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WO2019185046A1 - 四元内酰胺类化合物及其药学用途 - Google Patents

四元内酰胺类化合物及其药学用途 Download PDF

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Publication number
WO2019185046A1
WO2019185046A1 PCT/CN2019/080549 CN2019080549W WO2019185046A1 WO 2019185046 A1 WO2019185046 A1 WO 2019185046A1 CN 2019080549 W CN2019080549 W CN 2019080549W WO 2019185046 A1 WO2019185046 A1 WO 2019185046A1
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compound
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alkyl
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French (fr)
Inventor
余尚海
冯焱
李世强
王小林
胡治隆
丁雅雯
戴飞红
贺潜
王朝东
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Shanghai Meiyue Biotech Development Co Ltd
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Shanghai Meiyue Biotech Development Co Ltd
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Priority to EP19776356.8A priority Critical patent/EP3778588A4/en
Priority to US16/968,118 priority patent/US11345679B2/en
Priority to CN201980024128.2A priority patent/CN112292376A/zh
Publication of WO2019185046A1 publication Critical patent/WO2019185046A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and in particular relates to a quaternary lactam compound and its use in the preparation of a medicament for treating and/or preventing a thrombosis or thromboembolic disorder.
  • Blood coagulation is the result of coordinated activation of various plasma proteins, cofactors, and platelets. This cascade reaction is divided into an endogenous (contact activation) pathway, an exogenous (tissue factor activation) pathway, and a common (prothrombin and thrombin generation) pathway.
  • tissue factor forms a complex with Factor VIIa, which catalyzes activator factor X (FX), which in turn cleaves prothrombin to produce activated thrombin (FIIa).
  • FX activator factor X
  • Activated thrombin acts as a central catalytic enzyme in the coagulation process, catalyzing the cleavage of fibrinogen into fibrin, which acts as a coagulation.
  • the exogenous pathway is involved in a small number of enzymes and is effective.
  • the endogenous pathway is the body's intrinsic coagulation pathway, which activates factor FXIIa, factor F11a, factor FIXa, and factor VIII (FVIIIa) through cascades, thereby activating factor FXa and Downstream central thrombin (FIIa).
  • Thrombin activates factor 11 (FXIa), which produces a magnifying effect that accelerates coagulation.
  • Endogenous pathways are more involved in coagulation, and all come from the blood, which is generally slower.
  • FXa plays a key role throughout the coagulation process.
  • antagonists are widely used in the prevention and treatment of various thrombi.
  • a variety of antagonists of FXa are available on the market, and they occupy the cardiovascular drug market because of their remarkable efficacy.
  • the probability of their side effects is relatively large, the most prominent is the risk of bleeding.
  • the eleven factors (FXIa) on the endogenous pathway have become the research hotspots of major companies and institutions.
  • FXIa as a safer anticoagulation target is reflected in type C hemophilia patients.
  • FXIa-deficient C-type hemophilia patients do not have active bleeding, which is more obvious than the eight-factor deficiency type A hemophilia and the nine-factor deficiency type B hemophilia patients.
  • a limited number of samples 115 patients showed that FXIa factor deficiency did not protect patients from acute myocardial ischemia, they were found to have a lower incidence of ischemic stroke and deep vein thrombosis.
  • Knockout mice have found that mouse selective knockout of common pathway factors (factors X, V and II) and exogenous factors (tissue factor and factor VII) can lead to prenatal or perinatal mortality.
  • Factor VIII and Factor IX knockout mice although able to survive, are often accompanied by severe bleeding, similar to hemophilia A and B, which are deficient in the risk of severe bleeding in humans due to the lack of factors VIII and IX.
  • Mice that selectively knock out factor XI can multiply normally.
  • the absence of factor XI protects mice against the formation of arterial thrombosis induced by ferric chloride.
  • the absence of factor XI does not affect the bleeding and hemostasis of mice. Therefore, this experiment shows that inhibition of factor XI not only prevents thrombosis, but is also safe tolerated.
  • FXIa is closely related to human thrombotic diseases, inhibiting FXIa with significant anticoagulant effect, but no obvious bleeding tendency, which can greatly reduce the risk of bleeding in clinical anticoagulation process.
  • the present invention provides a quaternary lactam cyclic compound represented by the following formula (I), an isomer, a solvate, a prodrug or a mixture thereof, and a pharmaceutically acceptable salt thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) t NR 6 R 7 , -COR 5a , -COOR 5b , -C(O) m (CH 2 ) t NR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, -NHC(O) m (CH 2 ) n C(O) m C 1-6 alkyl, -S(O) m (CH 2 ) t NR 6 R 7 , -NH(CH 2 ) t S(O) m R 5a , -NH(CH 2 ) t S(O) m -OR 5b , -OR 5b , -SR 5b , -(CH 2 ) t CN, -O(CH 2 ) )
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, -(CH 2 ) t X(CH 2 ) n NR 6 R 7 , -(CH 2 ) t CN, -(CH 2 ) t COR 5a , -(CH 2 ) t COOR 5b , -(CH 2 ) t NR 6 R 7 , -C(O) m (CH 2 ) t NR 6 R 7 , -C(O) m (CH 2 ) t NR 6 R 7 , -C(O) m (CH 2 ) t -aryl, -C(O) m (CH 2 ) t -heteroaryl, -CONH(CH 2 ) t -heterocyclyl, -CONHS(O) m R 5a , -CONHS( O) m -OR 5b ;
  • X is selected from O, S;
  • A is an aryl group, a heteroaryl group, a C 3-10 cycloalkyl group or a heterocyclic group
  • B is a nitrogen-containing heterocyclic group in which a nitrogen atom is bonded to CX, which may be optionally substituted by 1 to 3 R 3 ; the R 3 's the same or different and each independently selected from hydrogen, oxo, halogen, Hydroxy, -(CH 2 ) t CN, -(CH 2 ) t NR 6 R 7 , -(CH 2 ) t CONR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy a heterocyclic group, a heterocyclic group, a benzoheterocyclic group, an aryl group or a heteroaryl group; and when B is substituted by R 3 , at least one R 3 is a C 3-10 cycloal
  • B is a nitrogen-containing fused bicyclic group wherein the nitrogen atom is bonded to CX, which may be further optionally substituted with from 1 to 3 R 4b ;
  • R 5a is the same or different and each independently selected from hydrogen, halogen, C 1-10 alkyl, halogen C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclic, aryl Heteroaryl;
  • R 5b , R 6 and R 7 are the same or different and are each independently selected from hydrogen, C 1-10 alkyl, halogenated C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclic ring.
  • Base aryl, heteroaryl;
  • n is the same or different, and each is independently selected from an integer of from 1 to 10;
  • n is the same or different and each is independently selected from an integer of 1 or 2;
  • t is the same or different and each is independently selected from an integer of 0 to 10.
  • B is a 3-10 membered nitrogen-containing heterocyclic group optionally substituted with 1-3 R 3 (eg, 3, 4, 5, 6, 7, 8, 9, or 10 members) Nitrogen-containing heterocyclic group).
  • B is a group that is optionally substituted with 1-3 R 3 :
  • B is a 5-12 membered nitrogen-containing fused bicyclic group (eg, a 5, 6, 7, 8, 9, 10, 11 or 12 membered nitrogen-containing fused bicyclic group), which is further Optionally substituted by 1 to 3 R 4b , including, but not limited to, benzopyrrolidinyl, benzopiperidinyl, benzopiperazinyl, triazolopyridyl Azinyl.
  • B is a group that is optionally substituted with 1-3 R 4b :
  • B is Where Y is C, S, O or N, Representing a 3-10 membered heterocyclic group, R 8 is a C 3-10 cycloalkyl, aryl, heteroaryl or benzoheterocyclyl group, said R 8 being optionally substituted by 1-3 R 10 , R 10 is hydrogen, oxo, halogen, -(CH 2 ) t CN, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halogen C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, heterocyclic, aryl, amino, nitro, -(CH 2 ) t NR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, -(CH 2 ) t CONR 6 R 7 , -(CH 2 ) t COR 5a , -(CH 2 ) t COOR
  • R 9 is the same or different and is each independently selected from the group consisting of hydrogen, oxo, halogen, hydroxy, -(CH 2 ) t CN, -(CH 2 ) t NR 6 R 7 , -(CH 2 ) t CONR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy a C 3-10 cycloalkyl group, a C 3-10 cycloalkoxy group, a heterocyclic group, an aryl group, a heteroaryl group; the above R 9 may be optionally substituted with from 1 to 3 of the following groups R 11 : hydrogen , oxo, halogen, -(CH 2 ) t CN, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1
  • R 8 is selected from C 3-10 cycloalkyl, aryl, heteroaryl, benzoheterocyclyl; and R 8 can be optionally substituted with: hydrogen, oxo, Halogen, -(CH 2 ) t CN, C 1-10 alkyl, C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy, C 3-10 naphthenic , C 3-10 cycloalkoxy, heterocyclic, heterocyclyloxy, oxoheterocyclyl, C 1-10 alkyl-oxoheterocyclyl, aryl, aryloxy, amino, Nitro, -(CH 2 ) t NR 6 R 7 , -NHCOOC 1-10 alkyl, -NHCOC 1-10 alkyl, CONR 6 R 7 , COR 5a , COOR 5b , -SR 5b , -OH.
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, aryl, -(CH 2 ) t NR 6 R 7 , -COR 5a , -COOR 5b , -C(O)(CH 2 ) t NR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkane Base, -NHC(O) m (CH 2 ) n C(O) m C 1-6 alkyl, -S(O) m (CH 2 ) t NR 6 R 7 , -NH(CH 2 ) t S( O) m R 5a , -SR 5b , -(CH 2 ) t CN, -O(CH 2 ) n NR 6 R 7 .
  • A is aryl or heteroaryl, preferably phenyl or pyridyl.
  • R 2 is selected from the group consisting of -(CH 2 ) t X(CH 2 ) n NR 6 R 7 , —(CH 2 ) t CN, —(CH 2 ) t NR 6 R 7 , —(CH 2 t COR 5a , -(CH 2 ) t COOR 5b -C(O) m (CH 2 ) t NR 6 R 7 , -C(O) m (CH 2 ) t aryl, -C(O) m ( CH 2 ) t heteroaryl, -CONH(CH 2 ) t heterocyclyl, -CONHS(O) m R 5a .
  • X is O.
  • n is the same or different and is each independently selected from an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • n is the same or different and is each independently selected from 1 or 2.
  • t is the same or different and is each independently selected from an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 5a are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl, aryl Base, heteroaryl;
  • R 5b , R 6 , R 7 are the same or different and are each independently selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, hetero a cyclic group, an aryl group, a heteroaryl group;
  • the present invention provides a quaternary lactam cyclic compound represented by the following formula (IA), an isomer, a solvate, a prodrug or a mixture thereof, and a pharmaceutically acceptable salt thereof:
  • the compound of formula (I) (or formula (IA)) is selected from the group consisting of, but not limited to, the following compounds, isomers, solvates, prodrugs or mixtures thereof, and pharmaceutically acceptable salts thereof ( When present, it is preferably trifluoroacetate or hydrochloride):
  • the invention also provides a process for the preparation of a compound of formula (I), an isomer, solvate, prodrug or mixture thereof, which comprises the following:
  • R 1 , R 2 , A, B, X, and n are as defined above.
  • the reagents used in the basic conditions in the step 2) include, but are not limited to, triethylamine, diisopropylethylamine, N,N-dimethylaminopyridine, sodium hydroxide and the like.
  • the compound (A 0 ) in the step 2) can be produced by the following method, comprising:
  • R 1 , R 2 , A, n are as defined above; LG is selected from a leaving group.
