such as tetrahydrofuran) in the presence of a fluorinated reagent (such as tetrabutylammonium fluoride) .
• Compound (3) can react with methanesulfonyl choride in the presence of a base (such as triethylamine, pyridine, and the like) to give compound (4) .
• Compound (4) can react with a trinitride (such as sodium azide) under heating to give compound (5) .
• Compound (5) can be reduced (such as Pd/C-catalyzed hydrogenation reaction, or staudinger reaction in the presence of Ph 3 P) to give compound (6) .
• Compound (7) can be prepared by the procedure described in scheme 2, and wherein each Z 1 , Z 2 , R 1 , R 2 , R 3 and n is as defined herein.
• a condensing agent such as HATU
• Compound (7) can be prepared by the procedure described in scheme 3, and wherein W is Cl, Br or I, each Z 1 , Z 2 , R 1 , R 2 , R 3 and n is as defined herein.
• Compound (9) can react with R 2 H in a suitable solvent to give compound (10) , followed by deprotection to give compound (3) in a pole solvent (such as tetrahydrofuran) in the presence of a fluorinated reagent (such as tetrabutylammonium fluoride) .
• Compound (3) can react with methanesulfonyl choride in the presence of a base (such as triethylamine, pyridine, and the like) to give compound (4) .
• Compound (4) can react with potassium phthalimide under heating to give compound (11) .
• Compound (11) can be converted to compound (6) in the presence of primary amine or hydrazine (such as methylamine) .
• Compound (7) can be prepared by the procedure described in scheme 4, and wherein W is Cl, Br or I, each Z 1 , Z 2 , R 1 , R 2 , R 3 and n is as defined herein.
• Compound (9) can be deprotected in a polar solvent (such as tetrahydrofuran) in the presence of a fluorinated reagent (such as tetrabutylammonium fluoride) to give compound (12) .
• Compound (12) can react with methanesulfonyl choride in the presence of a base (such as triethylamine, pyridine, and the like) to give compound (13) .
• Compound (13) can react with potassium phthalimide under heating to give compound (14) .
• Compound (14) can be converted to compound (15) in the presence of primary amine or hydrazine (such as methylamine) .
• Compound (16) can react with R 2 H in a suitable solvent to give compound (7) .
• Example 1 5-bromo-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -7- (3-oxomorpholino) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• Step 2 (3R, 3aS) -3- (hydroxymethyl) -7- (3-oxomorpholino) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• Step 3 ( (3R, 3aS) -1-oxo-7- (3-oxomorpholino) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin -3-yl) methyl methanesulfonate
• Step 4 (3S, 3aS) -3- (azidomethyl) -7- (3-oxomorpholino) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• Step 5 (3S, 3aS) -3- (aminomethyl) -7- (3-oxomorpholino) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin -1 (3H) -one
• Step 6 5-bromo-N- ( ( (3S, 3aS) -1-oxo-7- (3-oxomorpholino) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide
• the mixture was reacted at rt for 10 hours.
• the reaction mixture was concentrated in vacuo to remove the solvent, and to the residue was added dichloromethane (30 mL) .
• the resulting mixture was washed with aqueous sodium hydroxide (10 mL, 2.0 mol/L) and water (10 mL) in turn, dried over anhydrous sodium sulfate and filtered.
• the compound was characterized by the following spectroscopic data: MS (ESI, pos.
• the mixture was reacted at rt for 10 hours.
• the reaction mixture was concentrated in vacuo to remove the solvent, and to the residue was added dichloromethane (30 mL) .
• the resulting mixture was washed with aqueous sodium hydroxide (10 mL, 2.0 mol/L) and water (10 mL) in turn, dried over anhydrous sodium sulfate and filtered.
• the compound was characterized by the following spectroscopic data: MS (ESI, pos.
• the mixture was reacted at rt for 10 hours.
• the reaction mixture was concentrated in vacuo to remove the solvent, and to the residue was added dichloromethane (30 mL) .
