WO2015043364A1 - 作为凝血因子Xa抑制剂的苯并恶唑并恶嗪酮类化合物 - Google Patents

作为凝血因子Xa抑制剂的苯并恶唑并恶嗪酮类化合物 Download PDF

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WO2015043364A1
WO2015043364A1 PCT/CN2014/085844 CN2014085844W WO2015043364A1 WO 2015043364 A1 WO2015043364 A1 WO 2015043364A1 CN 2014085844 W CN2014085844 W CN 2014085844W WO 2015043364 A1 WO2015043364 A1 WO 2015043364A1
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methyl
oxo
oxazin
tetrahydrobenzo
carboxamide
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PCT/CN2014/085844
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English (en)
French (fr)
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高任龙
丁照中
赖光华
陈曙辉
颜小兵
段宝玲
朱秀良
路新华
胡军平
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华北制药集团新药研究开发有限责任公司
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Priority to CN201480048134.9A priority Critical patent/CN105593232B/zh
Publication of WO2015043364A1 publication Critical patent/WO2015043364A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • 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
    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel benzoxazoleoxazinone compounds, in particular compounds of formula (I), processes for their preparation, pharmaceutical compositions and their use as anticoagulants in the treatment and prevention of thromboembolic disorders.
  • Cardiovascular disease is the leading cause of disease and death in developed populations, most of which are mainly due to thrombosis.
  • Warfarin is the first oral anticoagulant to be marketed, and its application suffers from slow vitamin K-dependent antagonism, drug-drug interactions, and drug-food interactions. Continuous monitoring is required to obtain an accurate dose.
  • Other anticoagulants such as heparin, fondaparinux, etc. are only suitable for parenteral administration. The above-mentioned shortcomings of existing anticoagulants have driven the in-depth study of new anticoagulant drugs.
  • factor Xa In the blood coagulation cascade, factor Xa is balanced at a common junction that can be activated by internal pathways (contact activation) and external pathways (tissue factors) and is therefore a unique serine protease. Coagulation factor Xa only converts prothrombin to thrombin, but does not affect existing circulating thrombin levels, compared to the multiple effects of thrombin in the cascade system. In preclinical animal models, Factor Xa inhibitors reduce the risk of bleeding and increase safety/effectiveness relative to thrombin inhibitors.
  • VTE Pulse thromboembolism
  • the standard dose of rivaroxaban is 10 mg once daily.
  • the higher efficacy of rivaroxaban is associated with a higher tendency to hemorrhage, and the risk of major or fatal bleeding is not to be underestimated, especially if the patient is taking the drug for a prolonged period of time.
  • rivaroxaban is poorly water-soluble, making it difficult to develop intravenous preparations. Therefore, the widespread use of coagulation factor Xa inhibitors relies on improved research for the above problems.
  • WO2011/147259 discloses compounds of the formula (IV) for the treatment of infectious diseases, in particular infectious diseases caused by multi-drug resistant bacteria:
  • U is H or F
  • R 1 is acetamide or triazole:
  • R 1 represents an optionally substituted aryl or heteroaryl group, and the substituent is independently selected from the group consisting of F, Cl, Br, I, cyano, amino, CF 3 , C 1-8 alkoxy and C 1-8 alkane.
  • the number of substituents is one or more, and the C 1-8 alkyl group is optionally substituted by F, Cl, Br, I, cyano, amino or CF 3 ;
  • R 3 stands for H, or
  • A is selected from the group consisting of O, NH, N-CH 3 , S, SO, SO 2 and CH 2 ;
  • X, Y and Z are each independently selected from the group consisting of CH, C-Br, C-Cl, C-F, C-I and N;
  • the compound is a stereoisomer.
  • R 1 represents an optionally substituted phenyl, thienyl or pyridyl group, and the substituent is independently selected from the group consisting of F, Cl, Br, I, cyano, amino, CF 3 , C 1-8 alkoxy and C 1- 8 alkyl, the number of substituents is one or more, and the C 1-8 alkyl group is optionally substituted by F, Cl, Br, I, cyano, amino or CF 3 ;
  • R 3 is selected from H, or
  • A is selected from the group consisting of O, S, SO, SO 2 and CH 2 ;
  • X, Y and Z are each independently selected from the group consisting of CH, C-Br, C-Cl, C-F, C-I and N;
  • the compound is a stereoisomer.
  • R 1 is selected from:
  • R 3 is selected from H, or
  • A is selected from the group consisting of O, S, SO, SO 2 and CH 2 ;
  • X, Y and Z are each independently selected from the group consisting of CH, C-Br, C-Cl, C-F, C-I and N;
  • the compound is a stereoisomer.
  • R 1 represents an optionally substituted phenyl, thienyl or pyridyl group, said substituents being independently selected from the group consisting of F, Cl, Br, I, cyano, amino, CF 3 and optionally F, Cl, Br , I, cyano, amino or CF 3 substituted C 1-8 alkyl, the number of said substituents being one or more;
  • R 2 is selected from:
  • A is selected from the group consisting of O, S, SO, SO 2 and CH 2 ;
  • X, Y and Z are each independently selected from CH, C-Cl, C-F, and N;
  • the compound is a stereoisomer.
  • composition consisting of:
  • a base addition salt sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts
  • Acid addition salts hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.
  • Organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid , p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid Or glucuronic acid.
  • Organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid , p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, amino acid Or glucuronic acid.
  • Another object of the present invention is to provide a process for the preparation of a compound of formula (I) wherein R 1 , X, Y and Z are as defined in claim 1, A is O, R 3 is H, and R 2 is 3-9
  • the nitrogen heterocycle includes the following steps:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the use of the above compound for the preparation of a medicament for treating a thromboembolic disease, wherein the disease is preferably an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, or a cerebral arterial thromboembolism.
  • Sexual diseases venous cerebrovascular embolism, further preferred from unstable angina pectoris, myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, lower extremity Deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by: (a) prosthetic heart valves or other implants (b) indwelling catheter; (c) stent; (d) cardiopulmonary bypass; (e) hemodialysis; and (f) other procedures or procedures for exposing blood to an artificial surface to promote thrombosis.
  • the invention relates to the following definitions:
  • the invention includes all chiral, diastereomeric, racemic and all geometric isomeric forms.
  • Methods of preparing the compounds of the invention and intermediates thereof are part of the present invention. All of the compounds of the invention Tautomers are also part of the invention.
  • the compound of the invention has a molecular weight of less than 500 to 800 g/mol; in another preferred embodiment, the molecular weight is less than 800 g/mol; in another preferred embodiment, the molecular weight is less than 650 g/mol; another preferred embodiment The molecular weight is less than 550 g/mol.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • the present invention generally does not include groups such as N-halogen, S(O)H, and SO 2 H.
  • the invention includes all isotopes of atoms in the compounds of the invention.
  • Isotopes include atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium
  • isotopes of carbon include C-13 and C-14.
  • any variable e.g., R 6
  • its definition on each occurrence is independent.
  • R 6 when any variable (e.g., R 6) occurs more than once in the composition or structure of compound, its definition on each occurrence is independent.
  • R 6 when a group is substituted with 0-2 R 6, then said group may optionally be substituted with up to two R 6, and R 6 are independently in each case options.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl by itself or as part of another substituent means a straight-chain, branched or cyclic hydrocarbon radical, or a combination thereof, which may be fully saturated, unitary or polyunsaturated, It may comprise a divalent or polyvalent radical having the specified number of carbon atoms (i.e., C 1 -C 10 represents 1 to 10 carbons).
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • heteroalkyl by itself or in conjunction with another term, denotes a stable straight-chain, branched or cyclic hydrocarbon radical, or a combination thereof, having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the rest of the molecule.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl and heterocycloalkyl mean cyclized “alkyl” and “heteroalkyl”, respectively.
  • a hetero atom may occupy a position at which the heterocyclic ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monocyclic or polycyclic (preferably 1 to 3 rings) which are fused together or covalently bonded.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms.
  • the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl)
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group Oxyl a group or an aralkyl group.
  • each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • each R group is independently added. Selected as each of these groups when there is more than one R', R", R"', R"" and R""' groups.
  • the two substituents on the adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected from -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -(CRR')sX-(CR"R'")d- Wherein s and d are each independently selected from an integer from 0 to 3, and X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • Ring denotes a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group. .
  • the so-called ring includes a fused ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring.
  • “5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heteroatom as used herein includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum ( Al) and boron (B) and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • R is a general abbreviation representing an alkyl group selected from substituted or unsubstituted, a heteroalkyl group substituted or unsubstituted, an substituted or unsubstituted aryl group, substituted or unsubstituted. a substituent such as a heteroaryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group.
  • ⁇ ективное amount of a drug, formulation or permeate is meant a sufficient amount of active agent to achieve the desired local or systemic effect.
  • a “topically effective”, “cosmetically effective”, “pharmaceutically effective” or “clinically effective” amount refers to the amount of drug that is capable of achieving the desired therapeutic result.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulphate, hydroiodic acid, phosphorous acid, etc.; and relatively non-toxic organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, Acids of suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention. Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier means capable of delivering an effective amount of an active substance of the invention without interfering with
  • Representative agents including water, oil, vegetable and mineral, cream, lotion base, ointment base, and the like, are any agents or carrier media that are biologically active and have no toxic side effects to the host or patient. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Glycollyarsanilic, hexylresorcinic hydrabamic, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionate, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid , nitric acid,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • Remington's A list of suitable salts is disclosed in the Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.
  • prodrugs can enhance many qualities of the drug (e.g., solubility, bioavailability, industrialization, etc.), the compounds of the present invention can be administered as prodrugs. Accordingly, the invention is intended to cover prodrug forms of the compounds claimed herein, modes of administration thereof, and pharmaceutical compositions thereof. "Prodrug” is intended to include any covalently bonded carrier which, when administered to a mammalian receptor, will release the active parent drug of the invention in vivo.
  • the preparation of the prodrug of the present invention is carried out by modifying the functional group of the parent compound of the present invention, and the modified parent compound can be cleaved into the parent compound by a conventional operation or in an in vivo manner.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or thiol group is bonded to any functional group, and when a prodrug of the invention is administered to a mammalian receptor, it will be cleaved separately to form a free hydroxyl group, free amino acid Or free sulfhydryl.
  • Examples of prodrugs include, but are not limited to, acetic acid, formic acid, and benzoic acid derivatives of the alcohol or amine functional groups of the compounds of the present invention.
  • oral dosage form refers to the administration of any pharmaceutical composition by buccal administration.
  • oral dosage forms include tablets, capsules, films, powders, sachets, granules, solutions, solids, suspensions, or a plurality of different dosage units (eg, granules, tablets containing different active ingredients) And/or capsules are packaged together for administration, as well as other means known in the art.
  • Oral dosage forms can be one, two, three, four, five or six units. When the oral dosage form has multiple units, all units are packaged in a single package (eg, bottles or other forms of packaging, such as blister packs). Packaging); when the oral dosage form is a separate unit, it may or may not be present in a single package.
  • the oral dosage form is one, two or three units.
  • the oral dosage form is a unit.
  • Inhibiting and blocking refers to the blockage of part or all of an enzyme, such as a serine protease.
  • leaving group means that a functional group or atom in a substitution reaction may be substituted with another functional group or atom, such as an affinity substitution reaction.
  • representative leaving groups include trifluoromethanesulfonic acid, chlorine, bromine, and iodine; sulfonate groups such as methanesulfonate, tosylate, p-bromobenzenesulfonate, dimethylformamide a salt or the like; and an acyloxy group such as an acetoxy group, a trifluoroacetoxy group or the like.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (e.g., acet
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethyl Silyl group (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoren
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • the C 2-6 alkenyl group means an alkenyl group including C 2 , C 3 , C 4 , C 5 and C 6 .
  • Alkynyl is meant to include a straight or branched chain hydrocarbon chain wherein one or more carbon-carbon triple bonds, such as ethynyl and propynyl, are present at any of the stabilizing sites on the chain.
  • the C 2-6 alkynyl group means an alkynyl group including C 2 , C 3 , C 4 , C 5 and C 6 .
  • halo or halogen means fluoro, chloro, bromo and iodo; "counterion” is used to mean a small, negatively charged species such as chloride, bromide, hydroxide, B. Acid salts and sulfates.
  • C 1-8 may be C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 or C 8
  • the 3-9 membered carbocyclic or heterocyclic ring may be 3, 4, 5, 6, 7, 8, 9 carbon rings or heterocycles.
  • Carbocyclic or “carbocyclyl” refers to any stable 3, 4, 5, 6 or 7 membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13 membered bicyclic ring. Or tricyclic, they may be saturated, partially unsaturated or unsaturated (aromatic).
  • carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, Adamantyl, cyclooctyl, cyclooctene, cyclooctadienyl, [3,3,0]bicyclooctane, [4,3,0]bicyclononane, [4,4,0]bicyclodecane [2,2,2]bicyclooctane, indenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl.
  • the bridged ring is also included in the definition of carbocycle (eg [2,2,2]bicyclooctane).
  • a bridge ring is formed when one or more carbon atoms join two non-adjacent carbon atoms.
  • a bridge of one or two carbon atoms is preferred. It is worth noting that a bridge always converts a single ring into a three ring.
  • a substituent on the ring can also be present on the bridge.
  • heterocycle or “heterocyclyl” means a stable 5, 6 or 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic ring which may be saturated, partially non- Saturated or unsaturated (aromatic) which comprises a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a benzene A double ring is formed on the ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • “Stable compound” and “stable structure” refer to a compound which is capable of being detached from the reaction mixture and which is independently and stably present in a certain effective purity and which is formulated into an effective therapeutic drug.
  • Substituted means that one or more hydrogen atoms on the "substituted” atom are replaced by a substituent (which has been defined herein) as long as the valence of the particular atom is normal and replaced The compound is stable.
  • treatment is the treatment of a disease state in a mammal, particularly a human, including: (a) prevention of a disease state occurring in a mammal, especially when the mammal is predisposed to the disease but has not yet been diagnosed. Suffering from this disease; (b) inhibiting the state of the disease, ie preventing its development; and/or (c) alleviating The state of the disease, which causes the disease state to subside.
  • Therapeutically effective amount means the amount of the compound of the present invention which is effective for inhibiting Factor Xa when administered alone or in combination.
  • “Therapeutically effective amount” also refers to the amount of the compound of the present invention which is effective for inhibiting Factor Xa when used in combination.
  • the combined use of the compounds of the invention is preferably used in a synergistic combination. As taught by Chou and Talalay, Adv. Enzyme Regul. 1984, 22: 27-55, the synergistic effect of the combination of drugs (ie, inhibition of factor Xa) is better than that of drugs alone. effect. In general, suboptimal concentrations of compounds best show synergistic effects. The synergistic effect of the combination may be manifested in reducing cytotoxicity, increasing antithrombotic ability or other beneficial effects as compared to administration alone.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the hydroxy group is protected, and the benzoxazole oxazinone ring system is obtained by cyclization and LDA treatment.
  • the bromide is substituted with a heterocyclic ring in the presence of cuprous iodide to obtain an intermediate product, ie, substituted benzoxazole oxazinone.
  • Compound (1-3) After four steps of reaction, the silyl group (TBS) changes from protecting the hydroxyl group to protecting the amino group.
  • the compounds of formula (I) provided by the present invention can be prepared by Reaction Scheme 1 and standard procedures well known to those skilled in the art.
  • F- and Br- can be replaced by Other halogen, -OH, -NH 2 or protected -NH 2 , NO 2 on the ring of compound (1-1) may be replaced by -NH 2 or protected -NH 2 (such as CBzHN), etc.
  • X, Y Z is selected from CH, CF, CCl or N. All such changes and substitutions are detailed in the Detailed Description section. It will be appreciated by those skilled in the art that the order of the reaction steps in Reaction Scheme 1 may be varied in order to prepare the compounds of the present invention, which are also within the scope of the invention.
  • the reaction is generally carried out under an inert nitrogen atmosphere in an anhydrous solvent.
  • Nuclear magnetic resonance spectroscopy data was collected on a Bruker Avance III400 (400 MHz) nuclear magnetic resonance instrument with chemical shifts expressed in ⁇ (ppm) using tetramethylsilane calibration.
  • the liquid chromatography-mass spectrometer includes: Agilent 1200 Series HPLC equipped with a 6110 or 1956A mass spectrometer; and Shimadzu LC20 LC equipped with a 2020 mass spectrometer.
  • the mass spectrometer is equipped with an electrospray ion source (ESI) that is detected in positive or negative mode.
  • ESI electrospray ion source
  • the present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
  • High performance liquid chromatography was performed using a Shimadzu LC20AB system equipped with a Shimadzu SIL-20A autosampler and a Shimadzu DAD: SPD-M20A detector using Xtimate C18 (3 ⁇ m packing, 2.1 x 300 mm) column.
  • 0-60AB_6 min method Apply a linear gradient, start elution with 100% A (A is 0.0675% TFA in water), and end the elution with 60% B (B is 0.0625% TFA in MeCN solution). The whole process is 4.2 minutes, then eluted with 60% B for 1 minute. The column was equilibrated for 0.8 minutes to reach 100:0 with a total run time of 6 minutes.
  • 10-80AB_6 min method Apply a linear gradient, start elution with 90% A (A is 0.0675% TFA in water), and end the elution with 80% B (B in 0.0625% TFA in acetonitrile). 4.2 minutes, then eluted with 80% B for 1 minute.
  • the column was equilibrated for 0.8 minutes to 90:10 with a total run time of 6 minutes.
  • the column temperature was 50 ° C and the flow rate was 0.8 mL/min.
  • the diode array detector has a scanning wavelength of 200-400 nm.
  • Thin layer chromatography was performed on silica gel GF254 of Sanpont-group.
  • the spot was usually irradiated with ultraviolet light, and in some cases, the spot was also examined by other methods. In these cases, iodine (10 g of silica gel was added).
  • a common solvent for flash column chromatography or thin layer chromatography is a mixture of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
  • AS-H_3_40_2.35ML Chromatographic conditions Chiralpak AS-H column (specification 250x4.6mm ID, 5 ⁇ m packing); mobile phase 40% methanol (0.05% DEA)-CO 2 ; flow rate 2.35mL/min, detection wavelength It is 220 nm.
  • OD-H_3_40_2.35M Chromatographic conditions Chiralcel OD-H column (specification 250x4.6mm ID, 5 ⁇ m packing), mobile phase 40% methanol (0.05% DEA)-CO 2 , flow rate 2.35mL / min, detection wavelength It is 220 nm.
  • AD-H_2_50_2.35ML Chromatographic conditions Chiralpak AD-H column (specification 250x4.6mm ID, 5mm packing), mobile phase 50% methanol (0.1% MEA)-CO 2 , flow rate 2.35mL / min, detection wavelength It is 220 nm.
  • Preparative SFC analysis was performed on a Waters Thar80 Pre-SFC system using a Gilson UV detector using Chiralcel OD-H (250x4.6mm ID, 5 ⁇ m packing) or Chiralpak AD-H (250x4. 6mm ID, 5 ⁇ m filler).
  • Chiralcel OD-H 250x4.6mm ID, 5 ⁇ m packing
  • Chiralpak AD-H 250x4. 6mm ID, 5 ⁇ m filler.
  • the compound is eluted with a low gradient of ethanol-carbon dioxide or methanol-carbon dioxide, with methanol or ethanol containing 0.05% NH 3 ⁇ H 2 O, 0.05% DEA or 0.1% MEA, total run
  • the time is 20-30 minutes.
  • thromboembolic disease is a disease of the circulatory system caused by blood clots (i.e., a disease associated with platelet activation and/or platelet aggregation).
  • blood clots i.e., a disease associated with platelet activation and/or platelet aggregation.
  • thromboembolic disease as used herein includes arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, arterial cerebrovascular thromboembolic disease, and venous cerebrovascular thromboembolic disease.
  • thromboembolic disease includes a specific disease selected from, but not limited to, unstable angina, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, arteries.
  • thrombosis includes obstruction (eg, obstruction after bypass surgery) and reocclusion (eg, during or after percutaneous transluminal coronary angioplasty).
  • the anticoagulant effect of the compounds of the invention is derived from their inhibition of Factor Xa or thrombin.
  • novel series of benzoxazoleoxazinone compounds of formula (I) of the present invention are selective and potent inhibitors of factor Xa and are therefore useful as anticoagulants.
  • the invention is The composition has improved water solubility, enhanced efficacy, and a lower tendency to bleed. Therefore, the compound of the formula (I) can be a therapeutic or prophylactic agent for a thromboembolic disease.
  • the compound of the formula (I) of the present invention is also distinguished from the compound of WO2011/147259, and there are not only structurally significant differences, but in effect, the compound of WO2011/147259 does not have an inhibitory effect on coagulation factor Xa, WO2011/147259 also No guidance has been given in this regard.
  • Step A A solution of (Z)-but-2-ene-1,4-diol (39.7 g, 450 mmol) in dry THF (300 mL) was cooled to 0 ° C and sodium hydride (60% dissolved in mineral oil) 9.0 g, 225 mmol), then a solution of 4-bromo-2-fluoro-1-nitrobenzene (33.0 g, 150 mmol) in dry THF (450 mL). The reaction mixture was stirred at room temperature for 2 hrs, EtOAc (EtOAc)EtOAc. Oxy)but-2-en-1-ol (45 g), yellow solid. The crude product was used in the next step without further purification.
  • Step B Mix zinc powder (49.0 g, 750 mmol) and ammonium chloride (40.0 g, 750 mmol) in methanol (450 mL), then add (Z)-4-(5-bromo-2-) dropwise at room temperature A solution of nitrophenoxy)but-2-en-1-ol (43.2 g, 150 mmol) in methanol (300 mL). The reaction mixture was stirred at room temperature for 24 hours and then filtered. The filtrate was concentrated to give (Z)-4-(2-amino-5-bromophenoxy)but-2-en-1-ol as a black oil. The crude product was used in the next step without further purification.
  • Step C The crude product (Z)-4-(2-amino-5-bromophenoxy)but-2-en-1-ol was dissolved in THF (300 mL) and water (150 mL) at 0 ° C Sodium hydrogencarbonate (25.2 g, 300 mmol) and benzyl chloroformate (38.4 g, 225 mmol) were added, warmed to room temperature and stirred at room temperature for 16 hours. The mixture was extracted with EtOAc. The combined organic layers were dried and concentrated. The crude residue was purified by silica gel chromatography (EtOAc:EtOAc:EtOAc toEtOAc Benzyl ester (28.0 g, 48%), off white solid. LCMS (ESI) m/z 414, 416 (M+Na).
  • Step D -25 ° C, molecular sieve ( 40 g) was suspended in DCM (350 mL). To the cooled mixture were added L-(+)-diethyl tartrate (11.3 g, 54 mmol), Ti(Oi-Pr) 4 (14.1 g, 49.5 mmol) and t-butyl hydroperoxide (5 in decane) -6M, 27 mL, 135 mmol). After stirring at -25 ° for 1 hour, DCM containing (Z)-4-bromo-2-(4-hydroxybut-2-enyloxy)phenyl)carbamate (17.6 g, 45 mmol) was added dropwise (70 mL) The solution was stirred at -25 ° C for 24 hours.
  • Step E No-t-butyldimethylsilyl chloride ((5.2 g, 34.5 mmol), imidazole (3.1 g, 46 mmol) and 4-dimethylaminopyridine (280 mg, 2.3 mmol) at 0 ° C (4-Bromo-2-((2R,3S)-3-(hydroxymethyl)oxiran-2-yl)methoxy)phenyl)carbamic acid benzyl was added to a solution of water DMF (40 mL) A solution of the ester (9.4 g, 23 mmol) eluted elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut The aqueous solution was dried (MgSO4) (EtOAc:
  • Step F (4-bromo-2-((2R,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)))
  • 2-yl)methoxy)phenyl)carbamate 10.5 g, 20 mmol
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Step G (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3 ⁇ ,4-dihydrobenzo[b]oxazole And [3,4-d][1,4]oxazin-1(3H)-one (8.3g, 20mmol), morpholin-3-one (2.8g, 28mmol), K 2 CO 3 (3.3g, 24 mmol) was mixed with DMSO (60 mL) and stirred at room temperature for 1 hour. CuI (760 mg, 4 mmol) and 1,10-phenanthroline (200 mg) were added at room temperature. The resulting mixture was heated to 130 ° C and incubated for 24 hours.
  • Step H to (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(3-oxomorpholino)-3a at 0 °C , a solution of 4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (3.5 g, 8 mmol) in THF (20 mL) -Bu 4 NF (2.5 g, 9.6 mmol) in THF (10 mL). The resulting solution was stirred at 0 °C for 2 hours. The reaction was quenched with saturated aq. The combined organic layers were dried with anhydrous sodium sulfate and evaporated.
  • Step I to (3R,3aS)-3-(hydroxymethyl)-7-(3-oxomorpholino)-3 ⁇ ,4-dihydrobenzo[b]oxazole at 0 °C [ 3,4-d] [1,4] oxazin--1 (3H) - one (2.4g, 7.5mmol) and Et 3 N (2.3mL, 16.5mmol) in DCM (50mL) was added dropwise methanesulfonyl chloride (1.0 g, 9 mmol). The mixture was warmed to room temperature and stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL)EtOAc.
  • Step J The crude product (3S,3aS)-3-(azidomethyl)-7-(3-oxomorpholino)-3 ⁇ ,4-dihydrobenzo[b]oxazole[3, A mixture of 4-d][1,4]oxazine-1(3H)-one, sodium azide (540 mg, 8.3 mmol) and DMF (20 mL) was stirred at 80 ° C for 6 hr. And then add water, The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and evaporated to afford (3S, 3aS)-3-(azidomethyl)-7-(3-oxomorpholino)-3? -Dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (2.2 g) as a brown oil.
  • Step K to (3S,3aS)-3-(azidomethyl)-7-(3-oxomorpholino)-3 ⁇ ,4-dihydrobenzo[b]oxazole at room temperature
  • 3,4-d][1,4]oxazine-1(3H)-one (1.9 g, 5.5 mmol) in THF (20 mL). After stirring at 45 ° C for 2 hours, water (1 mL) was added and stirred at 45 ° C for 16 hours. After cooling to room temperature, the mixture was concentrated.
  • Step A Preparation of (3R,3aS)-3-((tert-butyldimethylsilyloxy)methyl)-7-(2-oxopiperidin-1-yl)-3 ⁇ according to Example 1.
  • the ketone is replaced by piperidin-2-one.
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(5-oxo-1,4-oxa) according to Example 1.
  • the morpholin-3-one in G was replaced by 1,4-oxazepan-5-one in a yield of 35%.
  • Example 3 The title compound of Example 3 was obtained as a white solid.
  • Step A EtOAc to piperazin-2-one (3.00g, 30.0mmol) is / H 2 O (30mL / 6mL ) was added K 2 CO 3 (4.32g, 31.5mmol ) and benzyl chloroformate (5.10 g , 30.0 mmol).
  • Step B Preparation of 4-((3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a, according to Example 1. 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)-3-oxopiperazine-1 -carboxylic acid benzyl ester, which will be in step G The morpholin-3-one was replaced with 3-oxopiperazine-1 - benzyl formate in 22% yield. LCMS (ESI) m/z: 568.2 (M+1).
  • Step C To 4-((3R,3aS)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a,4-tetrahydro Benzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)-3-oxopiperazine-1 -carboxylic acid benzyl ester (200 mg, 0.352 mmol of methanol (4 mL) Di-tert-butyl dicarbonate (115 mg, 0.529 mmol) and Pd/C (10%, 20 mg) were added to the solution, which was then treated with a hydrogen balloon. The reaction mixture was stirred at room temperature for 16 hours.
  • Step D Preparation of 4-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-) according to the procedure of Example 1, Steps G, I, J, K, L Oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-3-oxopiperazine-1- Tert-butyl formate.
  • Step E To 4-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[ b] oxazolo[3,4-d][1,4]oxazine-7-yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (425 mg, 0.756 mmol) in DCM (8 mL) The mixture was stirred for 2 hours at room temperature.
  • Step A To (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b] under nitrogen Oxazolo[3,4-d][1,4]oxazine-1(3H)-one (1.5g, 3.6mmol), Cs 2 CO 3 (2.4g, 7.2mmol) and 1,3–oxygen Pd 2 (dba) 3 (916 mg, 0.66 mmol) and Xantphos (420 mg, 0.7 mmol) were added to a solution of oxacyclohexane-2-one (550 mg, 5.4 mmol) in toluene (20 mL).
  • Step B The title compound of the present Example was prepared according to the procedure of Steps G, I, J, K, L of Example 1, wherein the morpholin-3-one in Step G was replaced with a 1,3-oxazacyclohexane- 2-ketone gave a white solid.
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(2-oxotetrahydropyrimidine-1 (2H) according to Example 1. )-yl)-3 ⁇ ,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one, wherein the morpholine in step G is The 3-ketone was replaced with tetrahydropyrimidin-2(1H)-one in a yield of 7%.
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(2-oxopyridine-1(2H)- according to Example 1 -3 ⁇ ,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one, wherein morpholine-3- in step G
  • the ketone was replaced by pyridine-2(1H)-one in a yield of 22%.
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(2-oxopyrazine-1 (2H) according to Example 1.
  • the ketone was replaced with pyrazine-2(1H)-one in a yield of 30%.
  • Step B The title compound of this example was prepared according to the procedure of Steps G, I, J, K, L of Example 1.
  • Step A To a solution of (R)-pyrrolidine-2-carboxamide (5.0 g, 49.9 mmol) in THF (150 mL) EtOAc. It was stirred for 1 hour and refluxed for 48 hours. The mixture was cooled to 0<0>C and quenched with water (12 mL). The mixture was filtered and the filter cake was washed with hot THF (150 mL EtOAc).
  • Step B To a solution of (R)-pyrrolidin-2-ylmethylamine (1.0 g, 1.0 mmol) in DCM (50 mL) A 1.0 mmol solution of DCM (20 mL) was stirred at 7 <0>C for 16 h then concentrated. The crude residue was purified by EtOAcqqq elut elut elut elut elut elut elut elut elut 24%), as a white solid.
  • Step C Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-((R)-3-oxotetrahydro- according to Example 6 1H-pyrrolo[1,2-c]imidazole-2(3H)-yl)-3 ⁇ ,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine- a 1(3H)-one in which the 1,3-oxazacyclo-2-one in step A is replaced by (R)-tetrahydro-1H-pyrrolo[1,2-c]imidazole- 3(2H)-one gave a white solid in a yield of 59%.
  • Step D The title compound of this example was obtained as a white solid in the order of the procedure of Steps G, I, J, K, L.
  • Step A The title compound of this example was prepared according to the procedure of Steps A, B, C, D of Example 10, wherein (S)-tetrahydro-1 hydrogen-pyrrole [1,2-c]imidazole in step A was The 3(2H)-one was replaced by (R)-tetrahydro-1 hydrogen-pyrrole [1,2-c]imidazole-3(2H)-one to give a white solid.
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(2-oxopyrrolidin-1-yl) according to Example 1. -3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one, wherein the morpholin-3-one in step G is replaced It is pyrrolidin-2-one in a yield of 32%.
  • Step B The title compound of this example was prepared according to the procedure of Steps G, I, J, K, L of Example 1.
  • Step A Concentrated sulfuric acid (14.8 mL, 0.151 mol) was added dropwise to a stirred solution of (S)-4-amino-2-hydroxybutyric acid (15.0 g, 0.126 mol) in MeOH (100 mL). minutes, refluxed for 4 hours, the reaction liquid may be cooled to 18 °C, diluted with water (15 mL), was added excess K 2 CO 3, stirred for 15 minutes, the reaction mixture was diluted with DCM (150mL), filtered through celite. The filtrate was evaporated to dryness to give a viscous liquid residue. The residue was slurried with 1-2% MeOH in DCM and filtered.
  • Step C To (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]oxazole [3,4-d][1,4]oxazine-1(3H)-one (2g, 4.83mmol) in toluene (30mL) was added (S)-3-((tert-butyldiphenyl) Silyl)oxy)pyrrolidin-2-one (2.5 g, 7.24 mmol), Cs 2 CO 3 (3.15 g, 9.66 mmol), Pd 2 (dba) 3 (440 mg, 0.483 mmol) and Ruphos (224 mg, 0.483) Mm).
  • Step D Preparation of 5-chloro-N-(((3S,3aS)-1-oxo-7-(2-oxopyrrolidine-3) according to the order of Steps G, I, J, K, L of Example 1. -yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide Wherein the morpholin-3-one in step G is replaced by (S)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one. LCMS (ESI) m/z: 7021.
  • Step E N-(((3S,3aS)-7-((S)-3-((tert-butyldiphenylsilyl)oxy)-2-oxopyrrolidine) at 0 °C -1-yl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d][1,4]oxazin-3-yl)methyl)
  • -5-chlorothiophene-2-carboxamide 500 mg, 0.713 mmol
  • THF 10 mL
  • Step A To ((3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a,4- at 0 °C Addition of NaH to tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)carbamic acid tert-butyl ester (991 mg, 2.2 mmol) in DMF (10 mL) (123 mg, 3.1 mmol) and stirred at 0 °C for 20 min. MeI (624 mg, 4.4 mmol) was then added at 0 ° C and stirred at 0 ° C for 1 hour.
  • Step B Preparation of ((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxyl according to the procedure of Example 1, Step H, I, J, K, and L a tert-butyl-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)(methyl)carbamate, wherein The morpholin-3-one in step H was replaced with t-butyl carbamate to give a yellow solid.
  • Step C To ((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzene at room temperature And [b] oxazolo[3,4-d][1,4]oxazin-7-yl)(methyl)carbamic acid tert-butyl ester (741 mg, 1.5 mmol) in DCM (5 mL) / Dioxane (5 mL, 4 M) was stirred at room temperature for 1 hour.
  • Step D To 5-chloro-N-(((3S,3aS)-7-(methylamino)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole[3] , 4-d] [1,4] oxazin-3-yl) methyl) thiophene-2-carboxamide (158mg, 0.4mmol) in DCM was added Et (4mL) solution of 3 N (202mg, 2.0mmol), Then a solution of 2-methoxyacetyl chloride (56 mg, 0.5 mmol) in DCM (1 mL) was evaporated. Saturated aqueous NaHCO 3 (10 mL) mixture was extracted with DCM (10mL x3).
  • Step A at 0 °C, 3-amino-propan-1-ol (5.0g, 66.6mmol) in THF (50mL) water was added portionwise Na 2 CO 3 (8.5g, 80.0mmol ) in (10 mL) solution of .
  • Di-tert-butyl dicarbonate (14.8 g, 67.9 mmol) was then added dropwise at 0 ° C, and added dropwise for 30 minutes. Stirred at 16 ° C for two hours. Water was added and the mixture was extracted with dichloromethane (200 mL x 2). The layers were washed with EtOAc EtOAc (EtOAc m. Further purification.
  • Step B tert-butyl (3-hydroxypropyl)carbamate (8.0 g, 45.7 mmol), aqueous NaOH (20 mL, 457 mmol, 50%) and n-Bu 4 NBr (736 mg, 2.3 mmol) at -10 °C
  • a solution of tert-butyl 2-bromoacetate (9.8 g, 50.2 mmol) in toluene (20 mL) was then evaporated. The mixture was stirred at 22 ° C for 16 hours.
  • Step C To a solution of 2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid (7.0 g, 30.0 mmol) in MeOH (50 mL) . The resulting mixture was stirred at 16 ° C for 2 hr then concentrated to afford ethyl 2-(3-aminopropoxy)acetate hydrochloride (5.5 g, yield 99%).
  • Step D at 0 °C, MeOH 2- (3-amino-propoxy) acetate hydrochloride (6.0g, 38.1mmol) in (100 mL) was added K 2 CO 3 (23g, 163.0mmol ), It was refluxed for 3 hours, concentrated, and then water was added. The resulting mixture was extracted with ethyl acetate (20 mL ⁇ 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate s Ketone, white solid (300mg, yield 10%).
  • Step E The title compound of this example was prepared according to the sequence of Steps G, H, I, J, K and L of Example 1, wherein the morpholin-3-one in Step G was replaced by 1,4-oxaza Cycloheptan-3-one gave a white solid.
  • Step A The title compound of the present Example was prepared according to the procedure of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced by ethyl 2-oxopiperidine-3-carboxylate . A white solid was obtained.
  • Step A To 1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4- at 0 °C Ethyl tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)-2-oxopiperidine-3-carboxylate (350 mg, 0.656 mmol) in MeOH CaCl 2 (72.8 mg, 0.656 mmol) and NaBH 4 (75 mg, 1.96 mmol) were added to a solution (5 mL), and stirred at 20 ° C for 16 hours. The mixture was poured into water (30 mL).
  • Step A at -10 °C, 3-amino-1,2-diol (7.5g, 82.3mmol) in CH 3 CN (270mL) and MeOH (45mL) was added triethylamine (9.98g, 98.8 Methyl chloride, then chloroacetyl chloride (10.2 g, 90.5 mmol) was added dropwise at -10 °C under nitrogen. The reaction mixture was warmed to room temperature and stirred for 16 h. Concentrated in vacuo, EtOAc (EtOAc:EtOAc) . .
  • Step B To a stirred solution of potassium tert-butoxide (5.61 g, 5.0 mmol) in 40 mL of tert-pentanol was added 2-chloro-N-(2,3-dihydroxypropyl)acetamide at room temperature under nitrogen. 3.35 g, 2.0 mmol) of 70 mL tert-amyl alcohol solution was added over 2 hours. After stirring for not less than 1 hour, MeOH (20mL) and H 2 O (1mL), and then stirred for 20 minutes. Concentration in vacuo, EtOAc (EtOAc:EtOAc)
  • Step C To a solution of 6-(hydroxymethyl)morpholin-3-one (1.4 g, 10.7 mmol) in pyridine (9 mL) and THF (17 mL), TBDPSCl (4.4 g, 16.0 mmol) and AgNO 3 (3.93) g, 23.5 mmol), and the mixture was stirred at 5 to 15 ° C for 15 hours. The THF and pyridine were removed in vacuo. The crude residue was purified by silica gel chromatography (EtOAc:EtOAc:EtOAc: 2.8 g, 71%), yellow solid.
  • Step D The title compound of the present Example was prepared according to the procedure of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced with 6-(hydroxymethyl)-morpholine-3. -ketone.
  • the product was a white solid isomer which was further purified by preparative SFC and preparative HPLC to afford two components, one was 8 mg and the other was 9 mg.
  • Step A To a solution of sodium hydride (3.27 g, 81.9 mmol) in toluene (80 mL) was added dropwise a solution of 2-ethanolamine (2.5 g, 40.9 mmol) in toluene (30 mL) at 0 ° C. Then, a solution of ethyl 2-chloropropionate (6.15 g, 45.0 mmol) in toluene (30 mL) was added dropwise at 25 °C. The resulting mixture was refluxed for 16 hours. Solid NH 4 Cl (6.0g), stirred for 0.5 hours. The mixture was filtered, and the filtrate was evaporated.jjjjjjjjjj .