  • any of the compound (a), the compound (b), the compound (c), the compound (e), the compound (f), and the compound (A 0 ) may be protected with a protecting group. After the reaction is completed, the appropriate method is used to remove the protecting group.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) (or formula (IA)) as described above, an isomer, solvate, prodrug or mixture thereof, and a pharmaceutically acceptable At least one of the salts, and optionally a pharmaceutically acceptable carrier and/or excipient.
  • the present invention also provides a compound of the above formula (I), an isomer, a solvate, a prodrug or a mixture thereof, and at least one of the pharmaceutically acceptable salts, or the pharmaceutical composition is prepared Use in a medicament for treating and/or preventing a thrombotic or thromboembolic related disorder; or use in the preparation of a thrombin inhibitor medicament.
  • Such thrombotic or thromboembolic related conditions include, but are not limited to, for example, arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, thromboembolic disorders in the heart or peripheral circulation, unstable angina, acute Coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary Arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis due to medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
  • the present invention also provides a pharmaceutical preparation comprising the pharmaceutical composition as described above, wherein the pharmaceutical preparation includes, but not limited to, a tablet, a pill, a granule, a capsule, an injection, a suspension, a drop, and an extract. , ointments, patches, emulsions, films, suppositories, pastes, gels, or sprays.
  • the present invention also provides a combined preparation comprising combining the pharmaceutical composition described above with at least one of other anticoagulant drugs, antithrombotic drugs or anti-venous embolization drugs;
  • Thrombotic drugs or anti-venous embolization drugs include, but are not limited to, heparin, low molecular weight heparin LMWH, enoxaparin, warfarin, rivaroxaban, apixaban, edoxaban, betrixaban, oromid Class, aspirin, ticlopidine, clopidogrel, tirofiban, coumarin, urokinase, platelet protein IIb/IIIa receptor antagonist.
  • the present invention also provides a method of treating and/or preventing a thrombosis- or thromboembolic-related disorder comprising administering the above-described pharmaceutical composition or pharmaceutical preparation or combination preparation to an individual in need thereof.
  • the thrombosis or thromboembolic related disorder has the definition as described above.
  • C 1-10 alkyl means a straight-chain and/or branched saturated aliphatic hydrocarbon group, for example, the aliphatic hydrocarbon group may include 1 to 10 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbons. Atom, 1-3 carbon atoms, 1 or 2 carbon atoms, etc.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
  • the adjacent carbon atoms of the alkyl group are optionally interrupted by one or more heteroatoms selected from O, S or N, for example propyl CH 3 CH 2 CH 2 - interrupted by O may be CH 3 -O- CH 2 CH 2 - or CH 3 CH 2 -O-CH 2 -, and so on.
  • C 1-10 alkoxy refers to a C 1-10 alkyl-oxy group, such as C 1-10 alkyloxy, C 1-6 alkyloxy, C 1-4 alkyloxy,
  • the alkyl group is as defined above.
  • representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • C 3-10 cycloalkyl refers to a saturated or partially unsaturated 3-10 membered all carbon monocyclic ring.
  • Examples of C 3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexadienyl, adamantyl, cycloheptyl, cyclooctyl Wait.
  • C 3-10 cycloalkyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, -(CH 2 ) t CN, linear or branched C 1- 10 alkyl or C 1-10 alkoxy, halo C 1-10 alkyl, halo C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, with 1 a saturated or partially unsaturated 3-10 membered heterocyclic group independently selected from nitrogen, oxygen or sulfur, aryl, amino, nitro, -(CH 2 ) t NR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, -(CH 2 ) t CONR 6 R 7 , -(CH 2 ) t C(O) m R 5a , -SR 5b , -OR 5b , -(CH 2 ) t COOH.
  • substituents selected from the group consisting
  • C 3-10 cycloalkoxy refers to a C 3-10 cycloalkyl-oxy group, and the C 3-10 cycloalkyl group is as defined above, and the oxy group means -O- group.
  • Examples of C 3-10 cycloalkyloxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy, cyclohexadienyloxy, adamantane Oxyl, cycloheptyloxy, cyclooctyloxy and the like.
  • C 3-10 cycloalkoxy may be optionally substituted with one or more substituents selected from halogen, -(CH 2 ) t CN, straight or branched C 1 a -10 alkyl or C 1-10 alkoxy group, a halogenated C 1-10 alkyl group, a halogenated C 1-10 alkoxy group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkoxy group, having a saturated or partially unsaturated 3-10 membered heterocyclic group independently selected from nitrogen, oxygen or sulfur ring heteroatoms, aryl, amino, nitro, -(CH 2 ) t NR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, -(CH 2 ) t CONR 6 R 7 , -(CH 2 ) t C(O) m R 5a , -SR 5b , -OR 5b , -((CH 2
  • heterocyclyl refers to a monocyclic ring system containing from 3 to 10 atoms wherein 1, 2, 3, 4 or 5 ring atoms are selected from heteroatoms such as nitrogen, sulfur or oxygen.
  • the heterocyclic ring may be fully saturated or contain one or more unsaturations, but is non-aromatic, having one or more attachment points attached to other molecules, which may be linked by carbon or nitrogen unless otherwise stated.
  • the -CH 2 - group is optionally replaced by -C(O)-.
  • heterocyclic group include, but are not limited to, a monocyclic ring composed of 3 to 10 atoms, which contains 1 to 5, preferably 1 to 3, hetero atoms selected from N, O or S.
  • a 3-10 membered monocyclic ring having 1-3 ring heteroatoms independently selected from nitrogen, oxygen or sulfur examples of which include, but are not limited to, oxiranyl, epithioethane, aziridine , oxacyclopropane, aziridine, thicyclopropyl, oxetanyl, thietane, azetidinyl, pyrrolidinyl, piperidinyl, piperidine Azinyl, morpholinyl, thiomorpholinyl, homopiperazinyl,
  • the "heterocyclyl” may be optionally substituted with one or more substituents selected from halogen, -(CH 2 ) t CN, straight or branched C 1-10 alkane Or a C 1-10 alkoxy group, a halogenated C 1-10 alkyl group, a halogenated C 1-10 alkoxy group, a C 3-10 cycloalkyl group,
  • benzoheterocyclyl refers to a phenyl group fused to a heterocyclic group wherein the phenyl group, heterocyclic group share a pair of adjacent ring atoms, and the heterocyclic group is as defined above.
  • Specific examples of the "benzoheterocyclyl” include, but are not limited to:
  • the benzoheterocyclic group may be optionally substituted by 1 to 3 substituents R 4a, R 4a the same or different, are each independently selected from halogen, - (CH 2) t CN , a straight-chain or Branched C 1-6 alkyl or C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy.
  • nitrogen-containing fused bicyclic group means a bicyclic ring system having 6 to 20 ring atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from hetero atoms such as nitrogen, sulfur or oxygen, and At least one ring contains at least one nitrogen heteroatom, and one ring of the two ring system shares a pair of adjacent ring atoms with another ring, wherein one ring may contain one or more double bonds, but the entire two ring system does not A fully conjugated Pi-electron system.
  • the "nitrogen-containing fused bicyclic group” includes a fused bicyclic ring composed of 6 yuan / 6 yuan, 6 yuan / 5 yuan, 6 yuan / 4 yuan, etc., and specific examples include, but are not limited to:
  • the nitrogen-containing fused bicyclic may be optionally substituted with 1 to 3 substituted with R 4b, R 4b the same or different, are each independently selected from halogen, - (CH 2) t CN , a straight-chain Or branched C 1-6 alkyl or C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 a cycloalkoxy group having 1-3 saturated or partially unsaturated 3-10 membered heterocyclic groups independently selected from nitrogen, oxygen or sulfur, heteroaryl, aryl, amino, nitro, -(CH 2 ) t NR 6 R 7 , -(CH 2 ) t NHC(O) m C 1-10 alkyl, -(CH 2 ) t CONR 6 R 7 , -(CH 2 ) t C(O) m R 5a , -SR 5b , -OR 5b , -(CH 2
  • aryl refers to a group having from 6 to 20 carbon atoms in its molecular structure and comprising at least one aromatic ring, i.e., having a conjugated pi-electron system.
  • the aryl group may be either a single aryl group or a combination of an aryl group and another group, such as an arylalkyl group, an alkylaryl group or the like.
  • Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenylalkyl, alkylphenyl, alkylenephenyl, alkylenephenyl, benzyl.
  • heteroaryl refers to an aromatic heterocyclic ring having at least one ring heteroatom such as sulfur, oxygen or nitrogen.
  • Heteroaryl groups include monocyclic systems and polycyclic systems (eg, having 2, 3 or 4 fused rings).
  • the heteroaryl group is a 1-3 ring hetero atom having 5-20 ring atoms and independently selected from nitrogen, oxygen or sulfur, preferably the heteroaryl group contains 1-3 ring impurities A 5-membered heteroaryl ring of an atom and a 6-membered heteroaryl ring.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl Acridine, Wait.
  • halogen means fluoro, chloro, bromo, iodo, preferably fluoro or chloro.
  • halogenated C 1-10 alkyl refers to a group formed by the substitution of one or more hydrogen atoms of a C 1-10 alkyl group with the same/different halogen atom, and representative examples include, but are not limited to, chloroform.
  • Base trifluoromethyl, 1-chloroethyl, 3-bromopropyl, and the like.
  • halogenated C 1-10 alkoxy refers to a group formed by the substitution of one or more hydrogen atoms of a C 1-10 alkoxy group with the same/different halogen atom, representative examples including but not limited to : chloromethoxy, trifluoromethoxy, 1-chloroethoxy, 3-bromopropoxy, and the like.
  • amino refers to an -NH 2 group.
  • acyl refers to a -C(O) R5a group.
  • amido refers to -C(O)NR 6 R 7 , and examples of representative amide groups such as -CO-NH 2 groups.
  • sulfonamido refers to a group having the structure -S(O) m NR 6 R 7 , -NHS(O) m R 5a .
  • cyano refers to a -C ⁇ N group.
  • hydroxy refers to an -OH group.
  • mercapto refers to a -SH group.
  • a substituent or group as defined or described herein has a plurality of sites capable of binding to a substituted structure
  • the corresponding chemical structure includes the substituent or group at all of these sites.
  • a C 1-4 alkylamino group includes a form in which a -C 1-4 alkylamino group or a C 1-4 alkylamino group is bonded to a site to be substituted.
  • substituted alkyl means that the alkyl group may be, but is not necessarily, substituted by a substituent, that is, both an unsubstituted alkyl group and a substituted alkyl group.
  • isomer is an abbreviation for an isomer, and refers to a compound having the same chemical formula, having the same chemical bond but having a different atomic arrangement.
  • isomers such as ethanol and diethyl ether.
  • isomers include structural isomers, stereoisomers, geometric isomers, optical isomers.
  • the "isomer” described in the present invention is preferably a stereoisomer.
  • solvate means a solvent-containing compound in which a solvent molecule may be bonded to other moieties by a coordinate bond or may be bonded by a covalent bond.
  • the solvent is a known solvent such as water, alcohols, ethers, benzenes, esters, aliphatic hydrocarbons, alicyclic hydrocarbons, ketones, and others.
  • the solvent include, but are not limited to, water, methanol, ethanol, isopropanol, diethyl ether, propylene oxide, benzene, toluene, xylene, methyl acetate, ethyl acetate, pentane, hexane, octane, cyclohexane. , cyclohexanone, acetone, methyl butanone, methyl isobutyl ketone, acetonitrile, pyridine, phenol, carbon tetrachloride, and the like.
  • prodrug also known as prodrug, prodrug, prodrug, etc.
  • prodrug means that the drug is chemically modified to have no activity or activity in vitro, but is released by enzyme or non-enzymatic conversion in the body.
  • a compound that exerts a pharmacological effect on an active drug means that the drug is chemically modified to have no activity or activity in vitro, but is released by enzyme or non-enzymatic conversion in the body.