• the resulting mixture was washed with aqueous sodium hydroxide (10 mL, 2.0 mol/L) and water (10 mL) in turn, dried over anhydrous sodium sulfate and filtered.
• the compound was characterized by the following spectroscopic data: MS (ESI, pos.
• Step 1 (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -7- (2-oxopyrrolidin-1-yl) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• cuprous iodide 92 mg, 0.48 mmol
• potassium carbonate 1.00 g, 7.24 mmol
• pyrrolidin-2-one (246 mg, 2.90 mmol
• trans- (1R, 2R) -N, N-dimethyl-cyclohexane-1, 2-diamine 196 ⁇ L, 177 mg, 1.21 mmol
• the mixture was reacted for a microwave heating time of 30 min at 240°Cunder a pressure of 11 bar.
• the mixture was cooled to 25°Cand filtered.
• To the filtrate was added water (100 mL) and the resulting mixture was extracted with dichloromethane (100 mL x 3) .
• the combined organic layers were dried over anhydrous sodium sulfate and filtered.
• the compound was characterized by the following spectroscopic data: MS (ESI, pos.
• Step 2 (3R, 3aS) -3- (hydroxymethyl) -7- (2-oxopyrrolidin-1-yl) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• Step 3 ( (3R, 3aS) -1-oxo-7- (2-oxopyrrolidin-1-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl methanesulfonate
• Step 4 (3S, 3aS) -3- (azidomethyl) -7- (2-oxopyrrolidin-1-yl) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• Step 5 (3S, 3aS) -3- (aminomethyl) -7- (2-oxopyrrolidin-1-yl) -3a, 4-dihydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one
• Step 6 5-chloro-N- ( ( (3S, 3aS) -1-oxo-7- (2-oxopyrrolidin-1-yl) -1, 3, 3a, 4-tetrahydrobenzo [b] oxazolo [3, 4-d] [1, 4] oxazin-3-yl) methyl) thiophene-2-carboxamide
• Example 7 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 lithium (Z) -5-hydroxypent-2-enoate
• Step 2 (Z) -methyl 5-hydroxypent-2-enoate
• N-dimethylformamide was dispersed lithium (Z) -5-hydroxypent-2-enoate (20 g, 163.87 mmol) .
• Iodomethane 25.8 g, 180 mmol was added dropwise slowly to the mixture at -5°C. At the end of the addition, the mixture was stirred at rt overnight.
• the reaction mixture was poured into ice water (50 g) and the resulting mixture was extracted with dichloromethane (30 mL x 6) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as light yellow oil (20 g, 93.78%) .
• Step 3 (Z) -methyl 5- (tosyloxy) pent-2-enoate
• reaction mixtue was diluted with dichloromethane (100 mL) and washed with diluted hydrochloric acid (100 mL, 1 mol/L) .
• Step 4 (Z) -5-hydroxypent-3-en-1-yl 4-methylbenzenesulfonate
• Step 5 (Z) -5- ( (tert-butyldimethylsilyl) oxy) pent-3-en-1-yl 4-methylbenzenesulfonate
• Step 6 (Z) - ( (5- (5-bromo-2-nitrophenoxy) pent-2-en-1-yl) oxy) (tert-butyl) dimethylsilane
• Step 7 (Z) -5- (5-bromo-2-nitrophenoxy) pent-2-en-1-ol
• Step 8 ( (2S, 3R) -3- (2- (5-bromo-2-nitrophenoxy) ethyl) oxiran-2-yl) methanol
• Step 9 ( ( (2S, 3R) -3- (2- (5-bromo-2-nitrophenoxy) ethyl) oxiran-2-yl) methoxy) (tert-butyl) dimethylsilane
• Step 10 4-bromo-2- (2- ( (2R, 3S) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) oxiran-2-yl) ethoxy) aniline
• Step 11 (R) -1- ( (S) -8-bromo-2, 3, 4, 5-tetrahydrobenzo [b] [1, 4] oxazepin-4-yl) -2- ( (tert-butyldimethylsilyl) oxy) ethanol
• Step 12 (3R, 3aS) -8-bromo-3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 13 (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 14 (3R, 3aS) -3- (hydroxymethyl) -8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 15 ( (3R, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin -3-yl) methyl methanesulfonate
• Step 16 2- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) isoindoline-1, 3-dione
• Step 17 (3S, 3aS) -3- (aminomethyl) -8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one hydrochloride
• Step 18 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 8 5-methyl-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 9 4, 5-dichloro-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 10 4-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) benzamide
• Example 12 6-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) nicotinamide
• Example 13 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (3-oxomorpholino) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) benzofuran-2-carboxamide
• Example 14 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 2 (3R, 3aS) -3- (hydroxymethyl) -8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 3 ( (3R, 3aS) -1-oxo-8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl methanesulfonate