  • Step B The title compound of the present Example was prepared according to the procedure of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced by 2-methylmorpholin-3-one.
  • the white solid isomer was further purified by preparative SFC and preparative HPLC to afford two components, one was 20 mg and the other was 17 mg.
  • Step A A solution of (R)-2-aminopropan-1-ol (5.0 g, 67.0 mmol) in toluene (60 mL) was added dropwise to a solution of sodium hydride (6.2 g, 145 mmol) in toluene (150 mL). . The mixture was stirred at 25 ° C for 0.5 hours. Then a solution of ethyl 2-chloroacetate (8.0 mL g, 73.8 mmol) in toluene (60 mL) was added dropwise at 25 ° C and the mixture was refluxed for 16 hr. Solid NH 4 Cl (6.0g), stirred for 0.5 hours. The mixture was filtered, and the filtrate was evaporatedjjjjjjjjjjjjjj Things.
  • Step B The title compound of the present Example was prepared according to the procedure of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced by (R)-5-methylmorpholine-3. a ketone which is a white solid.
  • Step A To a solution of methyl furan-2-carboxylate (10.0 g, 71.4 mmol) in dichloromethane (100 mL), anhydrous zinc chloride (2.9 g, 21.4 mmol) and paraformaldehyde (3.2 g, 107.0 mmol) The mixture was warmed to 40 ° C and anhydrous hydrogen chloride gas was bubbled for 1 hour. Water was added and the mixture was extracted with dichloromethane (100 mL ⁇ 2). The combined organic layers were washed with EtOAc EtOAc m.
  • Step B A solution of methyl 5-(chloromethyl)furan-2-carboxylate (3.5 g, 18.6 mmol) and sodium azide (2.2 g, 33.4 mmol) in DMF (20 mL). Water was added and the mixture was extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layers were washed with EtOAcq ⁇ Further purification.
  • Step C a solution of 5-(azidomethyl)furan-2-carboxylic acid methyl ester (3.6 g, 18.6 mmol) and Pd/C (0.5 g, 10%) in methanol (50 mL) stirred at 60 ° C under 30 psi of hydrogen. After 48 hours, the mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1.9 g, 75%), white solid.
  • Step D The title compound of the present Example was prepared according to the procedure of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced by 8-oxa-3-azabicyclo[3.2 .1] Octanone This product was a white solid isomer which was further purified by preparative SFC and preparative HPLC to give two components, one was 29 mg and the other was 28 mg.
  • Step A to (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(3-oxomorpholino)-3a at -78 °C , LDA was added dropwise to a solution of 4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (300 mg, 0.7 mmol) in THF (2 mL) (0.4 mL, 0.8 mmol, 2M in EtOAc) EtOAc (EtOAc)EtOAc. The mixture was stirred at -78 °C for 2 hours.
  • Step B The title compound of this example was prepared according to the procedure of Steps H, I, J, K, and L of Example 1, in which morpholin-3-one was replaced with ethyl 3-oxomorpholin-2-carboxylate. This product was a white solid.
  • Step A N-(((3S,3aS)-7-Amino-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d][1 , 4]oxazin-3-yl)methyl)-5-chlorothiophene-2-carboxamide (950 mg, 2.5 mmol), (S)-2-((tert-butoxycarbonyl)amino)-4-( A mixture of methylthio)butyric acid (623 mg, 2.5 mmol), EDC (959 mg, 5 mmol), HOBT (766 mg, 5 mmol), DIPEA (969 mg, 7.5 mmol) and DMF (10 mL) was stirred at room temperature for 16 hours.
  • Step B ((S)-1-(((3),3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a, 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazol-7-yl)amino)-4-(methylthio)-1-oxobutane-2
  • tert-butyl carbamate 880 mg, 1.4 mmol
  • Me 3 SI (881 mg, 4.3 mmol)
  • K 2 CO 3 (299 mg, 2.2 mmol
  • Step C To ((S)-1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a at room temperature , 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)-2-oxopyrrolidin-3-yl)carbamic acid tert-butyl ester ( A solution of 282 mg (0.5 mL) in EtOAc (3 mL) was evaporated. The title compound (10 mg, 4%) was obtained.
  • Step A A solution of 1H-imidazol-2-carbaldehyde (500 mg, 5.2 mmol) and methylamine (2 mL) in MeOH (20 mL) Then NaBH 4 (400 mg, 10.4 mmol) was added in small portions and then stirred at 60 ° C for 15 hours. The solvent was removed in vacuo. The residue was washed with DCM (3 ⁇ 25 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered and evaporated tolululululululululululululululululu
  • Step B 1-(1H-Imidazol-2-yl)-N-methylmethanamine (600 mg, 5.38 mmol), triethylamine (654 mg, 6.46 mmol) and di-tert-butyl dicarbonate (1.18 g, 5.38) A solution of mmol) in THF (15 mL) was stirred at &lt The solvent was concentrated in vacuo. The crude residue was purified with EtOAcqqq elut elut elut elut elut elut elut elut elut elut , colorless oil. LCMS (ESI) m/z:21.21.
  • Step C Preparation according to the procedure of Steps G, H, I, J, K and L of Example 1 ((1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido))) 1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-1H-imidazole- Tert-butyl 2-methyl)methyl)(methyl)carbamate in which morpholin-3-one is replaced by ((1H-imidazol-2-yl)methyl)(methyl)carbamic acid tert-butyl ester. This product was a yellow solid.
  • Step D To ((1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydro) Benzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)-1H-imidazol-2-yl)methyl)(methyl)carbamic acid tert-butyl ester (350 mg A solution of HCl/MeOH (4M, 2 mL) was then evaporated. The mixture was stirred at 20 ° C for two hours.
  • Step A To (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]oxazole And [3,4-d][1,4]oxazine-1(3H)-one (1g, 2.42mmol) in toluene (10mL) was added (S)-3-((tert-butyldiphenyl) Silyl)oxy)pyrrolidin-2-one (1.23 g, 3.62 mmol), Cs 2 CO 3 (1.58 g, 4.84 mmol), Pd 2 (dba) 3 (222 mg, 0.242 mmol) and Ruphos (113 mg, 0.242 mmol).
  • Step B To (3R,3aS)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-7-((S)-3-((tert-butyldiphenyl) Silyl)oxy)-2-oxopyrrolidin-1-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1 ( A solution of 3H)-ketone (600 mg, 0.892 mmol) in dioxane (15 mL) was evaporated.
  • Step C To (3R,3aS)-7-((S)-3-((tert-butyldiphenylsilyl)oxy)-2-oxopyrrolidin-1-yl) at 0 °C -3-(hydroxymethyl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (400 mg, 0.717 mmol) NaH (31 mg, 0.788 mmol) and BnBr (145 mg, 0.86 mmol) were added to a solution of DMF (5 mL).
  • Step D To (3R,3aS)-3-((benzyloxy)methyl)-7-((S)-3-((tert-butyldiphenylsilyl)oxy)-2-oxo Depyrrolidin-1-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (300 mg, 0.462 mmol) TBAF (242 mg, 0.925 mmol) was added to a solution of THF (8 mL).
  • Step E (3R,3aS)-3-((benzyloxy)methyl)-7-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)-3a at 0 °C , 4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (200 mg, 0.487 mmol) in DMF (3 mL) NaH (23 mg, 0.584 mmol) and MeI (344 mg, 2.44 mmol) were added. The mixture was stirred at 25 ° C for 3 hours.
  • Step F to (3R,3aS)-3-((benzyloxy)methyl)-7-((S)-3-methoxy-2-oxomorpholino-1-yl)-3a, Add Pd(OH) to a solution of 4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (180 mg, 0.425 mmol) in MeOH (5 mL) 2 (50 mg), stirred at 50 ° C under nitrogen (50 psi) for 16 hours.
  • Step G The title compound of this example was prepared according to the procedure of Steps I, J, K and L of Example 1, in which morpholin-3-one was replaced with (S)-3-methoxypyrrolidin-2-one. This product was a white solid.
  • Step A at 0 °C, to 4-oxo-cyclohexanecarboxylic acid ethyl ester (5.0g, 29.4mmol) in MeOH (250mL) passed through a solution of NH 3, followed by addition of Pd / C (1.0g, 10% ) , introducing hydrogen through a balloon. The mixture was heated under stirring at 40 ° C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to dry. The crude residue was purified by chromatography EtOAcjjjjjjjjjjjjj
  • Step C The title compound of this example was prepared according to the sequence of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced by 2-azabicyclo[2.2.2] s- 3-ketone. This product was a white solid.
  • Step A 2-Azabicyclo[2.2.1]hept-5-en-3-one (2.0 g, 18.3 mmol) and dry Pd/C (0.2 g, 10%). Hydrogen was introduced with a balloon, and then the mixture was stirred at 45 ° C for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to mjjjjjjj
  • Step B The title compound of this example was prepared according to the sequence of Steps G, H, I, J, K and L of Example 1, wherein morpholin-3-one was replaced by 2-azabicyclo[2.2.1]heptane- 3-ketone.
  • the product was a white solid isomer which was further purified by preparative SFC and preparative HPLC to afford two components, one was 28.5 mg and the other was 3.6 mg.
  • Step A After dissolving Na (1.06 g, 46 mmol) EtOAc. Oxazolidine-2-one (2.00 g, 23 mmol) was then added at room temperature and stirred at 100 ° C for 16 hours. The solvent was removed in vacuo and EtOAc (EtOAc)EtOAc. The combined organic layers were dried, filtered and evaporated elut elut elut elut elut elut elut elut eluting
  • Step B thiomorpholin-3-one (350 mg, 3 mmol), (3R, 3aS)-7-bromo-3-((tert-butyldimethylsilyl)methyl)-3a,4 -Dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one (1.04 g, 2.5 mmol), Cs 2 CO 3 (1.63 g, 5 mmol)
  • Pd 2 (dba) 3 230 mg
  • Xantphos 430 mg
  • 1,4-dioxane 30 mL
  • Step C The title compound of this example was prepared according to the procedure of Steps H, I, J, K and L of Example 1, in which morpholin-3-one was replaced with thiomorpholin-3-one. This product was a white solid.
  • Step A 5-chloro-N-(((3S,3aS)-1-oxo-7-(3-oxothiomorpholino)-1,3,3a,4-four at 0 °C Hydrogen benzo[b]oxazolo[3,4-d][1,4]oxazol-3-yl)methyl)thiophene-2-carboxamide (48 mg, 0.1 mmol) in DCM (3 mL) m-CPBA (41 mg, 0.24 mmol) was added portionwise and stirred at 0 ° C for 2 h. A saturated NaHCO 3 solution (10 mL) was added and extracted with DCM (10 mL x 3). The combined organic phases were dried and concentrated.
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-((R)-2-(methoxy) according to the method of Example 6.
  • Methyl)pyrrolidin-1-yl)-3 ⁇ ,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one which The 1,3-oxazacyclo-2-one in the step A was replaced with (R)-2-(methoxymethyl)pyrrolidine in a yield of 92%.
  • Step B The title solid compound of this example was prepared according to the procedure of Steps G, I, J, K, L of Example 1.
  • Step A The titled solid compound of this example was obtained as a white solid. Wherein (R)-2-(methoxymethyl)pyrrolidine in step A is replaced by (S)-2-(methoxymethyl)pyrrolidine.
  • Step A To (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]oxazole And [3,4-d][1,4]oxazin-1(3H)-one (4.0g, 9.65mmol), Pd(OAc) 2 (0.22g, 0.97mmol) and Xantphos (0.92g, 1.93mmol) (2-Ethoxy-2-oxoethyl)zinc(II) bromide (1.12 g, 48.27 mmol) was added to a solution of THF (60 mL). The mixture was stirred at reflux for 16 h, cooled and concentrated.
  • Step B 2-((3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a at -70 °C , 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)acetate (600 mg, 1.42 mmol) in THF (5 mL) LiHMDS (1.56 mL, 1M in THF), EtOAc (EtOAc) The resulting mixture was stirred at -70 ° C for an additional 1 hour, then heated to 15 ° C and stirred for 16 hours.
  • Step C To 2-((3R,3aS)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a,4-tetrahydro benzo [b] oxazolo [3,4-d] [1,4] oxazin-7-yl) -3-cyano-propanoate (366mg, 0.79mmol) in MeOH (20mL) and NH 3 ⁇ Raney Nickel (100 mg) was added to H 2 O (30% aqueous solution, 4 mL). The resulting mixture was stirred at room temperature under a hydrogen pressure of 30 psi for 16 hours. The mixture was filtered, and the filtrate was evaporated.
  • Step D The title compound of the present Example was prepared according to the procedure of Steps G, I, J, K, L of Example 1, wherein the morpholin-3-one in Step G was replaced by 2-oxopyrrolidine to give a white solid.
  • the isomer was further purified by preparative SFC and preparative HPLC to give two components, component 1 was 7.5 mg and component 2 was 3.5 mg.
  • Step A Preparation of N-(((3S,3aS)7-bromo-1-oxo-1,3,3a,4-tetrahydrobenzene according to the order of Steps G, I, J, K, L of Example 1. And [b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)-5-chlorothiophene-2-carboxamide, wherein morpholine-3 in step G - The ketone is replaced by bromine.
  • Step B Add N-(((3S,3aS)-7-bromo-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d] to the flask.
  • Pd(dppf)Cl 2 80 mg, 0.113 mmol
  • bis-sterol Boric acid ester 430 mg, 1.70 mmol
  • KOAc 332 mg, 3.39 mmol
  • 1,4-dioxane (6 mL) were used to rapidly displace the air in the reaction system with nitrogen.
  • Step C To 5-chloro-N-(((3S,3aS)-1-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2- Add 2-bromobenzenesulfonamide (452 mg, 1.74 mmol), Pd(t-Bu 3 P) 4 (90 mg, 0.174 mmol) to a solution of carbamide (430 mg, 0.87 mmol) in 1,4-dioxane (6 mL) Cs 2 CO 3 (572 mg, 1.74 mmol) and H 2 O (1 mL).
  • Step A Preparation of (3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-7-(1H-1,2,4-triazole- according to Example 1 1-yl)-3 ⁇ ,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-1(3H)-one, wherein the morpholine in step G is The 3-ketone was replaced by 1H-1,2,4-triazole in a yield of 30%.
  • Example 2 The title compound of Example 2 was obtained as a white solid.
  • Step A p-(3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]oxazole [ 3,4-d][1,4]oxazin-1 (3H) (2.0 g, 4.38 mmol), K 2 CO 3 (0.8 g, 5.80 mmol), 1-(1H-imidazol-2-yl)- A solution of N,N-dimethylmethylamine (0.9 g, 7.24 mmol) and 8-hydroxyquinoline (140 mg, 0.96 mmol) in DMSO (12 mL), then degassed with nitrogen and then added with CuI (500mg, 2.2mmol) .
  • Step B The title compound of Example 35 was prepared according to the procedure of Steps G, I, J, K and L of Example 1, wherein the morpholin-3-one in Step G was replaced by 1-(1H-imidazol-2-yl). -N,N-dimethylmethylamine as a white solid.
  • Step A Preparation of ((3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a, according to the method of Example 6.
  • the heterocyclohexane-2-one was replaced with t-butyl carbamate in a yield of 85%.
  • Step B Preparation of ((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo) according to the order of Steps G, I, J, K and L of Example 1. -1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)carbamic acid tert-butyl ester. LCMS (ESI) m/z: 480.1 (M+1).
  • Step C ((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxine
  • oxazolo[3,4-d][1,4]oxazin-7-yl)carbamic acid tert-butyl ester (0.62 g, 1.29 mmol) in 4M EtOAc MeOH (10 mL).
  • the mixture was filtered and the filter cake was washed with DCM.
  • Then adjusting the pH of the filtrate with saturated aqueous NaHCO 3 value of 7 to 8, and extracted with DCM (50mL x5).
  • Step E To a solution of 2-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetra Hydrogen benzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)amino)ethyl)carbamic acid tert-butyl ester (209 mg, 0.4 mmol), pyridine (63 mg, 0.8) Add a solution of propionyl chloride (56 mg, 0.6 mmol) in DCM (1 mL) EtOAc. aqueous NH 4 Cl (20mL) and extracted with DCM (20mL x3).
  • Step F To 2-(N-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a, at room temperature, 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazol-7-yl)propionamido)ethyl)carbamic acid tert-butyl ester (232 mg, 0.4 mmol) A solution of 4 M HCl in 1,4-dioxane (3 mL) was added to DCM (3 mL) and stirred at room temperature for one hour.
  • Step A Preparation of 2-(N-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3 according to the method of Example 36 , 3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)cyclopropanecarboxamido)ethyl)carbamic acid tert-butyl ester, Replace propionyl chloride in step E with cyclopropanecarbonyl chloride in yield 76%.
  • Step A Preparation of 3-(((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a according to the method of Example 36 , 4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazol-7-yl)amino)propyl)carbamic acid tert-butyl ester, which will be in step D ( tert-Butyl 2-oxoethyl)carbamate was replaced with (3-oxopropyl)carbamic acid tert-butyl ester in 65% yield.
  • Step B To (3-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4 at room temperature - tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazol-7-yl)amino)propyl)carbamic acid tert-butyl ester (215 mg, 0.4 mmol) in DCM (3 mL 4M HCl in 1,4-dioxane (3 mL) was added and the mixture was stirred at room temperature for 1 hour.
  • Step A N-(((3S,3aS)-7-bromo-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d][1 , 4]oxazin-3-yl)methyl)-5-chlorothiophene-2-carboxamide (200 mg, 0.45 mmol), CuCN (161 mg, 1.80 mmol) and CuI (9 mg, 45 umol) in NMP (15 mL) Stir at 180 ° C for 8 hours. The mixture was filtered and the filtrate washed with EtOAc (5 mL EtOAc). The organic layer was washed with water (25mL x2), dried over anhydrous dried over Na 2 SO 4, filtered and concentrated.
  • Step B 5-chloro-N-(((3S,3aS)-7-cyano-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole] at 0 °C 3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (200 mg, 0.513 mmol) in anhydrous methanol (5 mL). .
  • the reaction mixture was concentrated under reduced pressure to give (3,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, And [b] oxazolo[3,4-d][1,4]oxazine-7-methylimidate methyl ester as a yellow solid.
  • the crude product was used in the next step without further purification.
  • Step C (3S,3aS)-3-((-5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxine a solution of ox[3,4-d][1,4]oxazine-7-methylimidate methyl ester (85 mg, 0.205 mmol) and hexane-1,2-diamine (1 mL) in MeOH (10 mL) Stir at 12 ° C for 2 hours.
  • Step A The title compound of this example was prepared according to the method of Example 39, which was obtained from the ethane-1,2-diamine of The yield was 44%.
  • Step A The title compound of this example was prepared according to the method of Example 39, wherein the ethane-1,2-diamine in step C was replaced with N-methylpropyl-1,3-diaminomethylethane. , a white solid was obtained with a yield of 44%.
  • Step A Preparation of ((S)-1-((3R,3aS)-3-(((tert-butyldimethylsilyl))oxy)methyl)-1-oxo) according to the method of Example 6. -1,3,3a,4-tetrahydrobenzo[b]oxazolo[3-1,4-d][1,4]oxazin-7-yl)pyrrolidin-3-yl)carbamic acid Butyl ester in which the 1,3-oxazacyclohexan-2-one in Step A was replaced with tert-butyl (S)-pyrrolidin-3-ylcarbamate in a yield of 96%.
  • Step B Preparation according to the order of Steps G, I, J, K and L in Example 1 ((S)-1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)) Methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)pyrrolidine-3 -Base) tert-butyl carbamate.
  • Step C ((S)-1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetra Hydrogen benzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (45 mg, 0.1 mmol) in 4M HCl methanol The solution (2.0 mL) was stirred at 5 ° C for 1 hour. The mixture was concentrated and water was added.
  • Step A The title compound of the present Example was prepared according to the procedure of Steps A, B, and C of Example 42, wherein (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester was replaced by (R)-pyrrolidin-3- Tert-butyl carbamate is a white solid.
  • Step A To (R)-1-((3R,3aS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-1 at 0 °C ,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (1.0 A solution of g, 1.9 mmol) in DMF (10 mL) was added sodium hydride (60% sodium hydride in mineral oil, 110 mg, 2.7 mmol), then MeI (520 mg, 3.6 mmol) was added at 0 ° C.
  • Step B Preparation of (R)-1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl) according to the procedure of Example 1, Steps G, I, J, K and L )-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)pyrrolidin-3-yl a tert-butyl (meth)carbamate in which the morpholin-3-one in step G is substituted Change to tert-butyl pyrrolidin-3-yl (methyl)carbamate.
  • Step C ((R)-1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetra Hydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)pyrrolidin-3-yl)(methyl)carbamic acid tert-butyl ester (90 mg, 0.2 mmol) The mixture was stirred at 17 ° C for 1 hour in 4M HCl methanol (3 mL).
  • Step A To 5-chloro-N-(((3S,3aS)-7-((R)-3-(methylamino))pyrrolidin-1-yl)-1-oxo- at 10 °C 1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (74 mg, 0.2 mmol ) in MeOH (3.0mL) was added aqueous formic acid (1.0mL, 33%), stirred at 17 °C 30 minutes and then NaBH 3 CN (25mg, 1.0mmol) , and the mixture was stirred at 40 °C 2 hours water The reaction was quenched and extracted with DCM (20 mL EtOAc).
  • Step A To a solution of piperidin-3-ol (1.01 g, 10 mmol), TBDPSCl (3.30 g, 12 mmol) in THF/Py (21 mL, 4:3) was added AgNO 3 (3.57 g, 21 mmol) And stirred at room temperature for 16 hours. The mixture was filtered and concentrated. The crude residue was purified by EtOAcqqq elut elut elut elut elut elut It is a brown oil. LCMS (ESI) m/z: 340 (M+1).
  • Step B Preparation of N-(((3S,3aS)-7-(3-((tert-butyldiphenylsilyl))oxy) according to the order of Steps F, G, I, J, K and L of Example 1.
  • Step C To N-(((3S,3aS)-7-(3-((tert-butyldiphenylsilyl)oxy)piperidin-1-yl)-1-oxo-- at room temperature 1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d][1,4]oxazol-3-yl)methyl)-5-chlorothiophene-2-carboxamide stirring (913mg, 1.3mmol) in THF (10 mL) was dropwise added n-Bu 4 NF (1.23g, 4.7mmol) in THF under (10 mL) was at room temperature for 16 hours, the mixture was concentrated and the crude residue was purified by The title compound (480 mg, 79%) was obtained.
  • Step A a solution to the acetonitrile solution piperidin-3-ol (1.01g, 10mmol) in (50mL) was added Boc 2 O (2.18g, 10mmol) , and stirred at room temperature for 16 hours. The mixture was concentrated to give 3-hydroxypiperidine-l-carboxylic acid tert-butyl ester (2.01 g, crude). This crude product was used directly in the next step.
  • Step B To a solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.01 g, 10 mmol) in THF (20 mL), EtOAc (EtOAc) 10 mmol), gradually warmed to room temperature, and stirred at room temperature for 0.5 hr. MeI (1.42 g, 10 mmol) was added dropwise at room temperature and stirred for 16 hours. The mixture was concentrated in vacuo and EtOAc EtOAcjjjjjjjjj Colorless oil.
  • Step D The title compound of the present Example was prepared according to the procedure of Steps F, G, I, J, K and L of Example 1, wherein the morpholin-3-one in Step F was replaced with 3-methoxypiperidine. Light yellow solid form isomer. The isomers were further purified by preparative SFC and preparative HPLC to give two components, component 1 (60 mg) and component 2 (100 mg).
  • Step A The title compound of this example was prepared according to the procedure of Steps A, B, and C in Example 42, wherein (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester was replaced with (S)-piperidine- Tert-butyl 3-carbamic acid, the product was a white solid.
  • Step A The title compound of this example was prepared according to the procedure of Steps A, B, and C in Example 42, wherein (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester was replaced with (R)-piperidine- Tert-butyl 3-carbamic acid, the product was a white solid.
  • Step A The title compound of the present Example was prepared according to the procedure of Steps A, B, and C in Example 44, wherein (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester was replaced with (S)-piperidine- Tert-butyl 3-carbamic acid, the product was a white solid.
  • Step A The title compound of the present Example was prepared according to the procedure of Steps A, B, and C in Example 44, wherein (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester was replaced with (R)-piperidine- Tert-butyl 3-carbamic acid, the product was a white solid.
  • Step A The title compound of this example was prepared according to the procedure of Step A in Example 45, wherein (R)-3-(dimethylamino)pyrrolidine in Step A was replaced by (S)-3-(dimethylamino). Piperidine, yield 61%.
  • Step A The title compound of this example was prepared according to the procedure of Step A in Example 45, wherein (R)-3-(dimethylamino)pyrrolidine in Step A was replaced by (R)-3-(dimethylamino). Piperidine, the yield was 55%.
  • Step A Preparation of (R)-((3R,3AS)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-oxo-1, according to the method of Example 6, Methyl 3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)pyrrolidine-2-carboxylate, which will be in The 1,3-oxazacyclo-2-one was replaced by methyl (R)-pyrrolidine-2-carboxylate in a yield of 72%.
  • Step B The title compound of this example was prepared according to the procedure of Steps G, I, J, K and L of Example 1.
  • Step A The title compound of this example was prepared according to the procedure of Example 54 Steps A and B, wherein the methyl (R)-pyrrolidine-2-carboxylate in Step A was replaced with (S)-pyrrolidine-2-carboxylic acid. Methyl ester.
  • Step A (R)-1-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydro
  • a saturated NH 3 -ethylene glycol solution of benzo[b]oxazolo[3,4-d][1,4]oxazine-7-yl)pyrrolidine-2-carboxylate (100 mg, 0.203 mmol) (20 mL), sealed and stirred at 80 ° C for 2 hours. After cooling to rt, EtOAc (EtOAc)EtOAc.
  • Step A The title compound of this example was prepared according to the procedure of Example 56, Step A, substituting (R)-pyrrolidine-2-carboxamide in step A with (S)-pyrrolidine-2-carboxamide. The rate is 16%.
  • Step A (R)-((3S,3aS)-3-((5-chlorothiophene-2-carboxamido)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo [b] oxazolo [3,4-d] [1,4] oxazin-7-yl) pyrrolidine-2-carboxylate (50mg, 0.102mmol) in THF (6mL) was added LiBH 4 ( The mixture was stirred with MeOH (5 mL) EtOAc.
  • Step A The title compound of this example was prepared according to the procedure of Step A of Example 56, wherein (R)-2-(hydroxymethyl)pyrrolidine in Step A was replaced with (R)-pyrrolidine-2-carboxylic acid. 2-Hydroxyethyl ester, yield 35%.
  • Step A A solution of sodium sulfite (1.8 g, 14.2 mmol) in water (8 mL) was stirred vigorously at 20 ° C for 10 min. NaHCO 3 (2.4 g, 28.5 mmol) was added and stirred at 50 ° C for 1 hour. Cyclopropanesulfonyl chloride (2.0 g, 14.2 mmol) was carefully added. After the addition was completed, the mixture was vigorously stirred at 50 ° C for 4 hours. After cooling to 20 ° C, the mixture was dried by lyophilization to give a residue. Then methanol (2 mL) was added and stirred for 1 hour and filtered. The filtrate was concentrated to give EtOAc (EtOAc, m. 1 H NMR (400 MHz, methanol-d 4 ) ⁇ 1.84-1.89 (m, 1H), 0.74-0.77 (m, 2H), 0.61-0.64 (m, 2H).
  • Step B To (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b] under nitrogen Oxazolo[3,4-d][1,4]oxazine-1(3H)-one (400 mg, 0.97 mmol) was added to sodium cyclopropanesulfinate (186 mg, 1.5 mmol), N,N-dimethyl A solution of the ethane-1,2-diamine (17 mg, 0.19 mmol) in dry DMF (4 mL) and EtOAc (EtOAc) Water was added and the mixture was extracted with DCM (50 mL ⁇ 3).
  • Step C The title compound of this example was prepared according to the sequence of Steps G, I, J, K and L of Example 1, wherein the morpholine-3-one in Step G was replaced with a cyclopropanesulfonyl group.
  • Step A (3R,3aS)-7-bromo-3-((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]oxazole[ 3,4-d][1,4]oxazin-1(3H)-one (2.0 g, 4.82 mmol), benzyl mercaptan (1.8 g, 14.5 mmol), Pd 2 (dba) 3 (440 mg, 0.48) Mixture of mmol), Xantphos (560 mg, 0.96 mmol) and Cs 2 CO 3 (3.14 g, 9.64 mmol) and dioxane (30 mL) were heated at 100 ° C under nitrogen for 8 hours, cooled to room temperature and water was added.
  • Step B (3R,3aS)-7-(Benzylthio)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]
  • oxazole [3,4-d][1,4]oxazine-1(3H)-one 600 mg, 1.3 mmol
  • DCM DCM
  • NCS 0.9 g, 6.5 mmol
  • BnOH 650 mg, 6.3 mmol
  • DIPEA 300 mg, 2.33 mmol
  • pyrrolidine 150 mg, 2.1 mmol
  • Step C The title compound of this example was prepared according to the procedure of Steps G, I, J, K, and L of Example 1, wherein the morpholine-3-one in Step G was replaced with the pyrrolidin-1-ylsulfonyl group.
  • Step A The title compound of this example was prepared according to the procedure of Steps A, B, and C of Example 61, wherein the pyrrolidin-1-ylsulfonic acid in Step C was replaced by (4-methylpiperazin-1-yl). Sulfonyl.
  • Step A 0 ° C, to N-(((3S,3aS)-7-amino-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazole[3,4-d [1,4]oxazin-3-yl)methyl)-5-chlorothiophene-2-carboxamide (80 mg, 0.21 mmol) and triethylamine (43 mg, 0.42 mmol) in THF (3 mL) A solution of ethyl 1-chloro-2-isocyanate (33 mg, 0.32 mmol) in THF (0.5 mL). The reaction mixture was stirred at 15 ° C for 16 h and solvent was evaporated in vacuo.
  • Step A The title compound of this example was prepared according to the procedure of Steps A, B, and C in Example 46, in which the piperidin-3-ol was replaced with (S)-pyrrolidin-3-ol.
  • Step A The title compound of this example was prepared according to the procedure of Steps A, B, C and D in Example 47, in which 3-methoxypiperidine was replaced with (S)-3-methoxypyrrolidine.
  • Step A to (3S,3aS)-3-(aminomethyl)-7-(3-oxomorpholino)-3 ⁇ ,4-dihydrobenzo[b]oxazole[3, at room temperature [3, 4-d][1,4]oxazin-1(3H)-one (80 mg, 0.25 mmol), 4-methoxybenzoic acid (43 mg, 0.28 mmol) and DIPEA (48 mg, 0.38 mmol) in DMF (1 mL) HATU (110 mg, 0.28 mmol) was added to the solution and stirred at room temperature for 16 hours.
  • Step A The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 5-chloropicolinic acid.
  • Step B The title compound of this example was prepared according to the procedure of Example 66, in which 4-methoxybenzoic acid in Step A was replaced with 5-chloro-1H-indole-2-carboxylic acid.
  • Step A The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 5-methylthiophene-2-carboxylic acid.
  • Step A The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 5-bromothiophene-2-carboxylic acid.
  • Step A with an ice-water bath, a solution of 5-bromo-thiophene-2-carboxylic acid (500mg, 2.42mmol) in methanol (20mL) was added dropwise SOCl 2 (575mg, 4.83mmol). The reaction mixture was heated to reflux and stirred for 12 h. The mixture was concentrated in vacuo, the residue (50mL) and quenched with NaHCO 3 solution, and extracted with DCM (20mL x2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give ethyl 5-bromothiophene-2-carboxylate (500 mg,yield:
  • Step B A solution of ethyl 5-bromothiophene-2-carboxylate (450 mg, 2.04 mmol) and CuCN (550 mg, 6.11 mmol) After cooling, a solution of water (100 mL) and EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified mjjjjjjjj LCMS (ESI) m/z: 168 (M+1).
  • Step C A solution of methyl 5-cyanothiophene-2-carboxylate (100 mg, 0.60 mmol) and EtOAc (EtOAc (EtOAc) The mixture was concentrated to remove THF. The pH was adjusted to 5 with 1N hydrochloric acid and filtered. The residue was washed with EtOAcqqqqqqqli LCMS (ESI) m/z: 172 (M+1).
  • Step D A solution of 5-carbamoylthiophene-2-carboxylic acid (40 mg, 0.234 mmol) eluted elute The reaction mixture was then concentrated to give the crude product 5-cyanothiophene-2-carbonyl chloride. The crude product residue was used directly in the next reaction.
  • Step E The title compound of this example was prepared according to the procedure of Example 1 wherein 5-chlorothiophene-2-carbonyl chloride in Step K was replaced with 5-cyanothiophene-2-carbonyl chloride.
  • Step A The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 5-fluorothiophene-2-carboxylic acid.
  • Step A To a solution of 2,3-dibromothiophene (2 g, 8.27 mmol) in CS 2 (20 mL), EtOAc (1 ⁇ Acetyl chloride (0.974 g, 12.4 mmol) was added. Then, the resulting mixture was stirred at 18 ° C for 16 hours. The mixture was poured into ice water, extracted with EtOAc EtOAc EtOAc (EtOAc) Ethyl ketone (1.9 g, 81%) was obtained as an orange solid.
  • Step B To a solution of 1-(4,5-dibromothiophen-2-yl)ethanone (14.3 g, 0.05 mol) in toluene (150 mL), hexane-1,2-diol (12.5 g, 0.2) Mol) and TsOH.H 2 O (451 mg, 0.0025 mol). The mixture was heated to reflux under nitrogen for 16 hours in a flask equipped with a Dean-Stank apparatus. The mixture was poured into water (100 mL) in, (150mL x2) and extracted with EtOAc, washed with NaHCO 3 solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step C To a solution of 2-(4-bromo-5-fluorothiophen-2-yl)-2-methyl-1,3-dioxolan (6.2 g, 0.023 mol) at -78 °C n-BuLi (12.1 mL, 0.03 mol) was added in THF (60 mL), and the mixture was stirred for 1 hour, then EtOAc (0.03 mmol, 100 mL THF) was added dropwise. It was then warmed to 18 ° C and stirred for 16 hours. The reaction mixture was poured into NH 4 Cl solution (80 mL), washed with EtOAc (80mL x2) was extracted, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step D To a solution of 2-(4,5-difluorothiophen-2-yl)-2-methyl-1,3-dioxolan (3.4 g, 16.5 mmol) in acetone (30 mL) - water (3 mL) TsOH (1.42 g, 8.25 mmol) was added to the solution, and the mixture was stirred at ⁇ RTIgt; The mixture was then poured into water (80 mL) in, (80mL x2) extracted with EtOAc, NaHCO 3 (aq), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1- (4,5-difluoro-thiophen-2-yl) Ethyl ketone (2.4 g, 89%), yellow solid.
  • Step E A stirred suspension of 1-(4,5-difluorothiophen-2-yl)ethanone (200 mg, 1.23 mmol) in dioxane (3 mL) was warmed to 50. At the same time, a solution of sodium hypobromite was prepared by dropwise addition of Br 2 (969 mg, 6.17 mmol) to a solution of NaOH (861 mg, 21.5 mmol) in water (3 mL). The sodium hypobromite solution was added dropwise to the dioxane solution, stirred for 3 hours, and then the mixture was cooled to 18 °C. The mixture was poured into water (30 mL), EtOAc (EtOAc) The combined organics were dried with EtOAc EtOAc EtOAc EtOAc EtOAc
  • Step F The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 4,5-difluorothiophene-2-carboxylic acid.
  • Step A 3- aminothiophene-2-carboxylate (7.0g, 50.3mmol) in hydrochloric acid (6M, 14.0mL), cooled to 0 °C, was added NaNO 2 (3.5g, 50.7mmol), and at room temperature Stir for 2 hours. Then, HBF 4 (7.0 mL) was added and stirred at room temperature for 15 minutes. The solid was filtered diazonium salt with HBF 4 (35.0mL), MeOH ( 50.0mL) and diethyl ether (50mL) was washed solid was dried under vacuum to give 3-thiophene-2-azo-carboxylate tetrafluoroborate ( 8.0 g, 62%), white solid.
  • Step B Mixing 3-diazothiophene-2-carboxylic acid methyl ester tetrafluoroborate (5.0 g, 19.54 mmol) and sand (26.0 g) in a round bottom flask with a vacuum distillation apparatus, vacuum heating. The mixture was heated to 160 ° C under vacuum (0.1 Torr) for 2 hours, then raised to 200 ° C for 2 hours. The crude product was obtained as a pale yellow liquid and purified by silica gel chromatography (PE) to give methyl 3-fluorothiophene-2-carboxylate. (1.0 g, 32%), white solid.
  • PE silica gel chromatography
  • Step E The title compound was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 5-chloro-3-fluorothiophene-2-carboxylic acid.
  • Step A in an ice-water bath cooling conditions, the SOCl 2 (2.93g, 24.6mmol) was added dropwise to 5-chloro-thiophene-2-carboxylic acid (2.00g, 12.3mmol) in EtOH (20mL) solution. The reaction mixture was heated to reflux and stirred for 16 h. The solvent was then removed in vacuo, with aqueous NaHCO (50mL) and the residue was quenched and extracted with DCM (20mL x2). The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc EtOAc
  • Step B A mixture of ethyl 5-chlorothiophene-2-carboxylate (2.10 g, 11.0 mmol) and EtOAc (8 mL) was stirred at 20 ° C for 2 hr. Then water (50 mL) and EtOAc (20 mL)EtOAc. The combined organic layers were washed with aqueous NaHCO 3 (50mL), and dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to give 5-chloro-4-nitro-thiophene-2-carboxylate (1.6g, 61%), Yellow oil.
  • Step C ethyl 5-chloro-4-nitrothiophene-2-carboxylate (1.00 g, 4.24 mmol), iron powder (1.18 g, 21.2 mmol), NH 4 Cl (1.14 g, 21.2 mmol), A mixture of EtOH (9 mL) and H 2 O (3 mL) was stirred at 60 ° C for 16 hr. The reaction mixture was then filtered and the filtrate was concentrated to give crude. Water (50 mL) and EtOAc (20 mL). The combined organic layers were dried with EtOAc EtOAc EtOAcjjjjjjjjjj
  • Step D a mixture of ethyl 4-amino-5-chlorothiophene-2-carboxylate (0.30 g, 1.46 mmol), LiOH (70 mg, 2.92 mmol), water (5 mL) and THF (5 mL) Stir under 16 hours. The mixture was then concentrated to remove THF. pH was adjusted to 5 with 1N HCl (aq) and filtered. The crude residue was washed with EtOAcqqqqqqm
  • Step E Boc 2 O (147 mg, 0.675 mmol) was added to a mixture of 4-amino-5-chlorothiophene-2-carboxylic acid (100 mg, 0.56 mmol) and DMF (7 mL). . The mixture was concentrated to give EtOAc (EtOAc:MeOHMeOHMeOHMeOH ), yellow solid.