  • Suitable acid addition salts include, but are not limited to, formate, acetate, trifluoroacetate, ethanesulfonate, 2-hydroxyethanesulfonate, glycolate, propionate, 3-phenyl Propionate, malonate, butyrate, pivalate, hexanoate, adipate, heptanoate, alginate, aspartate, benzoate, besylate , hydrogen hydrogen sulfate, citrate, camphorate, camphor sulfonate, digluconate, lauryl sulfate, fumarate, glucoheptanoate, sulfate, thiocyanate, Hemisulfate, persulfate, hydrochloride, nitrate,
  • composition preparation refers to a pharmaceutical preparation comprising at least two preparations (active ingredients), one of which may be administered before, after and/or simultaneously with the administration of additional components (optional) Repeatable).
  • preparations active ingredients
  • additional components optionally administered
  • simultaneous administration includes administration within 24 hours of each other, such as within 24 hours.
  • pharmaceutically acceptable carrier or excipient refers to any type of solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (eg, antifungal, antibacterial agent) well known in the pharmaceutical formulation art.
  • any conventional carrier or excipient can be considered in the pharmaceutical compositions of the invention.
  • compositions and combination preparations provided by the present invention can be formulated into various suitable dosage forms depending on the route of administration.
  • the use of one or more pharmaceutically acceptable carriers or excipients facilitates the processing of the active ingredient into preparations which may be employed in a pharmaceutical form.
  • the appropriate form of formulation will depend on the route of administration chosen and may be prepared according to common general knowledge in the art.
  • the routes of administration of the compounds, compositions, and combination formulations provided herein may be oral, parenteral (e.g., by injection) or topical.
  • Pharmaceutical preparations which can be orally administered include capsules and tablets and the like. When the patient has difficulty swallowing, it can also be administered by sublingual tablets or other non-swallowing methods.
  • the compounds, compositions, and combination preparations provided by the present invention may also be formulated for parenteral administration or transdermal administration or by mucosal administration, or by the use of suppositories or implants.
  • the compounds of the present invention may employ a suitable drug delivery system to achieve a more advantageous effect.
  • the dosages and methods of use of the compounds, compositions, and combination preparations provided by the present invention depend on various factors including the age, weight, sex, natural health status, nutritional status, and the activity intensity of the compound. Time, metabolic rate, severity of the condition, and subjective judgment of the doctor.
  • the inventors have unexpectedly discovered that the compounds of formula (I), isomers, hydrates, solvates, prodrugs or mixtures thereof, and pharmaceutically acceptable salts thereof, as described herein, and
  • the pharmaceutical composition of the compound has excellent thrombin inhibitory activity.
  • TBSCl tert-butyldimethylchlorosilane
  • LDA lithium diisopropylamide
  • DCC dicyclohexylcarbodiimide
  • DMSO dimethyl sulfoxide
  • CDI N,N-carbonyl-diimidazole
  • DMF dimethylformamide
  • DIEA N,N-diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • CDCl 3 deuterated chloroform
  • PE/EA petroleum ether/ethyl acetate
  • TFA trifluoroacetic acid
  • DCM dichloromethane
  • EDCI 1-ethyl -(3-dimethylaminopropyl)carbonyldiimide
  • THF tetrahydrofuran
  • Step 1) Boc 2 O (88.0 g) was added to a solution of compound A1 (50.0 g) in tert-butanol (1000 ml) and stirred at 60 ° C overnight. The reaction solution was cooled to room temperature, and the resulting suspension was filtered. The filter cake was washed three times with ethyl acetate (250 mL). The filter cake was dried in vacuo to give 70 g (yield compound A2) as a white solid.
  • Step 3) Compound A3 (42.0 g) was dissolved in a mixed solvent of tetrahydrofuran and methanol (250 ml / 250 ml), and cooled in an ice water bath. Sodium borohydride (13.0 g) was slowly added to the system under nitrogen. After stirring at room temperature overnight, acetone (40 ml) was added to the reaction mixture to quench the reaction. The crude product was concentrated to give purified crystalljjjjjjjjjjjjjj
  • Step 4) Methanesulfonyl chloride (24.5 g) was slowly added dropwise to a solution of compound A4 (37.0 g) and triethylamine (21.7 g) in dichloromethane (500 ml). The reaction solution was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction mixture was concentrated, acetone was added, and the resulting suspension was filtered, and the filtrate was directly applied to the next reaction.
  • Step 5 The filtrate obtained by the above reaction was diluted to 500 ml, and lithium bromide (14 g) was added. The mixture was stirred at room temperature overnight. The reaction solution was filtered. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc:EtOAc)
  • Step 6) Compound A7 (50.0 g) was dissolved in dichloromethane (500 mL). DIEA (62.9 g) and tert-butyldimethylsilyl chloride (51.6 g) were added dropwise, and the reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated, EtOAc (EtOAc m. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The crude product was purified by silica gel column chromatography eluting elut elut elut elut
  • Step 7) 10% by weight of palladium on carbon (7.2 g) was added to a solution of compound A8 (35 g) in tetrahydrofuran (150 ml). After the addition, the gas was exchanged three times and charged with hydrogen, and the mixed system was stirred at room temperature under a hydrogen atmosphere overnight. After the reaction was completed, it was suction filtered. The filtrate was concentrated to give a white solid (23.6 g).
  • Step 8) After cooling a solution of diisopropylamine (24.7 g) in tetrahydrofuran (120 ml) to -78 ° C, a 2.5 M solution of n-butyl lithium n-hexane (98 ml) was added. The reaction solution was slowly warmed to 0 ° C and stirring was continued for 1 hour. The solution was again cooled to -78 ° C, and a solution of compound A9 (20.0 g) in tetrahydrofuran (100 ml) was added, and the dropwise addition was completed in 45 minutes. The reaction solution was stirred at -65 ° C for 30 minutes, and the temperature was raised to -20 ° C, and the reaction was stirred for 30 minutes.
  • Step 9) Compound A10 (58.8 g, crude) was dissolved in dichloromethane (500 ml). EDCI (21.0 g) and DMAP (1.03 g) and benzyl alcohol (11.0 g) were sequentially added at room temperature. The reaction solution was stirred at room temperature under nitrogen overnight. After quenching with water, the reaction solution was concentrated. The crude product was purified by silica gel column chromatography eluting elut elut elut elut elut elut
  • the trifluoroacetate salt of compound I-001 was prepared according to the following reaction formula and method.
  • Step 1) Compound 1a (400 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (631 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (309 mg) was added and reacted at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with dichloromethane (60 mL ⁇ 3).
  • Step 2) Intermediate A (300 mg) was dissolved in dichloromethane (3 mL), and triethylamine (171 mg) was added, and a solution of compound 1b (430 mg) in dichloromethane was added dropwise. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 1c (240mg).
  • Step 3) Compound 1c (240 mg) was dissolved in 5 mL of methanol and 5 mL of ethyl acetate was added. Palladium on carbon (3.4 mg) was added, and the mixture was reacted at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was filtered and purified with EtOAc EtOAc EtOAc
  • Step 4) Compound 1d (120 mg) was dissolved in dichloromethane (2 mL), cooled to 0 ° C, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction solution was directly dried to dryness and purified by reverse phase preparative HPLC to afford trifluoroacetate (28 mg) of Compound I-001.
  • the trifluoroacetate salt of compound I-002 was prepared according to the following reaction formula and method.
  • Step 1) Compound 2a (2.5 g) was dissolved in 80.0 mL of dichloromethane, cooled to 0 ° C, sodium carbonate (22.6 g) was added, and after stirring for 10 min, compound 2b (5.5 g) was added. The reaction was allowed to rise to room temperature for 6 h under nitrogen. The reaction mixture was poured into water and extracted with EtOAc (EtOAc) (EtOAc)
  • Step 2) Compound 2c (2.1 g) was dissolved in 50 mL of toluene, compound 2d (1.15 g) was added, and a water separator was added thereto, and the mixture was heated to 130 ° C and refluxed overnight. The reaction mixture was dried with EtOAc (EtOAc)EtOAc.
  • Step 3 Compound 2e (2g) was dissolved in 20.0 mL of 30% hydrobromic acid acetic acid solution, and reacted under nitrogen for 3 h at room temperature. The reaction mixture was dried and EtOAc (EtOAc)
  • Step 4) Compound 2f (400 mg) was dissolved in dichloromethane (3 mL) and triethylamine (721 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (212 mg) was added and reacted at room temperature for 1 h. The reaction mixture was poured into EtOAc (3 mL, EtOAc)
  • Step 5 Compound 2g (100 mg) was dissolved in dichloromethane (3 mL), triethylamine (57.1 mg) was added, and a solution of Intermediate A (410 mg) in dichloromethane was added dropwise. The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 6) Compound 2h (60 mg) was dissolved in methanol (3 mL) Palladium on carbon (0.9 mg) was added, and the mixture was reacted at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 2i (50 mg, 94.6%).
  • Step 7) Compound 2i (50 mg) was dissolved in dichloromethane (2 mL), cooled to 0 ° C, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction solution was directly dried to dryness and purified by preparative preparative HPLC to afford trifluoroacetate (28 mg) of Compound I-002.
  • the trifluoroacetate salt of compound I-003 was prepared according to the following reaction formula and method.
  • Step 1) Compound 3a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (377 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (185 mg) was added and reacted at room temperature for 2 h. After completion of the reaction, the mixture was washed with ice water, extracted with DCM, and then evaporated.
  • Step 2) Intermediate A (100 mg) was dissolved in 10 mL dichloromethane, triethylamine (377 mg). The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 3 Compound 3c (120 mg) was dissolved in 5 mL methanol and 5 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction mixture was filtered to give Compound 3d (m.
  • Step 4) Compound 3d (80 mg) was dissolved in dichloromethane (2 mL) and cooled to 0. Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of compound I-004 was prepared according to the following reaction formula and method.
  • Step 1) Compound 4a (100 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step.
  • Step 2) Compound 4b (100 mg) was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to a solution of Intermediate A in dichloromethane. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 4c (90mg).
  • Step 3) Compound 4c (90 mg) was dissolved in 5 mL methanol and 5 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 4d (70 mg).
  • Step 4) Compound 4d (70 mg) was dissolved in dichloromethane (5 mL) and cooled to 0. Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-005 was prepared according to the following reaction formula and method.
  • Step 1) Compound 5a (300 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step.
  • Step 2) Compound 5b was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to dichloromethane. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 5c (85mg).
  • Step 3) Compound 5c (85 mg) was dissolved in 5 mL methanol and 5 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 5d (m.
  • Step 4) Compound 5d (67 mg) was dissolved in 10 mL dichloromethane. Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of compound I-006 was prepared according to the following reaction formula and method.
  • Step 1) Compound 6a (300 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (606 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (302 mg) was added and reacted at room temperature for 2 h. After completion of the reaction, it was washed with ice water, extracted with DCM, and concentrated to give 280 mg (yield compound 6b).
  • Step 2) Intermediate A (324 mg) was dissolved in dichloromethane (3 mL), triethylamine (123 mg). The reaction solution was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 6c (175 mg) was dissolved in 5 mL methanol and 5 mL ethyl acetate. Palladium on carbon (0.2 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 6d (160 mg).
  • Step 4) Compound 6d (160 mg) was dissolved in dichloromethane (2 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction mixture was dried with EtOAc EtOAc m.
  • the trifluoroacetate salt of compound I-007 was prepared according to the following reaction formula and method.
  • Step 1) Compound 7a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (377 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (185 mg) was added and reacted at room temperature for 2 h. After completion of the reaction, the mixture was washed with ice water, extracted with DCM, and then evaporated to give a crude product (100 g).
  • Step 2) Intermediate A (100 mg) was dissolved in 10 mL dichloromethane, triethylamine (377 mg). The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 7c (90 mg) was dissolved in 5 mL of methanol and 5 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 7d (70 mg).