• Step 4 2- ( ( (3S, 3aS) -1-oxo-8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) isoindoline-1, 3-dione
• Step 5 (3S, 3aS) -3- (aminomethyl) -8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 6 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxopiperidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 15 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxopiperazin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 tert-butyl 4- ( (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -3-oxopiperazine-1-carboxylate
• Step 2 tert-butyl 4- ( (3R, 3aS) -3- (hydroxymethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -3-oxopiperazine-1-carboxylate
• Step 3 tert-butyl 4- ( (3R, 3aS) -3- ( ( (methylsulfonyl) oxy) methyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -3-oxopiperazine-1-carboxylate
• Step 4 tert-butyl 4- ( (3S, 3aS) -3- ( (1, 3-dioxoisoindolin-2-yl) methyl) -1-oxo-3, 3a, 4, 5-tetrahydro -1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -3-oxopiperazine-1-carboxylate
• Step 5 tert-butyl 4- ( (3S, 3aS) -3- (aminomethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -3-oxopiperazine-1-carboxylate
• Step 6 tert-butyl 4- ( (3S, 3aS) -3- ( (5-chlorothiophene-2-carboxamido) methyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -3-oxopiperazine-1-carboxylate
• Step 7 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxopiperazin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 16 5-chloro-N- ( ( (3S, 3aS) -8- (4-methyl-2-oxopiperazin-1-yl) -1-oxo-3, 3a, 4, 5-tetrahydro -1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 17 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxotetrahydropyrimidin-1 (2H) -yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 (3R, 3aS) -8-bromo-3- (hydroxymethyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 2 ( (3R, 3aS) -8-bromo-1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin -3-yl) methyl methanesulfonate
• Step 3 2- ( ( (3S, 3aS) -8-bromo-1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin -3-yl) methyl) isoindoline-1, 3-dione
• Step 4 (3S, 3aS) -3- (aminomethyl) -8-bromo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 5 N- ( ( (3S, 3aS) -8-bromo-1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) -5-chlorothiophene-2-carboxamide
• Step 6 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxotetrahydropyrimidin-1 (2H) -yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 18 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxopyrrolidin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 20 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxoindolin-1-yl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 21 5-chloro-N- ( ( (3S, 3aS) -8- (2- (methylsulfonyl) phenyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -8- (2- (methylsulfonyl) phenyl) -3, 3a, 4, 5 -tetrahydro -1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 2 (3R, 3aS) -3- (hydroxymethyl) -8- (2- (methylsulfonyl) phenyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 3 (3R, 3aS) -3- (chloromethyl) -8- (2- (methylsulfonyl) phenyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 4 (3S, 3aS) -3- (azidomethyl) -8- (2- (methylsulfonyl) phenyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 5 (3S, 3aS) -3- (aminomethyl) -8- (2- (methylsulfonyl) phenyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one
• Step 6 5-chloro-N- ( ( (3S, 3aS) -8- (2- (methylsulfonyl) phenyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 22 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-sulfamoylphenyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Step 1 N- (tert-butyl) -2- ( (3R, 3aS) -3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -1-oxo-3, 3a, 4, 5-tetrahydro -1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) benzenesulfonamide
• Step 2 N- (tert-butyl) -2- ( (3R, 3aS) -3- (hydroxymethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) benzenesulfonamide
• Step 3 N- (tert-butyl) -2- ( (3R, 3aS) -3- (chloromethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) benzenesulfonamide
• Step 4 2- ( (3S, 3aS) -3- (azidomethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) -N- (tert-butyl) benzenesulfonamide
• N- (tert-butyl) -2- ( (3R, 3aS) -3- (chloromethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-8-yl) benzenesulfonamide (90 mg, 0.19 mmol) in N, N-dimethylformamide (10 mL) was added sodium azide (30 mg, 0.46 mmol) .