  • Step F (3S,3aS)-3-(Aminomethyl)-7-(3-oxomorpholino)-3a,4-dihydrobenzo[b]oxazole [3,4-d] [1,4]oxazin-1(3H)-one (46 mg, 0.144 mmol), 4-((tert-butoxycarbonyl)amino)-5-chlorothiophene-2-carboxylic acid (40 mg, 0.144 mmol), HATU (66mg, 0.172mmol), Et 3 N (0.44mg, 0.432mmol) and a mixture of DMF (5mL) was stirred at 25 °C 16 h. The mixture was then concentrated.
  • Step G (2-Chloro-5-(((3S,3aS)-1-oxo-7-(3-oxomorpholino)-1,3,3a,4-tetrahydrobenzo) [b] Oxazolo[3,4-d][1,4]oxazol-3-yl)methyl)carbamoyl)thiophen-3-yl)carbamic acid tert-butyl ester (30 mg, 0.051 mmol) A solution of HCl / MeOH (4N, 5 mL) was stirred at 25 ° C for one hour.
  • Step A The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 3-methoxybenzoic acid.
  • Step A The title compound of this example was prepared according to the procedure of Example 66, wherein 4-methoxybenzoic acid in Step A was replaced with 5-methoxypicamic acid.
  • Step A Slowly add 4-bromo-2,6-difluoroaniline (20.0 g, 0.096 mol) to a stirred suspension of sodium perborate tetrahydrate (150 g, 0.96 mol) in acetic acid (500 mL) at 0 °C. a solution of acetic acid (200 mL). After stirring at 60 ° C for 4 hours, the solution was cooled to room temperature and poured into ice water and extracted with EtOAc (500 mL EtOAc). The combined organic extracts were washed with EtOAc EtOAc m.
  • Step B The title compound of this example was prepared according to the procedure of Step 1 of Example 1, wherein 4-bromo-2-fluoro-1-nitrobenzene in Step A was replaced with 5-bromo-1,3-difluoro- 2-nitrobenzene.
  • Step A To a stirred and cooled (-10 deg.] C) of 2-bromo-1,4-difluoro - benzene (32.0g, 0.17mol) in 1,2-dichloroethane (320 mL) was added HNO 3 (15.7 g, 0.25 mol) of H 2 SO 4 (81.3 g, 0.83 mol). The mixture was stirred at 29 ° C for 2 hours, poured into ice water (1500 g), and then extracted with DCM (300 mL x 3). The organics were concentrated to dryness to give 1-bromo-2,5-difluoro-4-nitrobenzene (36.3 g, 92%).
  • Step B The title compound of this example was prepared according to the procedure of Step 1 of Example 1, in which 4-bromo-2-fluoro-1-nitrobenzene in Step A was replaced by 1-bromo-2,5-difluoro-4. - Nitrobenzene.
  • Step A To a solution of 2-fluoro-6-nitro-phenol (47.1g, 300mmol) in DMF (125mL) was added in portions K 2 CO 3 (62.2g, 450mmol ) was added dropwise MeI (65.7g , 450 mmol). The mixture was stirred at rt EtOAc (3 mL). The organic layer was dried with anhydrous sodium s This crude product was used in the next step without further purification.
  • Step B To a solution of 1-fluoro-2-methoxy-3-nitrobenzene (51.3 g, 300 mmol) in EtOH (125 mL), 10% wt. Pd / C (10.0 g) The mixture was stirred at room temperature for 16 hours under an atmosphere (1 atm). Filtration and concentrating, EtOAc (EtOAc:EtOAc)
  • Step E at 0 °C, THF (100mL) solution of 6-amino-3-bromo-2-fluoro-phenol (5.77g, 28mmol) was added NEt 3 (5.9mL, 42mmol), followed by dropwise addition CbzCl (5.25g , 30.8 mmol), and stirred at 0 ° C for 2 hours. Ice water (100 mL) was added andEtOAc was evaporated. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated. The crude product was used directly in the next reaction without further purification. LCMS (ESI) m/z: 340, 342 (M+1).
  • Step F To a solution of (4-bromo-3-fluoro-2-hydroxyphenyl) carbamate (3.40g, 10mmol) in DMF (40mL) was added K 2 CO 3 (2.76g, 20mmol Then, a solution of (Z)-4-bromobut-2-enyloxy)(tert-butyl)dimethylsilane (2.65 g, 10 mmol) in DMF (10 mL) was evaporated. Water (150 mL) was added andEtOAc was evaporated. The organic layer was dried with anhydrous sodium sulfate, filtered and evaporated.
  • Step G (Z)-(4-bromo-2-((4-((tert-butyldimethylsilyl)oxy)butyl-2-en-1-yl)oxy) at 0 °C
  • n-Bu 4 NF (2.63 g, 10.1 mmol) in THF (20 mL) was added dropwise to THF (40 mL). The solution was warmed to room temperature and stirred at room temperature for 2 hours. The mixture was concentrated and purified by silica gel chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Benzene-1-yl)oxy)phenyl)carbamate (3.10 g, 90%), white oil.
  • Step H The title compound was obtained as a white solid.
  • Step C 6-Bromooxazolo[4,5-b]pyridine-2(3H)-one (3.4 g, 15.8 mmol) was diluted with a 10% aqueous NaOH solution, and the obtained mixture was stirred at 100 ° C for 6 hours. . The reaction was cooled to 5 ° C and 6N HCl was added until a precipitate formed. The solid was collected using a fritted glass funnel, washed with water (20 mL) and dried in vacuo Drying gave 2-amino-5-bromopyridin-3-ol (2.4 g, 80%).
  • Step D To a solution of 2-amino-5-bromopyridin-3-ol (4.32 g, 0.023 mol), NaOH (5.49 g, 0.138 mol) in THF (45 mL)-H2O (45 mL) CbzCl (14.04 g, 0.081 mol) was added, and the mixture was stirred at 25 to 30 ° C for 16 hours. The reaction mixture was extracted with EtOAc (100 mL ⁇ 3). The combined organic layers were concentrated to give a crude material. The residue was washed with EtOAc (EtOAc)EtOAc. LCMS (ESI) m/z: 189, 191 (M+1).
  • Step E Preparation of (Z)-5-bromo-3-(4-hydroxybut-2-enyloxy)pyridin-2-ylcarbamate according to the procedure of Example 80, Steps F and G, wherein Step E The 6-amino-3-bromo-2-fluorobenzene was replaced by 2-amino-3-hydroxy-5-bromopyridine.
  • Step F The title compound of this example was prepared according to the procedure of Step DL of Example 1.
  • Step A A THF (125mL) was cooled to -78 °C, then passed over anhydrous NH 3 (100mL). 4-Chloro-3-nitropyridine (20.0 g, 126 mmol) was added at 0 ° C, then TBHP (5M dissolved in decane, 25 mL, 125 mmol) was added over 5 min.
  • Step B Phosphoryl bromide (54.0 g, 189 mmol) was added to a suspension of 4-chloro-5-nitropyridine-2(1H)-one (15.0 g, 85.94 mmol) in acetonitrile (200 mL). It was heated to reflux for 3 hours. The reaction mixture was cooled and carefully poured into ice 2 CO 3 and aqueous saturated K and then extracted with EtOAc (200mL x3). The combined organic layers were washed with EtOAc EtOAc m. LCMS (ESI) m/z: 283 (M+1).
  • Step C 2,4-dibromo-5-nitropyridine (9.0g, 31.9mmol) in anhydrous DMF (120mL) was added Cs 2 CO (12.5g ,, 38.37mmol) 3, followed by addition of (Z ?-Butyl-2-ene-1,4-diol (3.1 g, 31.9 mmol), and the obtained mixture was stirred at room temperature for 16 hr. The mixture was filtered and the filtrate was concentrated in vacuo.
  • Step D The title compound of the present Example was prepared according to the procedure of Step 1 of Example 1, wherein 4-bromo-2-fluoro-1-nitrobenzene in Step B was replaced with 2,4-dibromo-5-nitropyridine. .
  • Step A Add 5-chloro-N-((3S,3aS)-1-oxo-7-(3-oxo) to a mixture of NaH powder (112 mg, 2.8 mmol) and DMF (2 mL). Morpholino)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-methyl A solution of the amide (649 mg, 1.4 mmol) in EtOAc (EtOAc)EtOAc.
  • Step B To 2-(5-chloro-N-((3S,3aS)-1-oxo-7-(3-oxomorpholino)-1,3,3a,4-tetra) at room temperature Hydrobenzo[b]oxazolo[3,4-d][1,4]oxazol-3-yl)methyl)thiophene-2-carboxamido)-2-oxoethyl-2-( A solution of (t-butoxycarbonyl)amino)acetate (41 mg, 0.06 mmol) inEtOAc (EtOAc) The reaction mixture was concentrated with EtOAc EtOAc m.
  • Step A The title compound of this example was prepared according to the sequence of Steps A and B of Example 83, wherein 2-((tert-butoxycarbonyl)amino)acetic acid in Step A was replaced by 2-((tert-butoxycarbonyl).
  • Step B at 0 °C, THF alkanediyl group to 2,2'-dithio-bis (4-bromo aniline) (10.0g, 24.6mmol) and NaHCO 3 (20.7g, 0.25mol) is / H 2 O ( Benzyl chloroformate (21.0 g, 0.12 mol) was added dropwise to a solution of 150 mL / 50 mL), and the mixture was stirred at 37 ° C for 16 hours.
  • the mixture was filtered, and the filter cake was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step C Di(disulfanediylbis(4-bromo-2,1-phenylene))dicarbamic acid dibenzyl ester (6.5 g, 9.6 mmol), ((3-(bromomethyl) epoxy) Ethyl-2-yl)methoxy)(tert-butyl)dimethylsilane (2.0 g, 7.1 mmol) and N-ethyl-N-isopropylpropan-2-amine (12 mL) in DMF (70 mL) The mixture of the solution was stirred at 110 ° C for 8 hours, water (200 mL) was added and extracted with ethyl acetate (100 mL x 2).
  • Step F Preparation of 5-chloro-N-((1-oxo-7-(3-oxomorpholino)-1,3,3a,4-tetrahydrobenzazole according to the procedure of Example 1 Step FL [ b] Oxazo[3,4-d][1,4]thiazin-3-yl)methyl)thiophene-2-carboxamide, wherein (4-bromo-2-((2R,3S) Benzyl 3-(((tert-butyldimethylsilyl)oxy)methyl)oxiran-2-yl)methoxy)phenyl)carbamate is replaced by (4-bromo) Benzyl-2-((3-(((tert-butyldimethylsilyl)oxy)methyl)oxiran-2-yl)methyl)thio)phenyl)carbamate.
  • Step A 5-chloro-N-((1-oxo-7-(3-oxomorpholino)-1,3,3a,4-tetrahydrobenzo[b]oxazole at 0 °C And a solution of [3,4-d][1,4]thiazin-3-yl)methyl)thiophene-2-carboxamide (200 mg, 0.4 mmol) in DCM (10 mL) The mixture was stirred at 37 ° C for 16 h, then water (30 mL) was evaporated.
  • Step A 5-chloro-N-((1-oxo-7-(3-oxomorpholino)-1,3,3a,4-tetrahydrobenzo[b]oxazole at 0 °C And [3,4-d][1,4]thiazin-3-yl)methyl)thiophene-2-carboxamide (200 mg, 0.4 mmol) in THF/MeOH/H 2 O (2.0 mL / 2.0 mL / 2.0 mL) solution was added potassium hydrogen persulfate (780 mg, 1.2 mmol), and the resulting mixture was stirred at 37 ° C for 16 hours. Water (10 mL) was added to the reaction mixture, and EA (20 mL ⁇ 2) was evaporated.
  • test compounds evaluated for their ability to inhibit human factor or other enzymes or Xa rats such as thrombin or trypsin, wherein the constant K i IC 50 values associated with inhibition.
  • Purified enzymes were used in the chromogenic assay. The initial rate of hydrolysis of the chromogenic substrate was measured using a FlexStation III (American Molecular Instruments Inc.) to determine the change in absorbance at 405 nm in the linear portion of the time course at 37 °C (usually after 2 to 10 minutes of substrate addition).
  • the concentration of the inhibitor which caused a 50% decrease in the rate of substrate hydrolysis was determined by linear regression calculation by plotting the logarithmic curve of the relative speed of the hydrolysis (compared to the uninhibited control) to the concentration of the test compound.
  • IC 50 values of the test compound obtained by GraphPad Prism software. The curve was fitted using a "form dose effect (variable slope)".
  • the inhibition of coagulation factor Xa activity in human or rat was determined using Tris-HCl buffer (50 mM, pH 8.3, 150 mM NaCl). Add 50 ⁇ L of human coagulation factor Xa (Enzyme Research Laboratories, Inc; final concentration 8.36 nM) or 50 ⁇ L of rat coagulation factor Xa (Enzyme Research Laboratories, Inc; final concentration 57.5 nM) to the Greiner384 microtiter plate. suitable methods well assay IC 50.
  • the test compound having K i ⁇ 10 ⁇ M is considered to be positive, and a compound of K i ⁇ 1 ⁇ M is preferred in the present invention, more preferably a compound having a K i ⁇ 0.1 ⁇ M, more preferably a compound having a K i ⁇ 0.01 ⁇ M, further preferably K i ⁇ 0.001 ⁇ M compound.
  • K i ⁇ 0.1 ⁇ M thus compounds of the invention may be used as an effective inhibitor of factor Xa.
  • the inhibition of human thrombin activity was measured using a buffer (10 mM HEPES buffer, pH 7.4, 2 mM CaCl 2 ).
  • Greiner384 select the appropriate microtiter plate well assay IC 50, 50 ⁇ L containing human thrombin (Sigma Corporation; T8885) buffer, final concentration 0.05NIH units / mL, containing 2 ⁇ L2% (V / V) DMSO in assay buffer (Unsuppressed control group) or various concentrations of test compound diluted in assay buffer containing 2% (V/V) DMSO; added with 48 ⁇ L of substrate S-2238 (Chromogenix; chemical formula: HD-Phe- Pip-Arg-pNA ⁇ 2HCl) buffer at a final concentration of 30 ⁇ M.
  • the test compound was preincubated with the enzyme for 10 minutes, and then the substrate was added to obtain a final volume of 100 ⁇ L to start the test.
  • the inhibition of human trypsin activity was measured using a buffer (50 mM Tris, pH 8.2, and 20 mM CaCl 2 ).
  • the appropriate wells in the Greiner384 microtiter plate were selected for IC50 , buffer containing 50 ⁇ L of human trypsin (Sigma; T6424), final concentration of 0.39 BAEE units/mL, assay buffer containing 2 ⁇ L of 2% (v/v) DMSO. (Unsuppressed control group) or various concentrations of test compound diluted in assay buffer containing 2% (V/V) DMSO; buffer containing substrate S-2222 (Chromogenix), final concentration 30 ⁇ M .
  • the test compound was preincubated with the enzyme for 10 minutes, and then 48 ⁇ L of the substrate was added to obtain a final volume of 100 ⁇ L to start the test.
  • the activity of the test compound against prothrombinase is measured by the production of thrombin. Briefly, 12.5 ⁇ L of human factor Xa was incubated in 10 mM HEPES buffer and pH 7.4, 2 mM CaCl 2 to a final concentration of 0.5 nM, and 12.5 ⁇ L of human platelets (1 ⁇ 10 7 mL -1 ) was added at 37 ° C. minute. 25 ⁇ L of prothrombin was added to start the reaction at a final concentration of 0.5 ⁇ M, assay buffer containing 2 ⁇ L of 2% (V/V) DMSO (uninhibited control) or various concentrations of the test compound diluted to 2% ( V/V) DMSO in assay buffer. After 20 minutes, 48 ⁇ L of substrate S-2238 (Chromogenix) was added to a final concentration of 50 ⁇ M to determine thrombin activity.
  • substrate S-2238 Chromogenix
  • the compounds of the invention exhibit potent anticoagulant activity through their specific anticoagulant factor Xa activity.
  • the prothrombin time (PT) of the test compound was measured to determine its anticoagulant activity in vitro.
  • PT Prothrombin time
  • test compounds rivaroxaban and inventive compound 1
  • DMSO fetal sulfate
  • test compounds rivaroxaban and inventive compound 1
  • DMSO fetal sulfate
  • 0.2 mL of PT reagent incubated at 37 ° C for 3 minutes
  • test plasma was added to 0.1 mL of test plasma and normal control plasma (incubated at 37 ° C for 3 minutes).
  • the clotting time was measured and compared to control plasma.
  • the test results are expressed as inhibitor concentrations that form the initial fibrin chain double time (2 x PT).
  • both rivaroxaban and Compound 1 of the present invention reached a double prothrombin time at a concentration of less than 1 [mu]M.
  • AV arteriovenous
  • Rivaroxaban and Compound 1 of the present invention are dissolved in [40%/10%/50% (v/v/v)] of solutol/ethanol/H 2 O, and male SD rats are orally administered (Shanghai Slack) Experimental Animal Co., Ltd., the number of test animals in each dose group is 8), SD rats weigh 350-450 grams, first anesthesia with sodium pentobarbital (ip, 50mg / Kg2.5mL / kg) for 90 minutes, then Turn on the shunt for 15 minutes.
  • sodium pentobarbital ip, 50mg / Kg2.5mL / kg
  • the left jugular vein and the right carotid artery were separated.
  • the jugular vein and contralateral carotid artery were intubated with a 6 cm long catheter filled with saline, and connected to an 8 cm long PE-160 polyethylene tube containing 6 cm long thick nylon thread (60 x 0.24 mm).
  • American Health & Medical Supply International Corp assembles a saline filled shunt. After 90 minutes of oral administration, the shunt was opened and blood was allowed to flow through the shunt for 15 minutes. The line with the associated thrombus was removed from the shunt and the average weight of the surgical suture 6 cm long was subtracted from the weight of the thrombus formed on the line.
  • Blood samples (2 mL) were removed from the carotid catheter immediately after removal of the thrombus.
  • Blood (1.8 mL) was collected in a plastic tube containing 1/10 volume of 3.8% trisodium citrate, centrifuged immediately at 2000 g, 4 ° C for 15 minutes, and plasma was collected and stored at -80 ° C for subsequent use (PT). Determination).
  • Blood (0.2 mL) was collected in a plastic tube containing 0.5 M EDTA-K 2 and immediately centrifuged at 7000 rpm (5204 g) at 4 ° C for 10 minutes to obtain plasma, and the plasma sample was stored at -80 ° C for measurement of the drug concentration. The animals are then euthanized with carbon dioxide.
  • test compound rivaroxaban and the present compound 1 or vehicle was orally administered for 90 minutes, then cross-cut 1 mm from the tail end of the anesthetized rat, and vertically immersed in 37 ° C saline.
  • the continuous blood flow was stopped for more than 30 seconds, and the longest observation time was 15 minutes (15 minutes belonged to a longer bleeding time).
  • the effective antithrombotic oral dose (the minimum dose to prevent thrombosis in the arteriovenous shunt model) was 3 mg/kg, and the bleeding time was the same as the baseline (0.8-1.2 fold).
  • the higher dose (10 mg/kg) showed a moderately prolonged bleeding time (about 2 fold).
  • the results showed that Compound 1 of the present invention showed no significant bleeding tendency compared to rivaroxaban.
  • test compound was dissolved in DMSO to prepare a 10 mmol/L stock solution.
  • 980 ⁇ L of dissolution medium was pipetted into a 2 mL screw-capped glass vial using a pipette (Eppendorf Research).
  • 20 ⁇ L of the stock solution of each test compound and the QC sample were added to a buffer solution corresponding to a kinetic detection solution of pH 6.5.
  • the final concentrations of test compound and DMSO solution were 200 ⁇ M and 2%, respectively. Pill cover.
  • the theoretical maximum concentration is 200 ⁇ M.
  • the mixture was shaken at 880 rpm for 24 hours at room temperature.
  • the vial was centrifuged for 30 minutes at 13,000 rpm. 200 ⁇ L of the supernatant was added to a 96-well plate using a digital pipette.
  • the solubility of the test compound was determined by high performance liquid chromatography.
  • the compounds of the invention are clearly more soluble in water than the prior art.

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Abstract

本发明涉及新的式（I）化合物或其溶剂化物、水合物、互变异构体、或药学上可接受的盐，其中R1代表被取代或未被取代的芳基或杂芳基；R2代表任选被取代的3-9元碳环或杂环等；R3代表H等；A选自O、NH、N-CH3、S、SO、SO2和CH2；X、Y和Z分别独立地选自CH、C-Br、C-Cl、C-F、C-I和N。本发明的化合物可以作为治疗和预防血栓异常疾病的抗凝剂，本发明通过提供凝血因子Xa的强力抑制剂以满足针对凝血Xa的选择性和强力抑制剂的现实需求。

Description

作为凝血因子Xa抑制剂的苯并恶唑并恶嗪酮类化合物 技术领域
本发明涉及新的苯并恶唑并恶嗪酮化合物，尤其是式(I)所示化合物，其制备方法、药物组合物及其作为抗凝剂在治疗和预防血栓栓塞性疾病中的用途。
背景技术
心血管疾病是发达国家人口致病和致死的主要原因，其中大多数的心血管事件主要归因于血栓形成。华法林是第一个获批上市的口服抗凝药物，其应用受困于缓慢的维生素K依赖型拮抗作用、药物与药物之间的相互作用以及药物与食物之间的相互作用，这导致了需要进行连续监测以获得准确剂量。其他的抗凝剂比如肝素、磺达肝素等只适合于肠胃外给药。现有抗凝剂的上述缺陷推动了新的抗凝血药物的深入研究。
在血液凝血级联系统中，凝血因子Xa在可以被内部路径(触点激活)和外部路径(组织因子)所激活的共同的交界处保持平衡，因此是一种独特的丝氨酸蛋白酶。与级联系统中凝血酶所发挥的多种作用相比，凝血因子Xa只将凝血酶原转化为凝血酶，但不影响现有的循环凝血酶水平。在临床前动物模型中，相对于凝血酶抑制剂，凝血因子Xa抑制剂降低了出血风险并提高了安全性/有效性。因此，在过去的十年中，在发现和开发选择性的和口服活性的小分子凝血因子Xa抑制剂作为治疗静脉或动脉血栓栓塞的抗凝血剂方面已经取得了巨大的进步，例如，预防术后深静脉血栓形成(DVT)和肺栓塞(PE)，预防在心房颤动时的中风，治疗急性冠脉综合征(ACS)，尤其是式(Ⅱ)所示利伐沙班(US2003/153610)和式(Ⅲ)所示阿哌沙班(WO2003/049681)分别于2011年和2013年经FDA批准上市。
Figure PCTCN2014085844-appb-000001
目前，为了预防经历了择期全髋关节置换术或全膝关节置换手术的患者的静 脉血栓栓塞(VTE)，利伐沙班的标准剂量是10毫克，每天一次。然而，利伐沙班的较高疗效伴随着较高的出血倾向，重大或致命性出血的风险也不容小觑，尤其是在病人长期服药的情况下。此外，利伐沙班水溶性差，因而难以开发静脉注射制剂。因此，凝血因子Xa抑制剂的广泛应用有赖于针对上述问题的改进研究。
在这方面，从临床的观点来看，开发对凝血因子Xa具有高特异性和强效抑制作用并且具有较高水溶性、口服给药更有效、更适合静脉给药、具有更大的治疗窗口和较少的出血倾向的药物已经引起人们的极大关注。
WO2011/147259公开了式(Ⅳ)所示化合物，用于治疗传染病、尤其是多重耐药细菌引起的传染病：
Figure PCTCN2014085844-appb-000002
其中，
U是H或F，
R1是乙酰胺或三唑：
Figure PCTCN2014085844-appb-000003
但是该化合物不具有针对凝血因子Xa的抑制作用，并且WO2011/147259也没有这方面的相关教导。
发明内容
本发明的目的在于提供式(Ⅰ)所示的化合物或其药学上可接受的盐、水合物或者前药：
Figure PCTCN2014085844-appb-000004
其中，
R1代表任选被取代的芳基或杂芳基，取代基独立地选自F、Cl、Br、I、氰基、氨基、CF3、C1-8烷氧基和C1-8烷基，取代基的个数为1个或多个，所述的C1-8烷基任选地被F、Cl、Br、I、氰基、氨基或CF3所取代；
R2代表任选被取代的
Figure PCTCN2014085844-appb-000005
Figure PCTCN2014085844-appb-000006
3-9元碳环或3-9元杂环，取代基选自＝O、F、Cl、Br、I、OH、SH、PH2、氰基、SO2、COOCH2CH2OH、COOCH2CH3、CONH2、COOCH3、C1-8烷基和氨基，所述取代基的个数为1个或多个，所述C1-8烷基任选地被F、Cl、Br、I、OH、NH2、SH、PH2、OCH3、N(CH3)2或NHCH3所取代，所述氨基任选地被CH3或COCH3所取代；
R3代表H、
Figure PCTCN2014085844-appb-000007
或
Figure PCTCN2014085844-appb-000008
A选自O、NH、N-CH3、S、SO、SO2和CH2；
X、Y和Z分别独立地选自CH、C-Br、C-Cl、C-F、C-I和N；和
任选地该化合物是立体异构体。
本发明的一个优选方案中：
R1代表任选被取代的苯基、噻吩基或吡啶基，取代基独立地选自F、Cl、Br、I、氰基、氨基、CF3、C1-8烷氧基和C1-8烷基，取代基的个数为1个或多个，所述的C1-8烷基任选地被F、Cl、Br、I、氰基、氨基或CF3所取代；
R2代表任选被取代的苯基或任选被取代的3-9元杂环，所述3-9元杂环含有至多三种杂原子/原子团，所述杂原子/原子团选自O、N、S、SO和SO2，所述杂环是饱和或部分不饱和的，所述杂环是单环或双环，所述杂环是任选苯并稠合的，所述取代基分别独立地选自＝O、F、Cl、Br、I、OH、SH、PH2、氰基、SO2、COOCH2CH2OH、任选被F、Cl、Br、I、OH、NH2、SH、PH2、OCH3、N(CH3)2、NHCH3所取代的C1-8烷基和任选被CH3、COCH3取代的氨基，所述取代基的个数为1个或多个；
R3选自H、
Figure PCTCN2014085844-appb-000009
或
Figure PCTCN2014085844-appb-000010
A选自O、S、SO、SO2和CH2；
X、Y和Z分别独立地选自CH、C-Br、C-Cl、C-F、C-I和N；和
任选地该化合物是立体异构体。
本发明的又一个优选方案中：
R1选自:
Figure PCTCN2014085844-appb-000011
R2代表任选被取代的苯基或任选被取代的3-9元杂环，所述3-9元杂环含有至多三种杂原子/原子团，所述杂原子/原子团选自O，N，S，SO和SO2，所述杂环是饱和或部分不饱和的，所述杂环是单环或双环，所述杂环是任选苯并稠合的，所述取代基分别独立地选自＝O、F、Cl、Br、I、OH、SH、PH2、氰基、SO2、COOCH2CH2OH、任选被F、Cl、Br、I、OH、NH2、SH、PH2、OCH3、N(CH3)2、NHCH3所取代的C1-8烷基和任选被CH3、COCH3取代的氨基，所述取代基的个数为1个或多个，所述取代基的个数为1个或多个；
R3选自H、
Figure PCTCN2014085844-appb-000012
或
Figure PCTCN2014085844-appb-000013
A选自O、S、SO、SO2和CH2；
X、Y和Z分别独立地选自CH、C-Br、C-Cl、C-F、C-I和N；和
任选地该化合物是立体异构体。
本发明的又一个优选方案中：
R1代表任选被取代的苯基、噻吩基或吡啶基，所述取代基分别独立地选自F、Cl、Br、I、氰基、氨基、CF3和任选被F、Cl、Br、I、氰基、氨基或CF3取代的C1-8烷基，所述取代基的个数为1个或多个；
R2选自:
Figure PCTCN2014085844-appb-000014
Figure PCTCN2014085844-appb-000015
A选自O、S、SO、SO2和CH2；
X、Y和Z分别独立地选自CH、C-Cl、C-F、和N；和
任选地该化合物是立体异构体。
进一步，本发明中药学上可接受的盐选自：
1)碱加成盐：钠、钾、钙、铵、有机氨或镁盐；或
2)酸加成盐：盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等以及相对无毒的有机酸如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、氨基酸 或葡糖醛酸。
进一步，本发明具有以下优选方案：
1)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
2)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代哌啶-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
3)5-氯-N-(((3S,3aS)-1-氧代-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
4)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧哌嗪-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
5)5-氯-N-(((3S,3aS)-7-(4-甲基-2-氧哌嗪-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
6)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代-1,3-氧杂氮杂环己烷-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
7)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡啶-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
8)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡啶-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
9)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡嗪-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
10)5-氯-N-(((3S,3aS)-1-氧代-7-((R)-3-氧代四氢-1H-吡咯[1,2-c]咪唑-2(3H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
11)5-氯-N-(((3S,3aS)-1-氧代-7-((S)-3-氧代四氢-1H-吡咯[1,2-c]咪唑-2(3H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
12)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
13)5-氯-N-(((3S,3aS)-7-((S)-3-羟基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
14)5-氯-N-(((3S,3aS)-7-(2-甲氧基-N-甲乙酰氨基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
15)5-氯-N-(((3S,3aS)-1-氧代-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
16)1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-2-氧代吡啶-3-甲酸乙酯；
17)5-氯-N-(((3S,3aS)-7-(3-(羟甲基)-2-氧代哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
18)5-氯-N-(((3S,3aS)-7-(2-(羟甲基)-5-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
19)5-氯-N-(((3S,3aS)-7-(2-甲基-3-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
20)5-氯-N-(((3S,3aS)-7-((R)-3-甲基-5-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
21)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代-8-氧杂-3-氮杂双环[3.2.1]辛-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
22)4-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-3-氧代吗啉-2-甲酰乙酯；
23)N-(((3S,3aS)-7-((S)-3-氨基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
24)5-氯-N-(((3S,3aS)-7-(2-((甲氨基)甲基)-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
25)5-氯-N-(((3S,3aS)-7-((S)-3-甲氧基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
26)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代-2-氮杂双环[2.2.2]辛-2-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
27)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氮杂双环[2,2,1]庚-3-酮)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
28)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代硫代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
29)5-氯-N-(((3S,3aS)-7-(1,1-二氧化-3-氧代硫代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
30)5-氯-N-(((3S,3aS)-7-((R)-2-(甲氧甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
31)5-氯-N-(((3S,3aS)-7-((S)-2-(甲氧甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
32)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
33)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氨磺酰基苯基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
34)5-氯-N-(((3S,3aS)-1-氧代-7-(1H-1,2,4-三唑-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
35)5-氯-N-(((3S,3aS)-7-(2-((二甲胺基)甲基)-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
36)5-氯-N-(((3S,3aS)-7-(2-乙基-4,5-二氢-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
37)5-氯-N-(((3S,3aS)-7-(2-环丙基-4,5-二氢-1H-咪唑-1-基)-1-氧-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
38)5-氯-N-(((3S,3aS)-7-(2-乙基-5,6-二氢嘧啶-1(4H)-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
39)5-氯-N-(((3S,3aS)-7-(4,5-二氢-1H-咪唑-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
40)5-氯-N-(((3S,3aS)-7-(1-甲基-4,5-二氢-1H-咪唑-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
41)5-氯-N-(((3S,3aS)-7-(1-甲基-1,4,5,6-四氢嘧啶-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
42)N-(((3S,3aS)-7-((S)-3-氨基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
43)N-(((3S,3aS)-7-((R)-3-氨基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
44)5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
45)5-氯-N-(((3S,3aS)-7-((R)-3-(二甲氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
46)5-氯-N-(((3S,3aS)-7-(3-羟基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
47)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
48)N-(((3S,3aS)-7-((S)-3-氨基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
49)N-(((3S,3aS)-7-((R)-3-氨基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
50)5-氯-N-(((3S,3aS)-7-((S)-3-(甲基氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
51)5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
52)5-氯-N-(((3S,3aS)-7-((S)-3-(二甲氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
53)5-氯-N-(((3S,3aS)-7-((R)-3-(二甲氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
54)(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯；
55)(S)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯；
56)(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酰胺；
57)(S)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酰胺；
58)5-氯-N-(((3S,3aS)-7-((R)-2-(羟甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
59)(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-羧酸-2-羟乙基酯；
60)5-氯-N-(((3S,3aS)-7-(环丙基磺酰基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
61)5-氯-N-(((3S,3aS)-1-氧代-7-(吡咯烷-1-基)磺酰基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
62)5-氯-N-(((3S,3aS)-7-((4-甲基哌嗪-1-基)磺酰基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
63)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代咪唑啉-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