  • Step 4) Compound 7d (70 mg) was dissolved in dichloromethane (2 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-008 was prepared according to the following reaction formula and method.
  • Step 1) Compound 8a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (377 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (185 mg) was added and reacted at room temperature for 2 h. After completion of the reaction, it was washed with ice water, extracted with DCM, and concentrated to give 150 mg (yield compound 8b).
  • Step 2) Intermediate A (100 mg) was dissolved in dichloromethane (10 mL), and triethylamine (377 mg) was added dropwise to a solution of compound 8b in dichloromethane. The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 8c (150 mg) was dissolved in 5 mL methanol and 5 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 8d (l.
  • Step 4) Compound 8d (120 mg) was dissolved in dichloromethane (2 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-009 was prepared according to the following reaction formula and method.
  • Step 1) Compound 9a (250 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (377 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (185 mg) was added and reacted at room temperature for 2 h. After completion of the reaction, it was washed with ice water, extracted with DCM, and concentrated to give a crude product (250 mg).
  • Step 2) Intermediate A (150 mg) was dissolved in 10 mL of dichloromethane, and then triethylamine (377 mg) was added dropwise to a solution of compound 9b in dichloromethane.
  • the reaction solution was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 9c (350 mg) was dissolved in 5 mL methanol and 5 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 9d (280 mg).
  • Step 4) Compound 9d (280 mg) was dissolved in dichloromethane (2 mL) and cooled to 0. Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-010 was prepared according to the following reaction formula and method.
  • Step 1) Compound 10a (200 mg) was dissolved in 10 mL THF. It was stirred at room temperature for 2 h and purified for use in the next step (Compound 10b).
  • Step 2) Compound 10b (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step (compound 10c).
  • Step 3 Compound 10c was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to dichloromethane. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 10d (102mg).
  • Step 4) Compound 10d (112 mg) was dissolved in 10 mL of a mixture of ethyl acetate and methanol. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 0.5 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 10e (85 mg).
  • Step 5 Compound 10e (86 mg) was dissolved in dichloromethane (5 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction mixture was dried with EtOAc EtOAc m.
  • the trifluoroacetate salt of compound I-011 was prepared according to the following reaction formula and method.
  • Step 1) Compound 11a (600 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step (comprising compound 11b).
  • Step 2) Compound 11b was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to a solution of Intermediate A in dichloromethane. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 11c (180 mg).
  • Step 3 Compound 11c (180 mg) was dissolved in 10 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 0.5 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 11d (150 mg).
  • Step 4) Compound 11d (150 mg) was dissolved in dichloromethane (10 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of compound 1-012 was prepared according to the following reaction formula and method.
  • Step 1) Compound 12a (200 mg) was dissolved in 10.0 mL dichloromethane, and triethylamine ( 396 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (194 mg) was added and reacted at room temperature for 2 h. After completion of the reaction, it was washed with ice water, extracted with DCM, and evaporated.
  • Step 2) Intermediate A (176 mg) was dissolved in 10 mL of dichloromethane, and triethylamine (101 mg) was added dropwise to a solution of compound 12b (240 mg) in dichloromethane.
  • the reaction solution was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 12c (170 mg) was dissolved in 5 mL of methanol and 5 mL ethyl acetate. Palladium on carbon (0.2 mg) was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 12d (l.
  • Step 4) Compound 12d (120 mg) was dissolved in dichloromethane (2 mL) and cooled to 0. Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of compound 1-013 was prepared according to the following reaction formula and method.
  • Step 1) Compound 13a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and the mixture was reacted at room temperature for 2 hours, and the reaction liquid was used in the next step (comprising compound 13b).
  • Step 2) Compound 13b was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to dichloromethane. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 13c (130mg).
  • Step 3 Compound 13c (130 mg) was dissolved in 10 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 0.5 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 13d (90 mg).
  • Step 4) Compound 13d (70 mg) was dissolved in dichloromethane (5 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction mixture was dried with EtOAc EtOAc m.
  • the trifluoroacetate salt of Compound 1-014 was prepared according to the following reaction formula and method.
  • Step 1) Compound 14a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and the mixture was reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step (comprising compound 14b).
  • Step 2) Compound 14b was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to a solution of Intermediate A in dichloromethane. The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 14c (98 mg) was dissolved in 10 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 0.5 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 14d (m.
  • Step 4) Compound 14d (70 mg) was dissolved in dichloromethane (5 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction mixture was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-015 was prepared according to the following reaction formula and method.
  • Step 1) Compound 15a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and the mixture was reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step (comprising compound 15b).
  • Step 2) Compound 15b was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to a solution of Intermediate A in dichloromethane. The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 3) Compound 15c (106 mg) was dissolved in 10 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 0.5 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 15d (m.
  • Step 4) Compound 15d (85 mg) was dissolved in dichloromethane (5 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction mixture was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-016 was prepared according to the following reaction formula and method.
  • Step 1) Compound 16a (200 mg) was dissolved in 10.0 mL dichloromethane and triethylamine (239 mg). The ice salt bath was cooled to 0 ° C, and triphosgene (87.9 mg) was added thereto, and reacted at room temperature for 2 hours, and the reaction liquid was directly used for the next step (comprising compound 16b).
  • Step 2) Compound 16b was dissolved in 10 mL of dichloromethane, and triethylamine (57.1 mg) was added dropwise to a solution of Intermediate A in dichloromethane. The reaction mixture was directly dried and purified by silica gel column chromatography.
  • Step 3 Compound 16c (106 mg) was dissolved in 10 mL ethyl acetate. Palladium carbon (0.8 mg) was added, and the mixture was reacted at room temperature for 0.5 h under a hydrogen atmosphere. The reaction solution was filtered to give Compound 16d (m.
  • Step 4) Compound 16d (85 mg) was dissolved in dichloromethane (5 mL). Add 3 mL of trifluoroacetic acid and react overnight at room temperature. The reaction mixture was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of compound I-017 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of Compound 1-018 was prepared according to the following reaction formula and procedure.
  • Step 1) Compound 7d (220 mg) was dissolved in dichloromethane (2 mL). Methanesulfonamide (48 mg), HATU (190 mg), and DIEA (68 mg) were sequentially added to react at room temperature overnight. The reaction mixture was dried and purified to give Compound 18a (170 mg).
  • Step 2) Compound 18a (170 mg) was dissolved in dichloromethane (2 mL) and cooled to 0. Add 2 mL of trifluoroacetic acid at room temperature overnight. The reaction mixture was directly dried and purified by silica gel column chromatography toield
  • the trifluoroacetate salt of Compound 1-019 was prepared according to the following reaction formula and method.
  • Step 1) Compound 7d (70 mg) was dissolved in dichloromethane (5 mL), and then methylamine hydrochloride (10.6 mg), DIEA (20.0 mg), and HATU (50.0 mg). Stir at room temperature for 1 h. The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 19a (80mg).
  • Step 2) Compound 19a (75 mg) was dissolved in 1 mL dichloromethane. Add 1 mL of trifluoroacetic acid and react at room temperature overnight. The reaction mixture was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of Compound 1-020 was prepared according to the following reaction formula and method.
  • Step 1) Compound 7d (70 mg) was dissolved in dichloromethane (5 mL), dimethylamine hydrochloride (10.6 mg), DIEA (20.0 mg), HATU (50.0 mg). The reaction solution was directly dried and purified by silica gel column chromatography to afford Compound 20a (75 mg).
  • Step 2) Compound 20a (75 mg) was dissolved in 1 mL dichloromethane and cooled to 0. Add 1 mL of trifluoroacetic acid and react at room temperature overnight. The reaction solution was dried with EtOAc (EtOAc m.
  • the trifluoroacetate salt of compound I-021 was prepared according to the following reaction formula and method.
  • Step 1) Compound 21a (7.05 g), Compound 21b (4.8 g), Pd(dppf)Cl 2 (249 mg), cesium carbonate (22.4 g) were added to 1,4-dioxane (140 ml) at room temperature. in. After the addition was completed, argon was replaced three times and stirred at 90 ° C under argon atmosphere overnight. After cooling, it was quenched with water, extracted with EtOAc EtOAc EtOAc m.
  • Step 4): Pd/C (58 mg, w/w 50%, 10%) was added to a solution of compound 21f (105 mg) in ethyl acetate / methanol (3 / 3 mL). Hydrogen was charged, and the mixed system was stirred under a hydrogen atmosphere for 2 hours. After completion of the reaction, the mixture was filtered and concentrated to give white crystals (yield: 21 g).
  • Step 5 21 g (100 mg) of the compound was added to a solution of TFA/DCM (3/3 mL) and stirred at room temperature for about 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature and purified by reverse-phase preparative HPLC. (i.e., the trifluoroacetate salt of Compound I-021).
  • the compound 21b was replaced with the compound 22b according to the method of Example 21 to give 23 mg (yield of trifluoroacetic acid salt of the compound I-022) as a white solid.
  • the trifluoroacetate salt of compound I-023 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of the compound I-024 was prepared according to the following reaction formula and method.
  • Step 1) To a solution of compound 16d (90 mg) in dichloromethane (20 mL), EtOAc (EtOAc) The silica gel preparation plate was purified to give 73 mg (i.e., compound 24a) as a colorless solid.
  • Step 4) Compound 24a (73 mg) was added to a solution of TFA/DCM (3/3 mL) and stirred at room temperature for about 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. That is, the trifluoroacetate salt of Compound 1-024).
  • the trifluoroacetate salt of compound I-025 was prepared according to the following reaction formula and method.
  • Step 1) DIEA (54 mg), HATU (82 mg) was added to a solution of compound 16d (90 mg) in methylene chloride (20 mL), and stirred for 10 min to add methylsulfonamide, stirred at room temperature for 1 hour and concentrated on silica gel. The plate was purified to give 60 mg (i.e. compound 25a) as a colorless solid.
  • Step 4) Compound 25a (60 mg) was added to a solution of TFA/DCM (3/3 mL) and stirred at room temperature for about 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. That is, the trifluoroacetate salt of Compound I-025).
  • the hydrochloride salt of compound I-026 was prepared according to the following reaction formula and method.
  • Step 1) Compound 26a (1.46 g), compound 26b (2.0 g) and potassium carbonate (1.70 g) were dissolved in 20 mL of a mixed solvent of dioxane and water (10/1), and Pd was added under nitrogen atmosphere. Dppf) Cl 2 (450 mg). The oil bath was stirred at 80 ° C for 90 minutes. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc
  • Step 3) Compound 26d was dissolved in 5 mL of HCl dioxane solution. It was stirred at room temperature for 2 hours and concentrated under reduced pressure. The obtained solid was diluted with ethyl acetate (20 mL) and washed successively with sat. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a white solid (1.2 g, Compound 26e).
  • Step 4) Diisopropylethylamine (642 mg) was added to a solution of compound 26e (400 mg) in dichloromethane (20 mL). Stir at room temperature overnight under nitrogen. The reaction solution was washed three times with saturated aqueous sodium hydrogen sulfate (5 mL) and dried over anhydrous sodium sulfate.
  • Step 5 Further, diisopropylethylamine (146 mg), DMAP (46 mg) and Intermediate A (200 mg) were added to the reaction mixture obtained from the above work. After the addition, the mixture was stirred at room temperature for 3 hours under argon gas. After LCMS detected the reaction was completed, 40 ml of water was added to the reaction system, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic layers were dried with anhydrous sodium The obtained crude product was purified by silica gel column chromatography (EtOAc(EtOAc)
  • Step 7) Compound 26h (50 mg) was added to a solution of TFA / DCM (2mL / 2mL) and stirred at 25 ° C for 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The crude product obtained was purified by C-HY---------------
  • Step 1) Compound 27a (3.44 g) was dissolved in 25 mL of dry dichloromethane. A solution of methyl chloroformate (2.46 g) in dichloromethane (5 mL) was added dropwise at 0 ° C under nitrogen. The reaction solution was stirred at room temperature for 1.5 hours. The reaction was quenched with water (30 mL)EtOAc. The organic layer was washed with EtOAc EtOAc m.