• Step 5 2- ( (3S, 3aS) -3- (aminomethyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin -8-yl) -N- (tert-butyl) benzenesulfonamide
• Step 6 N- ( ( (3S, 3aS) -8- (2- (N- (tert-butyl) sulfamoyl) phenyl) -1-oxo-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) -5-chlorothiophene-2-carboxamide
• Step 7 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-sulfamoylphenyl) -3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 23 5-chloro-N- ( ( (3S, 3aS) -1-oxo-8- (2-oxopyridin-1 (2H) -yl) -3, 3a, 4, 5-tetrahydro-1H -benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-3-yl) methyl) thiophene-2-carboxamide
• Example 35 Determination of human factor Xa (FXa) inhibition of the compounds of the invention
• Factor Xa can cleave the specific chromogenic substrate to release p-nitroaniline, which has a specific absorption spectrum at a vavelength of 405 nm. So the inhibitive effect of compound on recombinant human factor Xa (FXa) activity can be evaluated by determinating the absorbance of the p-nitroaniline at the vavelength of 405 nm.
• Example IC 50 (nM) Example IC 50 (nM) Example 1 3.02 Example 10 43.7 Example 2 47.46 Example 14 8.42 Example 3 169.9 Example 17 50.6 Example 4 177.5 Example 18 13.6 Example 5 >400 Example 19 30.8 Example 6 69.67 Example 21 8.82 Example 7 2.88 Example 22 8.06 Example 8 29.15 Example 23 2.43
• the compounds of the invention have potent FXa inhibition activities, and are especially suited as anti-coagulation drugs for the treatment of thromboembolic-related disorders.
• Example 36 Determination of the in vitro anticoagulant effects of the compounds of the invention
• Test compound solutions preparation Stock solution of each compound (4 ⁇ L, 100 mmol/L) was diluted with dimethyl sulfoxide (DMSO) independently to prepare series of test compound solutions in different concentrations (0-10000 ⁇ mol/L) .
• DMSO dimethyl sulfoxide
• Plasma preparation several rabbits were anesthetized by ear vein injection of 3%pentobarbital sodium (30 mg/kg) . 2 mL of blood was drawn off from abdominal arota using vacutainer as a receiver which contained a sodium citrate solution (0.2 mL, 3.8%) . Several tubes were collected, blended uniformly, and kept standing for 10 min, then centrifuged at about 3000 rpm for 10 minutes. The plasma of each tube was pipetted off and all of them were mixed in a centrifuge tube, then placed quickly into a -80°Crefrigerator for use.
• the concentration of the compound in the test solution (40 ⁇ L) was calculated using an External standard one point method base on the datum measured by HPLC.
• Test compound solutions preparation 5%dimethylsulfoxide, 5%Solutol HS 15 and 90%normal saline were mixed with the test compound to prepare the test compound solution, and the test compound solution was used for oral and intravenous administration.
• 190-250 g male SD rats were randomly divided into two groups with 3 rats in each group. Animals in group one were injected with the test compound solution at an intravenous dose of 1.0 mg/kg, while amimals in the other group received the test compound solution at an oral dose of 2.5 mg/kg. Then blood samples at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, and 24 h were collected. Appropriate range of standard curve was established according to the sample concentration, the test compound concentration in plasma sample was measured in MRM mode by AB SCIEX API4000 type LC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental method using WinNonLin 6.3 software based on drug concentration-time curves.

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