64)5-氯-N-(((3S,3aS)-7-(3-羟基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
65)5-氯-N-(((3S,3aS)-7-((S)-3-甲氧基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
66)4-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)苯甲酰胺；
67)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)吡啶甲酰胺；
68)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-1H-吲哚-2-甲酰胺；
69)5-甲基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
70)5-溴代-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
71)5-氰基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
72)5-氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
73)4,5-二氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
74)5-氯-3-氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
75)4-氨基-5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
76)3-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)苯甲酰胺；
77)5-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)吡啶甲酰胺；
78)5-氯-N-(((3S,3aS)-9-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
79)5-氯-N-(((3S,3aS)-8-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
80)5-氯-N-(((3S,3aS)-6-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
81)5-氯-N-(((6aS,7S)-9-氧代-3-(3-氧代吗啉代)-6,6a,7,9-四氢恶唑并[3,4-d]吡啶并[3,2-b][1,4]恶嗪-7-基)甲基)噻吩-2-甲酰胺；
82)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢恶唑并[3,4-d]吡啶并[4,3-b][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
83)2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基2-氨基乙酸盐酸盐；
84)(R)-2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基2-氨基-3-甲基丁酸盐酸盐；
85)5-氯-N-((1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺；
86)5-氯-N-((5-氧化-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺；和
87)5-氯-N-((5,5-二氧化-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺。其中，上述化合物分别被命名为化合物1～87，其结构式和制备方法依次详见实施例1～87。
本发明的另一目的在于提供式(Ⅰ)化合物的制备方法，其中R1、X、Y和Z如权利要求1所定义，A为O，R3为H，R2为3-9元含氮杂环，包括如下步骤：
Figure PCTCN2014085844-appb-000016
本发明的另一目的在于提供一种药物组合物，其包括治疗有效量的式(Ⅰ)化合物或其药学上可接受的盐、水合物或前药以及药学上可接受的载体。
本发明的另一目的在于提供上述化合物在制备治疗血栓栓塞性疾病的药物中的应用，其中，所述疾病优选自动脉心血管血栓栓塞性疾病、静脉心血管血栓栓塞性疾病、脑动脉血栓栓塞性疾病、静脉脑血管栓塞性疾病，进一步优选自不稳定型心绞痛、心肌梗死、再发心肌梗死、缺血性猝死、短暂性脑缺血发作、中风、动脉粥样硬化、静脉血栓形成、下肢深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞以及下述原因造成的血栓症：(a)人工心脏瓣膜或其他植入物；(b)留置导管；(c)支架；(d)心肺转流术；(e)血液透析；以及(f)将血液暴露于人工表面从而促进血栓形成的其他程序或操作。
本发明可以通过不脱离其发明实质的其他具体方式实现，包括上述本发明优选方案的所有组合。本发明的所有具体实施方式可以与其他方式结合形成更加优选的实施方式，其中的特定技术特征可以与任何相关的其他技术特征相结合形成新的实施方式；当然，也可以认为每个优选实施方式是独立的，其中的特定技术特征仅限于本优选实施方式本身。
本发明涉及下述定义：
本发明的化合物可能具有不对称中心，本发明中含有不对称取代原子的化合物可以被分离成光学活性或者消旋体形式，本领域技术人员知晓如何制备光学活性形式，比如通过消旋体拆分或者由光学活性的起始原料合成。许多几何异构体的烯烃、C＝N双键等等也可以存在于本发明的化合物中，所有这些稳定的异构体都属于本发明的一部分。本发明也描述了顺式和反式几何异构体，可以将它们分离成异构体的混合物或单一异构体形式。除非特别指明具体的立体化学或异构体形式，本发明包括所有手性、非对映异构体，消旋体和所有的几何异构体形式。制备本发明化合物的方法及其中间体属于本发明的一部分。本发明化合物的所有 互变异构体也属于是本发明的一部分。
在一个优选方案中，本发明化合物的分子量小于500～800g/mol；另一个优选方案中，所述分子量小于800g/mol；另一个优选方案中，所述分子量小于650g/mol；另一个优选方案中，所述分子量低于550g/mol。
术语“取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。环双键是指在两个相邻的环原子上形成的双键，比如C＝C、C＝N和N＝N。本发明一般不包括如N-卤素、S(O)H以及SO2H这样的基团。
本发明包括本发明的化合物中原子的所有同位素。同位素包括原子序数相同、但质量数不同的原子。例如但不限于，氢的同位素包括氚和氘，碳的同位素包括C-13与C-14。
当任何变量(例如R6)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R6所取代，则所述基团可以任选地至多被两个R6所取代，并且每种情况下的R6都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。除非另有规定，术语“烷基”本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价或多价原子团，具有指定数量的碳原子(即C1-C10表示1至10个碳)。在一些实施例中，术语“烷基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。
除非另有规定，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。 在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烷基的任何内部位置或者该烷基附着于分子其余部分的位置。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“环烷基”和“杂环烷基”本身或与其他术语联合分别表示环化的“烷基”和“杂烷基”。此外，就杂环烷基而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，它可以是单环或多环(优选1至3个环)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
为简便起见，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
每一个上述术语(例如“烷基”、“杂烷基”、“芳基”和“杂芳基”)意 在被取代或未被取代的所述原子团。下文会提供每种原子团所优选的取代基。
烷基和杂烷基原子团(包括通常被称为亚烷基、链烯基、亚杂烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基一般被称为“烷基取代基”，它们可以选自但不限于下列基团中的一个或多个：-R’、-OR’、＝O、＝NR’、＝N-OR’、-NR’R”、-SR’、卤素、-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2和氟代(C1-C4)烷基,取代基的数目为0～(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1～3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时，例如，每一个R基团是独立地加以选择的，如同当存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时，它们可与该氮原子结合形成5-，6-或7-元环。例如，-NR'R″意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中，本领域技术人员可以理解，术语“烷基”意在包括碳原子键合于非氢基团所构成的基团，如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
与烷基原子团所述取代基相似，芳基和杂芳基取代基一般统称为“芳基取代基”，选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等，取代基的数量为0到芳香环上开放化合价的总数之间；其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时，例如，每个R基团是独立地加以选择的，如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U独立地选自-NR-、-O-、CRR'-或单键，q是0到3的整数。
作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键，r是1～4的整数。任选地，由此形成的新环上的一个单键可以替换为双键。
作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–(CRR’)s-X-(CR”R’”)d-的取代基所取代，其中s和d分别独立的选自0～3的 整数，X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
本文所用的“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环烷基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
本文所用术语“杂原子”包括碳(C)和氢(H)以外的原子，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)和硼(B)等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
“R”是一个通用的缩写，代表选自被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基、被取代或未被取代的杂芳基、被取代或未被取代的环烷基、被取代或未被取代的杂环烷基等取代基。
所谓“有效”量的药物、制剂或渗透物是指能够获得所需的局部或全身性的效果的足够量的活性剂。“局部有效的”、“美容上有效的”、“药学上有效的”或“临床上有效的”量是指能够实现所期望的治疗结果的药物用量。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及相对无毒的有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。本文中消旋体、ambiscalemic和scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰 活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质，代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、glycollyarsanilic，hexylresorcinic hydrabamic，氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。Remington's  Pharmaceutical Sciences,18th ed.,Mack Publishing Company,Easton,PA,1990,p.1445批露了合适的盐的列表，其公开的内容在此引入本文作为参考。
由于前药可以提高药物的许多品质(如溶解度、生物利用度、工业化等)，因此本发明的化合物可以以前药形式给药。因此，本发明意在覆盖本发明要求保护的化合物的前药形式、其给药方式及其药物组合物。“前药”意在包括任何共价键合的载体，当将前药给予哺乳类受体时，它将在体内释放本发明的活性母体药物。本发明前药的制备方法是通过修饰本发明母体化合物的官能团实现的，修饰后的母体化合物可以通过常规操作的方式或者体内方式裂解为母体化合物。前药包括本发明的化合物，其中，羟基、氨基或巯基的基团键合到任何官能团，当本发明的前体药物被给予哺乳类受体时，它将分别裂解形成游离的羟基、游离氨基酸或游离的巯基。前体药物的实例包括但不限于本发明化合物醇或胺官能团的乙酸、甲酸及苯甲酸衍生物。
术语“口服剂型”是指通过口腔给予任意药物组合物。口服剂型的实例包括片剂、胶囊剂、薄膜、粉末、小药囊、颗粒剂、溶液、固体、悬浮液，或者将多个不同的药剂单元(例如含有不同的活性成分的颗粒剂、片剂和/或胶囊)包装在一起联合用药，以及本领域中已知的其他方式。口服剂型可以是一、二、三、四、五或六个单元，当口服剂型有多个单元时，所有的单元都是包装在一个包装中的(如瓶子或其他形式的包装，如泡罩包装)；当口服剂型是一个独立的单元时，它可能会也可能不会存在于单一包装中。在一个优选的实施方案中，口服剂型是一个、两个或三个单元。在一个特别优选的实施方案中，口服剂型是一个单元。
“抑制”和“阻挡”，在本文中可互换使用，是指对一种酶如丝氨酸蛋白酶的部分或全部的阻断。
术语“离去基团”是指在取代反应中一个功能团或原子可以被另一个功能团或原子取代，例如亲和取代反应。例如，代表性的离去基团包括三氟甲烷磺酸、氯、溴和碘基；磺酸酯基例如甲磺酸盐、甲苯磺酸盐、对溴苯磺酸盐、二甲基甲酰胺盐等；和酰氧基，如乙酰氧基、三氟乙酰氧基等。
术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲 基甲硅烷基(TBS)等等。
卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
C2-6链烯基是指包括C2、C3、C4、C5和C6的链烯基。“炔基”是指包括直链或支链构型烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳三键，如乙炔基和丙炔基。C2～6炔基是指包括C2、C3、C4、C5和C6的炔基。
本文所用的“卤”或“卤素”是指氟、氯、溴和碘；“抗衡离子”是用来表示一个小的、带负电荷的物质，如氯化物、溴化物、氢氧化物、乙酸盐和硫酸盐。
具体地，C1-8可以是C1、C2、C3、C4、C5、C6、C7或C8，3-9元碳环或杂环可以是3、4、5、6、7、8、9元碳环或杂环。
如本文所用，“碳环”或“碳环基”是指任何稳定的3、4、5、6或7元单环或双环或7、8、9、10、11、12或13元二环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)。这样的碳环的例子包括但不限于：环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环庚烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯、环辛二烯基，[3,3,0]双环辛烷、[4,3,0]双环壬烷、[4,4,0]双环癸烷、[2,2,2]双环辛烷、芴基、苯基、萘基、2,3-二氢化茚基、金刚烷基和四氢萘基。如上所示，桥环也包含在碳环的定义中(例如[2，2，2]双环辛烷)。当一个或多个碳原子连接两个不相邻的碳原子时形成桥环。优选一个或两个碳原子的桥。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
如本文所用，术语“杂环”或“杂环基”意指稳定的5、6或7元单环或双环或7、8、9或10元双环杂环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环， 它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p)。值得注意的是，芳香杂环上S和O原子的总数不超过1。
桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、isatinoyl、异苯并呋喃基、吡喃、异吲哚基、异二氢吲哚基、异吲哚基、吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2，5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、异恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、吡唑基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1，2，5-噻二嗪基、1,2,3-噻二唑基、1，2，4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1，2，3-三唑基、1，2，4-三唑基、1，2，5-三唑基、1，3，4-三唑基和呫吨基。还包括稠环和螺环化合物，例如上述杂环。
“稳定的化合物”和“稳定结构”是指这样一种化合物，它能够脱离于反应混合物并以一定的有效纯度独立、稳定地存在，并被配制成有效的治疗药物。
“被取代的”是指标识“被取代的”原子上的一个或多个氢原子被取代基(本文已对这些取代基做过限定)取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。
本文所用的“治疗”是对哺乳动物，特别是人的疾病状态的治疗，包括：(a)预防发生在哺乳动物的疾病状态，尤其是当该哺乳动物易患这种疾病但尚未确诊其已经患上这种疾病；(b)抑制疾病的状态，即阻止了它的发展；和/或(c)缓解 疾病状态，即造成疾病状态消退。
“治疗有效量”是指本发明化合物单独给药或联合用药时能够有效抑制凝血因子Xa所需要的用量。“治疗有效量”也指本发明化合物组合使用时能够有效抑制凝血因子Xa所需要的用量。本发明化合物的组合使用优选协同组合使用。正如Chou and Talalay,Adv.Enzyme Regul.1984,22:27-55一文所教导的，当组合使用药物所取得的效果(即对凝血因子Xa的抑制作用)优于单独使用时药物之间发生协同效应。在一般情况下，次佳浓度的化合物最能清楚地展示协同效应。与单独用药相比，联合用药的协同效应可以表现在降低细胞毒性、提高抗血栓能力或者其他的有益效果方面。
本发明部分化合物的制备方法：
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的(Protective Groups In Organic Synthesis,Wiley and Sons,1991)是这方面的权威。本发明引用的所有参考文献整体上并入本发明。
本发明所提供的式(I)化合物(当A＝O时)，可以通过反应流程1以及本领域技术人员所熟知的标准方法所制备。以溴代-氟-硝基苯(1-1,X＝Y＝Z＝CH)为例，在氢化钠的有机溶剂(比如THF)存在下与顺式-丁基-2-烯-1,4-二醇反应以取代氟，所得被取代的硝基苯经锌和氯化铵还原，得到中间产物即被取代的苯胺，其氨基被氯甲酸苄酯保护，然后经Sharpless不对称环氧化反应，得到环氧化物化合物(1-2)(任意立体化学)。羟基被保护，经环化、LDA处理得到苯并恶唑并恶嗪酮环系，在碘化亚铜存在下用杂环取代溴化物得到中间产物即被取代的苯并恶唑并恶嗪酮化合物(1-3)。经过四步反应，甲硅烷基(TBS)由保护羟基变为保护氨基。用四丁基氟化铵(TBAF)暴露的羟基脱去甲硅烷基保护基，由甲磺酰变为甲磺酸酯，用叠氮化钠取代得到叠氮化物，用还原剂如三苯基膦还原得到中间产物胺(1-4)。经与环酰氯的酰化反应生成被取代的苯并恶唑并恶嗪酮化合物(1-5)，即本发明的凝血因子Xa抑制剂。
Figure PCTCN2014085844-appb-000017
反应流程1
具体而言，本发明所提供的式(I)化合物(当A＝O时)，可以通过反应流程1以及本领域技术人员所熟知的标准方法所制备。从市售4-溴代-2-氟-1-硝基苯(1-1)衍生物开始，也可以从其他具有不同官能团修饰的近似衍生物开始，比如，F-和Br-可以替换为其他卤素、–OH、-NH2或者被保护的-NH2,化合物(1-1)环上的NO2可以替换为-NH2或者被保护的-NH2(比如CBzHN)等，X、Y、Z选自CH、CF、CCl或N。所有这些变化、替换将在具体实施方式部分予以详述。本领域技术人员应该知道，为了制备本发明化合物，反应流程1中反应步骤的顺序可以是不同的，这也属于本发明的范围。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。核磁共振氢谱数据由Bruker Avance III400(400MHz)核磁共振仪采集，化学位移以δ(ppm)表示，使用四甲基硅烷定标。液相色谱-质谱联用仪器包含有：安捷伦1200系列HPLC配备6110或1956A质谱检测器；以及岛津LC20液相色谱配备2020质谱检测器。质谱仪配备有正或负模式下检测的电喷雾离子源(ESI)。
本发明采用下述缩略词：aq代表水；HATU代表O-7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基 二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点。
化合物经手工或者
Figure PCTCN2014085844-appb-000018
软件命名，市售化合物采用供应商目录名称。
用配有Shimadzu SIL-20A自动进样器和日本岛津DAD：SPD-M20A探测器的岛津LC20AB系统进行高效液相色谱分析，采用Xtimate C18(3μm填料，规格为2.1x300mm)色谱柱。0-60AB_6分钟的方法：应用线性梯度，以100％A(A为0.0675％TFA的水溶液)开始洗脱，并以60％B(B为0.0625％TFA的MeCN溶液)结束洗脱，整个过程为4.2分钟，然后以60％B洗脱1分钟。将色谱柱再平衡0.8分钟达到100:0，总运行时间为6分钟。10-80AB_6分钟的方法：应用线性梯度，以90％A(A为0.0675％TFA的水溶液)开始洗脱，并以80％B(B为0.0625％TFA的乙腈溶液)结束洗脱，整个过程为4.2分钟，然后以80％B洗脱1分钟。将色谱柱再平衡0.8分钟达到90:10，总运行时间为6分钟。柱温为50℃，流速为0.8mL/min。二极管阵列检测器扫描波长为200-400nm。
在Sanpont-group的硅胶GF254上进行薄层色谱分析(TLC)，常用紫外光灯照射检视斑点，在某些情况下也采用其他方法检视斑点，在这些情况下，用碘(10g硅胶中加入约1g碘并彻底混合而成)、香草醛(溶解大约1g香草醛于100mL10％H2SO4中制得)、茚三酮(从Aldrich购得)或特殊显色剂(彻底混合25g(NH4)6Mo7O24·4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL H2O和50mL浓H2SO4而制得)展开薄层板，检视化合物。采用Still,W.C.；Kahn,M.；and Mitra,M.Journal of Organic Chemistry,1978,43,2923-2925.中所公开技术的类似方法，在Silicycle的40-63μm(230-400目)硅胶上进行快速柱色谱。快速柱色谱或薄层色谱的常用溶剂是二氯甲烷/甲醇、乙酸乙酯/甲醇和己烷/乙酸乙酯的混合物。
在Gilson-281Prep LC322系统上采用吉尔森UV/VIS-156探测器进行制备色谱分析,所采用的色谱柱是Agella Venusil ASB Prep C18,5μm、150x21.2mm；Phenomenex Gemini C18、5μm、150x30mm；Boston Symmetrix C18,5μm、150x30mm；或者Phenomenex Synergi C18、4μm、150x30mm。在流速约为25mL/min时，用低梯度的乙腈/水洗脱化合物，其中水中含有0.05％HCl、0.25％HCOOH或0.5％NH3·H2O，总运行时间为8-15分钟。
用带有Agilent1260自动进样器和Agilent DAD：1260检测器的Agilent1260 Infinity SFC系统进行SFC分析。色谱柱采用Chiralcel OD-H250x4.6mm I.D.,5μm或者Chiralpak AS-H250x4.6mm I.D.,5μm或者Chiralpak AD-H250x4.6mm I.D.,5μm。OD-H_5_40_2.35ML的色谱条件：Chiralcel OD-H色谱柱(规格为250x4.6mm I.D.，5μm填料)，流动相为40％乙醇(0.05％DEA)-CO2；流速为2.35mL/min；检测波长为220nm。AS-H_3_40_2.35ML色谱条件：Chiralpak AS-H色谱柱(规格为250x4.6mm I.D.,5μm填料)；流动相为40％甲醇(0.05％DEA)-CO2；流速为2.35mL/min，检测波长为220nm。OD-H_3_40_2.35M色谱条件：Chiralcel OD-H色谱柱(规格为250x4.6mm I.D，5μm填料)，流动相为40％甲醇(0.05％DEA)-CO2，流速为2.35mL/min，检测波长为220nm。AD-H_2_50_2.35ML色谱条件：Chiralpak AD-H色谱柱(规格为250x4.6mm I.D，5mm填料),流动相为50％甲醇(0.1％MEA)-CO2，流速为2.35mL/min，检测波长为220nm。
在使用Gilson UV检测器的Waters Thar80Pre-SFC系统上进行制备型SFC分析，所采用的色谱柱为Chiralcel OD-H(规格为250x4.6mm I.D，5μm填料)或者Chiralpak AD-H(规格为250x4.6mm I.D，5μm填料)。在流速约为40-80mL/min时，用低梯度的乙醇-二氧化碳或者甲醇-二氧化碳洗脱化合物，其中甲醇或乙醇含有0.05％NH3·H2O、0.05％DEA或者0.1％MEA，总运行时间为20-30分钟。
本发明的化合物可用作治疗或预防哺乳动物血栓栓塞性疾病的凝血剂。一般情况下，血栓栓塞性疾病是血液凝块引起的循环系统的疾病(即血小板活化和/或血小板聚集有关的疾病)。本文所用的术语“血栓栓塞性疾病”包括动脉心血管血栓栓塞性疾病、静脉心血管血栓栓塞性疾病、动脉脑血管血栓栓塞性疾病和静脉脑血管血栓栓塞性疾病。本文所用的术语“血栓栓塞性疾病”包括特定的疾病，选自但不限于：不稳定型心绞痛、首次心肌梗死、复发性心肌梗死、缺血性猝死、短暂性脑缺血发作、中风、动脉粥样硬化、静脉血栓形成、深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞以及由以下原因造成的血栓症：(a)人工心脏瓣膜或其他植入物；(b)留置导管；(c)支架；(d)心肺转流术；(e)血液透析；以及(f)将血液暴露于人工表面从而促进血栓形成的其他程序或操作。值得注意的是，血栓形成包括阻塞(例如旁路手术后的阻塞)和再阻塞(例如在经皮冠状动脉腔内成形术的过程中或之后)。本发明的化合物的抗凝血效果来源于其对Ⅹa因子或凝血酶的抑制作用。
Figure PCTCN2014085844-appb-000019
本发明的式(I)所示的一系列新的苯并恶唑并恶嗪酮化合物是凝血因子Xa的选择性的和强效的抑制剂，因此可用作抗凝血剂使用。与现有技术相比，本发明化 合物具有改进的水溶性、增强的疗效以及更低的出血倾向。因此，式(I)的化合物可以成为血栓栓塞性疾病的治疗或预防药物。
本发明的式(I)化合物也区别于WO2011/147259中的化合物，不仅结构上存在显著差异，从效果上看，WO2011/147259中的化合物不具有对凝血因子Xa的抑制作用，WO2011/147259也没有给出这方面的任何教导。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000020
反应流程：
Figure PCTCN2014085844-appb-000021
步骤A：将(Z)-丁-2-烯-1,4-二醇(39.7g,450mmol)的干燥THF(300mL)溶液冷却至0℃，分批加入氢化钠(60％溶解于矿物油中，9.0g,225mmol)，然后在0℃下滴加4-溴-2-氟-1-硝基苯(33.0g,150mmol)的干燥THF溶液(450mL)。反应液室温搅拌两小时，倒入600mL水，将混合物用EtOAc萃取，合并的有机层用无水硫酸钠干燥，过滤并浓缩，得到(Z)-4-(5-溴-2-硝基苯氧基)丁-2-烯-1-醇(45g)，黄色固体。将粗产物用于下一步骤中，无需进一步纯化。
步骤B：将锌粉(49.0g,750mmol)和氯化铵(40.0g,750mmol)加入甲醇(450mL)中混合，然后在室温下滴加(Z)-4-(5-溴代-2-硝基苯氧基)丁-2-烯-1-醇(43.2g,150mmol)的甲醇(300mL)溶液。将反应混合物在室温下搅拌24小时，然后过滤。将滤液浓缩，得到(Z)-4-(2-氨基-5-溴苯氧基)丁-2-烯-1-醇，为黑色油状物。将粗产物用于下一步骤中，无需进一步纯化。
步骤C：将粗产物(Z)-4-(2-氨基-5-溴苯氧基)丁-2-烯-1-醇溶解于THF(300mL)和水(150mL)中，在0℃下加入碳酸氢钠(25.2g,300mmol)和氯甲酸苄酯(38.4g,225mmol)，升温至室温，并在室温下搅拌16小时。将混合物用EtOAc萃取。合并的有机层干燥并浓缩。粗残余物用硅胶色谱(PE:EtOAc＝1:10～1:5)纯化，得到(Z)-4-溴代-2-(4-羟基丁-2-烯氧基)苯基)氨基甲酸苄酯(28.0g，48％)，灰白色固体。LCMS(ESI)m/z414,416(M+Na).
步骤D：-25℃,分子筛(
Figure PCTCN2014085844-appb-000022
40g)悬浮于DCM(350mL)中。向冷却的混合物中加入L-(+)-二乙基酒石酸盐(11.3g,54mmol)、Ti(Oi-Pr)4(14.1g,49.5mmol)和叔丁基过氧化氢(癸烷中5-6M,27mL,135mmol)。-25°搅拌1小时，滴加含有(Z)-4-溴代-2-(4-羟基丁-2-烯氧基)苯基)氨基甲酸苄酯(17.6g,45mmol)的DCM(70mL)溶液，将反应液在-25℃下搅拌24小时。向冷却液中倾入10％的L-(+)-酒石酸的水溶液(210mL)，并在0℃下搅拌1小时，过滤，将有机溶液分离，水相用DCM萃取。合并的有机层用盐水洗涤，无水硫酸钠干燥，浓缩。粗残余物用硅胶色谱(PE:EtOAc＝1:5～1:3)纯化，得到(4-溴代-2-(((2R，3S)-3-(羟甲基)环氧乙烷-2-基)甲氧基)苯基)氨基甲酸苄酯(9.4g，51％，ee值>88％)，为白色固体。LCMS(ESI)m/z:430,432(M+Na).
步骤E：0℃下，向叔丁基二甲基甲硅烷基氯((5.2g,34.5mmol)，咪唑(3.1g,46mmol)和4-二甲基氨基吡啶(280mg,2.3mmol)的无水DMF(40mL)溶液中加入(4-溴代-2-(((2R，3S)-3-(羟甲基)环氧乙烷-2-基)甲氧基)苯基)氨基甲酸苄酯(9.4g,23mmol)的无水DMF(20mL)溶液。将反应液的温度升至室温，并在室温下搅拌3小时。将混合物倾入冰水中，用EtOAc萃取。合并的有机层用无水硫酸钠干燥并浓缩。将粗的残余物经硅胶色谱(PE:EtOAc＝1:20～1:10)，得到(4-溴代-2-(((2R，3S)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)环氧乙烷-2-基)甲氧基)苯基)氨基甲酸苄酯(10.5g,87％)，为无色油状物。LCMS(ESI)m/z:522,524(M+1).
步骤F：-78℃下，向(4-溴-2-(((2R，3S)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)环氧乙烷-2-基)甲氧基)苯基)氨基甲苄酯(10.5g,20mmol)的THF(200mL)溶液中滴加二异丙基氨基锂(2.0M的THF溶液，,13mL,26mmol)。在-78℃下搅拌2小时后，将所得溶液升温至室温，并在室温下再搅拌16小时。在0℃下，加入饱和氯化铵溶液。将混合物用EtOAc萃取。合并的有机层用无水硫酸钠干燥并浓缩。将粗残余物通过硅胶色谱(PE:EtOAc＝1:30～1:20)纯化，得到(3R,3aS)-7-溴代-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(8.3g,99％)，为白色固体。MS(ESI)m/z:414,416(M+1).
步骤G：将(3R,3aS)-7-溴代-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3α，4-二氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-1(3H)-酮(8.3g,20mmol)、吗啉-3-酮(2.8g,28mmol)、K2CO3(3.3g,24mmol)和DMSO(60mL)相混合，室温下搅拌1小时。室温下加入CuI(760mg,4mmol)和1,10-邻菲咯啉(200mg)。将得到的混合物加热至130℃，保温24小时。冷却至室温后，加入水(180mL)。将混合物用EtOAc萃取。合并的有机层用无水硫酸钠干燥并浓缩。将粗的残余物经硅胶色谱(PE:EtOAc＝1:10～1:1))，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(3.5g，40％)，为红色油状物。LCMS(ESI)m/z:435(M+1).
步骤H：在0℃下，向(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(3-氧代吗啉代)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(3.5g,8mmol)的THF(20mL)溶液中滴加n-Bu4NF(2.5g,9.6mmol)的THF(10mL)溶液。将所得溶液在0℃下搅拌2小时。用饱和氯化铵水溶液淬灭反应，并用EtOAc萃取。合并的有机层用无水硫酸钠干燥并浓缩。将粗残余物通过硅胶色谱(PE:EtOAc＝1:1～0:1)纯化，得到(3R,3aS)-3-(羟甲基)-7-(3-氧代吗啉)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(2.4g,94％)，为无色油状物。LCMS(ESI)m/z:321(M+1).
步骤I：在0℃下，向(3R，3aS)-3-(羟甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(2.4g,7.5mmol)和Et3N(2.3mL,16.5mmol)的DCM(50mL)溶液中滴加甲磺酰氯(1.0g,9mmol)。将混合物加热至室温，并在室温下搅拌16小时。用水(20mL)淬灭反应，并用DCM萃取。将合并的有机相用盐水洗涤，用无水硫酸钠干燥，并浓缩，得到(3S,3aS)-3-(叠氮甲基)-7-(3-氧代吗啉代)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，为灰白色固体。将粗产物用于下一步反应，无需进一步纯化。
步骤J：将粗产物(3S,3aS)-3-(叠氮甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮、叠氮化钠(540mg,8.3mmol)和DMF(20mL)的混合物在80℃下搅拌6小时，将反应混合物冷却至室温，然后加入水， 将混合物用EtOAc萃取。将合并的有机相用盐水洗涤，用无水硫酸钠干燥，并浓缩，得到(3S,3aS)-3-(叠氮甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(2.2g)，为棕色的油状物。LCMS(ESI)M/Z：346(M+1).将粗产物用于下一步骤中，无需进一步纯化。
步骤K：在室温下，向(3S,3aS)-3-(叠氮甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(1.9g,5.5mmol)的THF(20mL)溶液中加入三苯基膦(1.7g,6.6mmol)，将所得溶液在45℃下搅拌2小时，然后加入水(1mL)，并在45℃下搅拌16小时。冷却至室温后，将混合物浓缩。将粗残余物通过硅胶色谱(MeOH:DCM＝1:30～1:20)纯化，得到(3S,3aS)-3-(氨基甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(1.1g,64％)，为灰白色固体。LCMS(ESI)m/z:320(M+1).
步骤L：在0℃下，向(3S,3aS)-3-(氨基甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(1.1g,3.5mmol)的DCM(30mL)溶液中加入三乙胺(2.4mL,17.5mmol)和5-氯噻吩-2-羰基氯(830mg,4.6mmol)的DCM(10mL)溶液，将反应混合物在0℃下搅拌1小时。加入水并用DCM萃取该混合物。将合并的有机相用无水硫酸钠干燥并浓缩。将粗的残余物经硅胶色谱(MeOH:DCM＝1:30to1:20)纯化，得到本实施例标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.71(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.05(d,J＝2.0Hz,1H),7.05(dd,J＝8.8,2.0Hz,1H),4.62-4.51(m,2H),4.18(s,2H),4.11-4.01(m,2H),3.95(t,J＝5.2Hz,2H),3.73(t,J＝5.2Hz,2H),3.68(t,J＝5.2Hz,2H).LCMS(ESI)m/z:464(M+1).
实施例2
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代哌啶-1-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000023
步骤A：根据实施例1制备(3R,3aS)-3-((叔丁基二甲基甲硅烷氧基)甲基)-7-(2-氧代哌啶-1-基)-3α，4-二氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-1(3H)-酮，产率为7％，其中将步骤G中的吗啉-3-酮替换为哌啶-2-酮。LCMS(ESI)m/z:433.2(M+1).
步骤B：根据实施例1步骤G,I,J,K和L顺序制备实施例2的标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),7.83(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),6.87-6.93(m,2H),4.50-4.64(m,2H),3.99-4.13(m,2H),3.73(t,J＝5.6Hz,2H),3.52-3.60(m,2H),2.37(t,J＝6.0Hz,2H),1.77-1.90(m,4H)；LCMS(ESI)m/z:462.1(M+1).
实施例3
5-氯-N-(((3S,3aS)-1-氧代-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-1,3,3a,4-四氢苯并[b] 恶唑[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000024
步骤A：根据实施例1制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将步骤G中的吗啉-3-酮替换为1,4-氧杂氮杂环庚烷-5-酮，收率为35％。LCMS(ESI)m/z:449.2(M+1).
步骤B：根据实施例1步骤G、I、J、K和L顺序制备实施例3的标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.82(d,J＝8.4Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),6.87-6.83(m,2H),4.60-4.54(m,2H),4.10-4.00(m,2H),3.80-3.65(m,8H),2.78(t,J＝4.8Hz,2H)；LCMS(ESI)m/z:478.1(M+1).
实施例4
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧哌嗪-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000025
步骤A：向哌嗪-2-酮(3.00g,30.0mmol)的EtOAc/H2O(30mL/6mL)溶液中加入K2CO3(4.32g,31.5mmol)和氯甲酸苄酯(5.10g,30.0mmol)。该混合物在室温下搅拌12小时，然后将反应液倒入水(50mL)中，并用乙酸乙酯(40mL x2)萃取，用无水硫酸钠干燥，并浓缩。粗残余物用硅胶色谱(PE:EtOAc＝50:1)纯化，得到3-氧代哌嗪-1-甲酸苄酯(6.3克，88％)，为白色固体。1H NMR(400MHz,CDCl3)δ7.34-7.33(m,5H),6.87-6.76(m,1H),5.17(s,2H),4.17(s,2H),3.71(t,J＝5.2Hz,2H),3.39(s,2H).LCMS(ESI)m/z:235.1(M+1).
步骤B：根据实施例1制备4-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)-3-氧代哌嗪-1–甲酸苄酯，其中将步骤G中吗啉-3-酮替换为3-氧代哌嗪-1–甲酸苄酯，产率为22％。LCMS(ESI)m/z:568.2(M+1).
步骤C：向4-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)-3-氧代哌嗪-1–甲酸苄酯(200mg,0.352mmol的甲醇(4mL)溶液中加入二-叔丁基二碳酸酯(115mg,0.529mmol)和Pd/C(10％,20mg)，然后用氢气球处理。反应液室温搅拌16小时。LCMS显示反应完成，然后过滤除去Pd/C，浓缩滤液。将粗残余物通过硅胶柱色 谱法(PE:EA＝5:1～1:1)纯化，得到4-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)-3-氧代哌嗪-1–甲酸叔丁酯(160mg,85％)，为白色固体。LCMS(ESI)m/z:534.1(M+1).
步骤D：根据实施例1步骤G、I、J、K、L的顺序制备4-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1，3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)-3-氧代哌嗪-1-甲酸叔丁酯。LCMS(ESI)m/z:563.1(M+1).
步骤E：向4-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1，3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)-3-氧代哌嗪-1-甲酸叔丁酯(425mg,0.756mmol)的DCM(8mL)溶液中加入2,2,2-三氟乙酸(259mg,2.27mmol)，室温下将混合物搅拌4小时后倾入水(30mL)中，用DCM萃取，将合并的有机相用无水硫酸钠干燥并浓缩，将残余物粗品经制备型HPLC纯化，得到5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧哌嗪-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(38mg,14％)，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.63(s,2H),9.07(t,J＝6.0Hz,1H),7.88(d,J＝8.8Hz,1H),7.74(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.95-6.93(m,2H),4.61-4.55(m,2H),4.13-4.03(m,2H),3.85-3.81(m,2H),3.72(t,J＝4.2Hz,2H),3.50(s,2H).LCMS(ESI)m/z:463.1(M+1).
实施例5
5-氯-N-(((3S,3aS)-7-(4-甲基-2-氧哌嗪-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000026
步骤A：5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代哌嗪-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(100mg,0.216mmol)的DMF(2mL)溶液中加入K2CO3(29.8mg,0.216mmol)和碘甲烷(35mg,0.216mmol)，室温下搅拌16小时后，将混合物倾入水(15mL)中，用EtOAc(20mL x2)洗涤，用无水硫酸钠干燥并浓缩，将粗残余物制备型TLC(乙酸乙酯)纯化，制备型HPLC(甲酸)再次纯化，得本实施例标题化合物(5.7mg,5％)，白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),8.23(s,1H),7.83(d,J＝8.8Hz,1H),7.71(d,J＝4.4Hz,1H),7.21(d,J＝4.0Hz,1H),6.97-6.92(m,2H),4.61-4.53(m,2H),4.07-4.03(m,2H),3.72(t,J＝4.4Hz,2H),3.61-3.58(m,2H),3.07(s,2H),2.69(t,J＝5.2Hz,2H),2.26(s,3H).LCMS(ESI)m/z:477.1(M+1).
实施例6
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代-1,3-氧杂氮杂环己烷-3-基)-1,3,3a,4-四氢苯并[b] 恶唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000027
步骤A：在氮气下，向(3R,3aS)-7-溴-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(1.5g,3.6mmol)、Cs2CO3(2.4g,7.2mmol)和1,3–氧杂氮杂环己烷-2-酮(550mg,5.4mmol)的甲苯(20mL)溶液中加入Pd2(dba)3(916mg,0.66mmol)和Xantphos(420mg,0.7mmol)，回流16小时，将反应液冷却至室温，然后倒入水(30mL)中，用EtOAc(30mL x2)萃取。合并的有机层用无水硫酸钠干燥并浓缩。将粗的残余物经硅胶色谱(PE:EtOAc＝20:1～3:1)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2-氧代-1,3-氧杂氮杂环己烷-3-基)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(250mg,16％)。LCMS(ESI)m/z:435.1(M+1).
步骤B：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物，其中将步骤G中的吗啉-3-酮替换为1,3-氧氮杂己环-2-酮，得到白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.6Hz,1H),7.83(d,J＝8.2Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.4Hz,1H),7.01-6.97(m,2H),4.61-4.55(m,2H),4.32(t,J＝5.6Hz,2H),4.07-4.04(m,2H),3.73(t,J＝5.6Hz,2H),3.63-3.60(m,2H),2.11-2.05(m,2H)；LCMS(ESI)m/z:464.1(M+1).
实施例7
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡啶-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000028
步骤A：根据实施例1制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2–氧代四氢嘧啶-1(2H)-基)-3α,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将步骤G中的吗啉-3-酮替换为四氢嘧啶-2(1H)-酮，产率为7％。LCMS(ESI)m/z:434.2(M+1).
步骤B：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.69-7.75(m,2H),7.20(d,J＝4.0Hz,1H),6.85-6.95(m,2H),6.55(s,1H),4.47-4.62(m,2H),3.94-4.10(m,2H),3.71(t,J＝5.6Hz,2H),3.56(t,J＝5.6Hz,2H),3.20(td,J＝5.2,2.0Hz,2H),1.91(t,J＝6.0Hz,2H)；LCMS(ESI)m/z:463.0(M+1).
实施例8
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡啶-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000029
步骤A：根据实施例1制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2-氧代吡啶-1(2H)-基)-3α,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将步骤G中的吗啉-3-酮替换为吡啶-2(1H)-酮，产率为22％。LCMS(ESI)m/z:429.1(M+1).
步骤B：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),7.95(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.59(dd,J＝6.8,1.6Hz,1H),7.49(ddd,J＝9.2,6.8,2.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.06(d,J＝2.4Hz,1H),7.01(dd,J＝8.8,2.4Hz,1H),6.45(d,J＝9.2Hz,1H),6.29(td,J＝6.8,1.2Hz,1H),4.56-4.69(m,2H),4.03-4.16(m,2H),3.75(t,J＝5.6Hz,2H)；LCMS(ESI)m/z:458.1(M+1).
实施例9
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡嗪-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000030
步骤A：根据实施例1制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2-氧代吡嗪-1(2H)-基)-3α,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将步骤G中的吗啉-3-酮替换为吡嗪-2(1H)-酮，产率为30％。LCMS(ESI)m/z:430.2(M+1).
步骤B：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物。1H NMR(400MHz,DMSO-d6)δ9.02(t,J＝6.0Hz,1H),8.10(d,J＝1.2Hz,1H),7.98(d,J＝8.4Hz,1H),7.72(d,J＝4.0Hz,1H),7.61(dd,J＝4.4,1.0Hz,1H),7.37(d,J＝4.4Hz,1H),7.17-7.24(m,2H),7.11(dd,J＝8.8,2.4Hz,1H),4.54-4.71(m,2H),4.04-4.18(m,2H),3.74(t,J＝5.6Hz,2H)；LCMS(ESI)m/z:459.0(M+1).
实施例10
5-氯-N-(((3S,3aS)-1-氧代-7-((R)-3-氧代四氢-1H-吡咯[1,2-c]咪唑-2(3H)-基)-1,3,3a,4- 四氢苯并[b]恶唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000031
步骤A：0℃下，向(R)-吡咯烷-2-甲酰胺(5.0g,49.9mmol)的THF(150mL)溶液中分批加入氢化铝锂(9.5mg,0.25mol)，在0℃下搅拌1小时，并回流48小时。将混合物冷却至0℃，并用水(12mL)淬灭。将混合物过滤，滤饼用热THF(150mL x3)洗涤。将合并的滤液浓缩，减压蒸馏，得到(R)-吡咯烷-2-基甲 胺(1.6g，25％)，为无色油状物。1H NMR(400MHz,DMSO-d6)δ2.90-2.87(m,1H),2.76-2.68(m,2H),2.44-2.36(m,2H),1.69-1.55(m,3H),1.26-1.21(m,1H).
步骤B：0℃下，向(R)-吡咯烷-2-基甲胺(1.0g,1.0mmol)的DCM(50mL)溶液中加入二(1H-咪唑-1-基)甲酮(1.6g,1.0mmol)的DCM(20mL)溶液，7℃下搅拌16小时，然后浓缩。将粗的残余物经硅胶色谱(PE:EtOAc＝1:1to DCM)纯化，得到(R)-四氢-1H-吡咯并[1,2-c]咪唑-3(2H)-酮(300mg,24％)，为白色固体。1H NMR(400MHz,CDCl3)δ5.35-5.32(brs,1H),3.64-3.76(m,1H),3.63-3.62(m,2H),3.32-3.30(m,1H),3.07-3.05(m,1H),1.98-1.94(m,3H),1.48-1.42(m,1H).
步骤C：根据实施例6制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-((R)-3-氧代四氢-1H-吡咯并[1,2-c]咪唑-2(3H)-基)-3α，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将步骤A中的1,3-氧杂氮杂环己烷-2-酮替换为(R)-四氢-1H-吡咯并[1,2-c]咪唑-3(2H)-酮，得白色固体，产率为59％。LCMS(ESI)m/z:460.2(M+1).
步骤D：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.76(d,J＝9.2Hz,1H),7.72(d,J＝4.4Hz,1H),7.33(d,J＝2.4Hz,1H),7.22(d,J＝2.4Hz,1H),7.16(dd,J＝8.8,2.4Hz,1H),4.58-4.52(m,2H),4.05-4.02(m,2H),3.92-3.90(m,1H),3.76-3.70(m,4H),3.51-3.50(m,1H),3.02-3.01(m,1H),2.03-2.00(m,1H),1.92-1.79(m,2H),1.37-1.31(m,1H)；LCMS(ESI)m/z:489.2(M+1).
实施例11
5-氯-N-(((3S,3aS)-1-氧代-7-((S)-3-氧代四氢-1H-吡咯[1,2-c]咪唑-2(3H)-基)-1,3,3a,4- 四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000032
步骤A：根据实施例10步骤A、B、C、D的顺序制备本实施例标题化合物，其中将步骤A中的(S)-四氢-1氢-吡咯[1,2-c]咪唑-3(2氢)-酮替换为(R)-四氢-1氢-吡咯[1,2-c]咪唑-3(2氢)-酮，得白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.6Hz,1H),7.76(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.36(d,J＝2.4Hz,1H),7.22(d,J＝4.0Hz,1H),7.15(dd,J＝9.2,2.4Hz,1H),4.58-4.52(m,2H),4.05-4.02(m,2H),3.92-3.90(m,1H),3.75-3.72(m,4H),3.51-3.49(m,1H),3.02-2.98(m,1H),2.03-1.99(m,1H),1.95-1.75(m,2H),1.37-1.31(m,1H)；LCMS(ESI)m/z:489.2(M+1).
实施例12
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-1-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000033
步骤A：根据实施例1制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将步骤G中的吗啉-3-酮替换为吡咯烷-2-酮，产率为32％。LCMS(ESI)m/z:419.1(M+1).
步骤B：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物。1H NMR(400MHz,DMSO-d6)δ8.98(t,J＝5.6,1H),7.80(d,J＝9.2Hz,1H),7.70(d,J＝4.4Hz,1H),7.40(d,J＝2.4Hz,1H),7.22-7.19(m,2H),4.58-4.52(m,2H),4.05-4.02(m,2H),3.79-3.69(m,4H),2.48-2.47(m,2H),2.06-1.99(m,2H)；LCMS(ESI)m/z:448.1(M+1).
实施例13
5-氯-N-(((3S,3aS)-7-((S)-3-羟基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000034
反应流程：
Figure PCTCN2014085844-appb-000035
步骤A：向搅拌着的(S)-4-氨基-2-羟基丁酸(15.0g,0.126mol)的MeOH(100mL)溶液中滴加浓硫酸(14.8mL,0.151mol)，滴加超过5分钟，回流4小时，反应液可以降温至18℃，用水(15mL)稀释，分批加入过量K2CO3，搅拌15分钟，反应混合物用DCM(150mL)稀释，硅藻土过滤。将滤液蒸发至干，得到粘稠液体残留物。将残余物用1-2％MeOH的DCM溶液进行打浆，并过滤。合并有机层，浓缩，得到(S)-3-羟基吡咯烷-2-酮(11g,86％)，为白色固体。1H NMR(400MHz,CDCl3)δ6.74(brs,1H),4.35(t,J＝8.8,1H),3.49-3.39(m,1H),3.36-3.30(m,1H),2.52-2.47(m,1H),2.11-2.05(m,1H).