  • Step 2) Boc 2 O (6.56 g) and DMAP (3.63 g) were sequentially added to a solution of compound 27b (5.77 g, crude) in tetrahydrofuran (125 mL). Under nitrogen, the mixture was stirred at 78 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj
  • Step 3) Compound 27c (5.0 g), compound pyridine-3-boronic acid (2.24 g) and potassium carbonate (3.13 g) were dissolved in a mixed solvent of dioxane and water (30 mL / 3 mL) under nitrogen Pd(dppf)Cl 2 (260 g) was added. The oil bath was stirred at 110 ° C overnight. The reaction solution was filtered, and the filtrate was evaporated. The crude product was purified by EtOAc EtOAcjjjjjjjjjjjj
  • Step 4) Compound 27d (3.2 g) was dissolved in 10 mL of dry methylene chloride, and then, under nitrogen, benzyl bromide (4.16 g) was added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced vacuo. The organic phase was washed twice with water (50 mL) and EtOAc (EtOAc)
  • Step 5 Sodium borohydride (160 mg) was added to a solution of compound 27e ( 880 mg, EtOAc) Stir at room temperature for 2 hours under nitrogen. The reaction mixture was concentrated, diluted with EtOAc EtOAc EtOAc. This oil was dissolved in 10 mL of tetrahydrofuran, followed by Boc 2 O (384 mg) and DMAP (215 mg). The reaction solution was stirred at 78 ° C for 2.5 hours. The reaction mixture was concentrated, diluted with water and evaporated with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by EtOAc EtOAcjjjjjjjjj
  • Step 6) Pd/C (350 mg, 10% wet) was added to a solution of compound 27f (720 mg) in methanol (15 mL). After the addition was completed, the gas was exchanged three times and charged with hydrogen. The mixed system was under a hydrogen atmosphere. Stir at 30 ° C for 1.5 hours. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated.
  • Step 7) Diisopropylethylamine (139 mg) was added to a solution of compound 27 g (120 mg) in dichloromethane (7 mL). Stir at room temperature for 3 hours under nitrogen. The reaction solution was washed once with a saturated aqueous solution of sodium hydrogen sulfate (4 mL), which was cooled with ice water, dried over anhydrous sodium sulfate and filtered, and the filtrate was applied to the next reaction.
  • Step 9) Pd/C (115 mg, 10% wet) was added to a solution of compound 27i (330 mg) in ethyl acetate/methanol (5 mL/5 mL). After the addition was completed, the gas was exchanged three times and charged with hydrogen. Stir under a hydrogen atmosphere for 3 hours. After the reaction was completed, it was filtered with suction and evaporated to ethylamine.
  • Step 10) Compound 27j (250 mg) was added to a solution of TFA / DCM (5mL / 2.5mL) and stirred at 25 ° C for 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The crude product was purified by preparative EtOAc (EtOAc:EtOAc)
  • the hydrochloride salt of Compound I-028 was prepared according to the following reaction formula and method.
  • Step 1) Compound 28a (868 mg), Compound 26b (2.0 g) and potassium carbonate (1.08 g) were dissolved in 11 mL of a mixed solvent (10/1) of dioxane and water. Pd(dppf)Cl 2 (120 mg) was added, and the reaction solution was stirred at 110 ° C overnight under nitrogen. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj
  • Step 4) Diisopropylethylamine (469 mg) was added to a solution of compound 28d (200 mg) in dichloromethane (10 mL). Stir at room temperature overnight under nitrogen. The reaction mixture was washed four times with aq. The filtrate was applied directly to the next reaction.
  • Step 5 Further, diisopropylethylamine (155 mg), DMAP (44 mg) and Intermediate A (191 mg) were added to the reaction mixture obtained from the above work. After the addition was completed, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was completed by LCMS, and 10 ml of water was added to the reaction system. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried with anhydrous sodium The obtained crude product was purified by silica gel column chromatography eluting eluting
  • Step 6) Pd/C (60 mg, 10% wet) was added to a solution of compound 28f (199 mg) in ethyl acetate / methanol (4 mL / 4 mL). After the addition was completed, the gas was exchanged three times and charged with hydrogen. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was evaporated.
  • Step 7) To a solution of TFA/DCM (8 mL / 2 mL) was added, and the mixture was stirred at 30 ° C for 2 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. Purification by C-18 reverse phase column (5-95% acetonitrile / water (EtOAc EtOAc))
  • the trifluoroacetate salt of Compound 1-029 was prepared according to the following reaction formula and method.
  • Step 1) To a solution of the compound 21 g (290 mg, EtOAc, m. The reaction solution was stirred at 0 ° C for 6 hours. After diluting with dichloromethane (20 mL), it was washed successively with saturated aqueous ammonium chloride (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. EtOAc m.
  • Step 2) Compound 29a (149 mg) was added to a solution of TFA / DCM (3mL / 1.5mL). Stir at room temperature for about 2 hours, and the reaction was complete by LCMS. The reaction mixture was concentrated at rt. EtOAc (EtOAc)
  • Step 1) To a solution of compound 22 g (136 mg) in dichloromethane (3 mL). Methylamine tetrahydrofuran solution (0.21 mL) was added. After stirring at 0 ° C for 2 hours, the reaction solution was quenched with water. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The crude product was purified by silica gel column chromatography (MeOH /EtOAc
  • Step 2) Compound 30a (106 mg) was added to a solution of TFA/DCM (6 mL / 2 mL) and stirred at room temperature for about 2 hours. After the reaction was completed by LCMS, it was concentrated at room temperature. The reaction mixture was purified to give a white solid (31.4 mg, m.
  • Compound I-031 was prepared according to the following reaction formula and method.
  • Step 1) Diisopropylethylamine (69.7 mg) and HATU (90.7 mg) were added to a solution of compound 15d (100 mg) in dichloromethane (10 mL). After stirring at 0 ° C for 10 min, ammonium chloride (17.0 mg) was added. The reaction solution was further stirred at 0 ° C for 2 hours. The reaction was quenched by the addition of 2 mL EtOAc EtOAc. The combined organic layers were purified by EtOAc EtOAc EtOAc EtOAc EtOAc
  • Step 2) Compound 31e (62 mg) was added to a solution of TFA / DCM (2mL / 1mL) and stirred at 25 ° C for 2 hours. After the reaction was completed by LCMS, it was concentrated at room temperature. The reaction mixture was concentrated and taken up in 1 mL of EtOAc EtOAc (EtOAc)
  • the hydrochloride salt of compound I-032 was prepared according to the following reaction formula and method.
  • Step 1) Diisopropylethylamine (51.9 mg) and HATU (76.4 mg) were added to a solution of compound 26h (95 mg) in dichloromethane (5 mL). After stirring at 0 ° C for 10 min, ammonium chloride (14.3 mg) was added. Stir at 0 ° C for 2 hours. After quenching the reaction with a saturated aqueous solution of sodium hydrogencarbonate, water was added and then extracted with dichloromethane. The combined organic layers were purified by silica gel chromatography eluting elut elut
  • Step 2) Compound 32a (90 mg) was added to a solution of TFA/DCM (4 mL / 2 mL) and stirred at 20 ° C for about 3 hours. After the reaction was completed by LCMS, it was concentrated at room temperature. The reaction mixture was purified by EtOAc EtOAcjjjjj:
  • Compound I-033 was prepared according to the following reaction formula and method.
  • Step 1) Under a nitrogen atmosphere, diisopropylethylamine (51.9 mg) and HATU (76.4 mg) were added to a solution of compound 26h (95 mg) in dichloromethane (5 mL) and stirred at 0 ° C for 10 min.
  • the methylamine tetrahydrofuran solution (0.134 mL) was diluted with 0.5 mL of dry dichloromethane, and then added to the reaction system at 0 ° C, and stirred at this temperature for 2 hours. After quenching the reaction with a saturated aqueous solution of sodium hydrogencarbonate, water was added and then extracted with dichloromethane. The organic phases were combined, and then purified,jjjjjjjj
  • Step 8) Compound 33a (60 mg) was added to a solution of TFA / DCM (4mL / 2mL) and stirred at 20 ° C for 3 hours. After the reaction was completed by LCMS, it was concentrated at room temperature. The reaction mixture was concentrated and taken up in 1 mL of EtOAc EtOAc (EtOAc)
  • the trifluoroacetate salt of Compound 1-034 was prepared according to the following reaction formula and method.
  • Step 1) Compound 34a (2.5 g), Compound 26b (3.53 g) and potassium carbonate (2.86 g) were dissolved in a mixed solvent of dioxane and water (50 mL / 5 mL). Under nitrogen, Pd(dppf)Cl 2 (1.27 g) was added, and the mixture was stirred at 80 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj
  • Step 3) Compound 34c (3.21 g) was dissolved in 30 mL MeOH MeOH. After stirring at room temperature overnight, the reaction mixture was concentrated. The obtained solid was dissolved in EtOAc EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a brown solid (2 g).
  • Step 4) Diisopropylethylamine (1.22 g) was added to a solution of compound 34d (770 mg) in dichloromethane (16 mL). Stir at room temperature overnight under nitrogen. The reaction mixture was washed with saturated aqueous sodium hydrogen sulfate (10 mL) The filtrate was concentrated to give a yellow oil (1.1 g, crude product, Compound 34e) which was applied directly to the next step.
  • Step 5 Compound 34e (964 mg, crude) from m. Intermediate A (500 mg), diisopropylethylamine (365 mg) and DMAP (115 mg) were added in that order. After the addition, the mixture was stirred at room temperature for two hours under argon gas. After the reaction was completed by LCMS, it was washed with saturated brine (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated. The obtained crude product was purified to silica gel elution elution
  • Step 7) Compound 34 g (150 mg, crude) was added to a solution of TFA/DCM (3mL / 1.5mL) and stirred at 30 ° C for 2 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The crude product was purified by reverse phase preparative HPLC to afford white crystals (yield: ⁇ RTIgt;
  • the trifluoroacetate salt of Compound 1-035 was prepared according to the following reaction formula and method.
  • Step 1) Under a nitrogen atmosphere, diisopropylethylamine (109 mg) and HATU (213 mg) were added to a solution of compound 34 g (200 mg, crude) in dichloromethane (4 mL). After stirring at 0 ° C for 30 min, ammonium chloride (45 mg) was added. Stir at 0 ° C for 2 hours. The reaction was quenched by the addition of aqueous ammonium chloride (10 mL). The organic phase was combined and evaporated to purified crystals eluted eluted elut elut elut elut
  • Step 2) Compound 35a (228 mg, crude) was added to a solution of TFA / DCM (3mL / 1.5mL) and stirred at 30 ° C for 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The crude product was purified by reverse phase preparative HPLC to yield 40.3 g (yield of trifluoroacetate as compound I- 035).
  • the trifluoroacetate salt of compound I-036 was prepared according to the following reaction formula and method.
  • Step 1) Under a nitrogen atmosphere, diisopropylethylamine (108 mg) and HATU (202 mg) were added to a solution of compound 34 g (200 mg, crude) in dichloromethane (4 mL). After stirring at 0 ° C for 30 min, a solution of methylamine tetrahydrofuran (2.0 M, 0.28 mL) was added. Stirring was continued for 3 hours at 0 °C. The reaction was quenched by the addition of aqueous ammonium chloride (10 mL) andEtOAc. The organic phase was combined and evaporated to purified crystallitejjjjjjjjjj
  • Step 2) Compound 36a (247 mg, crude) was added to a solution of TFA / DCM (3mL / 1.5mL) and stirred at 30 ° C for 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The crude product was purified by reverse phase preparative HPLC to afford 58.2 mg (yield of trifluoroacetate as compound I- 036).