步骤B：向(S)-3-羟基吡咯烷-2-酮(2g,19.7mmol)的DMF(20mL)溶液中加入咪唑(3.37g,49.4mmol)，然后滴加TBDPSCl(9.24g,33.6mmol)。将所得混合物加热至90℃，并搅拌15小时。将混合物倾入NaHCO3水溶液(100mL)中，用EtOAc(50mL)萃取。将合并的有机相用盐水洗涤，用无水硫酸钠干燥，浓缩。将粗残余物通过硅胶柱色谱(PE：EA＝10:1～1:1)纯化，得到(S)-3-((叔丁基二苯基甲硅烷基)氧基)吡咯烷-2-酮(5g,74％)，为白色固体。LCMS(ESI)m/z:340.2(M+1).
步骤C：向(3R,3aS)-7-溴-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-1(3H)-酮(2g,4.83mmol)的甲苯(30mL) 溶液中加入(S)-3-((叔丁基二苯基甲硅烷基)氧基)吡咯烷-2-酮(2.5g,7.24mmol)、Cs2CO3(3.15g,9.66mmol)、Pd2(dba)3(440mg,0.483mmol)和Ruphos(224mg,0.483mmol)。将混合物加热至80℃持续16小时。将混合物倾入水(50mL)中，用EtOAc(50mL x2)萃取。有机物用Na2SO4干燥，浓缩。将粗残余物通过硅胶柱色谱(PE：EA＝20:1～3:1)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)-酮(1.15g,35％)，为黄色固体。LCMS(ESI)m/z:673.3(M+1).
步骤D：根据实施例1步骤G、I、J、K、L的顺序制备5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺,其中将步骤G中的吗啉-3-酮替换为(S)-3-((叔丁基二苯基甲硅烷基)氧基)吡咯烷-2-酮。LCMS(ESI)m/z:702.2(M+1).
步骤E：在0℃下，向N-(((3S,3aS)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺(500mg,0.713mmol)的THF(10mL)溶液中滴加TBAF(3.72g,1.43mmol)，将混合物在20℃下搅拌1小时，减压除去溶剂，将粗产物通过制备型HPLC(甲酸)纯化，得到5-氯-N-(((3S,3aS)-7-((S)-3-羟基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(115mg,35％)，为白色固体。1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝6.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.71(d,J＝4.0Hz,1H),7.45(d,J＝2.8 Hz,1H),7.26-7.20(m,2H),5.74(d,J＝5.4Hz,1H),4.58-4.53(m,2H),4.28-4.27(m,1H),4.06-4.04(m,2H),3.73-3.63(m,4H),2.39-2.34(m,1H),1.84-1.79(m,1H)；LCMS(ESI)m/z:464.1(M+1).
实施例14
5-氯-N-(((3S,3aS)-7-(2-甲氧基-N-甲乙酰氨基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000036
步骤A：0℃下,向((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)氨基甲酸叔丁酯(991mg,2.2mmol)的DMF(10mL)溶液中滴加NaH(123mg,3.1mmol)，并在0℃下搅拌20分钟。然后在0℃下加入MeI(624mg,4.4mmol)并在0℃下搅拌1小时。加入饱和NH4Cl水溶液(30mL)并用EtOAc(30mL x2)萃取混合物。合并有机相经无水硫酸钠干燥，过滤并浓缩得到((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)(甲基)氨基甲酸叔丁酯(1.00g)，褐色油状物，直接用于下一步反应，无需进一步纯化。LCMS(ESI)m/z: 409(M+1).
步骤B：根据实施例1步骤H、I、J、K和L的顺序制备((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)(甲基)氨基甲酸叔丁酯，其中将步骤H中的吗啉-3-酮替换为甲氨基甲酸叔丁酯，得到黄色固体。LCMS(ESI)m/z:438(M+1).
步骤C：室温下，向((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)(甲基)氨基甲酸叔丁酯(741mg,1.5mmol)的DCM(5mL)溶液中加入HCl/二氧六环(5mL,4M)并室温搅拌1小时。将混合物蒸发，粗残余物经硅胶色谱(MeOH:DCM＝1:100～1:50)纯化，得到5-氯-N-(((3S,3aS)-7-(甲氨基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(450mg,76％)，黄色固体。LCMS(ESI)m/z:394(M+1).
步骤D：向5-氯-N-(((3S,3aS)-7-(甲氨基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(158mg,0.4mmol)的DCM(4mL)溶液中加入Et3N(202mg,2.0mmol)，然后在0℃下滴加2-甲氧基乙酰氯(56mg,0.5mmol)的DCM(1mL)溶液并在0℃下搅拌两小时。加入饱和NaHCO3水溶液(10mL)然后用DCM(10mL x3)萃取混合物。合并有机相用无水Na2SO4干燥，过滤并浓缩。粗产物经制备型HPLC(甲酸)纯化，得到本实施例标题化合物(60mg,32％)，黄色固体。1H NMR(400MHz,DMSO-d6)δ9.03(t,J＝6.0Hz,1H),7.88(d,J＝8.4Hz,1H),7.73(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),7.04(s,1H),6.96(d,J＝8.4Hz,1H),4.61-4.55(m,2H),4.09-4.06(m,2H),3.74-3.71(m,4H),3.18(s,3H),3.11(s,3H)；LCMS(ESI)m/z:466(M+1).
实施例15
5-氯-N-(((3S,3aS)-1-氧代-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-1,3,3a,4-四氢苯并[b] 恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000037
步骤A：0℃下，向3-氨基丙-1-醇(5.0g,66.6mmol)的THF(50mL)溶液中分批加入Na2CO3(8.5g,80.0mmol)的水(10mL)溶液。然后在0℃下滴加二碳酸二叔丁酯((14.8g,67.9mmol)，滴加30分钟。16℃下搅拌两小时。加入水，用二氯甲烷(200mL x2)萃取混合物。合并有机层并用无水碳酸氢钠水溶液洗涤,用无水硫酸钠干燥并浓缩，得到(3-羟丙基)氨基甲酸叔丁酯(11.7g,产率99％)，直接用于下一步反应，无需进一步纯化。
步骤B：-10℃下，向(3-羟丙基)氨基甲酸叔丁酯(8.0g,45.7mmol)、NaOH水溶液(20mL,457mmol,50％)和n-Bu4NBr(736mg,2.3mmol)的甲苯(80mL)溶液中滴加2-溴乙酸叔丁酯(9.8g,50.2mmol)的甲苯(20mL)溶液。将混合物在22℃下搅拌16小时。分离出有机层，用乙酸乙酯萃取水层(25mL x1)，然后将 水层调节至pH＝2并用甲苯(100mL x2)萃取。将合并的有机相用盐水洗涤，无水硫酸钠干燥并浓缩，得到粗产品2-(3-((叔丁氧基羰基)氨基)丙氧基)乙酸(7.4g,产率56％)，直接用于下一步，无需进一步纯化。
步骤C：0℃下向2-(3-((叔丁氧基羰基)氨基)丙氧基)乙酸(7.0g,30.0mmol)的MeOH(50mL)溶液中滴加氯化亚砜(10mL)。所得混合物在16℃下搅拌2小时，然后浓缩得到2-(3-氨基丙氧基)乙酸甲酯盐酸盐(5.5g，产率99％)，直接用于下一步，无需进一步纯化。
步骤D：0℃下，向2-(3-氨基丙氧基)乙酸甲酯盐酸盐(6.0g,38.1mmol)的MeOH(100mL)溶液中加入K2CO3(23g,163.0mmol)，回流3小时，浓缩，然后加水。所得混合物用乙酸乙酯(20mL x3)萃取。用盐水洗涤有机相，用无水硫酸钠干燥，浓缩，然后经柱色谱法(PE:EtOAc＝5:1～1:1)纯化，得到1,4-氧杂氮杂环庚烷-3-酮，白色固体(300mg,收率10％).
步骤E:根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将步骤G中的吗啉-3-酮替换为1,4-氧杂氮杂环庚烷-3-酮，得白色固体。1H NMR(400MHz,DMSO-d6)δ9.03-9.00(m,1H),7.82(d,J＝9.2Hz,1H),7.73(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),6.85-6.80(m,2H),4.61-4.55(m,2H),4.26(s,2H),4.10-4.00(m,2H),3.85-3.75(m,4H),3.74-3.72(m,2H),1.96-1.93(m,2H)；LCMS(ESI)m/z:479.1(M+1).
实施例16
1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-7-基)-2-氧代吡啶-3-甲酸乙酯
Figure PCTCN2014085844-appb-000038
步骤A：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为2-氧代哌啶-3-甲酸乙酯。得到白色固体。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝6.0Hz,1H),7.83(d,J＝9.2Hz,1H),7.71(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),4.59-4.53(m,2H),4.12-4.06(m,4H),3.73-3.52(m,6H),2.12-2.01(m,3H),1.19(t,J＝6.8Hz,3H)；LCMS(ESI)m/z:534.1(M+1).
实施例17
5-氯-N-(((3S,3aS)-7-(3-(羟甲基)-2-氧代哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000039
步骤A：0℃下，向1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-2-氧代哌啶-3-甲酸乙酯(350mg, 0.656mmol)的MeOH(5mL)溶液中加入CaCl2(72.8mg,0.656mmol)和NaBH4(75mg,1.96mmol)，20℃下搅拌16小时。将混合物倾入水(30mL)中，用EtOAc(30mL x2)萃取，无水硫酸钠干燥，过滤并浓缩。粗残余物经硅胶色谱(EtOAc)纯化，得到5-氯-N-(((3S,3aS)-7-(3-羟基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(120mg,42％)，为浅黄色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化得到两个组分，一个是10mg，另一个也是10mg。组分1:1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝6.0Hz,1H),7.81(d,J＝8.4Hz,1H),7.71(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.89-6.86(m,2H),4.67-4.53(m,3H),4.07-4.01(m,2H),3.55-3.51(m,6H),2.43-2.42(m,1H),1.93-1.78(m,4H).MS(ESI)m/z:492(M+1).组分2：1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝6.0Hz,1H),7.81(d,J＝8.4Hz,1H),7.71(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.89-6.86(m,2H),4.67-4.53(m,3H),4.07-3.99(m,2H),3.55-3.53(m,6H),2.43-2.42(m,1H),1.93-1.77(m,4H).MS(ESI)m/z:492(M+1).
实施例18
5-氯-N-(((3S,3aS)-7-(2-(羟甲基)-5-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000040
步骤A：-10℃下，向3-氨基丙烷-1,2-二醇(7.5g,82.3mmol)的CH3CN(270mL)和MeOH(45mL)溶液中加入三乙胺(9.98g,98.8mmol)，然后在-10℃、氮气下滴加氯乙酰氯(10.2g,90.5mmol)。将反应混合物升至室温并搅拌16小时。真空浓缩，粗残余物经硅胶色谱(MeOH:EtOAc＝1:11)纯化，得到2-氯-N-(2,3-二羟基丙基)乙酰胺(10.2g,74.2％)，黏稠油状物。.
步骤B：室温和氮气下，向搅拌着的叔丁醇钾(5.61g,5.0mmol)的40mL叔戊醇溶液中加入2-氯-N-(2,3-二羟丙基)乙酰胺(3.35g,2.0mmol)的70mL叔戊醇溶液，2小时加完。搅拌不少于1小时后，加入MeOH(20mL)和H2O(1mL)，然后再搅拌20分钟。真空浓缩，粗残余物经硅胶色谱(MeOH:EA＝1:4)纯化，得到6-(羟甲基)吗啉-3-酮(1.4g,53％)，黄色油状物。
步骤C：向6-(羟甲基)吗啉-3-酮(1.4g,10.7mmol)的吡啶(9mL)和THF(17mL)溶液中加入TBDPSCl(4.4g,16.0mmol)和AgNO3(3.93g,23.5mmol)，将混合物在5～15℃下搅拌15小时。真空除去THF和吡啶。粗残余物经硅胶色谱(PE:EtOAc＝1:10～1:1)纯化，得到6-(((叔丁基二苯基甲硅烷基)氧基)甲基)吗啉-3-酮(2.8g,71％)，黄色固体。
步骤D：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为6-(羟甲基)-吗啉-3-酮。该产物是白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，一个是8mg， 另一个是9mg。组分1:1H NMR(400MHz,DMSO-d6)δ9.03(t,J＝6.0Hz,1H),7.87(d,J＝6.0Hz,1H),7.73(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),7.05(d,J＝0.6Hz,1H),7.01(dd,J＝5.2,2.0Hz,1H),4.55-4.62(m,2H),4.23(s,2H),4.03-4.12(m,2H),3.93–3.99(m,1H),3.73(t,J＝6.0Hz,2H),3.65(t,J＝12.0Hz,1H),3.50-3.58(m,4H).LCMS(ESI)m/z:494(M+1).组分2：1H NMR(400MHz,DMSO-d6)δ9.02(t,J＝5.6Hz,1H),7.86(d,J＝8.8Hz,1H),7.73(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.99-7.05(m,2H),4.54-4.60(m,2H),4.22(s,2H),4.05-4.09(m,2H),3.95-3.97(m,1H),3.72(t,J＝6.0Hz,2H),3.65(m,1H),3.45-3.51(m,4H).LCMS(ESI)m/z:494(M+1).
实施例19
5-氯-N-(((3S,3aS)-7-(2-甲基-3-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000041
步骤A：0℃下，向氢化钠(3.27g,81.9mmol)的甲苯(80mL)溶液中滴加2-乙醇胺(2.5g,40.9mmol)的甲苯(30mL)溶液.，25℃下搅拌0.5小时，然后在25℃下滴加2-氯丙酸乙酯(6.15g,45.0mmol)的甲苯(30mL)溶液。所得混合物回流16小时。加入固体NH4Cl(6.0g)，再搅拌0.5小时。过滤混合物，浓缩滤液，粗残余物经硅胶色谱(PE:EtOAc＝5:1～1:1)纯化，得到2-甲基吗啉-3-酮(2.0g,43％)，无色油状物。
步骤B：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为2-甲基吗啉-3-酮该产物为白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，一个是20mg，另一个是17mg。组分1:1H NMR(400MHz,DMSO-d6)δ9.04-8.96(m,1H),7.50(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),7.03-6.98(m,2H),4.57-4.55(m,2H),4.30-4.28(m,1H),4.07-3.95(m,3H),3.92-3.76(m,2H),3.74-3.70(m,2H),3.57-3.52(m,1H),1.36(d,J＝6.8Hz,3H).LCMS(ESI)m/z:478(M+1).组分2:1H NMR(400MHz,DMSO-d6)δ9.04-8.96(m,1H),7.50(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),7.03-6.98(m,2H),4.57-4.55(m,2H),4.30-4.28(m,1H),4.07-3.95(m,3H),3.92-3.76(m,2H),3.74-3.70(m,2H),3.57-3.52(m,1H),1.36(d,J＝6.8Hz,3H).LCMS(ESI)m/z:478(M+1).
实施例20
5-氯-N-(((3S,3aS)-7-((R)-3-甲基-5-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000042
步骤A：0℃下，向氢化钠(6.2g,145mmol)的甲苯(150mL)溶液中滴加(R)-2-氨基丙烷-1-醇(5.0g,67.0mmol)的甲苯(60mL)溶液。将混合物在25℃下搅拌0.5小时。然后在25℃下滴加2-氯乙酸乙酯(8.0mL g,73.8mmol)的甲苯(60mL)溶液，将混合物回流16小时。加入固体NH4Cl(6.0g)，搅拌0.5小时。过滤混合物，浓缩滤液，经硅胶色谱(PE:EtOAc＝5:1～0:1)纯化，得到(R)-5-甲基吗啉-3-酮(3.5g,46％)，无色油状物。
步骤B：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为(R)-5-甲基吗啉-3-酮,该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.02(dd,J＝12.0,6.0Hz,1H),7.88(d,J＝8.4Hz,1H),7.72(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),6.95-6.90(m,2H),4.61-4.55(m,2H),4.50-4.01(m,4H),4.00-3.80(m,2H),3.75-3.65(m,3H),1.03(d,J＝6.8Hz,3H).LCMS(ESI)m/z:478(M+1).
实施例21
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代-8-氧杂-3-氮杂双环[3.2.1]辛-3-基)-1,3,3a,4-四氢 苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000043
步骤A：向呋喃-2-甲酸甲酯(10.0g,71.4mmol)的二氯甲烷(100mL)溶液中加入无水氯化锌(2.9g,21.4mmol)和多聚甲醛(3.2g,107.0mmol)，将混合物温热至40℃，无水氯化氢气体鼓泡1小时。加水，混合物用二氯甲烷(100mL x2)萃取。合并有机层用盐水洗涤，无水硫酸钠干燥，过滤并浓缩，得到5-(氯甲基)呋喃-2-甲酸甲酯(13.5g,99％)，无色油状物。
步骤B：5-(氯甲基)呋喃-2-甲酸甲酯(3.5g,18.6mmol)和叠氮化钠(2.2g,33.4mmol)的DMF(20mL)溶液70℃下搅拌5小时。加水，混合物用乙酸乙酯(100mL x2)萃取。合并有机层用盐水洗涤，经无水硫酸钠干燥，过滤并浓缩，得到5-(叠氮甲基)呋喃-2-甲酸甲酯(3.6g,99％)，直接用于下一步反应，无需进一步纯化。
步骤C：5-(叠氮甲基)呋喃-2-甲酸甲酯(3.6g,18.6mmol)和Pd/C(0.5g,10％)的甲醇(50mL)溶液60℃和30psi氢气压下搅拌48小时，将混合物过滤，浓缩滤液，经硅胶色谱(PE:EtOAc＝5:1～1:1)纯化，得到8-氧杂-3-氮杂双环[3.2.1]辛-2-酮(1.9g,75％)，白色固体。
步骤D：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为8-氧杂-3-氮杂双环[3.2.1]辛-2-酮该产物为白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，一个是29mg，另一个是28mg。组分1:1H NMR(400MHz,DMSO-d6)δ9.01(m,1H),7.83(d,J＝8.8Hz,1H),7.71(d,J＝4.4Hz,1H),7.21(d,J＝4.0Hz,1H),7.02-6.97(m, 2H),4.72-4.70(m,1H),4.60-4.54(m,2H),4.45(d,J＝6.0Hz,1H),4.10-4.00(m,2H),3.85-3.80(m,1H),3.74-3.72(m,2H),3.55-3.50(m,1H),2.09-2.00(m,4H).LCMS(ESI)m/z:490(M+1).组分2：1H NMR(400MHz,DMSO-d6)δ9.01(m,1H),7.83(d,J＝8.8Hz,1H),7.71(d,J＝4.4Hz,1H),7.21(d,J＝4.0Hz,1H),7.02-6.97(m,2H),4.72-4.70(m,1H),4.60-4.54(m,2H),4.45(d,J＝6.0Hz,1H),4.10-4.00(m,2H),3.85-3.80(m,1H),3.74-3.72(m,2H),3.55-3.50(m,1H),2.09-2.00(m,4H).LCMS(ESI)m/z:490(M+1).
实施例22
4-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-7-基)-3-氧代吗啉-2-甲酰乙酯
Figure PCTCN2014085844-appb-000044
步骤A：-78℃下，向(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(3-氧代吗啉代)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(300mg,0.7mmol)的THF(2mL)溶液中滴加LDA(0.4mL,0.8mmol,2M的THF溶液)，在-78℃搅拌1小时，然后分批加入乙基氯甲酸酯(67mg,0.6mmol)的THF(1mL)溶液。将混合物在-78℃下搅拌2小时。加入无水NH4Cl溶液，混合物用乙酸乙酯(20mL x2)萃取。合并有机层用盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶色谱(PE:EtOAc＝1:1～0:1)纯化，得到4-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-3-氧代吗啉-2-甲酸乙酯(100mg,29％)，白色固体。LCMS(ESI)m/z:507(M+1).
步骤B:根据实施例1步骤H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为3-氧代吗啉-2-甲酸乙酯。该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.03-9.01(m,1H),7.87(d,J＝8.8Hz,1H),7.73(d,J＝4.0Hz,1H),7.22(d,J＝4.0Hz,1H),7.04-7.00(m,2H),4.78(s,1H),4.58-4.50(m,2H),4.12-4.09(m,1H),4.08-3.80(m,3H),3.76-3.71(m,4H).LCMS(ESI)m/z:509(M+1).
实施例23
N-(((3S,3aS)-7-((S)-3-氨基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000045
制备流程：
Figure PCTCN2014085844-appb-000046
步骤A：将N-(((3S,3aS)-7-氨基-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺(950mg,2.5mmol)、(S)-2-((叔丁氧羰基)氨基)-4-(甲硫基)丁酸(623mg,2.5mmol)、EDC(959mg,5mmol)、HOBT(766mg,5mmol)、DIPEA(969mg,7.5mmol)和DMF(10mL)混合物在室温下搅拌16小时。加入60mL水，并用EtOAc(60mL x2)萃取。将合并有机层干燥并真空浓缩，粗残余物经硅胶色谱(PE:EtOAc＝3:1～1:2)纯化，得到((S)-1-(((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)氨基)-4-(甲硫基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(1.10g,71％)，黄色固体。LCMS(ESI)m/z:555(M-55).
步骤B：将((S)-1-(((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)氨基)-4-(甲硫基)-1-氧代丁烷-2-基)氨基甲酸叔丁酯(880mg,1.4mmol)、Me3SI(881mg,4.3mmol)和K2CO3(299mg,2.2mmol)的DMSO(10mL)溶液在80℃搅拌16小时。将混合物冷却至室温然后倾入水(60mL)中，并用EtOAc(60mL x2)萃取。合并有机层用盐水(30mL)洗涤，经无水硫酸钠干燥，过滤并浓缩。粗残余物经制备型HPLC(盐酸)纯化，得到((S)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯(300mg,37％)，黄色固体。LCMS(ESI)m/z:507(M-55).
步骤C：室温下，向((S)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯(282mg,0.5mmol)的DCM(3mL)溶液中加入HCl/二氧六环溶液(3mL,4M)，并在室温下搅拌1小时。真空浓缩，粗残余物经制备型SFC和制备型HPLC纯化，得到本实施例标题化合物(10mg,4％)，白色固体。1H NMR(400MHz,DMSO-d6)δ9.12(t,J＝6.0Hz,1H),8.61(brs,3H),7.88(d,J＝8.8Hz,1H),7.78(d,J＝4.0Hz,1H),7.45(d,J＝2.4Hz,1H),7.28(dd,J＝8.8,2.4Hz,1H),7.22(d,J＝4.0Hz,1H),4.63-4.55(m,2H),4.25-4.20(m,1H),4.10-4.03(m,2H),3.87-3.79(m,2H), 3.73(t,J＝5.6Hz,2H),2.55-2.45(m,1H),2.13-2.02(m,1H).LCMS(ESI)m/z:463(M+1).
实施例24
5-氯-N-(((3S,3aS)-7-(2-((甲氨基)甲基)-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b] 恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000047
步骤A：25℃下，将1H-咪唑-2-甲醛(500mg,5.2mmol)和甲胺(2mL)的MeOH(20mL)溶液搅拌30分钟。然后分小份加入NaBH4(400mg,10.4mmol)，然后在60℃搅拌15小时。真空除去溶剂。用DCM(3x25mL)洗涤残余物。合并有机相用无水硫酸钠干燥，过滤并浓缩，得到粗产品1-(1H-咪唑-2-基)-N-甲基甲胺(600mg)，直接用于下一步。
步骤B：将1-(1H-咪唑-2-基)-N-甲基甲胺(600mg,5.38mmol)、三乙胺(654mg,6.46mmol)和二碳酸二叔丁酯(1.18g,5.38mmol)的THF(15mL)溶液在18℃搅拌2小时。溶剂用真空浓缩。粗残余物用硅胶色谱(PE:EtOAc＝10:1～3:1)纯化，得到((1H-咪唑-2-基)甲基)(甲基)氨基甲酸叔丁酯(712mg,65％)，无色油状物。LCMS(ESI)m/z:212(M+1).
步骤C：根据实施例1步骤G、H、I、J、K和L的顺序制备((1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-1H-咪唑-2-基)甲基)(甲基)氨基甲酸叔丁酯，其中将吗啉-3-酮替换为((1H-咪唑-2-基)甲基)(甲基)氨基甲酸叔丁酯。该产物是黄色固体。LCMS(ESI)m/z:574(M+1).
步骤D：向((1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-1H-咪唑-2-基)甲基)(甲基)氨基甲酸叔丁酯(350mg,0.61mmol)的DCM(5mL)溶液中滴加HCl/MeOH溶液(4M,2mL)。将混合物在20℃搅拌两小时。真空除去溶剂，粗残余物经制备型HPLC(盐酸)纯化，得到本实施例标题化合物(140mg,50％)，黄色固体。1H NMR(400MHz,DMSO-d6)δ9.30(brs,1H),9.15(t,J＝5.6Hz,1H),8.01(d,J＝8.4Hz,1H),7.78(d,J＝4.0Hz,1H),7.58(s,1H),7.29(s,1H),7.21-7.22(m,2H),7.15(dd,J＝8.2,2.4Hz,1H),4.63-4.68(m,2H),4.25(brs,2H),4.07-4.16(m,2H),3.75-3.77(m,2H),2.62(s,3H)；LCMS(ESI)m/z:474(M+1).
实施例25
5-氯-N-(((3S,3aS)-7-((S)-3-甲氧基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b] 恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000048
步骤A:向(3R,3aS)-7-溴代-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(1g,2.42mmol)的甲苯(10mL)溶液中加入(S)-3-((叔丁基二苯基甲硅烷基)氧基)吡咯烷-2-酮(1.23g,3.62mmol)、Cs2CO3(1.58g,4.84mmol)、Pd2(dba)3(222mg,0.242mmol)和Ruphos(113mg,0.242mmol)。在氮气氛下，将混合物加热至80℃，加热16小时。将混合物倒入水(50mL)中，用EA(50mL x2)萃取，无水硫酸钠干燥，过滤并浓缩。粗残余物经硅胶色谱(PE:EA＝10:1～1:1)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(600mg,38％)，白色固体。
步骤B：向(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(600mg,0.892mmol)的二氧六环(15mL)溶液中加入盐酸水溶液(10mL,4M)，将混合物在25℃下搅拌3小时。将混合物倒入水(50mL)中，用EA(50mL x2)萃取，盐水洗涤，无水硫酸钠干燥，过滤并浓缩，得到(3R,3aS)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3-(羟甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(400mg,86％)，黄色固体。
步骤C：0℃下，向(3R,3aS)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3-(羟甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(400mg,0.717mmol)的DMF(5mL)溶液中加入NaH(31mg,0.788mmol)和BnBr(145mg,0.86mmol)。将混合物在25℃搅拌3小时，倒入水(30mL)中，用EA(30mL x2)萃取，无水硫酸钠干燥，过滤并浓缩。粗残余物经硅胶色谱(PE:EA＝5:1～1:1)纯化，得到(3R,3aS)-3-((苄氧基)甲基)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(300mg,64％)，白色固体。
步骤D：向(3R,3aS)-3-((苄氧基)甲基)-7-((S)-3-((叔丁基二苯基甲硅烷基)氧基)-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(300mg,0.462mmol)的THF(8mL)溶液中加入TBAF(242mg,0.925mmol)。将混合物在25℃搅拌16小时，然后倾入水(20mL)中，EA(30mL x2)萃取，无水硫酸钠干燥，过滤并浓缩，得到(3R,3aS)-3-((苄氧基)甲基)-7-((S)-3-羟基-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(200mg,90％)，黄色固体。LCMS(ESI)m/z:411(M+1).
步骤E：0℃下，向(3R,3aS)-3-((苄氧基)甲基)-7-((S)-3-羟基-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(200mg,0.487mmol)的DMF (3mL)溶液中加入NaH(23mg,0.584mmol)和MeI(344mg,2.44mmol)。将混合物在25℃下搅拌3小时。然后将混合物倾入水(20mL)中，EA(30mL x2)萃取，合并有机相经无水硫酸钠干燥，过滤并浓缩，得到(3R,3aS)-3-((苄氧基)甲基)-7-((S)-3-甲氧基-2-氧代吗啉代-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(180mg,87％)，黄色固体。LCMS(ESI)m/z:425(M+1).
步骤F：向(3R,3aS)-3-((苄氧基)甲基)-7-((S)-3-甲氧基-2-氧代吗啉代-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(180mg,0.425mmol)的MeOH(5mL)溶液中加入Pd(OH)2(50mg)，50℃、氮气(50psi)下搅拌16小时。冷却至室温后，过滤混合物，浓缩滤液，得到(3R,3aS)-3-(羟甲基)-7-((S)-3-甲氧基-2-氧代吡咯烷-1-基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(100mg,60％)，黄色固体。LCMS(ESI)m/z:335(M+1).
步骤G：根据实施例1步骤I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为(S)-3-甲氧基吡咯烷-2-酮。该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝6.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.71(d,J＝4.0Hz,1H),7.41(d,J＝2.4Hz,1H),7.26-7.21(m,2H),4.59-4.53(m,2H),4.13-4.04(m,3H),3.74-3.69(m,4H),3.45(s,3H),3.31-3.30(m,1H),2.43-2.41(m,1H),1.92-1.87(m,1H)；LCMS(ESI)m/z:478(M+1).
实施例26
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代-2-氮杂双环[2.2.2]辛-2-基)-1,3,3a,4-四氢苯并[b] 恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000049
步骤A：0℃下，向4-氧代环己烷羧酸乙酯(5.0g,29.4mmol)的MeOH(250mL)溶液中通入NH3，然后加入Pd/C(1.0g,10％)，通过气球引入氢气。在40℃下搅拌加热16小时。过滤反应混合物，浓缩滤液至干。粗残余物经硅胶色谱(PE:EtOAc＝40:1～10:1)纯化，得到4-氨基环己烷羧酸乙酯(1.9g,38.2％)，棕色固体。
步骤B：将4-氨基环己烷羧酸乙酯(1.9g,11.1mmol)溶于PhMe(10mL)并加热至170℃持续3小时，冷却至室温后，粗残余物经硅胶色谱(PE:EtOAc＝80:1～30:1)纯化，得到2-氮杂双环[2.2.2]辛-3-酮(0.51g,28.2％)，棕色固体。
步骤C：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为2-氮杂双环[2.2.2]辛-3-酮。该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ8.17(t,J＝5.6Hz,1H),6.96(d,J＝8.8Hz,1H),6.87(d,J＝4.0Hz,1H),6.16(d,J＝2.4Hz,1H),6.11(d,J＝8.8Hz,1H),3.76-3.68(m,2H),3.24-3.17(m,3H),2.89-2.86(m,2H),1.63(s,1H),1.93-1.87(m,3H),1.01-0.86(m,8H.LCMS(ESI)m/z:488(M+1).
实施例27
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氮杂双环[2,2,1]庚-3-酮)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000050
步骤A：将2-氮杂双环[2.2.1]庚-5-烯-3-酮(2.0g,18.3mmol)和干燥的Pd/C(0.2g,10％)加入到MeOH(40mL)中，用气球引入氢气，然后将混合物在45℃下搅拌16小时。过滤反应混合物，滤液浓缩至干，得到2-氮杂双环[2.2.1]庚-3-酮(1.6g,78.8％)，白色固体。
步骤B：根据实施例1步骤G、H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为2-氮杂双环[2.2.1]庚-3-酮。该产物为白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，一个是28.5mg，另一个3.6mg。组分1：1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.6Hz,1H),7.76(d,J＝8.8Hz,1H),7.70(d,J＝4.0Hz,1H),7.26(d,J＝4.0Hz,1H),7.20(d,J＝2.0Hz,1H),7.13(dd,J＝8.8,2.0Hz,1H),4.57-4.52(m,3H),4.02(m,2H),3.69-3.72(m,2H),2.78(s,1H),1.93-1.87(m,3H),1.65-1.60(m,1H),1.50-1.48(m,2H).MS(ESI)m/z:474(M+1).组分2:1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),7.76(d,J＝8.8Hz,1H),7.70(d,J＝4.0Hz,1H),7.27(d,J＝4.0Hz,1H),7.20(d,J＝2.4Hz,1H),7.13(m,1H),4.57-4.53(m,3H),4.07-3.98(m,2H),3.72-3.69(m,2H),2.78(s,1H),1.95-1.87(m,3H),1.65-1.60(m,1H),1.50-1.48(m,2H).MS(ESI)m/z:474(M+1).
实施例28
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代硫代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000051
步骤A：将Na(1.06g,46mmol)溶解于PrOH(100mL)之后，室温下加入2-巯基乙酸乙酯(8.29g,69mmol)并在室温下搅拌0.5小时。然后在室温下加入恶唑烷-2-酮(2.00g,23mmol)并在100℃搅拌16小时。真空除去溶剂，加入水(20mL)，EtOAc(20mL x3)萃取。合并有机层经干燥、过滤、浓缩后，用硅胶色谱(PE:EtOAc＝1:1～1:3)纯化，得到硫代吗啉-3-酮(1.10g,40％)，浅黄色固体。
步骤B：将硫代吗啉-3-酮(350mg,3mmol)、(3R,3aS)-7-溴代-3-((叔丁基二甲基甲硅烷基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(1.04g,2.5mmol)、Cs2CO3(1.63g,5mmol)、Pd2(dba)3(230mg),Xantphos(430mg)的1,4-二氧六环(30mL)溶液的混合物在90℃下搅拌16小时。将混合物冷却至室温，过滤并浓缩。粗残余物经硅胶色谱(PE:EtOAc＝5:1～2:1)纯化，得到(3R,3aS)-3-(((叔丁基 二甲基甲硅烷基)氧基)甲基)-7-(3-氧代硫代吗啉代)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(640mg,56％)，黄色固体。MS(ESI)m/z:451(M+1).
步骤C：根据实施例1步骤H、I、J、K和L的顺序制备本实施例标题化合物，其中将吗啉-3-酮替换为硫代吗啉-3-酮。该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.71(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.93-6.90(m,2H),4.60-4.53(m,2H),4.10-4.01(m,2H),3.91(t,J＝5.6Hz,2H),3.72(t,J＝5.6Hz,2H),3.39(s,2H),3.01(t,J＝5.6Hz,2H).MS(ESI)m/z:480(M+1).
实施例29
5-氯-N-(((3S,3aS)-7-(1,1-二氧化-3-氧代硫代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000052
步骤A：0℃下，向5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代硫代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(48mg,0.1mmol)的DCM(3mL)溶液中分批加入m-CPBA(41mg,0.24mmol)并在0℃搅拌2小时。加入饱和NaHCO3溶液(10mL)，DCM(10mL x3)萃取。合并有机相干燥、浓缩。粗残余物经制备型TLC和制备型HPLC(盐酸)纯化，得到本实施例标题化合物(20mg,50％)，白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.71(d,J＝4.0Hz,1H),7.20(d,J＝4.0Hz,1H),6.94-6.91(m,2H),4.62-4.55(m,2H),4.41(s,2H),4.11-4.02(m,4H),3.74-3.68(m,4H).MS(ESI)m/z:512(M+1).
实施例30
5-氯-N-(((3S,3aS)-7-((R)-2-(甲氧甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000053
步骤A：根据实施例6的方法制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-((R)-2-(甲氧基甲基)吡咯烷-1-基)-3α,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮，其中将骤A中的1,3-氧杂氮杂环己烷-2-酮替换为(R)-2-(甲氧基甲基)吡咯烷，产率92％。LCMS(ESI)m/z:449.2(M+1).
步骤B：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题固体化合物。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝5.4Hz,1H),7.71(d,J＝4.0Hz,1H),7.57(d,J＝9.2Hz,1H),7.21(d,J＝4.0Hz,1H),6.27(dd,J＝9.2,2.8Hz,1H),6.16(d,J＝2.8Hz,1H),4.53-4.46(m,2H),3.97-3.95(m,2H),3.78-3.73(m,1H),3.70(t,J＝ 5.6Hz,2H),3.33-3.31(m,2H),3.27(s,3H),3.21-3.17(m,1H),3.01-2.95(m,1H),1.99-1.87(m,4H)；LCMS(ESI)m/z:478.1(M+1).
实施例31
5-氯-N-(((3S,3aS)-7-((S)-2-(甲氧甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000054
步骤A：根据实施例30步骤A和B的顺序制备本实施例标题固体化合物，为白色固体。其中将步骤A中的(R)-2-(甲氧基甲基)吡咯烷替换为(S)-2-(甲氧基甲基)吡咯烷。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.71(d,J＝4.0Hz,1H),7.58(d,J＝8.8Hz,1H),7.21(d,J＝4.0Hz,1H),6.27(dd,J＝9.2,2.4Hz,1H),6.15(d,J＝2.8Hz,1H),4.53-4.46(m,2H),3.98-3.96(m,2H),3.71-3.68(m,3H),3.36-3.32(m,2H),3.27(s,3H),3.21-3.16(m,1H),3.01-2.95(m,1H),2.01-1.84(m,4H)；LCMS(ESI)m/z:478.1(M+1).
实施例32
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-3-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000055
步骤A：向(3R，3aS)-7-溴代-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(4.0g,9.65mmol)、Pd(OAc)2(0.22g,0.97mmol)和Xantphos(0.92g,1.93mmol)的THF(60mL)溶液中加入(2-乙氧基-2-氧代乙基)锌(II)溴(1.12g,48.27mmol)。将混合物回流搅拌16小时，冷却、浓缩。将粗残余物通过硅胶色谱(石油醚：乙酸乙酯＝15:1～10:1)纯化，得到2-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-7-基)乙酸盐(2.38克，58％)，浅黄色油状物。LCMS(ESI)m/z:422.2(M+1).
步骤B：-70℃下，向2-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)乙酸盐(600mg,1.42mmol)的THF(5mL)溶液中滴加LiHMDS(1.56mL,1M in THF)，所得混合物在-70℃下搅拌1小时，然后在-70℃下滴加2-溴乙腈(307mg,2.56mmol)的THF(2mL)溶液。所得混合物在-70℃下再搅拌1小时，然后加热至15℃并搅拌16小时。将混合物倾入饱和NH4Cl水溶液(30mL)中，用EtOAc(30mL x3)萃取。合并的有机相用无水硫酸钠干燥，过滤并浓缩。将粗残余物通过硅胶色谱(石油醚：乙酸乙酯＝10:1～ 5:1)纯化，得到2-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-3-氰基丙酸酯(366mg,56％)，为黄色油状物。LCMS(ESI)m/z:461.2(M+1).
步骤C：向2-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-3-氰基丙酸酯(366mg,0.79mmol)的MeOH(20mL)和NH3·H2O(30％水溶液，4mL)中加入Raney Nickel(100mg)。所得混合物在30psi的氢气压力下室温搅拌16小时。过滤混合物并浓缩滤液，粗残余物用硅胶色谱(石油醚：乙酸乙酯＝1:1～1:5)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2-氧代吡咯烷-3-基)-3α,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(160mg,48％)，为无色油状物。LCMS(ESI)m/z:419.2(M+1).
步骤D：根据实施例1步骤G、I、J、K、L的顺序制备本实施例标题化合物，其中将步骤G中的吗啉-3-酮替换为2-氧代吡咯烷，得白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，组分1是7.5mg，组分2是3.5mg。组分1：1H NMR(400MHz,DMSO-d6)δ8.8(t,J＝5.6Hz,1H),7.68-7.84(m,3H),7.20(d,J＝4.0Hz,1H),6.80-6.88(m,2H),4.43-4.66(m,2H),3.93-4.13(m,2H),3.72(t,J＝5.2Hz,2H),3.46(t,J＝8.8Hz,1H),3.20-3.30(m,2H),2.38-2.48(m,1H),2.02(m,1H)；MS(ESI)m/z:465(M+1).组分2:1H NMR(400MHz,DMSO-d6)δ9.0(t,J＝5.6Hz,1H),7.70-7.80(m,3H),7.20(d,J＝4.0Hz,1H),6.80-6.88(m,2H),4.43-4.66(m,2H),3.93-4.13(m,2H),3.73(t,J＝5.2Hz,2H),3.47(t,J＝8.8Hz,1H),3.21-3.31(m,2H),2.39-2.49(m,1H),2.03(dq,J＝12.4,8.8Hz,1H).MS(ESI)m/z:465(M+1).
实施例33
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氨磺酰基苯基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000056
制备流程：
Figure PCTCN2014085844-appb-000057
步骤A：根据实施例1步骤G、I、J、K、L的顺序制备N-(((3S,3aS)7-溴代-1-氧代-1，3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯噻吩-2-甲酰胺，其中将步骤G中的吗啉-3-酮替换为溴。LCMS(ESI)m/z:443,445(M+1).
步骤B：烧瓶中加入N-(((3S,3aS)-7-溴-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯噻吩-2-甲酰胺(500mg,1.13mmol)、Pd(dppf)Cl2(80mg,0.113mmol)、双联嚬呐醇硼酸酯(430mg,1.70mmol)、KOAc(332mg,3.39mmol)和1,4-二恶烷(6mL)，快速地用氮气置换反应体系中的空气。将反应加热至80℃，持续16小时。冷却至室温后，倒入水(25mL)中，用EtOAc(30mL x2)萃取。合并有机相用无水硫酸钠干燥，过滤并浓缩。将粗的残余物经硅胶色谱(PE：EA＝5:1至1:1)纯化，得到5-氯-N-(((3S,3aS)-1-氧代-7-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(430mg,77％)，为白色固体。LCMS(ESI)m/z:491.2(M+1).
步骤C：向5-氯-N-(((3S,3aS)-1-氧代-7-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(430mg,0.87mmol)的1,4-二恶烷(6mL)溶液中加入2-溴苯磺酰胺(452mg,1.74mmol)、Pd(t-Bu3P)4(90mg,0.174mmol)、Cs2CO3(572mg,1.74mmol)和H2O(1mL)。将混合物加热至80℃，并持续16小时。将所得混合物冷却，然后倒入水(30mL)，用DCM(30mL x3)萃取，用无水Na2SO4干燥，过滤并浓缩。粗残余物用硅胶色谱(PE：EA＝1:2)纯化，然后用制备型HPLC(甲酸)再次纯化，得到本实施例标题化合物(52mg,11％)，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.02(t,J＝6.0Hz,1H),8.01(d,J＝7.6Hz,1H),7.86(d,J＝8.8Hz,1H),7.73(d,J＝4.0Hz,1H),7.62-7.56(m,2H),7.31-7.30(m,1H),7.23-7.21(m,3H),6.99(d,J＝7.6Hz,2H),4.62-4.55(m,2H),4.12-4.04(m,2H),3.75-3.74(m,2H)；LCMS(ESI)m/z:520.0(M+1).
实施例34
5-氯-N-(((3S,3aS)-1-氧代-7-(1H-1,2,4-三唑-1-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000058
步骤A：根据实施例1制备(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(1H-1,2,4-三唑-1-基)-3α，4-二氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-1(3H)-酮，其中将步骤G中的吗啉-3-酮替换为1H-1,2,4-三唑，产率为30％。LCMS(ESI)m/z:403(M+1).
步骤B：根据实施例1步骤G,I,J,K和L顺序制备实施例2的标题化合物，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),9.05(t,J＝5.6Hz,1H),8.22(s,1H),8.02(d,J＝8.4Hz,1H),7.75(d,J＝4.0Hz,3H),7.52(m,2H),7.22(d,J＝4.0Hz,1H),4.64(m,2H),4.14(m,2H),3.75(t,J＝5.6Hz,2H)；LCMS(ESI)m/z:432(M+1).
实施例35
5-氯-N-(((3S,3aS)-7-(2-((二甲胺基)甲基)-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b] 恶唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000059
步骤A：对(3R,3aS)-7-溴-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)(2.0g,4.38mmol)、K2CO3(0.8g,5.80mmol)、1-(1H-咪唑-2-基)-N，N-二甲基甲胺(0.9g,7.24mmol)和8-羟基喹啉(140mg,0.96mmol)的DMSO(12mL)溶液，先用氮气脱气，再加入CuI(500mg,2.2mmol)。将混合物在130℃下搅拌16小时。冷却至室温后，倒入水(25mL)中，用EtOAc(30mL x2)萃取，用无水硫酸钠干燥，并浓缩。将粗残余物通过硅胶色谱(PE：EA＝5:1～1:1)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(2-((二甲氨基)甲基)-1H-咪唑-1-基)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)-酮，为黄色固体。LCMS(ESI)m/z:459(M+1).
步骤B：根据实施例1步骤G,I,J,K和L顺序制备实施例35的标题化合物，其中将步骤G中的吗啉-3-酮替换为1-(1H-咪唑-2-基)-N，N-二甲基甲胺，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.06(t,J＝5.6Hz,1H),8.7(d,J＝8.8Hz,1H),7.74(d,J＝4.0Hz,1H),7.53(d,J＝1.2Hz,1H),7.22(m,3H),7.12(dd,J＝8.8,2.0Hz,1H),4.66(m,2H),4.4(s,2H),4.1(m,2H),3.76(m,2H),2.78(s,2H)；LCMS(ESI)m/z:488(M+1).
实施例36
5-氯-N-(((3S,3aS)-7-(2-乙基-4,5-二氢-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四苯并[b]恶唑 并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000060
制备流程：
Figure PCTCN2014085844-appb-000061
步骤A：根据实施例6的方法制备((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基甲酸叔丁酯，其中将骤A中的1,3-氧杂氮杂环己烷-2-酮替换为氨基甲酸叔丁酯，产率为85％。LCMS(ESI)m/z:451.2(M+1).
步骤B：根据实施例1步骤G、I、J、K和L的顺序制备((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基甲酸叔丁酯。LCMS(ESI)m/z:480.1(M+1).
步骤C：((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基甲酸叔丁酯(0.62g,1.29mmol)的4M HCl甲醇溶液(10mL)，在15℃时搅拌16小时。将混合物过滤，滤饼用DCM洗涤。然后用饱和NaHCO3水溶液调节滤液的pH值为7～8，并用DCM(50mL x5)萃取。将合并的有机相用无水Na2SO4干燥，过滤，浓缩，得到N-(((3S,3aS)-7-氨基-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺(340mg,69％)，黄色固体。LCMS(ESI)m/z:380,382(M+1).
步骤D：向N-(((3S,3aS)-7-氨基-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺(380mg,1mmol)的甲醇(8mL)和二甲基甲酰胺(8mL)溶液中加入(2-氧代乙基)氨基甲酸叔丁酯((159mg,1mmol))，然 后加入醋酸调节pH＝5～6。将混合物在室温下搅拌1小时，然后加入NaBH3CN(126mg,2mmol)，并在室温下搅拌16小时。向所得混合物中加入饱和NH4Cl(15mL)水溶液(15mL)，并浓缩混合物。将粗残余物通过硅胶色谱(PE：乙酸乙酯＝3:1～1:1)得到(2-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基甲酸叔丁酯(300mg,57％)，为白色固体。LCMS(ESI)m/z:523,525(M+1).
步骤E：室温下，向(2-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基)乙基)氨基甲酸叔丁酯(209mg,0.4mmol)、吡啶(63mg,0.8mmol)和DMAP(10mg,0.08mmol)的DCM(3mL)溶液中加入丙酰氯(56mg,0.6mmol)的DCM(1mL)溶液中，将混合物在室温下搅拌16小时，向所得的混合物中加入饱和NH4Cl水溶液(20mL)中，并用DCM(20mL x3)萃取。合并的有机层用无水硫酸钠干燥，过滤并浓缩。将粗残余物通过硅胶色谱(PE：乙酸乙酯＝3:1～1:1)纯化，得到(2-(N-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)丙酰胺基)乙基)氨基甲酸叔丁酯(200mg,86％)，白色固体。LCMS(ESI)m/z:579,581(M+1).
步骤F：室温下，向(2-(N-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)丙酰胺基)乙基)氨基甲酸叔丁酯(232mg,0.4mmol)的DCM(3mL)溶液中加入4M HCl的1,4-二恶烷溶液(3mL)，并在室温下搅拌1小时。真空除去溶剂，将残余物溶解在AcOH(4mL)中，并在120℃下搅拌16小时，将反应溶液浓缩。将粗残余物通过薄层色谱法(DCM：甲醇＝10:1)纯化，得到粗产物，将粗产物通过制备型HPLC(甲酸)进一步纯化，得到本实施例标题化合物(27mg,14％)，为白色固体1H NMR(400MHz,DMSO-d6)δ9.05(t,J＝5.6Hz,1H),8.28(brs,1H),7.83(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.92-6.88(m,2H),4.61-4.56(m,2H),4.07-4.04(m,2H),3.85-3.82(m,2H),3.74-3.69(m,4H),2.30(q,J＝7.2Hz,2H),1.01(t,J＝7.2Hz,3H).LCMS(ESI)m/z:461,463(M+1).
实施例37
5-氯-N-(((3S,3aS)-7-(2-环丙基-4,5-二氢-1H-咪唑-1-基)-1-氧-1,3,3a,4-四氢苯并[b]恶 唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000062
步骤A:根据实施例36的方法制备(2-(N-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)环丙烷甲酰氨基)乙基)氨基甲酸叔丁酯，其中将步骤E中的丙酰氯替换为环丙烷基甲酰氯，产率为 76％。LCMS(ESI)m/z:591,593(M+1).
步骤B:根据实施例36中步骤F的方法制备本实施例标题化合物，得白色固体。1H NMR(400MHz,DMSO-d6)δ9.04(t,J＝5.6Hz,1H),8.28(brs,1H),7.83(d,J＝8.8Hz,1H),7.72(d,J＝4.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.97-6.91(m,2H),4.60-4.55(m,2H),4.07-4.04(m,2H),3.82-3.79(m,2H),3.74-3.70(m,2H),3.63-3.60(m,2H),1.53-1.48(m,1H),0.97-0.86(m,4H)；LCMS(ESI)m/z:473,475(M+1).
实施例38
5-氯-N-(((3S,3aS)-7-(2-乙基-5,6-二氢嘧啶-1(4H)-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000063
步骤A:根据实施例36的方法制备(3-(((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基)丙基)氨基甲酸叔丁酯，其中将步骤D中的(2-氧代乙基)氨基甲酸叔丁酯替换为(3-氧代丙基)氨基甲酸叔丁酯，产率为65％.LCMS(ESI)m/z:537,539(M+1).
步骤B:在室温下，向(3-(((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1，4]恶嗪-7-基)氨基)丙基)氨基甲酸叔丁酯(215mg,0.4mmol)的DCM(3mL)溶液中加入4M HCl的1,4-二恶烷溶液(3mL)，将混合物在室温下搅拌1小时。减压除去溶剂，将残余物溶解在1,1,1-三乙氧基丙烷/醋酸((6mL,1:1))中，并在120℃下搅拌2小时。冷却至室温后，将反应混合物浓缩。残余物粗品经制备型HPLC(盐酸)纯化，得到本实施例标题化合物((50mg,26％)，为黄色固体。1H NMR(400MHz,DMSO-d6)δ10.10(brs,1H),9.12(brs,1H),7.99(d,J＝8.8Hz,1H),7.78-7.75(m,1H),7.24(d,J＝2.4Hz,1H),7.21(d,J＝4.0Hz,1H),7.00(dd,J＝8.8,2.4Hz,1H),4.64-4.58(m,2H),4.13-4.09(m,2H),3.75-3.71(m,2H),3.66-3.64(m,2H),3.36-3.33(m,2H),2.30-2.23(m,2H),2.10-2.05(m,2H),0.99(t,J＝7.2Hz,2H)；LCMS(ESI)m/z:475,477(M+1).
实施例39
5-氯-N-(((3S,3aS)-7-(4,5-二氢-1H-咪唑-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000064
制备流程：
Figure PCTCN2014085844-appb-000065
步骤A：N-(((3S,3aS)-7-溴代-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯噻吩-2-甲酰胺(200mg,0.45mmol)、CuCN(161mg,1.80mmol)和CuI(9mg,45umol)的NMP(15mL)溶液，在180℃下搅拌8小时。将混合物过滤，将滤液用EtOAc(5mL x3)洗涤。将有机层用水(25mL x2)洗涤，用无水Na2SO4干燥，过滤并浓缩。将粗残余物通过硅胶色谱(PE：乙酸乙酯＝3:1～1:1)纯化，得到5-氯-N-(((3S,3aS)-7-氰基-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(120mg,68％)，为黄色固体。LCMS(ESI)m/z:390,392(M+1).
步骤B:0℃下，5-氯-N-(((3S,3aS)-7-氰基-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(200mg,0.513mmol)的无水甲醇(5mL)溶液中，用氯化氢气体鼓泡30分钟。减压浓缩该反应混合物，得到(3S,3aS)-3-((-5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-甲亚氨酸甲酯，为黄色固体。将粗产物用于下一步骤中，无需进一步纯化。
步骤C：(3S,3aS)-3-((-5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-7-甲亚氨酸甲酯(85mg,0.205mmol)和乙烷-1,2-二胺(1mL)的MeOH(10mL)溶液，在12℃下搅拌2小时。将反应混合物浓缩，粗的残余物经制备型HPLC(甲酸)纯化，得到本实施例标题化合物(20mg,20％)，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.06(t,J＝5.6Hz,1H),8.32(s,1H),7.99(d,J＝7.2Hz,1H),7.73(d,J＝4.4Hz,1H),7.52-7.49(m2H),7.21(d,J＝4.4Hz,1H),4.64-4.58(m,2H),4.16-4.07(m,2H),3.73-3.71(m,6H)；LCMS(ESI)m/z:433,435(M+1).
实施例40
5-氯-N-(((3S,3aS)-7-(1-甲基-4,5-二氢-1H-咪唑-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000066
步骤A:根据实施例39的方法制备本实施例标题化合物，其中将步骤C中的乙烷-1,2-二胺替换为N-甲基乙基-1,2-二胺，得白色固体，产率为44％。1H NMR(400MHz,DMSO-d6)δ9.08(t,J＝5.2Hz,1H),8.31(s,1H),8.02(d,J＝8.4Hz,1H),7.74(d,J＝4.0Hz,1H),7.23-7.20(m,3H),4.65-4.59(m,2H),4.14-4.07(m,2H),3.75-3.74(m,3H),3.67-3.65(m,3H),2.87(s,3H)；LCMS(ESI)m/z:447,449(M+1).
实施例41
5-氯-N-(((3S,3aS)-7-(1-甲基-1,4,5,6-四氢嘧啶-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000067
步骤A:根据实施例39的方法制备本实施例标题化合物，其中将步骤C中的乙烷-1,2-二胺替换为N-甲基丙基-1,3–二氨基甲基乙烷，得白色固体，产率为44％。1H NMR(400MHz,DMSO-d6)δ9.08(t,J＝5.2Hz,1H),8.31(s,1H),8.02(d,J＝8.4Hz,1H),7.74(d,J＝4.0Hz,1H),7.23-7.20(m3H),4.65-4.59(m,2H),4.14-4.07(m,2H),3.75-3.74(m,3H),3.67-3.65(m,3H),2.87(s,3H)；LCMS(ESI)m/z:461,463(M+1).
实施例42
N-(((3S,3aS)-7-((S)-3-氨基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶 -3-基)甲基)-5-氯代噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000068
步骤A：根据实施例6的方法制备((S)-1-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3-1,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)氨基甲酸叔丁酯，其中将步骤A中的1,3-氧杂氮杂环己烷-2-酮替换为(S)-吡咯烷-3-基氨基甲酸叔丁酯，产率96％。LCMS(ESI)m/z:520.2(M+1).
步骤B：根据实施例1中步骤G、I、J、K和L的顺序制备((S)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)氨基甲酸叔丁酯。LCMS(ESI)m/z:549.2(M+1).
步骤C:((S)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)氨基甲酸叔丁酯(45mg,0.1mmol)的4M HCl甲醇溶液(2.0mL)，在5℃下搅拌1小时。将混合物浓缩，并加 入水。除去溶剂，将残余物冻干，得到本实施例标题化合物(35mg,94％)，黄色固体。1H NMR(400MHz,DMSO-d6)δ9.11(t,J＝5.6Hz,1H),8.27(brs,3H),7.77(d,J＝4.0Hz,1H),7.64(d,J＝9.2Hz,1H),7.22(d,J＝4.0Hz,1H),6.26(dd,J1＝2.4Hz,J2＝9.2Hz,1H),6.15(d,J＝2.8Hz,1H),4.55-4.48(m,2H),4.01-3.97(m,3H),3.71-3.68(m,2H),3.46-3.44(m,2H),3.27-3.22(m,2H),2.32-2.29(m,1H),2.08-2.05(m,1H)；LCMS(ESI)m/z:449,451(M+1).
实施例43
N-(((3S,3aS)-7-((R)-3-氨基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000069
步骤A：根据实施例42步骤A、B、C的顺序制备本实施例标题化合物，其中将(S)-吡咯烷-3-基氨基甲酸叔丁酯替换为(R)-吡咯烷-3-基氨基甲酸叔丁酯，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.11(t,J＝5.6Hz,1H),8.27(br s,3H),7.77(d,J＝4.0Hz,1H),7.64(d,J＝9.2Hz,1H),7.22(d,J＝4.0Hz,1H),6.26(dd,J1＝2.4Hz,J2＝9.2Hz,1H),6.15(d,J＝2.8Hz,1H),4.55-4.48(m,2H),4.01-3.97(m,3H),3.71-3.68(m,2H),3.46-3.44(m,2H),3.27-3.22(m,2H),2.32-2.29(m,1H),2.08-2.05(m,1H)；LCMS(ESI)m/z:449,451(M+1).
实施例44
5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000070
步骤A:在0℃下，向(R)-1-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)氨基甲酸叔丁酯(1.0g,1.9mmol)的DMF(10mL)溶液中加入氢化钠(含60％氢化钠的矿物油溶液，110mg,2.7mmol)，然后在0℃下添加MeI(520mg,3.6mmol)，所得混合物在5℃搅拌1小时，将该混合物倾入饱和氯化铵溶液中，并用EtOAc(100mL x3)萃取。有机相用盐水洗涤，用无水硫酸钠干燥，浓缩，得到((R)-1-((3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)(甲基)氨基甲酸叔丁酯(1.0g,99％)，为黄色固体，将其直接用于下一步骤反应。LCMS(ESI)m/z:534.3(M+1).
步骤B：根据实施例1步骤G,I,J,K和L顺序制备((R)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)(甲基)氨基甲酸叔丁酯，其中将步骤G中的吗啉-3-酮替 换为吡咯烷-3-基(甲基)氨基甲酸叔丁酯。LCMS(ESI)m/z:563.2(M+1).
步骤C：((R)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-3-基)(甲基)氨基甲酸叔丁酯(90mg,0.2mmol)的4M HCl甲醇溶液(3mL)中，在17℃下搅拌1小时。将反应混合物浓缩，并用制备型HPLC(盐酸)纯化，得到本实施例标题化合物(50mg,67％)，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.26(brs,2H),9.12(d,J＝6.0Hz,1H),7.77(d,J＝4.4Hz,1H),7.63(d,J＝8.8Hz,1H),7.22(d,J＝4.0Hz,1H),6.28(dd,J＝8.8,2.4Hz,1H),6.18(d,J＝2.4Hz,1H),4.55-4.48(m,2H),4.00-3.97(m,2H),3.84-3.75(m,1H),3.57-3.52(m,2H),3.48-3.40(m,3H),3.21-3.19(m,1H),2.60-2.58(m,3H),2.34-2.16(m,2H)；LCMS(ESI)m/z:463,465(M+1).
实施例45
5-氯-N-(((3S,3aS)-7-((R)-3-(二甲氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶 唑并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000071
步骤A：在10℃下，向5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(74mg,0.2mmol)的MeOH(3.0mL)溶液中加入甲酸水溶液(1.0mL,33％)，17℃下搅拌30分钟，然后加入NaBH3CN(25mg,1.0mmol)，并在40℃搅拌该混合物2小时，用水淬灭反应，用DCM(20mL x3)萃取。合并有机相用无水硫酸钠干燥，浓缩，粗残余物通过制备型HPLC(盐酸)纯化，得到本实施例标题化合物(25mg,33％)，为白色固体1H NMR(400MHz,DMSO-d6)δ11.09(brs,1H),9.10(t,J＝6.4Hz,1H),7.77(d,J＝4.0Hz,1H),7.63(d,J＝8.8Hz,1H),7.22(d,J＝4.0Hz,1H),6.30(dd,J＝8.8,2.4Hz,1H),6.22(d,J＝2.4Hz,1H),4.55-4.48(m,2H),4.00-3.80(m,3H),3.71-3.68(m,2H),3.56-3.55(m,1H),3.48-3.46(m,2H),3.21-3.19(m,1H),2.80-2.78(m,6H),2.40-2.20(m,2H)；LCMS(ESI)m/z:477,479(M+1).
实施例46
5-氯-N-(((3S,3aS)-7-(3-羟基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000072
步骤A：室温下，向哌啶-3-醇(1.01g,10mmol)、TBDPSCl(3.30g,12mmol)的THF/Py的(21mL,4:3)溶液中加入AgNO3(3.57g,21mmol)，并在室温下搅拌16小时。将混合物过滤并浓缩。将粗残余物通过硅胶色谱(甲醇：DCM＝1:50～1:20)纯化，得到3-((叔丁基二苯基甲硅烷基)氧基)哌啶(3.00g,88％)，为棕 色油状物。LCMS(ESI)m/z:340(M+1).
步骤B：根据实施例1步骤F、G、I、J、K和L的顺序制备N-(((3S,3aS)-7-(3-((叔丁基二苯基甲硅烷基)氧基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺，其中将吗啉-3-酮替换为3-((叔丁基二苯基甲硅烷基)氧基)哌啶。LCMS(ESI)m/z:702(M+1).
步骤C：在室温下向N-(((3S,3aS)-7-(3-((叔丁基二苯基甲硅烷基)氧基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺(913mg,1.3mmol)的THF(10mL)溶液中，逐滴加入n-Bu4NF(1.23g,4.7mmol)的THF(10mL)溶液，室温下搅拌16小时，浓缩混合物，粗的残余物经硅胶色谱(甲醇：DCM＝1:50～1:20)纯化，得到本实施例标题化合物(480mg,79％)，为浅黄色固体形态同分异构体。同分异构体经制备型SFC和制备型HPLC进一步纯化得到两个组分，组分1是120mg，组分2是120mg。组分1:1H NMR(400MHz,CD3OD)δ8.12(d,J＝8.8Hz,1H),7.58(d,J＝4.0Hz,1H),7.35(d,J＝2.4Hz,1H),7.28(dd,J＝8.8,2.4Hz,1H),7.05(d,J＝4.0Hz,1H),4.68-4.63(m,2H),4.08-4.07(m,1H),4.06-4.04(m,1H),4.03-4.01(m,1H),3.83-3.81(m,2H),3.70-3.63(m,2H),3.53-3.42(m,2H),2.35-2.33(m,1H),1.94-1.82(m,3H).MS(ESI)m/z:464(M+1).组分2:1H NMR(400MHz,CD3OD)δ8.04(d,J＝8.4Hz,1H),7.57(d,J＝4.0Hz,1H),7.19-7.16(m,2H),7.04(d,J＝4.0Hz,1H),4.65-4.60(m,2H),4.10-4.08(m,2H),4.03-4.01(m,1H),3.82-3.80(m,2H),3.65-3.61(m,2H),3.43-3.35(m,2H),2.27-2.24(m,1H),1.92-1.75(m,3H).MS(ESI)m/z:464(M+1).
实施例47
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶 嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000073
步骤A：室温下，向哌啶-3-醇(1.01g,10mmol)的乙腈溶液(50mL)中加入Boc2O(2.18g,10mmol)，并在室温下搅拌16小时。将混合物浓缩，得到3-羟基哌啶-1-甲酸叔丁酯(2.01g,粗品)，为无色油状物。该粗品直接用于下一步骤。
步骤B：0℃下，向3-羟基哌啶-1-甲酸叔丁酯(2.01g,10mmol)的THF(20mL)的溶液中加入氢化钠(含60％氢化钠的矿物油溶液，400mg,10mmol)，逐渐升至室温，并在室温下搅拌0.5小时，室温滴加MeI(1.42g,10mmol)并搅拌16小时。将混合物真空浓缩，残余物粗品经硅胶色谱纯化(PE:EtOAc＝1:50～1:20)，得到3-甲氧基哌啶-1-甲酸叔丁酯(1.50g,69％)，为无色油状物。
步骤C：室温下，向3-甲氧基哌啶-1-甲酸叔丁酯(1.51g,7mmol)的DCM(5mL)溶液中加入4M HCl的甲醇溶液(5mL)，然后在室温下搅拌16小时，真空浓缩，得到3-甲氧基哌啶盐酸盐(1.05g,粗产物)，为黄色油状物。该粗产物直接 用于下一步反应。
步骤D：根据实施例1步骤F、G、I、J、K和L顺序制备本实施例标题化合物，其中将步骤F中的吗啉-3-酮替换为3-甲氧基哌啶，得到浅黄色固体形态同分异构体。同分异构体经制备型SFC和制备型HPLC进一步纯化得到两个组分，组分1(60mg)，组分2(100mg)。组分1:1H NMR(400MHz,CD3OD)δ8.11(d,J＝8.8Hz,1H),7.57(d,J＝4.0Hz,1H),7.31(d,J＝2.4Hz,1H),7.25(dd,J＝8.8,2.4Hz,1H),7.05(d,J＝4.0Hz,1H),4.68-4.63(m,2H),4.12-4.10(m,1H),4.02-3.99(m,1H),3.83-3.80(m,3H),3.67-3.53(m,3H),3.49-3.45(m,4H),2.25-2.20(m,1H),2.05-2.01(m,1H),1.93-1.87(m,2H).MS(ESI)m/z:478(M+1).组分2:1H NMR(400MHz,CD3OD)δ8.13(d,J＝8.8Hz,1H),7.58(d,J＝4.4Hz,1H),7.36(d,J＝2.4Hz,1H),7.29(dd,J＝8.8,2.4Hz,1H),7.04(d,J＝4.4Hz,1H),4.68-4.64(m,2H),4.06-4.02(m,1H),4.00-3.97(m,1H),3.84-3.81(m,3H),3.69-3.58(m,3H),3.53-3.50(m,1H),3.46(s,3H),2.25-2.23(m,1H),1.95-1.92(m,1H),1.90-1.84(m,2H).MS(ESI)m/z:478(M+1).
实施例48
N-(((3S,3aS)-7-((S)-3-氨基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000074
步骤A：根据实施例42中步骤A、B、C的顺序制备本实施例标题化合物，其中将(S)-吡咯烷-3-基氨基甲酸叔丁基酯替换为(S)-哌啶-3-基氨基甲酸叔丁基酯，该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝4.0Hz,1H),8.41(br.s.,3H),7.81(t,J＝2.8Hz,1H),7.74(dd,J＝8.4,3.2Hz,1H),7.21(d,J＝4.0Hz,1H),6.79(br.s.,2H),4.53-4.57(m,2H),3.98-4.09(m,2H),3.70(t,J＝5.6Hz,2H),3.58(d,J＝11.2Hz,1H),3.35(d,J＝11.6Hz,2H),2.92-3.12(m,2H),1.80-2.01(m,2H),1.51-1.77(m,2H)；LCMS(ESI)m/z:463,465(M+1).
实施例49
N-(((3S,3aS)-7-((R)-3-氨基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000075
步骤A：根据实施例42中步骤A、B、C的顺序制备本实施例标题化合物，其中将(S)-吡咯烷-3-基氨基甲酸叔丁基酯替换为(R)-哌啶-3-基氨基甲酸叔丁基酯，该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.15(t,J＝5.6Hz,1H),8.31(brs.,3H),7.79(d,J＝4.0Hz,1H),7.71(d,J＝8.8Hz,1H),7.21(d,J＝4.0Hz,1H),6.74(d,J＝8.8Hz,1H),6.67(brs.,1H),4.49-4.59(m,2H),3.96-4.05(m,2H), 3.70(t,J＝5.4Hz,2H),3.51-3.57(m,1H),3.31(d,J＝12.4Hz,2H),2.99-3.08(m,1H),2.92(t,J＝9.6Hz,1H),1.95(d,J＝9.2Hz,1H),1.82(d,J＝9.2Hz,1H),1.52-1.73(m,2H)；LCMS(ESI)m/z:463,465(M+1).
实施例50
5-氯-N-(((3S,3aS)-7-((S)-3-(甲基氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000076
步骤A：根据实施例44中步骤A、B、C的顺序制备本实施例标题化合物，其中将(S)-吡咯烷-3-基氨基甲酸叔丁基酯替换为(S)-哌啶-3-基氨基甲酸叔丁基酯，该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.35-9.48(m,1H),9.18(t,J＝5.6Hz,2H),7.80(d,J＝4.0Hz,1H),7.72(d,J＝8.8Hz,1H),7.20(d,J＝4.0Hz,1H),6.67-6.91(m,2H),4.52-4.55(m,2H),3.96-4.09(m,2H),3.61-3.75(m,3H),3.24-3.38(m,2H),3.07-3.17(m,1H),2.93(t,J＝8.8Hz,1H),2.57(t,J＝5.6Hz,3H),2.03(brs.,1H),1.84(brs.,1H),1.65(t,J＝7.6Hz,2H)；LCMS(ESI)m/z:477,479(M+1).
实施例51
5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000077
步骤A：根据实施例44中步骤A、B、C的顺序制备本实施例标题化合物，其中将(S)-吡咯烷-3-基氨基甲酸叔丁基酯替换为(R)-哌啶-3-基氨基甲酸叔丁基酯，该产物为白色固体。1H NMR(400MHz,DMSO-d6)δ9.34(d,J＝4.8Hz,1H),9.15(t,J＝5.6Hz,1H),9.08(d,J＝4.4Hz,1H),7.79(d,J＝4.0Hz,1H),7.69(d,J＝8.8Hz,1H),7.20(d,J＝4.0Hz,1H),6.76(dd,J＝8.8,2.4Hz,1H),6.70(s,1H),4.49-4.58(m,2H),3.97-4.05(m,2H),3.59-3.72(m,3H),3.19-3.34(m,2H),3.08(dd,J＝11.6,8.8Hz,1H),2.89(t,J＝8.8Hz,1H),2.57(t,J＝5.2Hz,3H),2.00(brs.,1H),1.82(d,J＝9.2Hz,1H),1.56-1.70(m,2H)；LCMS(ESI)m/z:477,479(M+1).
实施例52
5-氯-N-(((3S,3aS)-7-((S)-3-(二甲氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000078
步骤A：根据实施例45中步骤A的方法制备本实施例标题化合物，其中将步骤A中的(R)-3-(二甲氨基)吡咯烷替换为(S)-3-(二甲氨基)哌啶，产率为61％。1H NMR(400MHz,DMSO-d6)δ10.91(brs,1H),9.13(t,J＝5.6Hz,1H),7.78(d,J＝4.0Hz,1H),7.69(d,J＝8.8Hz,1H),7.20(d,J＝4.0Hz,1H),6.66-6.82(m,2H),4.49-4.58(m,2H),3.88-4.04(m,2H),3.66-3.74(m,2H),3.53(d,J＝11.6Hz,1H),3.37(d,J＝13.2Hz,1H),2.97(t,J＝11.2Hz,1H),2.68-2.80(m,7H),2.12(brs,1H),1.84(d,J＝5.6Hz,1H),1.56-1.70(m,2H)；LCMS(ESI)m/z:491,493(M+1).
实施例53
5-氯-N-(((3S,3aS)-7-((R)-3-(二甲氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000079
步骤A：根据实施例45中步骤A的方法制备本实施例标题化合物，其中将步骤A中的(R)-3-(二甲氨基)吡咯烷替换为(R)-3-(二甲氨基)哌啶，产率为55％。1H NMR(400MHz,DMSO-d6)δ11.16(brs,1H),9.21(t,J＝5.6Hz,1H),7.81(d,J＝4.0Hz,1H),7.73(d,J＝8.4Hz,1H),7.20(d,J＝4.0Hz,1H),6.75-7.02(m,2H),4.50-4.59(m,2H),4.05-4.11(m,1H),3.91-4.03(m,2H),3.70(brs,2H),3.53(d,J＝12.0Hz,1H),3.45(brs,1H),3.12(t,J＝11.2Hz,1H),2.80-2.89(m,1H),2.75(t,J＝4.8Hz,6H),2.14(d,J＝9.2Hz,1H),1.81-1.93(m,1H),1.60-1.79(m,2H)；LCMS(ESI)m/z:491,493(M+1).
实施例54
(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯
Figure PCTCN2014085844-appb-000080
步骤A：根据实施例6的方法制备(R)-((3R，3AS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-氧代-1，3，3a，4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯，其中将骤A中的1,3-氧杂氮杂环己烷-2-酮替换为(R)-吡咯烷-2-甲酸甲酯，产率72％。LCMS(ESI)m/z:463.2(M+1).
步骤B：根据实施例1步骤G、I、J、K和L的顺序制备本实施例标题化合物。1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝6.0Hz,1H),7.71(d,J＝4.0Hz,1H),7.57(d,J＝9.2Hz,1H),7.21(d,J＝4.4Hz,1H),6.14(dd,J＝8.8,2.4Hz,1H),6.04(d,J＝2.8Hz,1H),4.55-4.50(m,1H),4.47(d,J＝6.8Hz,1H),4.26-4.23(m,1H),3.98-3.93(m,2H),3.69(t,J＝5.6Hz,2H),3.63(s,3H),3.21-3.17(m,1H),3.01-2.95(m,1H),1.99-1.87(m,4H)；LCMS(ESI)m/z:492.1(M+1).
实施例55
(S)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯
Figure PCTCN2014085844-appb-000081
步骤A：根据实施例54步骤A和B的方法制备本实施例标题化合物，其中将步骤A中的(R)-吡咯烷-2-甲酸甲酯替换为(S)-吡咯烷-2-甲酸甲酯。1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝6.0Hz,1H),7.71(d,J＝4.0Hz,1H),7.58(d,J＝9.2Hz,1H),7.21(d,J＝4.4Hz,1H),6.17(dd,J＝8.8,2.4Hz,1H),6.04(d,J＝2.8Hz,1H),4.53-4.46(m,2H),4.25-4.23(m,1H),3.98-3.95(m,2H),3.70(t,J＝5.6Hz,2H),3.63(s,3H),3.21-3.17(m,1H),3.01-2.95(m,1H),2.04-1.87(m,4H)；LCMS(ESI)m/z:492.1(M+1).
实施例56
(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酰胺
Figure PCTCN2014085844-appb-000082
步骤A：(R)-1-((3S,3aS)-3-((5-氯噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯(100mg,0.203mmol)的饱和NH3-乙二醇溶液(20mL)，80℃密封搅拌2小时。冷却至室温后，加入水(100mL)，并用EtOAc(30mLx3)萃取，将合并的有机相用无水硫酸钠干燥并浓缩。将粗的残余物经制备型HPLC(甲酸)纯化，得到本实施例标题化合物(18mg,18％)，为白色固体。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),7.71(d,J＝4.0Hz,1H),7.57(d,J＝8.8Hz,1H),7.33(brs,1H),7.21(d,J＝4.0Hz,1H),7.21(brs,1H),6.15(dd,J＝9.2,2.8Hz,1H),6.04(d,J＝2.4Hz,1H),4.55-4.51(m,1H),4.48(d,J＝7.6Hz,1H),3.97-3.92(m,2H),3.84-3.82(m,1H),3.69(t,J＝5.2Hz,2H),3.51-3.48(m,1H),3.16-3.13(m,1H),2.20-2.16(m,1H),1.98-1.87(m,3H)；LCMS(ESI)m/z:477,479(M+1).
实施例57
(S)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3，4-d][1，4]恶嗪-7-基)吡咯烷-2-甲酰胺
Figure PCTCN2014085844-appb-000083
步骤A：根据实施例56步骤A的方法制备本实施例标题化合物，其中将步骤A中的(R)-吡咯烷-2-甲酰胺替换为(S)-吡咯烷-2-甲酰胺，产率为16％。1H NMR(400MHz,DMSO-d6)δ8.98(t,J＝6.0Hz,1H),7.70(d,J＝4.0Hz,1H),7.56(d,J＝8.8Hz,1H),7.32(brs,1H),7.20(d,J＝4.0Hz,1H),7.01(brs,1H),6.15(dd,J＝8.8,2.4Hz,1H),6.02(d,J＝2.4Hz,1H),4.52-4.45(m,2H),3.97-3.93(m,2H),3.84-3.79(m,1H),3.69(t,J＝5.6Hz,2H),3.51-3.48(m,1H),3.14-3.12(m,1H),2.17-2.15(m,1H),1.98-1.90(m,3H)；LCMS(ESI)m/z:477,479(M+1).
实施例58
5-氯-N-(((3S,3aS)-7-((R)-2-(羟甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000084
步骤A：(R)-((3S,3aS)-3-((5-氯噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯(50mg,0.102mmol)的THF(6mL)溶液中加入LiBH4(39mg,1.02mmol)，15℃搅拌16小时，然后用MeOH(5mL)淬灭反应，并浓缩。残余物粗品经制备型HPLC(甲酸)纯化，得到本实施例标题化合物，为白色固体(15mg,32％)。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝6.4Hz,1H),7.71(d,J＝4.0Hz,1H),7.56(d,J＝8.8Hz,1H),7.21(d,J＝4.0Hz,1H),6.26(dd,J＝8.8,2.4Hz,1H),6.17(d,J＝2.8Hz,1H),4.77-4.74(m,1H),4.53-4.52(m,1H),4.48-4.46(m,1H),3.98-3.95(m,2H),3.71-3.68(m,2H),3.60-3.56(m,1H),3.46-3.31(m,2H),3.08-3.19(m,1H),2.99-2.93(m,1H),1.99-1.81(m,4H)；LCMS(ESI)m/z:464,466(M+1).