  • Compound I-037 was prepared according to the following reaction formula and method.
  • Step 1) Compound 37a (2.0 g) was dissolved in 15 mL of THF. After stirring at this temperature for 30 minutes, a solution of the compound PhN(Tf) 2 (6.8 g) in tetrahydrofuran (20 mL) was added. Warm slowly to room temperature and stir overnight. After quenching with water, EtOAc was evaporated. The crude product was purified by EtOAcjjjjjjjj
  • Step 2) Compound 37b (2.0 g), compound 26b (2.39 g) and potassium carbonate (2.13 g) were dissolved in a mixed solvent of dioxane and water (20 mL / 3 mL), and Pd (dppf) was added under nitrogen atmosphere. )Cl 2 ⁇ DCM (566 mg). The oil bath was stirred at 85 ° C for 3 hours. The reaction solution was concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc/EtOAc:EtOAc:
  • Step 3) Pd/C (300 mg, 10%) was added to a solution of compound 37c (1.9 g) in methanol (20 mL). After the addition was completed, the gas was exchanged three times and charged with hydrogen, and the mixture was stirred overnight under a hydrogen atmosphere. . After completion of the reaction, the mixture was filtered and evaporated.
  • Step 5 Diisopropylethylamine (1.79 g) was added to a solution of compound 37e (900 mg) in dichloromethane (20 mL). (20 mL) solution. Stir at room temperature overnight under nitrogen. The reaction solution was washed three times with saturated aqueous sodium hydrogen sulfate (20 mL), dried over anhydrous sodium sulfate and filtered.
  • Step 6) Further, diisopropylethylamine (327 mg), DMAP (103 mg) and Intermediate A (450 mg) were added to the reaction mixture ( ⁇ 50 mL) obtained from the above work. After the addition was completed, the mixture was stirred at room temperature under argon atmosphere overnight. After the reaction was completed by LCMS, the reaction was quenched with water and extracted with dichloromethane. The combined organic layers were dried with anhydrous sodium The obtained crude product was purified by silica gel column chromatography (EtOAc(EtOAc)
  • Step 7) Pd/C (250 mg, 10%) was added to a solution of 37 g (570 mg) of ethyl acetate/methanol (20 mL / 20 mL). After the addition was completed, the gas was exchanged three times and charged with hydrogen. Stir under a hydrogen atmosphere for 1 hour. After completion of the reaction, the mixture was filtered and evaporated to ethylamine.
  • Step 8) Compound 37h (150 mg) was added to a solution of TFA / DCM (4mL / 2mL) and stirred at 25 ° C for 4 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The crude product was purified by EtOAc EtOAc EtOAc.
  • the trifluoroacetate salt of compound I-038 was prepared according to the following reaction formula and method.
  • Step 1) Diisopropylethylamine (93 mg) and HATU (137 mg) were added to a solution of compound 15d (150 mg) in dichloromethane (3 mL). After stirring at 0 ° C for 20 min, n-propylamine (29 mg) was added. Stirring was continued for 4 hours at 0 °C. The reaction solution was diluted with methylene chloride, and then washed with aqueous sodium chloride (10 mL) and brine (10 mL). The organic phase was dried, filtered and concentrated. The crude product was purified by EtOAcjjjjjjjjj
  • Step 2) Compound 38a (150 mg) was added to a solution of TFA / DCM (3mL / 1.5mL) and stirred at 30 ° C for 2 hours. After the reaction was completed by LCMS, it was concentrated at room temperature. The crude product was purified by reverse phase preparative HPLC to yield white crystals (yield:
  • Step 5 Compound 39b (140 mg) was added to a solution of TFA / DCM (4mL / 2mL) and stirred at 25 ° C for 2 hours. After the reaction was completed by LCMS, it was concentrated at room temperature. After concentrating the reaction mixture, it was purified by preparative preparative EtOAc (EtOAc)
  • Step 1) Compound 40a (1.00 g), Compound 26b (1.49 g) and potassium carbonate (1.33 g) were dissolved in 15 mL of a mixed solvent of dioxane and water (5/1). Pd(dppf)Cl 2 (353 mg) was added under nitrogen. The oil bath was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated to dryness crystalljjjjlililililililili
  • Step 3) Compound 40c (1.3 g) was dissolved in 10 mL of HCl dioxane. After stirring at room temperature for 3 hours, it was concentrated under reduced pressure. The obtained solid was dissolved in saturated aqueous sodium hydrogen sulfate (5 mL). The organic phase was washed with brine (5 mL). The organic layer was dried over anhydrous sodium
  • Diisopropylethylamine 550 mg was added to a solution of compound 40d (300 mg) in dichloromethane (10 mL). After warming to 0 ° C, a solution of triphos (168 mg) in dichloromethane (10 mL) was added in one portion. . Stir at room temperature overnight under nitrogen. The reaction solution was washed three times with saturated aqueous sodium hydrogen sulfate (10 mL) and dried over anhydrous sodium sulfate.
  • Step 5 Further, diisopropylethylamine (109 mg), DMAP (34.5 mg) and Intermediate A (150 mg) were added to the reaction mixture (40e) ( ⁇ 25mL) obtained from the above work. After the addition was completed, the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. After the reaction was completed by LCMS, 20 ml of water was added to the reaction system. The organic phase was separated and the aqueous extracted with dichloromethane (30 mL). The combined organic layers were dried over anhydrous sodium The obtained crude product was purified by silica gel column chromatography eluting elut elut elut elut elut
  • Step 7) Compound 40 g (160 mg) was added to a solution of TFA / DCM (4mL / 2mL) and stirred at 25 ° C for 3 hours. After the reaction was completed by LCMS, the reaction mixture was concentrated at room temperature. The obtained solid was dissolved in 1 mL of EtOAc (EtOAc) (EtOAc)
  • the trifluoroacetate salt of compound I-041 was prepared according to the following reaction formula and method.
  • Step 1) DIEA (14 mg), HATU (18 mg) was added to a solution of compound 15d (20 mg) in dichloromethane (5 mL), and the mixture was stirred for 10 min. The plate was purified to give 18 mg (yield compound 41a) as a colorless solid.
  • Step 4) Compound 41a (37 mg) was added to a solution of TFA/DCM (1.5/1.5 mL), and stirred at room temperature for about 3 hours. The reaction was concentrated by LCMS and then concentrated at room temperature. (i.e., the trifluoroacetate salt of Compound I-041).
  • the trifluoroacetate salt of compound I-042 was prepared according to the following reaction formula and method.
  • Compound I-043 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of Compound 1-044 was prepared according to the following reaction formula and method.
  • Compound I-046 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of Compound 1-047 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of compound I-048 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of compound I-049 was prepared according to the following reaction formula and method.
  • the starting material 49a is replaced with the starting material 50a to prepare a trifluoroacetate salt of the compound 1-050.
  • the trifluoroacetate salt of compound I-051 was prepared according to the following reaction formula and method.
  • Compound I-052 was prepared according to the following reaction formula and method.
  • the trifluoroacetate salt of Compound 1-053 was prepared according to the following reaction formula and method.
  • Trifluoroacetate salts of compounds I-054 and I-054 were prepared according to the following reaction schemes and procedures.
  • test sample The test compound was dissolved in DMSO, and a stock solution of 3000, 600, 120, 24, 4.8 ⁇ M was obtained by gradient dilution, and each concentration was 1:49 (V/V) and the prepared person was respectively prepared. Plasma is mixed.
  • Negative control DMSO solvent without test compound was diluted by gradient to obtain stock solutions of 3000, 600, 120, 24, 4.8 ⁇ M, and each concentration was mixed with the prepared human plasma at 1:49 (V/V). .
  • Test Mix the above test sample and the negative control test solution for 3 to 5 minutes, then take 30 ⁇ L of test solution on the machine (MC-2000 blood coagulation instrument), pre-warm at 37 °C for 2 min, and then add 30 ⁇ L of APTT reagent. (MDC Hemostasis, Cat: 300025) Incubate for 5 min at 37 ° C, then add 30 ⁇ L of CaCl 2 to start the APTT assay.
  • the APTT ratio is calculated according to the following formula.
  • APTT ratio (APTT test compound / APTT negative control )
  • the APTT of the other exemplary compounds of the present invention were tested in the same manner as above, and it was found that the EC 150 of the other exemplary compounds of the present invention or their salts were substantially in the range of 1.41 to 30.00 ⁇ M, and the EC 200 was in the range of 4.4 to 60.00 ⁇ M. Within the range, it shows very good clotting activity.
  • test compound was dissolved in DMSO to 10 mM mother liquor, and stored at -80 ° C until use.
  • the mother liquor was frozen and then diluted with DMSO to 2 m ⁇ as the initial reaction concentration, and diluted to a concentration of 9 in DMSO as a working solution.