实施例59
(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑 并[3，4-d][1，4]恶嗪-7-基)吡咯烷-2-羧酸-2-羟乙基酯
Figure PCTCN2014085844-appb-000085
步骤A：根据实施例56步骤A的方法制备本实施例标题化合物，其中将步骤A中的(R)-2-(羟甲基)吡咯烷替换为(R)-吡咯烷-2-羧酸-2-羟乙基酯，产率为35％。1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝6.0Hz,1H),7.71(d,J＝4.4Hz,1H),7.58(d,J＝8.8Hz,1H),7.21(d,J＝4.0Hz,1H),6.16(dd,J＝9.2,2.8Hz,1H),6.06(d,J＝ 2.4Hz,1H),4.84(t,J＝5.6Hz,1H),4.53-4.50(m,1H),4.48-4.46(m,1H),4.24-4.22(m,1H),4.14-4.19(m,1H),4.06-4.01(m,1H),3.98-3.96(m,2H),3.69(t,J＝6.0Hz,2H),3.58-3.54(m,2H),3.36-3.41(m,1H),3.29-3.21(m,1H),2.34-2.22(m,1H),2.08-1.96(m,3H)；LCMS(ESI)m/z:522,524(M+1).
实施例60
5-氯-N-(((3S,3aS)-7-(环丙基磺酰基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000086
步骤A：将亚硫酸钠(1.8g,14.2mmol)的水(8mL)溶液在20℃下剧烈搅拌10分钟。加入NaHCO3(2.4g,28.5mmol)，并在50℃下搅拌1小时。小心加入环丙磺酰氯(2.0g,14.2mmol)。加完后，将混合物在50℃下剧烈搅拌4小时。冷却至20℃后，将混合物用冷冻干燥法干燥，得到残余物。然后加入甲醇(2mL)，并搅拌1小时，过滤。将滤液浓缩，得到的环丙烷亚磺酸钠(1.0g,55％)，为白色固体。1H NMR(400MHz,甲醇-d4)δ1.84-1.89(m,1H),0.74-0.77(m,2H),0.61-0.64(m,2H).
步骤B：氮气下，向(3R,3aS)-7-溴-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(400mg,0.97mmol)加入环丙烷亚磺酸钠(186mg,1.5mmol)、N，N-二甲基乙烷-1,2-二胺(17mg,0.19mmol)的无水DMF(4mL)和CuI(37mg,0.19mmol)溶液，50℃下在密封的微波管中搅拌20分钟。加入水，将混合物用DCM(50mLx3)萃取。将合并的有机相用盐水洗涤，用无水硫酸钠干燥，浓缩。将粗的残余物经硅胶色谱(PE：乙酸乙酯＝10:1～1:1)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(环丙基磺酰基)-3a,4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(300mg,71％)，为白色固体。LCMS(ESI)m/z:440.1(M+1).
步骤C：根据实施例1步骤G、I、J、K和L的顺序制备本实施例标题化合物，其中将步骤G中的吗啡啉-3-酮替换为环丙烷磺酰基。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝11.6,5.6Hz,1H),8.15(d,J＝8.4Hz,1H),7.72(d,J＝4.0Hz,1H),7.52(dd,J＝8.4,2.0Hz,1H),7.44(d,J＝2.0Hz,1H),7.22(d,J＝4.0Hz,1H),4.63-4.65(m,2H),4.12-4.20(m,2H),3.74-3.76(m,2H),2.82-2.88(m,1H),1.01-1.10(m,4H)；LCMS(ESI)m/z:469(M+1).
实施例61
5-氯-N-(((3S,3aS)-1-氧代-7-(吡咯烷-1-基)磺酰基)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000087
步骤A：将(3R，3aS)-7-溴-3-((叔丁基二甲基甲硅烷基)氧基)甲基)-3a，4-二氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-1(3H)-酮(2.0g,4.82mmol)、苯甲硫醇(1.8g,14.5mmol)、Pd2(dba)3(440mg,0.48mmol)、Xantphos(560mg,0.96mmol)和Cs2CO3(3.14g,9.64mmol)和二恶烷(30mL)的混合物在100℃、氮气氛下加热8小时，冷却至室温并加入水，用EtOAc(50mL x3)萃取。将合并的有机相用盐水洗涤，用无水硫酸钠干燥，浓缩。将粗残余物通过硅胶色谱(PE：乙酸乙酯＝10:1～1:1)，得到(3R,3aS)-7-(苄硫基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)-酮(1.2g,55％)，为油状物。LCMS(ESI)m/z:488(M+1).
步骤B：将(3R,3aS)-7-(苄硫基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)-酮(600mg,1.3mmol)的DCM(12mL)溶液在室温下搅拌，然后加入NCS(0.9g,6.5mmol)和BnOH(650mg,6.3mmol)，室温搅拌14小时。加入DIPEA(300mg,2.33mmol)，并逐滴加入吡咯烷(150mg,2.1mmol)。在室温下搅拌该混合物12小时，然后真空浓缩。将粗残余物通过硅胶色谱(PE:EtOAc＝10:1～1:1)纯化，得到(3R,3aS)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)-7-(吡咯烷-1-基磺酰基)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)-酮(280mg,46％)，为黄色固体。LCMS(ESI)m/z:469(M+1).
步骤C：根据实施例1步骤G、I、J、K和L的顺序制备本实施例标题化合物，其中将步骤G中的吗啡啉-3-酮替换为吡咯烷-1-基磺酰基。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),8.14(d,J＝8.8Hz,1H),7.73(d,J＝4.0Hz,1H),7.45(dd,J＝9.4,2.0Hz,1H),7.33(d,J＝2.0Hz,1H),7.22(d,J＝4.0Hz,1H),4.63(m,2H),4.15(m,2H),3.75(t,J＝5.2,5.2Hz,2H),3.13(t,J＝6.4Hz,4H),1.65(m,4H)；LCMS(ESI)m/z:498(M+1).
实施例62
5-氯-N-(((3S,3aS)-7-((4-甲基哌嗪-1-基)磺酰基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000088
步骤A：根据实施例61步骤A、B、C的顺序制备本实施例标题化合物，其中将步骤C中的吡咯烷-1-基磺酸替换为(4-甲基哌嗪-1-基)磺酰基。1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.18(d,J＝8.4Hz,1H),7.72(d,J＝4.0Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),7.35(d,J＝2.0Hz,1H),7.22(d,J＝4.0Hz,1H),4.68(m,2H),4.12(m,2H),3.76(t,J＝5.2Hz,2H),3.74(s,2H),3.16(s,2H),2.79(s,3H),2.51(s,2H)；LCMS(ESI)m/z:528(M+1).
实施例63
5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代咪唑啉-1-基)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000089
步骤A：0℃，向N-(((3S,3aS)-7-氨基-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯噻吩-2-甲酰胺(80mg,0.21mmol)和三乙胺(43mg,0.42mmol)的THF(3mL)溶液中滴加1-氯-2-异氰酸乙酯(33mg,0.32mmol)的THF(0.5mL)溶液。将反应混合物在15℃时搅拌16小时，真空除去溶剂。粗残余物用硅胶色谱(EtOAc:PE＝1:1)纯化，得到5-氯-N-(((3S,3aS)-7-(3-(2-氯乙基)脲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(100mg,98％)，浅黄色固体。LCMS(ESI)m/z:485(M+1).
步骤B：在0℃,向氢化钠(含60％氢化钠的矿物油溶液，12mg,0.31mmol)的THF(3mL)溶液中加入5-氯-N-(((3S,3aS)-7-(3-(2-氯乙基)脲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(100mg,0.21mmol)的DMF(1.5mL)。将反应混合物在15℃下搅拌1小时。将反应混合物倾入饱和NH4Cl水溶液(20mL)中，并用DCM(20mL x5)萃取。合并的有机物用无水硫酸钠干燥，过滤并浓缩。将粗的残余物经制备型HPLC(甲酸)纯化，得到本实施例标题化合物(30mg,32％)，为浅黄色固体。1H NMR(400MHz,DMSO-d6)δ9.01(t,J＝5.6Hz,1H),7.67-7.78(m,2H),7.29(d,J＝2.4Hz,1H),7.21(d,J＝4.0Hz,1H),7.10(dd,J＝9.2,2.4Hz,1H),6.95(s,1H),4.46-4.61(m,2H),3.97-4.08(m,2H),3.76-3.83(m,2H),3.71(t,J＝5.6Hz,2H),3.37(t,J＝8.0Hz,2H)；LCMS(ESI)m/z:449(M+1).
实施例64
5-氯-N-(((3S,3aS)-7-(3-羟基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000090
步骤A：根据实施例46中步骤A、B、C的顺序制备本实施例标题化合物，其中将哌啶-3-醇替换为(S)-吡咯烷-3-醇。1H NMR(400MHz,DMSO-d6)δ7.71(d,J＝4.0Hz,1H),7.59(d,J＝8.8Hz,1H),7.19(d,J＝4.0Hz,1H),6.29(d,J＝8.8Hz,1H),6.18(s,1H),4.5(m,2H),4.38(m,1H),3.97(m,2H),3.38(dd,J＝10.4,4.8Hz,1H),3.26(m,2H),3.04(d,J＝10.4Hz,2H),2.03(m,1H),1.93-1.87(m,1H)；LCMS(ESI)m/z:450(M+1).
实施例65
5-氯-N-(((3S,3aS)-7-((S)-3-甲氧基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000091
步骤A：根据实施例47中步骤A、B、C和D的顺序制备本实施例标题化合物，其中将3-甲氧基哌啶替换为(S)-3-甲氧基吡咯烷。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H)7.73(d,J＝4.0Hz,1H),7.59(d,J＝8.8Hz,1H),7.22(d,J＝4.0Hz,1H),6.22(dd,J＝8.82.4Hz,1H),6.11(d,J＝2.4Hz,1H),4.54-4.43(m,2H),4.06-3.94(m,3H),3.69(t,J＝5.2Hz,1H),3.36(dd,J＝10.8,5.2Hz,1H),3.19(m,2H),2.25-2.20(m,1H),2.04-2.01(m,2H)；LCMS(ESI)m/z:464(M+1).
实施例66
4-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)苯甲酰胺
Figure PCTCN2014085844-appb-000092
步骤A：室温下，向(3S,3aS)-3-(氨基甲基)-7-(3-氧代吗啉代)-3α，4-二氢苯并[b]恶唑并[3，4-d][1,4]恶嗪-1(3H)-酮(80mg,0.25mmol)、4-甲氧基苯甲酸(43mg,0.28mmol)和DIPEA(48mg,0.38mmol)的DMF(1mL)溶液中加入HATU(110mg,0.28mmol)，并在室温下搅拌16小时。将该混合物通过制备型HPLC(甲酸)纯化，得到本实施例标题化合物(81mg,71％)，白色固体。1H NMR(400MHz,DMSO-d6)δ8.73(t,J＝5.6Hz,1H),7.87-7.83(m,3H),7.05-7.00(m,4H),4.64-4.59(m,1H),4.55-4.51(m,1H),4.17(s,2H),4.15-4.02(m,2H),3.95(t,J＝5.2Hz,2H),3.81(s,3H),3.76-3.71(m,2H),3.70-3.66(m,2H)；LCMS(ESI)m/z:454(M+1).
实施例67
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)吡啶甲酰胺
Figure PCTCN2014085844-appb-000093
步骤A：根据实施例66的方法制备本实施例标题化合物，其中将步骤A中4-甲氧基苯甲酸替换为5-氯吡啶甲酸。1H NMR(400MHz,DMSO-d6)δ9.18(t,J＝6.0Hz,1H),8.74(d,J＝2.4Hz,1H),8.14(dd,J＝8.4,2.4Hz,1H),8.06(d,J＝8.4Hz,1H),7.84(d,J＝8.8Hz,1H),7.04(d,J＝2.0Hz,1H),7.05(dd,J＝8.8,2.0Hz,1H),4.66-4.63(m,1H),4.53-4.48(m,1H),4.19-4.16(m,3H),4.06-4.03(m,1H),3.95(t,J＝5.2Hz,2H),3.79-3.75(m,2H),3.70-3.66(m,2H)；LCMS(ESI)m/z:459(M+1).
实施例68
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)-1H-吲哚-2-甲酰胺
Figure PCTCN2014085844-appb-000094
步骤A：在室温下，5-氯-1H-吲哚-2-羧酸乙酯(45mg,0.2mmol)的乙醇(3mL)溶液中加入NaOH(16mg,0.4mmol)的H2O(3mL)溶液中，室温搅拌16小时。用1N盐酸水溶液调节该混合物pH＝5，用EtOAc(3x10mL)萃取。合并有机层用盐水洗涤，用无水硫酸钠干燥，过滤并浓缩，得到5-氯-1H-吲哚-2-羧酸(30mg,90％)，为浅白色固体。LCMS(ESI)m/z:220(M+1).
步骤B：按照实施例66的方法制备本实施例标题化合物，其中将步骤A中4-甲氧基苯甲酸替换为5-氯-1H-吲哚-2-羧酸。1H NMR(400MHz,DMSO-d6)δ11.86(brs,1H),8.97(t,J＝5.2Hz,1H),7.85(d,J＝8.8Hz,1H),7.72(s,1H),7.43(d,J＝4.4Hz,1H),7.20-7.18(m,2H),7.05(s,1H),7.01(d,J＝8.8Hz,1H),4.66-4.61(m,1H),4.59-4.56(m,1H),4.17-4.13(m,3H),4.10-4.04(m,1H),3.94(t,J＝5.2Hz,2H),3.83-3.75(m,2H),3.70-3.68(m,2H)；LCMS(ESI)m/z:497(M+1).
实施例69
5-甲基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000095
步骤A：按照实施例66的方法制备本实施例标题化合物，其中将步骤A中4-甲氧基苯甲酸替换为5-甲基噻吩-2-羧酸。1H NMR(400MHz,DMSO-d6)δ8.77(t,J＝5.6Hz,1H),7.84(d,J＝8.8Hz,1H),7.62(d,J＝7.6Hz,1H),7.05-6.99(m,2H),6.85(d,J＝3.6Hz,1H),4.59-5.20(m,2H),4.17(s,2H),4.08-4.04(s,2H),3.96-3.93(m,2H),3.71-3.67(m,4H),2.45(s,3H)；LCMS(ESI)m/z:444(M+1).
实施例70
5-溴代-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000096
步骤A：按照实施例66的方法制备本实施例标题化合物，其中将步骤A中的4-甲氧基苯甲酸替换为5-溴噻吩-2-羧酸。1H NMR(400MHz,DMSO-d6)δ8.99(t,J＝5.2Hz,1H),7.85(d,J＝8.8Hz,1H),7.66(d,J＝4.0Hz,1H),7.31(d,J＝4.0Hz,1H), 7.06(d,J＝2.0Hz,1H),7.02(dd,J＝8.4,2.0Hz,2H),4.62-4.54(m,2H),4.18(s,2H),4.07-4.02(m,2H),3.95(t,J＝4.8Hz,2H),3.74-3.68(m,4H)；LCMS(ESI)m/z:508(M+1).
实施例71
5-氰基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000097
反应流程：
Figure PCTCN2014085844-appb-000098
步骤A：用冰水浴冷却，向5-溴噻吩-2-羧酸(500mg,2.42mmol)的甲醇(20mL)溶液中滴加SOCl2(575mg,4.83mmol)。将反应混合物加热至回流，并搅拌12小时。将混合物真空浓缩，残余物用NaHCO3溶液(50mL)淬灭，并用DCM(20mL x2)萃取。将合并的有机相用无水硫酸钠干燥并过滤。将滤液浓缩，得到5-溴噻吩-2-羧酸乙酯(500mg,94％)，为黄色固体LCMS(ESI)m/z:221(M+1).
步骤B：将5-溴噻吩-2-羧酸乙酯(450mg,2.04mmol)和CuCN(550mg,6.11mmol)的DMF(20mL)溶液在氮气下回流2小时。冷却后，加入水(100mL)和EtOAc(50mL)溶液，并过滤。将有机层用无水硫酸钠干燥并过滤。将滤液浓缩，粗的残余物经硅胶色谱(PE:EtOAc＝20:1～10:1)纯化，得到5-氰基噻吩-2-羧酸甲酯(320mg,94％)，为黄色固体。LCMS(ESI)m/z:168(M+1).
步骤C：将5-氰基噻吩-2-羧酸甲酯(100mg,0.60mmol)和NaOH(72mg,1.80mmol)的水(5mL)-THF(5mL)溶液在25℃下搅拌16小时。将混合物浓缩除去THF，用1N盐酸溶液将pH调节至5，过滤。残余物用水(3mL)洗涤，并用无水硫酸钠干燥，然后浓缩，得到5氨基甲酰噻吩-2-羧酸(60mg,58％)，为黄色固体。LCMS(ESI)m/z:172(M+1).
步骤D：5-氨基甲酰噻吩-2-羧酸(40mg,0.234mmol)的氯化亚砜(20mL)溶液，回流2小时。然后将反应混合物浓缩，得到粗产品5-氰基噻吩-2-羰基氯。将粗产品残余物直接用于下一步反应。
步骤E：根据实施例1的方法制备本实施例标题化合物，其中将步骤K中的5-氯噻吩-2-羰基氯替换为5-氰基噻吩-2-羰基氯。1H NMR(400MHz,DMSO-d6)δ9.32(t,J＝5.6Hz,1H),8.00(d,J＝4.0Hz,1H),7.92(d,J＝4.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.05(d,J＝2.0Hz,1H),7.02(dd,J＝8.4,2.0Hz,2H),4.65-4.57(m,2H),4.18(s,2H),4.13-4.03(m,2H),3.95(t,J＝4.4Hz,2H),3.79-3.76(m,2H),3.69(t,J＝5.6Hz,2H)；LCMS(ESI)m/z:455(M+1).
实施例72
5-氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4] 恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000099
步骤A：根据实施例66的方法制备本实施例标题化合物，其中将步骤A中的4-甲氧基苯甲酸替换为5-氟噻吩-2-羧酸。1H NMR(400MHz,DMSO-d6)δ8.97(t,J＝11.6,6.4Hz,1H),7.86(d,J＝8.8Hz,1H),7.61(t,J＝8.0,4.0Hz,1H),7.06-7.01(m,12H),6.84(dd,J＝8.4,2.0Hz,1H),4.57-4.55(m,2H),4.18(s,2H),4.08-4.03(m,2H),3.96-3.92(m,2H),3.73-3.69(m,4H)；LCMS(ESI)m/z:448(M+1).
实施例73
4,5-二氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000100
反应流程：
Figure PCTCN2014085844-appb-000101
步骤A：氮气下，向2,3-二溴噻吩(2g,8.27mmol)的CS2(20mL)溶液中一次加入三氯化铝(1.65g,12.4mmol)，将混合物冷却到0℃，滴加乙酰氯(0.974g,12.4mmol)。然后，将所得混合物在18℃下搅拌16小时。将混合物倾入冰水中，用DCM(50mL x2)萃取，用水(50mL)和盐水(50mL)洗涤，无水硫酸钠干燥，过滤并浓缩，得到1-(4,5-二溴噻吩-2-基)乙酮(1.9g,81％)，为橙色固体。
步骤B：向1-(4,5-二溴噻吩-2-基)乙酮(14.3g,0.05mol)的甲苯(150mL)溶液中加入乙烷-1,2-二醇(12.5g,0.2mol)和TsOH·H2O(451mg,0.0025mol)。在配有Dean-Stank装置的烧瓶中、在氮气下将该混合物加热回流16小时。将混合物倾入水(100mL)中，用EtOAc(150mL x2)萃取，用NaHCO3水溶液和盐水洗涤，用无水硫酸钠干燥，过滤并浓缩。将粗的残余物经硅胶色谱(PE：乙酸乙酯＝50：1)纯化，得2-(4,5-二溴噻吩-2-基)-2-甲基-1，3-二氧戊环(12g,72％)，为黄色固体。
步骤C：在-78℃下，向2-(4-溴代-5-氟代噻吩-2-基)-2-甲基-1，3-二氧戊环(6.2g,0.023mol)的THF(60mL)溶液中，加入n-BuLi(12.1mL,0.03mol)，将混合物搅拌1小时，然后逐滴加入NFSI(0.03mmol，100mL THF中)。然后升温至18℃并搅拌16小时。将反应混合物倾入NH4Cl溶液(80mL)中，用EtOAc(80mL x2)萃取，无水硫酸钠干燥，过滤并浓缩。将粗的残余物经硅胶色谱(PE：EA＝100：1～50：1)纯化，得到2-(4,5-二氟噻吩-2-基)-2-甲基-1，3-二氧戊环(3.5g,73％)，为黄色油状物。
步骤D：向2-(4,5-二氟噻吩-2-基)-2-甲基-1，3-二氧戊环(3.4g,16.5mmol) 的丙酮(30mL)-水(3mL)溶液中加入TsOH(1.42g,8.25mmol)，将反应混合物在18℃下搅拌3小时。然后将混合物倾入水(80mL)中，EtOAc(80mL x2)萃取，NaHCO3(aq)洗涤，无水硫酸钠干燥，过滤并浓缩，得到1-(4,5-二氟噻吩-2-基)乙酮(2.4g,89％)，黄色固体。
步骤E：将搅拌着的1-(4,5-二氟噻吩-2-基)乙酮(200mg,1.23mmol)的二恶烷(3mL)悬浮液加热至50℃。同时，在搅拌条件下通过向NaOH(861mg,21.5mmol)的水(3mL)溶液中滴加Br2(969mg,6.17mmol)来制备次溴酸钠的溶液。将次溴酸钠溶液滴加到二恶烷溶液中，搅拌3小时，然后将该混合物冷却至18℃。将混合物倾入水(30mL)中，用12M HCl水溶液酸化至pH＝1，EtOAc(30mL x2)萃取。合并的有机物用无水硫酸钠干燥，过滤并浓缩，得到4,5-二氟噻吩-2-羧酸(180mg,89％)，黄色固体。
步骤F：按照实施例66的方法制备本实施例标题化合物，其中将步骤A中的4-甲氧基苯甲酸替换为4,5-二氟噻吩-2-羧酸。1H NMR(400MHz,DMSO-d6)δ9.06(t,J＝4.2Hz,1H),7.85(d,J＝8.8Hz,1H),7.79(d,J＝3.6Hz,1H),7.05-7.00(m,2H),4.59-4.55(m,2H),4.17(s,2H),4.06-4.04(m,2H),3.96-3.93(m,2H),3.74-3.66(m,4H)；LCMS(ESI)m/z:466(M+1).
实施例74
5-氯-3-氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000102
步骤A：3-氨基噻吩-2-甲酸甲酯(7.0g,50.3mmol)的盐酸溶液(6M,14.0mL)，冷却至0℃，加入NaNO2(3.5g,50.7mmol)，并在室温下搅拌2小时。然后，加入HBF4(7.0mL)，并在室温下搅拌15分钟。过滤固体重氮盐，用HBF4(35.0mL)、MeOH(50.0mL)和乙醚(50mL)洗涤固体，真空下干燥，得到3-二偶氮噻吩-2-甲酸甲酯四氟硼酸盐(8.0g,62％)，白色固体。
步骤B：将3-二偶氮噻吩-2-甲酸甲酯四氟硼酸盐(5.0g,19.54mmol)和沙子(26.0g)在带有减压蒸馏装置的圆底烧瓶中混合均匀，真空加热。真空(0.1Torr)加热至160℃、持续2小时，然后升高至200℃、持续2小时，粗品为淡黄色液体，硅胶色谱(PE)纯化，得到3-氟噻吩-2-羧酸甲酯(1.0g,32％)，白色固体。
步骤C：3-氟噻吩-2-羧酸甲酯在DMF(10mL)(1.0g,6.24mmol)的DMF(10mL)溶液在室温下搅拌10分钟，加入NCS(2.5g,18.8mmol)，然后升温至70℃、持续24小时。将混合物真空浓缩，粗残余物通过硅胶色谱(PE：EA＝100：1～PE：EA＝50：1)纯化，得到5-氯-3-氟噻吩-2-羧酸甲酯(200mg,17％)，灰白色固体。
步骤D：向5-氯-3-氟噻吩-2-羧酸甲酯(150mg,0.77mmol)的MeOH(4mL)溶液中加入氢氧化锂(80mg,1.90mmol)的水(2mL)溶液。将混合物加热至40℃、 持续3小时。用1M HCl溶液调节反应混合物至pH＝2.0，然后用EtOAc(3×10mL)萃取。合并的有机层用无水硫酸钠干燥，过滤，然后浓缩，得到5-氯-3-氟噻吩-2-羧酸(100mg,78％)，灰白色固体。
步骤E：按照实施例66的方法制备本标题化合物，其中将步骤A中的4-甲氧基苯甲酸替换为5-氯-3-氟噻吩-2-羧酸。1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.86(d,J＝8.8Hz,1H),7.36(s,1H),7.02(m,2H),4.57(m,2H),4.18(s,2H),4.08(m,2H),3.96(t,J＝5.2Hz,2H),3.72(m,4H)；LCMS(ESI)m/z:482(M+1).
实施例75
4-氨基-5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3，4-d][1，4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000103
制备流程：
Figure PCTCN2014085844-appb-000104
步骤A：在冰水浴冷却条件下，将SOCl2(2.93g,24.6mmol)滴加到5-氯代噻吩-2-羧酸(2.00g,12.3mmol)的EtOH(20mL)溶液中。将反应混合物加热至回流并搅拌16小时。然后真空除去溶剂，用NaHCO3水溶液(50mL)淬灭残余物，并用DCM(20mL x2)萃取。合并有机层用无水硫酸钠干燥并过滤，浓缩滤液，得到5-氯代噻吩-2-羧酸乙酯(2.10g,89％)，黄色油状物。
步骤B：将5-氯代噻吩-2-羧酸乙酯(2.10g,11.0mmol)和发烟硝酸的混合物(8mL)在20℃下搅拌2小时。然后加入水(50mL)和EtOAc(20mL)，水层用EtOAc(20mL x2)萃取。合并有机层用NaHCO3水溶液(50mL)洗涤，并用无水硫酸钠干燥并过滤，浓缩滤液，得到5-氯代-4-硝基噻吩-2-羧酸乙酯(1.6g,61％)，黄色油状物。
步骤C：将5-氯代-4-硝基噻吩-2-羧酸乙酯(1.00g,4.24mmol)、铁粉(1.18g,21.2mmol)、NH4Cl(1.14g,21.2mmol)、EtOH(9mL)和H2O(3mL)的混合物在60℃下搅拌16小时。然后将反应混合物过滤，浓缩滤液得到粗产物。向粗产物中加入水 (50mL)和EtOAc(20mL)，用EtOAc(20mL x2)萃取水层。合并有机层经无水硫酸钠干燥，过滤，浓缩滤液，得到4-氨基-5-氯代噻吩-2-羧酸乙酯(600mg,68％)，黄色油状物。
步骤D:将4-氨基-5-氯代噻吩-2-羧酸乙酯(0.30g,1.46mmol)、LiOH(70mg,2.92mmol)、水(5mL)和THF(5mL)的混合物在25℃下搅拌16小时。然后将混合物浓缩除去THF，用1N HCl(aq)调节pH值至5，过滤。用水(3mL)洗涤粗残余物，无水硫酸钠干燥，得到4-氨基-5-氯代噻吩-2-羧酸(150mg,58％)，黄色固体。
步骤E：将Boc2O(147mg,0.675mmol)加入到4-氨基-5-氯代噻吩-2-羧酸(100mg,0.56mmol)和DMF(7mL)的混合物中，在25℃搅拌16小时。浓缩混合物除去DMF，残余物经制备型TLC(DCM:MeOH＝10:1)纯化，得到4-((叔丁氧羰基)氨基)-5-氯代噻吩-2-羧酸(80mg,51％)，黄色固体。
步骤F：将(3S,3aS)-3-(氨基甲基)-7-(3-氧代吗啉代)-3a,4-二氢苯并[b]恶唑[3,4-d][1,4]恶嗪-1(3H)-酮(46mg,0.144mmol)、4-((叔丁氧羰基)氨基)-5-氯代噻吩-2-羧酸(40mg,0.144mmol)、HATU(66mg,0.172mmol)、Et3N(0.44mg,0.432mmol)和DMF(5mL)的混合物在25℃下搅拌16小时。然后浓缩混合物。粗残余物经制备型TLC(DCM:MeOH＝30:1)纯化，得到(2-氯代-5-((((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)氨甲酰基)噻吩-3-基)氨基甲酸叔丁酯(30mg,36％)，白色固体。
步骤G：将(2-氯代-5-((((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)氨甲酰基)噻吩-3-基)氨基甲酸叔丁酯(30mg,0.051mmol)的HCl/MeOH(4N,5mL)溶液在25℃下搅拌1小时。浓缩混合物得到粗残余物，经制备型HPLC(甲酸)纯化，得到本实施例标题化合物(10mg,40％)，白色固体。1H NMR(400MHz,DMSO-d6)δ8.88(t,J＝6.0Hz,1H),7.86(d,J＝8.8Hz,1H),7.28(s,1H),7.05(s,1H),7.02(d,J＝8.8Hz,1H),5.23(s,2H),4.59-4.52(m,2H),4.18(s,2H),4.06-4.04(m,2H),3.96-3.94(m,2H),3.70-3.67(m,4H).LCMS(ESI)m/z:479(M+1).
实施例76
3-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)苯甲酰胺
Figure PCTCN2014085844-appb-000105
步骤A：根据实施例66的方法制备本实施例标题化合物，其中将步骤A中的4-甲氧基苯甲酸替换为3-甲氧基苯甲酸。1H NMR(400MHz,DMSO-d6)δ8.89(t,J＝6.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.45-7.38(m,3H),7.06(d,J＝2.4Hz,1H),7.03(d,J＝2.4Hz,1H),7.01(d,J＝2.4Hz,1H),4.64-4.62(m,1H),4.57-4.54(m,1H), 4.18(s,2H),4.08-4.06(m,2H),3.95(t,J＝4.8Hz,2H),3.81(s,3H),3.75-3.74(m,2H),3.70-3.69(m,2H)；LCMS(ESI)m/z:454(M+1).
实施例77
5-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)吡啶甲酰胺
Figure PCTCN2014085844-appb-000106
步骤A：根据实施例66的方法制备本实施例标题化合物，其中将步骤A中的4-甲氧基苯甲酸替换为5-甲氧基吡啶甲酸。1H NMR(400MHz,DMSO-d6)δ8.98-8.90(m,1H),8.34(d,J＝2.8Hz,1H),8.04(d,J＝8.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.57(dd,J＝8.8,2.8Hz,1H),7.05-7.00(m,2H),4.65-4.60(m,1H),4.50-4.45(m,1H),4.18-4.12(m,3H),4.10-4.00(m,1H),3.98-3.88(m,5H),3.80-3.75(m,2H),3.70-3.65(m,2H)；LCMS(ESI)m/z:455(M+1).
实施例78
5-氯-N-(((3S,3aS)-9-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000107
步骤A：0℃下，向搅拌着的过硼酸钠四水合物(150g,0.96mol)的乙酸(500mL)悬浮液中缓慢加入4-溴-2,6-二氟苯胺(20.0g,0.096mol)的乙酸(200mL)溶液。60℃下搅拌4小时后，将溶液冷却至室温，并倾入冰水中，并用EtOAc(500mL x3)萃取。合并的有机萃取液依次用盐水洗涤，并用无水硫酸钠干燥，真空浓缩，得到5-溴-1,3-二氟-2-硝基苯(17g,74％)，白色固体。
步骤B：按照实施例1步骤A-L的方法制备本实施例标题化合物，其中将步骤A中的4-溴-2-氟-1-硝基苯替换为5-溴-1,3-二氟-2-硝基苯。1H NMR(400MHz,DMSO-d6)δ8.96-8.93(m,1H),7.67-7.65(m,1H),7.21(d,J＝4.0Hz,1H),7.04(dd,J＝11.6,2.0Hz,1H),6.94-6.92(m,1H),4.62-4.58(m,2H),4.19(s,2H),4.05-3.92(m,4H),3.72-3.58(m,4H)；LCMS(ESI)m/z:482(M+1).
实施例79
5-氯-N-(((3S,3aS)-8-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000108
步骤A：向搅拌并冷却(-10℃)的2-溴-1,4-二氟-苯(32.0g,0.17mol)的1,2- 二氯乙烷(320mL)溶液中，加入HNO3(15.7g,0.25mol)的H2SO4(81.3g,0.83mol)溶液，将混合物在29℃搅拌2小时，倾入冰水(1500g)，然后用DCM(300mL x3)萃取。有机液浓缩至干，得到1-溴-2,5-二氟-4-硝基苯(36.3g,92％)，黄色固体。
步骤B：按照实施例1步骤A-L的方法制备本实施例标题化合物，其中将步骤A中4-溴-2-氟-1-硝基苯替换为1-溴-2,5-二氟-4-硝基苯。1H NMR(400MHz,DMSO-d6)δ9.02(t,J＝5.6Hz,1H),7.80-7.72(m,2H),7.22-7.14(m,2H),4.64-4.56(m,2H),4.21(s,2H),4.05-3.95(m,4H),3.76-3.74(m,2H),3.64(t,J＝4.8Hz,2H)；LCMS(ESI)m/z:482(M+1)
实施例80
5-氯-N-(((3S,3aS)-6-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000109
反应流程：
Figure PCTCN2014085844-appb-000110
步骤A：室温下，向2-氟-6-硝基苯酚(47.1g,300mmol)的DMF(125mL)溶液中分批加入K2CO3(62.2g,450mmol)并逐滴加入MeI(65.7g,450mmol)。将混合物在室温下搅拌16小时，加入水(350毫升)，并用EtOAc(350mL)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩，得到粗品1-氟-2-甲氧基-3-硝基苯，棕色油状物。该粗品无需进一步纯化，直接用于下一步反应。
步骤B：室温下，向1-氟-2-甲氧基-3-硝基苯(51.3g,300mmol)的EtOH(125mL)溶液中加入10％wt.Pd/C(10.0g)，在氢气氛下(1大气压)室温搅拌16小时。过滤并浓缩，粗残余物用硅胶色谱(PE：乙酸乙酯＝1：40)纯化，得到3-氟-2-甲氧基苯胺(40g,94％)，棕色油状物。
步骤C：室温下，向3-氟-2-甲氧基苯胺(9.33g,66mmol)的AcOH(50mL)溶液中滴加Br2(2.7mL,52mmol)的AcOH(50mL)溶液，室温搅拌1小时。将混合物过滤，将固体溶解于水(30mL)中，用饱和NaHCO3溶液调整至pH＝8-9，EtOAc(30mL)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩。残余物粗品4-溴-3-氟-2-甲氧基苯胺(7.5g)，无需进一步纯化即可用于下面的反应。LCMS(ESI)m/z:220,222(M+1).
步骤D：室温下，向4-溴-3-氟-2-甲氧基苯胺(7.26g,33mmol)的DCM(100mL)溶液中滴加BBr3(33.07g,132mmol)的DCM(50mL)溶液，并在室温下搅拌1小时。用饱和NaHCO3溶液调整混合物至pH＝8～9，EtOAc(30mL)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩。将残余物粗品6-氨基-3-溴-2-氟苯酚(6.0g)直接用于下一步反应，无需进一步纯化。LCMS(ESI)m/z:206,208(M+1).
步骤E：0℃下，向6-氨基-3-溴-2-氟苯酚(5.77g,28mmol)的THF(100mL)溶液中加入NEt3(5.9mL,42mmol)，然后滴加CbzCl(5.25g,30.8mmol)，并在0℃下搅拌2小时。加入冰水(100mL)，并用EtOAc(100mL)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩，得到粗产物(4-溴-3-氟-2-羟基苯基)氨基甲酸苄酯(7.0g)，浅白色固体。将粗产品直接用于下一步的反应，无需进一步纯化。LCMS(ESI)m/z:340,342(M+1).
步骤F：室温下，向(4-溴-3-氟-2-羟基苯基)氨基甲酸苄酯(3.40g,10mmol)的DMF(40mL)溶液中，加入K2CO3(2.76g,20mmol)，然后滴加(Z)-4-溴丁-2-烯氧基)(叔丁基)二甲基硅烷(2.65g,10mmol)的DMF(10mL)溶液，并在室温下搅拌2小时。加入水(150mL)，并用EtOAc(150mL)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩。将粗的残余物经硅胶色谱(PE：乙酸乙酯＝50：1～20：1)纯化，得到(Z)-(4-溴-2-((4-((叔丁基二甲基甲硅烷基)氧基)丁基-2-烯-1-基)氧基)-3-氟苯基)氨基甲酸苄酯(4.50g,86％)，黄色油状物。LCMS(ESI)m/z:524,526(M+1).
步骤G：0℃下，向(Z)-(4-溴-2-((4-((叔丁基二甲基甲硅烷基)氧基)丁基-2-烯-1-基)氧基)-3-氟苯基)氨基甲酸苄酯(4.40g,8.4mmol)的THF(40mL) 溶液中滴加n-Bu4NF(2.63g,10.1mmol)的THF(20mL)溶液，将所得溶液温热至室温，并在室温下搅拌2小时。将混合物浓缩，并通过硅胶色谱(PE：乙酸乙酯＝5：1～3：1)纯化，得到(Z)-(4-溴-3-氟-2-((4-羟基丁-2-烯-1-基)氧基)苯基)氨基甲酸苄酯(3.10g,90％)，白色油状物。LCMS(ESI)m/z:410,412(M+1).
步骤H：按照实施例1步骤D-L的方法制备本实施例标题化合物，白色固体。1H NMR(400MHz,DMSO-d6)δ9.03(t,J＝5.6Hz,1H),7.73-7.71(m,2H),7.21(d,J＝4.0Hz,1H),7.05(dd,J＝8.8,2.0Hz,1H),4.69-4.62(m,2H),4.22(s,2H),4.15-4.12(m,2H),3.96(t,J＝5.2Hz,2H),3.74(t,J＝5.2Hz,2H),3.64(t,J＝5.2Hz,2H)；LCMS(ESI)m/z:482(M+1).
实施例81
5-氯-N-(((6aS,7S)-9-氧代-3-(3-氧代吗啉代)-6,6a,7,9-四氢恶唑并[3,4-d]吡啶并 [3,2-b][1,4]恶嗪-7-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000111
反应流程：
Figure PCTCN2014085844-appb-000112
步骤A：向2-氨基-3-羟基吡啶(2.60g，23.6mmol)的THF(40mL)溶液中加入CDI(5.74g,35.4mmol)，将所得反应混合物在70℃下搅拌14小时，冷却至室温，并减压浓缩。将残余物溶解于DCM(50mL)中，用2N氢氧化钠(3×10mL)洗涤。将合并的水层冷却至0℃，并用6N盐酸酸化至pH为6。用在多孔漏斗收集形成的沉淀物，用冷水(10mL)洗涤，真空下干燥，得到恶唑并[4,5-b]吡啶-2(3H)-酮((2.6g,81％))，黄色固体。
步骤B：将溴(1.08mL,21.0mmol)经20分钟逐滴加入到搅拌着的恶唑并[4,5-b]吡啶-2(3H)-酮的DMF(20mL)溶液中。将反应混合物在室温下搅拌14小时。将混合物倾入碎冰中，用多孔漏斗收集所形成的沉淀物。用水(20mL)洗涤固体，真空干燥，得到6-溴代恶唑并-[4,5-b]吡啶-2(3H)-酮(3.7g,91％)，浅黄色固体。
步骤C：用10％NaOH水溶液稀释6-溴恶唑并[4,5-b]吡啶-2(3H)-酮(3.4g,15.8mmol)，并将得到的混合物在100℃下搅拌6小时。将反应冷却至5℃，加入6N HCl直到形成沉淀。用多孔玻璃漏斗收集固体，用水(20mL)洗涤，真空干 燥，得到2-氨基-5-溴吡啶-3-醇(2.4g,80％)，褐色固体。
步骤D：在25～30℃，向2-氨基-5-溴吡啶-3-醇(4.32g,0.023mol)、NaOH(5.49g,0.138mol)的THF(45mL)-H2O(45mL)溶液中加入CbzCl(14.04g,0.081mol)，并将混合物在25～30℃下搅拌16小时。将反应混合物EtOAc(100mL x3)萃取。合并的有机层浓缩得到粗产物。残余物用水(50mL)洗涤，然后真空干燥，得到(5-溴-3-羟基吡啶-2-基)氨基甲酸苄酯(5.5克，75％)，灰色固体。LCMS(ESI)m/z:189,191(M+1).
步骤E：按照实施例80步骤F、G的方法制备(Z)-5-溴-3-(4-羟基丁-2-烯氧基)吡啶-2-基氨基甲酸苄酯，其中将步骤E中6-胺基-3-溴-2-氟苯替换为2-胺基-3-羟基-5-溴吡啶。LCMS(ESI)m/z:189,191(M+1).
步骤F：按照实施例1步骤D-L的方法制备本实施例标题化合物。1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.09(d,J＝2.4Hz,1H),7.71(d,J＝4.0Hz,1H),7.53(d,J＝2.0Hz,1H),7.21(d,J＝4.0Hz,1H),4.57(d,J＝6.8Hz,2H),4.22(s,2H),4.06-4.17(m,2H),3.97(t,J＝4.8Hz,2H),3.66-3.79(m,4H)；LCMS(ESI)m/z:465(M+1).
实施例82
5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢恶唑并[3,4-d]吡啶并 [4,3-b][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000113
步骤A：将THF(125mL)冷却至-78℃，然后通入无水NH3(100mL)。0℃下加入4-氯-3-硝基吡啶(20.0g,126mmol)，然后经5分钟加入TBHP(5M溶解于癸烷中,25mL,125mmol)。将叔丁醇钾(35.7g,318mmol)的THF(100mL)溶液加热至-35℃，然后将所得溶液滴加到上述叔丁醇钾溶液中，用时1小时，然后在-35℃下搅拌2小时，然后小心地用25毫升饱和NH4Cl水溶液淬灭反应。将混合物升温至室温放置16小时，然后分离有机层，浓缩，过滤残余物。用冰水洗涤固体，真空干燥，得到4-氯-5-硝基吡啶-2(1H)-酮(15.0g,69％)，黑色固体.
步骤B：室温下，将磷酰溴(54.0g,189mmol)加入到4-氯-5-硝基吡啶-2(1H)-酮(15.0g,85.94mmol)的乙腈(200mL)悬浮液中，并加热回流3小时。将反应混合物冷却并小心地倾入冰和饱和K2CO3水溶液中，然后用EtOAc(200mL x3)萃取。合并有机层，用水和盐水洗涤，用无水硫酸钠干燥，过滤并浓缩，得到2,4-二溴-5-硝基吡啶((9.0g,38％))，黄色固体。LCMS(ESI)m/z:283(M+1).
步骤C：向2,4-二溴-5-硝基吡啶(9.0g,31.9mmol)的无水DMF(120mL)溶液中加入Cs2CO3(12.5g,,38.37mmol)，然后加入(Z)-丁基-2-烯-1,4-二醇(3.1g,31.9mmol)，将得到的混合物室温搅拌16小时。将混合物过滤，将滤液真空浓缩。将粗残余物通过硅胶色谱(PE：EA＝8：1)纯化，得到(Z)-4-((2-溴-5-硝基 吡啶-4-基)氧基)丁-2-烯-1-醇(4.5g,50％)，淡黄色固体。LCMS(ESI)m/z:289(M+1).
步骤D：根据实施例1步骤B-L的方法制备本实施例标题化合物，其中将步骤B中4-溴-2-氟-1-硝基苯替换为2,4-二溴-5-硝基吡啶。1H NMR(400MHz,DMSO-d6)δ9.00(t,J＝6.0Hz,1H),8.76(s,1H),7.71(d,J＝4.0Hz,1H),7.60(s,1H),7.21(d,J＝4.0Hz,1H),4.67-4.63(m,2H),4.22-4.17(m,1H),4.15-4.10(m,1H),3.98-3.96(m,2H),3.92-3.89(m,2H),3.74(d,J＝5.6Hz,2H)；LCMS(ESI)m/z:465(M+1).
实施例83
2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基2-氨基乙酸盐酸盐
Figure PCTCN2014085844-appb-000114
制备流程:
Figure PCTCN2014085844-appb-000115
步骤A:室温下，向NaH粉末(112mg,2.8mmol)和DMF(2mL)的混合物中加入5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺(649mg,1.4mmol)的DMF(6mL)溶液，搅拌20分钟，室温下加入2-氯乙酰氯(474mg,4.2mmol)的DMF(2mL)溶液并搅拌3小时。然后在室温下加入2-((叔丁氧基羰基)氨基)乙酸(1.96g,11.2mmol)和CsCO3(1.37g,4.2mmol)并搅拌16小时。将所得混合物加入到饱和的NH4Cl溶液(30mL)中并用EtOAc(30mL x3)萃取。将合并的有机相用无水Na2SO4干燥，过滤并真空浓缩。将粗残余物经硅胶色谱(PE:EtOAc＝1:2～4:1)纯化，得到2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b] 恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基-2-((叔丁氧羰基)氨基)乙酸盐(55mg,6％yield)，淡黄色固体。LCMS(ESI)m/z:579,191(M+1-100).
步骤B：室温下，向2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基-2-((叔丁氧羰基)氨基)乙酸盐(41mg,0.06mmol)的DCM(4mL)溶液中加入TFA(0.8mL)并搅拌30分钟。室温下浓缩反应混合物，粗残余物经制备型HPLC纯化，得到本实施例标题化合物(7mg,20％)，黄色固体。1H NMR(400MHz,DMSO)δ8.42(brs,3H),7.82(d,J＝8.8Hz,1H),7.74(d,J＝4.4Hz,1H),7.36(d,J＝4.0Hz,1H),7.05(d,J＝2.0Hz,1H),7.05(dd,J＝8.8,2.4Hz,1H),5.23-5.18(m,2H),4.67-4.64(m,1H),4.64-4.61(m,1H),4.39-4.34(m,2H),4.17(s,2H),4.05-4.02(m,2H),3.96-3.93(m,4H),3.68(t,J＝4.8Hz,2H).LCMS(ESI)m/z:579(M+1).
实施例84
(R)-2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基2-氨基-3-甲基丁酸盐酸 盐
Figure PCTCN2014085844-appb-000116
步骤A：根据实施例83步骤A和B的顺序制备本实施例标题化合物，其中将步骤A中2-((叔丁氧基羰基)氨基)乙酸替换为2-((叔丁氧基羰基)氨基)-3-甲基丁酸，得白色固体1H NMR(400MHz,DMSO-d6)δ8.29(brs,3H),7.81(d,J＝8.8Hz,1H),7.74(d,J＝4.4Hz,1H),7.36(d,J＝4.4Hz,1H),7.05(d,J＝2.0Hz,1H),7.01(dd,J＝8.82.4Hz,1H),5.27-5.11(m,2H),4.65-4.55(m,2H),4.40-4.35(m,2H),4.17(s,2H),4.05-4.01(m,2H),3.96-3.92(m,4H),3.68(t,J＝4.8Hz,2H)；LCMS(ESI)m/z:621.1(M+1).
实施例85
5-氯-N-((1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基) 甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000117
制备流程：
Figure PCTCN2014085844-appb-000118
步骤A：将6-溴代苯并[d]噻唑-2(3H)-酮(10.0g,43.5mmol)和NaOH溶液(26g NaOH溶解于80mL H2O中)的混合物在105℃下搅拌16小时，将混合物冷却至室温，并在0～10℃下添加醋酸调节该混合物至pH＝8。过滤混合物，水洗滤饼，真空干燥，得到2,2'-二硫烷二基双(4-溴代苯胺)(9.9g,100％)，黄色固体，无需进一步纯化直接用于下一步反应。LCMS(ESI)m/z:405(M+1).
步骤B：0℃下，向2,2'-二硫烷二基双(4-溴代苯胺)(10.0g,24.6mmol)和NaHCO3(20.7g,0.25mol)的THF/H2O(150mL/50mL)溶液中滴加氯甲酸苄酯(21.0g,0.12mol)，将所得混合物在37℃下搅拌16小时。过滤混合物，水洗滤饼，真空干燥，得到(二硫烷二基双(4-溴-2,1-亚苯基))二氨基甲酸二苄酯(10.0g,60％)，白色固体。LCMS(ESI)m/z:673(M+1).
步骤C：将(二硫烷二基双(4-溴-2,1-亚苯基))二氨基甲酸二苄酯(6.5g,9.6mmol)、((3-(溴甲基)环氧乙烷-2-基)甲氧基)(叔丁基)二甲基硅烷(2.0g,7.1mmol)和N-乙基-N-异丙基丙-2-胺(12mL)的DMF(70mL)溶液的混合物在110℃下搅拌8小时，加入水(200mL)，并用乙酸乙酯萃取(100mL x2)。合并有机层用盐水洗涤，无水硫酸钠干燥，过滤并浓缩。粗残余物经柱层析(PE:EtOAc＝100:1)纯化，得到(4-溴代-2-(((3-(((叔丁基二甲基甲硅烷基)氧基)甲基)环氧乙烷-2-基)甲基)硫基)苯基)氨基甲酸苄酯(0.93g,24％)，白色固体。LCMS(ESI)m/z:538(M+1).
步骤F：根据实施例1步骤F-L的方法制备5-氯-N-((1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺，其中将(4-溴代-2-(((2R,3S)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)环氧乙烷-2-基)甲氧基)苯基)氨基甲酸苄酯替换为(4-溴代-2-(((3-(((叔丁基二甲基甲硅烷基)氧基)甲基)环氧乙烷-2-基)甲基)硫基)苯基)氨基甲酸苄酯。标题化合物是白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，组分1是360mg，组分2是380mg。组分1：1H NMR(400MHz,DMSO-d6)δ9.00-8.93(m,1H),7.96(d,J＝8.8Hz,1H),7.70(d,J＝4.0Hz,1H),7.29(d,J＝2.4Hz,1H),7.21(d,J＝4.0Hz,1H),7.16-7.14(m,1H),4.56-4.52(m,1H),4.15(s,2H),4.12-4.08(m,1H),3.96-3.94(m,2H),3.71-3.68(m,4H),3.32-3.27(m,2H).MS(ESI)m/z:480(M+1).组分2：1H NMR(400MHz,DMSO-d6)δ9.00-8.93(m,1H),7.96(d,J＝8.8Hz,1H),7.70(d,J＝4.0Hz,1H),7.29(d,J＝2.4Hz,1H),7.21(d,J＝4.0Hz,1H),7.16-7.14(m,1H),4.56-4.52(m,1H),4.15(s,2H),4.12-4.08(m,1H),3.96-3.94(m,2H),3.71-3.68(m,4H),3.32-3.27(m,2H).MS(ESI)m/z:480(M+1).
实施例86
5-氯-N-((5-氧化-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻 嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000119
步骤A：0℃下，向5-氯-N-((1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺(200mg,0.4mmol)的DCM(10mL)溶液中加入m-CPBA(85mg,0.4mmol)，将所得混合物在37℃下搅拌16小时，加入水(30mL)，DCM(20mL x2)萃取。将合并有机层用盐水洗涤，无水硫酸钠干燥，过滤并真空浓缩，粗残余物经制备型HPLC纯化，得到本实施例标题化合物，为白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，组分1是35mg，组分2是32mg。组分1：1H NMR(400MHz,DMSO-d6)δ9.08-9.03(m,1H),8.42(d,J＝9.2Hz,1H),7.96(d,J＝2.4Hz,1H),7.73-7.67(m,2H),7.21(d,J＝4.0Hz,1H),4.75-4.71(m,1H),4.58-4.52(m,1H),4.23(s,2H),4.00-3.98(m,2H),3.77-3.74(m,4H),3.52-3.50(m,1H),3.41-3.38(m,1H).MS(ESI)m/z:496(M+1).组分2：1H NMR(400MHz,DMSO-d6)δ9.08-9.03(m,1H),8.42(d,J＝9.2Hz,1H),7.96(d,J＝2.4Hz,1H),7.73-7.67(m,2H),7.21(d,J＝4.0Hz,1H),4.75-4.71(m,1H),4.58-4.52(m,1H),4.23(s,2H),4.00-3.98(m,2H),3.77-3.74(m,4H),3.52-3.50(m,1H),3.41-3.38(m,1H).MS(ESI)m/z:496(M+1).
实施例87
5-氯-N-((5,5-二氧化-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并 [3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺
Figure PCTCN2014085844-appb-000120
步骤A：0℃下，向5-氯-N-((1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺(200mg,0.4mmol)的THF/MeOH/H2O(2.0mL/2.0mL/2.0mL)溶液加入过硫酸氢钾(780mg,1.2mmol)，将所得混合物在37℃下搅拌16小时。向反应混合物中加入水(10mL)，EA(20mL x2)萃取。合并有机层经无水硫酸钠干燥，真空浓缩。粗残余物经制备型HPLC纯化，得标题化合物，为白色固体同分异构体，经制备型SFC和制备型HPLC进一步纯化，得到两个组分，组分1是33mg，组分2是31mg。组分1：1H NMR(400MHz,DMSO-d6)δ9.02-8.95(m,1H),8.32(d,J＝9.2Hz,1H),7.96(d,J＝2.8Hz,1H),7.72-7.71(m,2H),7.21(d,J＝4.0Hz,1H),4.75-4.68(m,2H),4.23(s,2H),4.15-4.05(m,2H),3.95-3.90(m,2H),3.77-3.72(m,4H).MS(ESI)m/z:512(M+1).组分2：1H NMR(400MHz,DMSO-d6)δ8.99(t,J1＝6.0Hz,J2＝12.0Hz,1H),8.32(d,J＝9.2Hz,1H),7.96(d,J＝2.8Hz,1H),7.72-7.71(m,2H),7.21(d,J＝4.0Hz,1H),4.75-4.69(m,2H),4.23(s,2H),4.17-4.05(m,2H),3.99-3.98(m,2H),3.79-3.77(m,4H).MS(ESI)m/z:512(M+1).
实验例1：体外评价
通过测定IC50值来评价受试化合物对人或大鼠的Ⅹa因子或其他酶如凝血酶或胰蛋白酶的抑制能力，其中IC50值与抑制常数Ki相关联。在显色测定中使用纯化的酶。使用FlexStation III(美国分子仪器公司)测定37℃下时间进程中线性部分(通常是加入底物2～10分钟后)在405nm处的吸光度的变化来测量发色底物水解的初始速度。通过绘制水解的相对速度(与未受抑制的对照组相比)对受试化合物浓度的对数曲线后，通过线性回归计算，测定导致底物水解的速率降低50％的抑制剂的浓度。根据Cheng-Prusoff equation:Ki＝IC50/(1+[S]/Km)计算酶抑制常数(Ki)，其中[S]为底物浓度，Km为通过双倒数作图法确定的米-曼二氏常数。通过GraphPad Prism软件得到受试化合物的IC50值。使用"形剂量效应(可变斜率)"拟合曲线。
人/大鼠凝血因子Xa试验：
采用Tris-HCl缓冲液(50mM,pH8.3,150mM NaCl)测定人或大鼠的凝血因子Xa活性抑制作用。通过将50μL人凝血因子Xa(Enzyme Research Laboratories,Inc；终浓度为8.36nM)或50μL大鼠凝血因子Xa(Enzyme Research Laboratories,Inc；终浓度为57.5nM)的缓冲液滴加到Greiner384微量滴定板的合适孔中的方法测定IC50。含2μL2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中，并添加48μL衬底S-2222(Chromogenix；化学式：Bz-IIe-Glu(γ-OR)-Gly-Arg-pNA·HCl R＝H (50％)，其中R＝CH3(50％))的测定缓冲液，终浓度为0.172mM。该试验中将受试化合物与酶预培养10分钟，然后加入底物S-2222得到100μL终体积以开始试验。
Ki<10μM的受试化合物被认为是积极的，本发明优选Ki<1μM的化合物，更优选Ki<0.1μM的化合物，更优选Ki<0.01μM的化合物，进一步优选Ki<0.001μM的化合物。经上述试验方法测定，本发明的一些化合物Ki<0.1μM，因此本发明的化合物可作为有效的Ⅹa因子抑制剂。
人凝血酶试验：
采用缓冲液(10mM的HEPES缓冲液，pH7.4,2mM CaCl2)测定人凝血酶活性抑制作用。选择Greiner384微量滴定板中合适的孔测定IC50，含有50μL人凝血酶(Sigma公司；T8885)的缓冲液，终浓度为0.05NIH单位/mL，含2μL2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中；加入含有48μL底物S-2238(Chromogenix；化学式：H-D-Phe-Pip-Arg-pNA·2HCl)的缓冲液，终浓度为30μM。该试验中将受试化合物与酶预培养10分钟，然后加入底物得到100μL终体积以开始试验。
人胰蛋白酶试验：
采用缓冲液(50mM Tris,pH8.2,and20mM CaCl2)测定人胰蛋白酶活性抑制作用。选择Greiner384微量滴定板中合适的孔测定IC50，含有50μL人胰蛋白酶(Sigma公司；T6424)的缓冲液，终浓度为0.39BAEE单位/mL，含2μL2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中；含有底物S-2222(Chromogenix)的缓冲液，终浓度为30μM。该试验中将受试化合物与酶预培养10分钟，然后加入底物48μL，得到终体积100μL以开始试验。
凝血酶原试验：
通过凝血酶的生成测量受试化合物对凝血酶原酶的活性。简单地说，在10mM HEPES缓冲液和pH7.4,2mM CaCl2中温育12.5μL人因子Xa，终浓度为0.5nM，并在37℃加入12.5μL人血小板(1×107mL-1)10分钟。加入25μL凝血酶原以开始反应，终浓度为0.5μM，含2μL2％(V/V)DMSO的测定缓冲液(未受抑制的对照组)或各种浓度的待测化合物稀释在含有2％(V/V)DMSO的测定缓冲液中。20分钟后，加入48μL底物S-2238(Chromogenix)至终浓度为50μM以测定凝血酶活性。
表1：本发明化合物体外筛选试验结果
Figure PCTCN2014085844-appb-000121
Figure PCTCN2014085844-appb-000122
Figure PCTCN2014085844-appb-000123
Figure PCTCN2014085844-appb-000124
“a”和“b”分别代表经SFC分离后的组分1和组分2
结论：与已知抗凝剂利伐沙班相比，本发明化合物通过其特定的抗凝血因子Xa活性表现出很强的抗凝血活性。
测量受试化合物的凝血酶原时间(PT)以确定其在体外的抗凝血活性。
凝血酶原时间(PT)试验：
从麻醉状态下的大鼠腹主动脉抽血。用含有1/10体积的0.11M柠檬酸钠的塑料管收集血液，在2500g、4℃立即进行离心分离10分钟，得到血浆，并-80℃下保存。通过使用市售的试剂盒(武汉塞力斯生物科技有限公司，中国)的温控全自动血凝分析仪(Compact-X,Behnk-Elektronik(BE),德国)测量凝血酶原时间(PT)。用DMSO(10μM)制备受试化合物(利伐沙班和发明化合物1)的原液，血浆中进行系列稀释(分别为0、0.3125、0.625、1.25、2.5、5μM)。将0.2mL PT试剂(在37℃下温育3分钟)加入到0.1mL的受试血浆和正常对照血浆(在37℃下温育3分钟)。测量凝血时间，并与对照血浆相对比。试验结果用形成初始血纤维蛋白链双倍时间(2×PT)的抑制剂浓度表示。
表2
化合物 2x PT(μM)
利伐沙班 0.54
化合物1 0.99
如表2所示，利伐沙班和本发明化合物1均在小于1μM的浓度达到双倍凝血酶原时间。
实验例2：体内研究
动静脉分流大鼠模型：
用大鼠动静脉(AV)分流血栓形成模型验证本发明化合物的抗血栓作用，测试方法与Journal of Thrombosis and Haemostasis2005；3:514-521所公开的方法基本相同。在这个模型中，大鼠组分别给予2mpk、3mpk、6mpk,和10mpk剂量的受试化合物。将利伐沙班和本发明化合物1溶解在solutol/乙醇/H2O的[40％/10％/50％(v/v/v)]中，并口服给予雄性SD大鼠(上海斯莱克实验动物有限公司，每个剂量组的受试动物数为8)，SD大鼠重350-450克，先用戊巴比妥钠(i.p.,50mg/Kg2.5mL/kg)麻醉90分钟，然后打开分流器15分钟。
分离左颈静脉和右颈动脉。颈静脉及对侧颈动脉用一个生理盐水填充的6厘米长的导管插管，通过连接一个包含6厘米长的粗尼龙线(60×0.24mm)的8厘米长的PE-160聚乙烯管(American Health&Medical Supply International Corp)组装成一个生理盐水填充的分流器。口服给药90分钟后打开分流器，让血液流过分流器15分钟。从分流器中取出带有相关血栓的线，在计算线上形成的血栓重量时减去6厘米长的手术缝合线的平均重量。除去血栓后立即从颈动脉导管中取出血液样本(2mL)。用含有1/10体积的3.8％柠檬酸三钠的塑料管收集血液(1.8mL)，在2000g、4℃立即进行离心分离15分钟，收集血浆，并保存在-80℃下供后续使用(PT测定)。用含0.5MEDTA-K2的塑料管收集血液(0.2mL)，立即在7000rpm(5204g)、4℃下离心分离10分钟得到血浆，将血浆样品保存在-80℃下用于药浓度的测定。然后用二氧化碳使动物安乐死。
表3
Figure PCTCN2014085844-appb-000125
如表3中所示，口服给予本发明化合物1表现出显著的血栓形成抑制效果，化合物1的3mpk的抗血栓效果与利伐沙班6mpk的效果相当。
鼠尾出血模型：
口服给药受试化合物(利伐沙班和本发明化合物1)或赋形剂90分钟，然后从麻醉大鼠的尾部前端横切1mm，并垂直浸入37℃盐水中。测量连续血流停止30秒以上的时间，最长观察时间为15分钟(15分钟属于更长的出血时间)。
表4
Figure PCTCN2014085844-appb-000126
*P<0.05；**P<0.01相对于赋形剂对照组.
如表4中所示，有效的抗血栓口服剂量(在动静脉分流模型中预防血栓形成的最小剂量)为3mg/kg时，出血时间与基线(0.8-1.2倍)相同。更高剂量(10mg/kg)显示出中度延长的出血时间(约2倍)。结果表明，与利伐沙班相比，本发明的化合物1没有显示出显著的出血倾向。
实验例3：动力学溶解度的测定
将受试化合物溶解在DMSO中，以制备10mmol/L的原液。用移液管(Eppendorf Research公司)将980μL溶出介质加入到2mL的螺旋盖的玻璃管形瓶中。将20μL各受试化合物的原液以及QC样品添加到相当于pH6.5的动力学检测溶液的缓冲溶液中。受试化合物和DMSO溶液的终浓度分别是为200μM和2％。药瓶压盖。最大浓度的理论值为200μM。室温下以每分钟880转的速度旋转摇动该混合物24小时。将小瓶离心30分钟，每分钟13000转。用数字移液管将200μL上清液加入到96-孔板中。用高效液相色谱法光谱测定的受试化合物的溶解度。
表5
化合物 溶解度(μM)pH6.5
利伐沙班 11.02
化合物1 17.85
如表5中所示，与利伐沙班相比，本发明化合物1表现出优异的水溶解度(在pH＝6.5)。因此，本发明的化合物比现有技术显然更易溶于水。

Claims (13)

  1. 式(I)所示化合物或其药学上可接受的盐、水合物或前药，
    Figure PCTCN2014085844-appb-100001
    其中，
    R1代表任选被取代的芳基或杂芳基，取代基独立地选自F、Cl、Br、I、氰基、氨基、CF3、C1-8烷氧基和C1-8烷基，取代基的个数为1个或多个，所述的C1-8烷基任选地被F、Cl、Br、I、氰基、氨基或CF3所取代；
    R2代表任选被取代的
    Figure PCTCN2014085844-appb-100002
    Figure PCTCN2014085844-appb-100003
    3-9元碳环或3-9元杂环，取代基独立地选自＝O、F、Cl、Br、I、OH、SH、PH2、氰基、SO2、COOCH2CH2OH、COOCH2CH3、CONH2、COOCH3、C1-8烷基和氨基，所述取代基的个数为1个或多个，所述C1-8烷基任选地被F、Cl、Br、I、OH、NH2、SH、PH2、OCH3、N(CH3)2或NHCH3所取代，所述氨基任选地被CH3或COCH3所取代；
    R3代表H、
    Figure PCTCN2014085844-appb-100004
    或
    Figure PCTCN2014085844-appb-100005
    A选自O、NH、N-CH3、S、SO、SO2和CH2；
    X、Y和Z分别独立地选自CH、C-Br、C-Cl、C-F、C-I和N；以及
    任选地该化合物是立体异构体。
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中所述的R1代表任选被取代的苯基、噻吩或吡啶。
  3. 根据权利要求2所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中所述的R1选自：
    Figure PCTCN2014085844-appb-100006
  4. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中所述的R2含有至多三种杂原子或原子团，所述杂原子分别独立地选自O、N、S、SO和SO2。
  5. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中所述R2的杂环是饱和或者部分不饱和的单环或者任选苯并稠合的双环。
  6. 根据权利要求4或者5所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中所述R2选自：
    Figure PCTCN2014085844-appb-100007
    Figure PCTCN2014085844-appb-100008
  7. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中药学上可接受的盐选自：
    1)碱加成盐：钠、钾、钙、铵、有机氨或镁盐；或
    2)酸加成盐：盐酸、氢溴酸、硝酸、碳酸，碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等、乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、氨基酸或葡糖醛酸。
  8. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐、水合物或前药，其中该化合物选自：
    1)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    2)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代哌啶-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    3)5-氯-N-(((3S,3aS)-1-氧代-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    4)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧哌嗪-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    5)5-氯-N-(((3S,3aS)-7-(4-甲基-2-氧哌嗪-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    6)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代-1,3-氧杂氮杂环己烷-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    7)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡啶-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    8)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡啶-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    9)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡嗪-1(2H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    10)5-氯-N-(((3S,3aS)-1-氧代-7-((R)-3-氧代四氢-1H-吡咯[1,2-c]咪唑-2(3H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    11)5-氯-N-(((3S,3aS)-1-氧代-7-((S)-3-氧代四氢-1H-吡咯[1,2-c]咪唑-2(3H)-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    12)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    13)5-氯-N-(((3S,3aS)-7-((S)-3-羟基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    14)5-氯-N-(((3S,3aS)-7-(2-甲氧基-N-甲乙酰氨基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    15)5-氯-N-(((3S,3aS)-1-氧代-7-(5-氧代-1,4-氧杂氮杂环庚烷-4-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    16)1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-2-氧代吡啶-3-甲酸乙酯；
    17)5-氯-N-(((3S,3aS)-7-(3-(羟甲基)-2-氧代哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    18)5-氯-N-(((3S,3aS)-7-(2-(羟甲基)-5-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    19)5-氯-N-(((3S,3aS)-7-(2-甲基-3-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    20)5-氯-N-(((3S,3aS)-7-((R)-3-甲基-5-氧代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    21)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代-8-氧杂-3-氮杂双环[3.2.1]辛-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    22)4-((3S,3aS)-3-((5-氯代噻吩-2-甲酰氨基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)-3-氧代吗啉-2-甲酰乙酯；
    23)N-(((3S,3aS)-7-((S)-3-氨基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
    24)5-氯-N-(((3S,3aS)-7-(2-((甲氨基)甲基)-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    25)5-氯-N-(((3S,3aS)-7-((S)-3-甲氧基-2-氧代吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    26)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代-2-氮杂双环[2.2.2]辛-2-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    27)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氮杂双环[2,2,1]庚-3-酮)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    28)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代硫代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    29)5-氯-N-(((3S,3aS)-7-(1,1-二氧化-3-氧代硫代吗啉代)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    30)5-氯-N-(((3S,3aS)-7-((R)-2-(甲氧甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    31)5-氯-N-(((3S,3aS)-7-((S)-2-(甲氧甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    32)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代吡咯烷-3-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    33)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氨磺酰基苯基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    34)5-氯-N-(((3S,3aS)-1-氧代-7-(1H-1,2,4-三唑-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    35)5-氯-N-(((3S,3aS)-7-(2-((二甲胺基)甲基)-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    36)5-氯-N-(((3S,3aS)-7-(2-乙基-4,5-二氢-1H-咪唑-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    37)5-氯-N-(((3S,3aS)-7-(2-环丙基-4,5-二氢-1H-咪唑-1-基)-1-氧-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    38)5-氯-N-(((3S,3aS)-7-(2-乙基-5,6-二氢嘧啶-1(4H)-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    39)5-氯-N-(((3S,3aS)-7-(4,5-二氢-1H-咪唑-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    40)5-氯-N-(((3S,3aS)-7-(1-甲基-4,5-二氢-1H-咪唑-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    41)5-氯-N-(((3S,3aS)-7-(1-甲基-1,4,5,6-四氢嘧啶-2-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    42)N-(((3S,3aS)-7-((S)-3-氨基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
    43)N-(((3S,3aS)-7-((R)-3-氨基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
    44)5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    45)5-氯-N-(((3S,3aS)-7-((R)-3-(二甲氨基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    46)5-氯-N-(((3S,3aS)-7-(3-羟基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    47)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    48)N-(((3S,3aS)-7-((S)-3-氨基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
    49)N-(((3S,3aS)-7-((R)-3-氨基哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-5-氯代噻吩-2-甲酰胺；
    50)5-氯-N-(((3S,3aS)-7-((S)-3-(甲基氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    51)5-氯-N-(((3S,3aS)-7-((R)-3-(甲基氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    52)5-氯-N-(((3S,3aS)-7-((S)-3-(二甲氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    53)5-氯-N-(((3S,3aS)-7-((R)-3-(二甲氨基)哌啶-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    54)(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯；
    55)(S)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酸甲酯；
    56)(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酰胺；
    57)(S)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-甲酰胺；
    58)5-氯-N-(((3S,3aS)-7-((R)-2-(羟甲基)吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    59)(R)-1-((3S,3aS)-3-((5-氯代噻吩-2-甲酰胺基)甲基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-7-基)吡咯烷-2-羧酸-2-羟乙基酯；
    60)5-氯-N-(((3S,3aS)-7-(环丙基磺酰基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    61)5-氯-N-(((3S,3aS)-1-氧代-7-(吡咯烷-1-基)磺酰基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    62)5-氯-N-(((3S,3aS)-7-((4-甲基哌嗪-1-基)磺酰基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    63)5-氯-N-(((3S,3aS)-1-氧代-7-(2-氧代咪唑啉-1-基)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    64)5-氯-N-(((3S,3aS)-7-(3-羟基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    65)5-氯-N-(((3S,3aS)-7-((S)-3-甲氧基吡咯烷-1-基)-1-氧代-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    66)4-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)苯甲酰胺；
    67)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)吡啶甲酰胺；
    68)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)-1H-吲哚-2-甲酰胺；
    69)5-甲基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    70)5-溴代-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    71)5-氰基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    72)5-氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    73)4,5-二氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    74)5-氯-3-氟-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    75)4-氨基-5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    76)3-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)苯甲酰胺；
    77)5-甲氧基-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)吡啶甲酰胺；
    78)5-氯-N-(((3S,3aS)-9-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    79)5-氯-N-(((3S,3aS)-8-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    80)5-氯-N-(((3S,3aS)-6-氟-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    81)5-氯-N-(((6aS,7S)-9-氧代-3-(3-氧代吗啉代)-6,6a,7,9-四氢恶唑并[3,4-d]吡啶并[3,2-b][1,4]恶嗪-7-基)甲基)噻吩-2-甲酰胺；
    82)5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢恶唑并[3,4-d]吡啶并[4,3-b][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰胺；
    83)2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基2-氨基乙酸盐酸盐；和
    84)(R)-2-(5-氯-N-(((3S,3aS)-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]恶嗪-3-基)甲基)噻吩-2-甲酰氨基)-2-氧代乙基2-氨基-3-甲基丁酸盐酸盐；
    85)5-氯-N-((1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺；
    86)5-氯-N-((5-氧化-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺；和
    87)5-氯-N-((5,5-二氧化-1-氧代-7-(3-氧代吗啉代)-1,3,3a,4-四氢苯并[b]恶唑并[3,4-d][1,4]噻嗪-3-基)甲基)噻吩-2-甲酰胺。
  9. 根据权利要求1～8任意一项所述的式(Ⅰ)化合物的制备方法，其中R1、X、Y和Z如权利要求1所定义，A为O，R3为H，R2为3-9元含氮杂环，包括 如下步骤：
    Figure PCTCN2014085844-appb-100009
  10. 一种药物组合物，其包括权利要求1～8任意一项所述的治疗有效量的式(Ⅰ)化合物或其药学上可接受的盐、水合物或前药以及药学上可接受的载体。
  11. 根据权利要求1～8任意一项所述的式(Ⅰ)化合物或其药学上可接受的盐、水合物或前药，或根据权利要求10所述的药物组合物，在制备预防或治疗血栓栓塞性疾病的药物中的应用。
  12. 根据权利要求11所述的应用，其中所述的血栓栓塞性疾病选自动脉心血管血栓栓塞性疾病、静脉心血管血栓栓塞性疾病、脑动脉血栓栓塞性疾病和静脉脑血管栓塞性疾病。
  13. 根据权利要求12所述的应用，其中所述的血栓栓塞性疾病选自不稳定型心绞痛、心肌梗死、再发心肌梗死、缺血性猝死、短暂性脑缺血发作、中风、动脉粥样硬化、静脉血栓形成、下肢深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞以及下述原因造成的血栓症：a)人工心脏瓣膜或其他植入物；b)留置导管；c)支架；d)心肺转流术；e)血液透析；以及f)将血液暴露于人工表面从而促进血栓形成的其他程序或操作。
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085542A (zh) * 2014-05-22 2015-11-25 广东东阳光药业有限公司 噁唑烷酮类化合物的晶型和无定形
WO2015188787A1 (en) * 2014-06-14 2015-12-17 Sunshine Lake Pharma Co., Ltd. Method for preparing oxazolidinone compound and intermediates thereof
CN105348275A (zh) * 2015-12-10 2016-02-24 中国药科大学 噁唑烷酮类化合物及其合成方法与医药应用
CN106478661A (zh) * 2015-08-25 2017-03-08 华北制药集团新药研究开发有限责任公司 苯并恶唑并恶嗪酮类化合物wa1-089的晶型e及其制备方法
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CN114163452A (zh) * 2021-12-24 2022-03-11 广东医科大学 一种1,3-恶嗪并1,3-恶唑衍生物的制备方法
CN114685529A (zh) * 2020-12-29 2022-07-01 中国科学院上海药物研究所 噁唑烷酮类化合物的无定形物及其制备方法和应用
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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218564A (zh) * 2014-07-02 2016-01-06 中国科学院上海药物研究所 三环噁唑烷酮类化合物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101420980A (zh) * 2006-02-16 2009-04-29 菲布罗根公司 治疗中风的化合物和方法
CN102260277A (zh) * 2010-05-24 2011-11-30 中国科学院上海药物研究所 新型苯并噁嗪噁唑烷酮类化合物及其制备方法和用途
CN103936763A (zh) * 2013-01-18 2014-07-23 中国科学院上海药物研究所 噁唑烷酮类化合物及其制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015110024A1 (en) * 2014-01-24 2015-07-30 Sunshine Lake Pharma Co., Ltd. Oxazolidinone compounds and their uses in pharmaceuticals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101420980A (zh) * 2006-02-16 2009-04-29 菲布罗根公司 治疗中风的化合物和方法
CN102260277A (zh) * 2010-05-24 2011-11-30 中国科学院上海药物研究所 新型苯并噁嗪噁唑烷酮类化合物及其制备方法和用途
CN103936763A (zh) * 2013-01-18 2014-07-23 中国科学院上海药物研究所 噁唑烷酮类化合物及其制备方法和用途

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WO2015188787A1 (en) * 2014-06-14 2015-12-17 Sunshine Lake Pharma Co., Ltd. Method for preparing oxazolidinone compound and intermediates thereof
CN106478661A (zh) * 2015-08-25 2017-03-08 华北制药集团新药研究开发有限责任公司 苯并恶唑并恶嗪酮类化合物wa1-089的晶型e及其制备方法
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CN109476677B (zh) * 2016-08-08 2024-06-07 辉诺生物医药科技（杭州）有限公司 抗hcmv病毒化合物
CN108727406A (zh) * 2017-03-28 2018-11-02 中国医学科学院药物研究所 含氮杂环取代的苯并噁嗪噁唑烷酮类化合物及其制备方法和用途
CN108727406B (zh) * 2017-03-28 2021-12-07 北京协和制药二厂 含氮杂环取代的苯并噁嗪噁唑烷酮类化合物及其制备方法和用途
CN107827907A (zh) * 2017-11-10 2018-03-23 浙江普洛得邦制药有限公司 一种噁唑烷酮药物中间体的制备方法及应用
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CN108912142B (zh) * 2018-08-08 2021-06-18 延边大学 吡咯并苯并恶嗪酮类化合物及其注射剂和在抗血栓中的用途
WO2021123051A1 (en) 2019-12-20 2021-06-24 Bayer Aktiengesellschaft Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof
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