  • reaction solution is diluted 2 ⁇ buffer FXIa protein (Cat # ab62411 ) to the desired concentration of 0.25 ng / ⁇ l, 10 ⁇ l / well; 2 ⁇ S-2366 reaction solution, the S-2366 reaction solution was prepared into 2 mM, 10 ⁇ l / well with deionized water; first add the enzyme reaction solution to the 384-well plate Then, the diluted test compound reaction solution was sequentially added to the corresponding well; the negative control was DMSO solvent; the blank was replaced with buffer; centrifuged at 1000 rpm for 1 min at room temperature, and after 30 min in the dark, finally added S-2366 reaction solution per well. The mixture was shaken for 30 s, reacted at 37 ° C for 20 min, the

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Abstract

一种四元内酰胺类化合物及其制备方法和药学用途，特别是在用于制备治疗和/或预防血栓形成或血栓栓塞病症的药物中的用途。

Description

四元内酰胺类化合物及其药学用途
本申请要求2018年3月30日向中国国家知识产权局提交的，专利申请号为201810276765.6，发明名称为“四元内酰胺类化合物及其药学用途”的在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物化学技术领域，具体涉及一种四元内酰胺类化合物及其在用于制备治疗和/或预防血栓形成或血栓栓塞病症的药物中的用途。
背景技术
血液凝固是各种血浆蛋白、共因子和血小板协调激活的结果。这一级联反应被分成内源性(接触激活)途径、外源性(组织因子激活)途径和共同(凝血酶原和凝血酶的产生)途径。血液凝固过程中最重要的生理过程是激活组织因子。组织因子与因子VIIa形成复合物，催化激活因子十(FX)，活化的FXa进而裂解凝血酶原产生活化的凝血酶(FIIa)。活化的凝血酶(FIIa)作为凝血过程的中心催化酶，催化纤维蛋白原裂解为纤维蛋白，起到凝血作用。该外源性途径参与的酶数量少，见效快。内源性途径是机体固有的凝血途径，通过级联反应激活十二因子(FXIIa)、十一因子(FXIa)、九因子(FIXa)和八因子(FVIIIa)，进而激活十因子(FXa)和下游的中心凝血酶(FIIa)。凝血酶反过来又激活十一因子(FXIa)，产生放大效应，加速凝血。内源性途径参与凝血的酶较多，且全部来自血液，一般见效比较慢。
整个凝血过程中，FXa起到非常关键的作用。作为外源性和内源性凝血途径的下游共同调节因子，其拮抗剂被广泛用于各种血栓的预防和治疗。现有多种FXa的拮抗剂上市，因其显著疗效而占据了心血管药物市场。然而，它们的副作用发生概率也是比较大的，最突出的就是出血风险。为解决出血问题，内源性途径上的十一因子(FXIa)就成为了各大公司和机构的研究热点。
FXIa作为更安全的抗凝靶点的潜力在C型血友病人身上得以体现。FXIa缺乏的C型血友病患者没有主动出血的现象，这与八因子缺乏的A型血友病及九因子缺乏的B型血友病患者容易出血对比明显。虽然有限的样本数(115名患者)研究表明FXIa因子缺陷不能保护患者免受急性心肌缺血，但却发现这类患者具有较低的缺血性脑卒中和深静脉血栓发病率。
基因敲除小鼠实验发现，小鼠选择性基因敲除共同通路因子(因子X、V及II)和外源性因子(组织因子和因子VII)会导致产前或围产期致死。因子VIII和因子IX基因敲除小鼠虽然能够存活，但是经常会伴随严重出血，这与人类体内缺乏因子VIII和IX会造成严重出血风险的血友病A和B类似。而选择性敲除因子XI的小鼠则能正常繁殖。并且，XI因子缺失能够保护小鼠抵抗氯化铁诱导的动脉血栓的形成。同时，XI因子的缺失并不影响小鼠的出血及止血功能。因此，该实验表明，抑制XI因子不仅可以阻止血栓形成，而且是安全耐受的。
许多针对FXIa的抗体、小分子及反义核苷酸也在动物或者是临床上证实了抑制FXIa可以有效地预防血栓形成。但是与现有的抗血栓药物(例如依诺肝素)相比，出血的风险大大降低。以上表明，FXIa与人类血栓性疾病密切联系，抑制FXIa具有显著的抗凝效果，但无明显的出血倾向，可以大大降低临床抗凝过程的出血风险。
因此，开发具有抗凝血效果好、且副作用小的化合物具有重要的研究意义。
发明内容
为解决上述技术问题，本发明提供下式(I)所示的四元内酰胺环状化合物，其异构体、溶剂化物、前药或其混合物，以及它们药学上可接受的盐：
Figure PCTCN2019080549-appb-000001
其中，R 1选自氢、卤素、C 1-10烷基、C 3-10环烷基、杂环基、芳基、杂芳基、-(CH 2) tNR 6R 7、-COR 5a、-COOR 5b、-C(O) m(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-NHC(O) m(CH 2) nC(O) mC 1-6烷基、-S(O) m(CH 2) tNR 6R 7、-NH(CH 2) tS(O) mR 5a、-NH(CH 2) tS(O) m-OR 5b、-OR 5b、-SR 5b、-(CH 2) tCN、-O(CH 2) nNR 6R 7；
R 2选自氢、卤素、羟基、C 1-10烷基、C 1-10烷氧基、-(CH 2) tX(CH 2) nNR 6R 7、-(CH 2) tCN、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-(CH 2) tNR 6R 7、-C(O) m(CH 2) tNR 6R 7、-C(O) m(CH 2) t-芳基、-C(O) m(CH 2) t-杂芳基、-CONH(CH 2) t-杂环基、-CONHS(O) mR 5a、-CONHS(O) m-OR 5b；
X选自O、S；
A为芳基、杂芳基、C 3-10环烷基或杂环基；
B为含氮杂环基，其中氮原子与CX相连，其可任选地被1～3个R 3所取代；所述R 3相同或不同，分别独立地选自氢、氧代、卤素、羟基、-(CH 2) tCN、-(CH 2) tNR 6R 7、-(CH 2) tCONR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷基氧基、杂环基、苯并杂环基、芳基或杂芳基；并且当B被R 3取代时，至少一个R 3为C 3-10环烷基、芳基、苯并杂环基或杂芳基；所述R 3可任选地被1～3个R 4a所取代；
或者，B为含氮稠合二环基，其中氮原子与CX相连，其进一步可任选地被1～3个R 4b所取代；
所述R 4a、R 4b相同或不同，分别独立地选自氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷基氧基、杂环基、杂环基氧基、芳基、氨基、硝基、-(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-(CH 2) tCONR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-SR 5b、-OR 5b；进一步地，所述R 4a、R 4b任选地被如下的一个或多个基团取代：氢、＝O、卤素、C 1-10烷基、C 1-10烷氧基或芳基；
上述基团中，R 5a相同或不同，各自独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷基、C 3-10环烷基、杂环基、芳基、杂芳基；
上述基团中，R 5b、R 6、R 7相同或不同，各自独立地选自氢、C 1-10烷基、卤代C 1-10烷基、C 3-10环烷基、杂环基、芳基、杂芳基；
上述基团中，n相同或不同，各自独立地选自1～10的整数；
上述基团中，m相同或不同，各自独立地选自1或2的整数；
上述基团中，t相同或不同，各自独立地选自0～10的整数。
在一些实施方案中，B为可任选地被1-3个R 3所取代的3-10元含氮杂环基(例如3、4、5、6、7、8、9或10元的含氮杂环基)。
在一些实施方案中，B为可任选地被1-3个R 3所取代的如下基团：
Figure PCTCN2019080549-appb-000002
在一些实施方案中，B为5-12元含氮稠合二环基(例如5、6、7、8、9、10、11或12元的含氮稠合二环基)，其进一步可任选地被1～3个R 4b所取代，所述含氮稠合二环基例如包括但不限于：苯并吡咯烷基、苯并哌啶基、苯并哌嗪基、三唑并哌嗪基。
在一些实施方案中，B为任选地被1-3个R 4b取代的如下基团：
Figure PCTCN2019080549-appb-000003
在一些实施方案中，B为
Figure PCTCN2019080549-appb-000004
其中，Y为C、S、O或N，
Figure PCTCN2019080549-appb-000005
代表3-10元杂环基，R 8为C 3-10环烷基、芳基、杂芳基或苯并杂环基，所述R 8可任选地被1-3个R 10所取代，所述R 10为氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、芳基、氨基、硝基、-(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-(CH 2) tCONR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-SR 5b、-OR 5b；进一步地，所述取代基R 10可任选地被如下一个或多个基团取代：氢、＝O、卤素、C 1-10烷基、C 1-10烷氧基或芳基。R 9相同或不同，各自独立地选自氢、氧代、卤素、羟基、-(CH 2) tCN、-(CH 2) tNR 6R 7、-(CH 2) tCONR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、芳基、杂芳基；上述R 9可任选地被1-3个如下基团R 11取代：氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、芳基、氨基、硝基、-(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-(CH 2) tCONR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-SR 5b、-OR 5b；w为1或2。
在一些实施方案中，R 8选自C 3-10环烷基、芳基、杂芳基、苯并杂环基；所述R 8可任选地被如下基团取代：氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、杂环基氧基、氧代杂环基、C 1-10烷基-氧代杂环基、芳基、芳基氧基、氨基、硝基、-(CH 2) tNR 6R 7、-NHCOOC 1-10烷基、-NHCOC 1-10烷基、CONR 6R 7、COR 5a、COOR 5b、-SR 5b、-OH。
在一些实施方案中，R 1选自氢、卤素、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷基氧基、芳基、 -(CH 2) tNR 6R 7、-COR 5a、-COOR 5b、-C(O)(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-NHC(O) m(CH 2) nC(O) mC 1-6烷基、-S(O) m(CH 2) tNR 6R 7、-NH(CH 2) tS(O) mR 5a、-SR 5b、-(CH 2) tCN、-O(CH 2) nNR 6R 7。
在一些实施方案中，A为芳基或杂芳基，优选苯基或吡啶基。
在一些实施方案中，R 2选自-(CH 2) tX(CH 2) nNR 6R 7、-(CH 2) tCN、-(CH 2) tNR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b-C(O) m(CH 2) tNR 6R 7、-C(O) m(CH 2) t芳基、-C(O) m(CH 2) t杂芳基、-CONH(CH 2) t杂环基、-CONHS(O) mR 5a。
在一些实施方案中，X为O。
在一些实施方案中，n相同或不同，各自独立地选自1、2、3、4、5、6、7、8、9或10的整数。
在一些实施方案中，m相同或不同，各自独立地选自1或2。
在一些实施方案中，t相同或不同，各自独立地选自0、1、2、3、4、5、6、7、8、9或10的整数。
在一些实施方案中，R 5a相同或不同，各自独立地选自氢、卤素、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、杂环基、芳基、杂芳基；
在一些实施方案中，R 5b、R 6、R 7相同或不同，各自独立地选自氢、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、杂环基、芳基、杂芳基；
在一些实施方案中，本发明提供下式(IA)所示的四元内酰胺环状化合物，其异构体、溶剂化物、前药或其混合物，以及它们药学上可接受的盐：
Figure PCTCN2019080549-appb-000006
各基团如上文所定义。
作为实例，所述式(I)(或式(IA))化合物选自包括但不限于以下的化合物，其异构体、溶剂化物、前药或其混合物，以及它们药学上可接受的盐(当存在时优选为三氟乙酸盐或盐酸盐)：
Figure PCTCN2019080549-appb-000007
Figure PCTCN2019080549-appb-000008
Figure PCTCN2019080549-appb-000009
Figure PCTCN2019080549-appb-000010
本发明还提供一种式(I)化合物，其异构体、溶剂化物、前药或其混合物的制备方法，包括如下：
Figure PCTCN2019080549-appb-000011
1)化合物(e)与三光气或二氯化硫在碱性条件下反应得到化合物(f)；
2)化合物(f)与化合物(A 0)在碱性条件下反应得到式(I)化合物；
其中，R 1、R 2、A、B、X、n具有如上所述定义。
根据本发明，步骤2)中所述碱性条件使用的试剂包括但不限于三乙胺、二异丙基乙基胺、N,N-二甲基氨基吡啶、氢氧化钠等。
根据本发明，步骤2)中化合物(A 0)可以通过如下方法制备，包括：
Figure PCTCN2019080549-appb-000012
A)化合物(a)在LDA存在下与化合物(b)反应，得到化合物(c)；
B)化合物(c)脱保护基得到化合物(A 0)；
其中，R 1、R 2、A、n具有如上所述定义；LG选自离去基团。
如果有必要，可以使用保护基对化合物(a)、化合物(b)、化合物(c)、化合物(e)、化合物(f)、化合物(A 0)中的任意基团进行保护。待反应完成后，再选择合适的方法脱去保护基。
本发明还提供一种药物组合物，其包含上文所述的式(I)(或式(IA))化合物，其异构体、溶剂化物、前药或其混合物，以及药学上可接受的盐中的至少一种，和任选存在的药学上可接受的载体和/或赋形剂。
本发明还提供上文所述的式(I)化合物，其异构体、溶剂化物、前药或其混合物，以及药学上可接受的盐中的至少一种，或所述药物组合物在制备治疗和/或预防血栓形成或血栓栓塞相关病症的药物中的用途；或者在制备凝血酶抑制剂药物中的用途。
所述血栓形成或血栓栓塞相关病症包括但不限于，例如动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、心脏腔室或外周循环中的血栓栓塞性病症，不稳定型心绞痛、急性冠状动脉综合征、心房纤维性颤动、心肌梗塞、短暂性缺血发作、中风、动脉粥样硬化、外周闭塞性动脉病、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，以及由于其中血液暴露于促进血栓形成的人造表面的医疗植入物、装置或过程而引起的血栓形成。
本发明还提供一种药物制剂，其包括如上所述药物组合物，其中，所述药物制剂包括但不限于片剂、丸剂、颗粒剂、胶囊剂、注射剂、混悬剂、滴剂、浸膏剂、软膏剂、贴剂、乳剂、膜剂、栓剂、糊剂、凝胶剂、或喷雾剂。
本发明还提供一种联合制剂，其包括将上文所述的药物组合物与其它抗凝血药物、抗血栓药物或抗静脉栓塞药物中的至少一种合用；所述抗凝血药物、抗血栓药物或抗静脉栓塞药物包括但不限于：肝素、低分子量肝素LMWH、依诺肝素、华法林、利伐沙班、阿哌沙班、依度沙班、贝曲沙班、奥米沙班、阿司匹林、噻氯匹啶、氯吡格雷、替罗非班、香豆素、尿激酶、血小板蛋白IIb/IIIa受体拮抗剂。
本发明还提供一种治疗和/或预防血栓形成或血栓栓塞相关病症的方法，包括将上述药物组合物或药物制剂或联合制剂施用于有此需要的个体。
所述血栓形成或血栓栓塞相关的病症具有如上所述的定义。
术语定义和说明
除非另有说明，在说明书和权利要求书中使用的术语含义定义如下。
术语“C 1-10烷基”是指直链和/或支链的饱和脂肪族烃基，例如该脂肪族烃基可包括1-10个碳原子，1-6个碳原子，1-4个碳原子，1-3个碳原子，1或2个碳原子等。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、正己基等。所述烷基的相邻碳原子任选地被一个或多个选自O、S或N的杂原子间隔，例如丙基CH 3CH 2CH 2-被O中断后可以是CH 3-O-CH 2CH 2-或CH 3CH 2-O-CH 2-，其他依次类推。
术语“C 1-10烷氧基”是指C 1-10烷基-氧基，例如C 1-10烷基氧基、C 1-6烷基氧基、C 1-4烷基氧基，烷基定义如上。代表性的烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
术语“C 3-10环烷基”是指饱和或部分不饱和的3-10元全碳单环。C 3-10环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己二烯基、金刚烷基、环庚基、环辛基等。进一步地，所述“C 3-10环烷基”可任选地被选自以下的一个或多个取代基取代：卤素，-(CH 2) tCN，直链或支链的C 1-10烷基或C 1-10烷氧基，卤代C 1-10烷基，卤代C 1-10烷氧基，C 3-10环烷基，C 3-10环烷氧基，具有1-3个独立地选自氮、氧或硫的环杂原子的饱和或部分不饱和的3-10元杂环基，芳基，氨基，硝基，-(CH 2) tNR 6R 7，-(CH 2) tNHC(O) mC 1-10烷基，-(CH 2) tCONR 6R 7，-(CH 2) tC(O) mR 5a，-SR 5b，-OR 5b，-(CH 2) tCOOH。
术语“C 3-10环烷氧基”或“环烷基氧基”是指C 3-10环烷基-氧基，C 3-10环烷基的定义如上文所述，氧基是指-O-基团。C 3-10环烷基氧基的实例包括但不限于环丙氧基、环丁氧基、环戊氧基、环戊烯氧基、环己氧基、环己二烯氧基、金刚烷氧基、环庚基氧、环辛基氧基等。进一步地，所述“C 3-10环烷氧基”可任选地被选自以下的一个或多个取代基取代：卤素，-(CH 2) tCN，直链或支链的C 1-10烷基或C 1-10烷氧基，卤代C 1-10烷基，卤代C 1-10烷氧 基，C 3-10环烷基，C 3-10环烷氧基，具有1-3个独立地选自氮、氧或硫的环杂原子的饱和或部分不饱和的3-10元杂环基，芳基，氨基，硝基，-(CH 2) tNR 6R 7，-(CH 2) tNHC(O) mC 1-10烷基，-(CH 2) tCONR 6R 7，-(CH 2) tC(O) mR 5a，-SR 5b，-OR 5b，-(CH 2) tCOOH。
术语“杂环基”是指包含3至10个原子的单环体系，其中1、2、3、4或5个环原子选自例如氮、硫或氧等杂原子。所述杂环可以是完全饱和的或包含一个或多个不饱和度，但无芳香性，有一个或多个连接点连接到其他分子上，除非另有说明，其可通过碳或氮来连接，其中-CH 2-基团任选被-C(O)-代替。所述“杂环基”的实例包括但不限于由3-10个原子组成的单环，其包含1-5个，优选1-3个选自N、O或S的杂原子。例如，具有独立地选自氮、氧或硫的1-3个环杂原子的3-10元的单环，其实例包括但不限于环氧乙烷基、环硫乙烷基、吖丙啶基、氧杂环丙烷基、氮杂环丙烷基、硫杂环丙烷基、氧杂环丁烷基、硫杂环丁烷基、氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、
Figure PCTCN2019080549-appb-000013
等；进一步地，所述“杂环基”可任选地被选自以下的一个或多个取代基取代：卤素，-(CH 2) tCN，直链或支链的C 1-10烷基或C 1-10烷氧基，卤代C 1-10烷基，卤代C 1-10烷氧基，C 3-10环烷基，C 3-10环烷氧基，具有1-3个独立地选自氮、氧或硫的环杂原子的饱和或部分不饱和的3-10元杂环基，芳基，氨基，硝基，-(CH 2) tNR 6R 7，-(CH 2) tNHC(O) mC 1-10烷基，-(CH 2) tCONR 6R 7，-(CH 2) tC(O) mR 5，-SR 5b，-OR 5b，-(CH 2) tCOOH。
术语“苯并杂环基”是指苯基与杂环基稠合，其中苯基、杂环基共享一对相邻环原子，杂环基定义如上所述。所述“苯并杂环基”的具体实例包括但不限于:
Figure PCTCN2019080549-appb-000014
进一步地，所述苯并杂环基可任选地被1～3个R 4a所取代，所述R 4a相同或不同，各自独立地选自卤素，-(CH 2) tCN，直链或支链的C 1-6烷基或C 1-6烷氧基，卤代C 1-6烷基，卤代C 1-6烷氧基。
术语“含氮稠合二环基”是指具有6～20个环原子的二环系统，其中1、2、3、4或5个环原子选自例如氮、硫或氧等杂原子，且至少一个环中含有至少一个氮杂原子，且该二环系统中的一个环与另一个环共享一对相邻环原子，其中一个环可以包含一个或多个双键，但整个二环系统不具有完全共轭的Pi-电子系统。所述“含氮稠合二环基”包括6元/6元、6元/5元、6元/4元等构成的稠合二环，具体实例包括但不限于：
Figure PCTCN2019080549-appb-000015
进一步地，所述含氮稠合二环可任选地被1～3个R 4b所取代，所述R 4b相同或不同，各自独立地选自卤素，-(CH 2) tCN，直链或支链的C 1-6烷基或C 1-6烷氧基，卤代C 1-6烷基，卤代C 1-6烷氧基，C 3-10环烷基，C 3-10环烷氧基，具有1-3个独立地选自氮、氧或硫的环杂原子的饱和或部分不饱和的3-10元杂环基，芳基，氨基，硝基，-(CH 2) tNR 6R 7，-(CH 2) tNHC(O) mC 1-10烷基，-(CH 2) tCONR 6R 7，-(CH 2) tC(O) mR 5a，-SR 5b，-OR 5b，-(CH 2) tCOOH。
术语“芳基”是指其分子结构中具有6-20个碳原子且包含至少一个芳环的基团，即有一个共轭pi-电子系统。在本发明中，所述芳基既可以是一个独立的芳基基团，也可以是芳基与其他基团的组合基团，例如芳基烷基、烷基芳基等。芳基的实例包括但不限于苯基、萘基、蒽基、苯基烷基、烷基苯基、亚烷基苯基、次烷基苯基、苄基。
术语“杂芳基”是指具有至少一个环杂原子(例如硫、氧或氮)的芳香性杂环。杂芳基包括单环系统和多环系统(例如具有2、3或4个稠环)。优选的，所述杂芳基为具有5-20个环原子且具有独立地选自氮、氧或硫的1-3个环杂原子，优选所述杂芳基为含有1-3个环杂原子的5元杂芳环、6元杂芳环。杂芳基的实例包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、嘧啶基、吡嗪基、咪唑基、酞嗪基、哌啶基、哌嗪基、吗啉基、喹啉基、喋啶基、
Figure PCTCN2019080549-appb-000016
等。
术语“卤素”是指氟、氯、溴、碘，优选氟或氯。
术语“卤代C 1-10烷基”是指C 1-10烷基的一个或多个氢原子被相同/不同的卤原子取代而形成的基团，代表性的实例包括但不限于氯甲基、三氟甲基、1-氯乙基、3-溴丙基等。
术语“卤代C 1-10烷氧基”是指C 1-10烷氧基的一个或多个氢原子被相同/不同的卤原子取代而形成的基团，代表性的实例包括但不限于：氯甲氧基、三氟甲氧基、1-氯乙氧基、3-溴丙氧基等。
术语“氨基”是指-NH 2基团。
术语“酰基”是指-C(O)R 5a基团。
术语“酰胺基”是指-C(O)NR 6R 7，代表性的酰胺基的实例如-CO-NH 2基团。
术语“磺酰胺基”是指具有-S(O) mNR 6R 7、-NHS(O) mR 5a结构的基团。
其中，所述t、m、R 5a、R 5b、R 6、R 7具有上文所述定义。
术语“氰基”是指-C≡N基团。
术语“羟基”是指-OH基团。
术语“羧基”是指-COOH基团。
术语“巯基”是指-SH基团。
术语“氧代”是指＝O基团。
除非特别限定，当本文定义或描述的取代基或基团存在多个能够与被取代的结构彼此结合的位点时，相应的化学结构包括所述取代基或基团在全部这些位点上与被取代的结构彼此结合的形式。例如，C 1-4烷基氨基包括以-C 1-4烷基氨基或C 1-4烷基氨基-与被取代位点结合的形式。
术语“任选”、“任选的”、“任选地”是指随后所描述的事件或环境可以但非必须发生，即该事件或环境发生或不发生的场合，例如“任选的被取代的烷基”是指所述烷基可以但非必须被取代基所取代，即包括了未取代的烷基和被取代的烷基两种情况。
术语“异构体”是同分异构体的简称，指具有相同化学式、有同样的化学键但有不同原子排列的化合物。具有相同分子式而结构式不同的化合物互称为异构体，如乙醇和乙醚。异构体包括结构异构体、立体异构体、几何异构体、光学异构体。本发明所述的“异构体”优选立体异构体。
术语“溶剂化物”是指含有溶剂的化合物，其中溶剂分子可以以配位键与其他部分相连，也可以以共价键相结合。所述溶剂为已知溶剂，例如水、醇类、醚类、苯类、酯类、脂肪烃、脂环烃、酮类以及其他。溶剂的实例包括但不限于水，甲醇、乙醇、异丙醇，乙醚、环氧丙烷，苯、甲苯、二甲苯，醋酸甲酯、醋酸乙酯，戊烷、己烷、辛烷，环己烷、环己酮，丙酮、甲基丁酮、甲基异丁酮，乙腈、吡啶、苯酚、四氯化碳等。
术语“前药”又称前体药物、药物前体、前驱药物等，是指药物经过化学结构修饰后得到的在体外无活性或活性较小，而在体内经酶或非酶的转化释放出活性药物从而发挥药效的化合物。
术语“药学上可接受的盐”是指保持游离态的化合物与无毒的无机碱或有机碱、或者无毒的无机酸或有机酸反应获得的那些盐。合适的酸加成盐包括但不限于甲酸盐、乙酸盐、三氟乙酸盐、乙磺酸盐、2-羟基乙磺酸盐、羟乙酸盐、丙酸盐、3-苯基丙酸盐、丙二酸盐、丁酸盐、新戊酸盐、己酸盐、己二酸盐、庚酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、十二烷基硫酸盐、富马酸盐、葡糖庚酸盐、硫酸盐、硫氰酸盐、半硫酸盐、过硫酸盐、盐酸盐、硝酸盐、磷酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、水杨酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐和十一烷酸盐；合适的碱加成盐包括碱金属盐(如钠盐、钾盐、锂盐等)、碱土金属盐(如钙盐、镁盐等)、其他金属盐(如铁盐、铜盐、钴盐等)、有机碱盐(如铵盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、乙二胺盐、胍盐、异丙基胺盐、三甲基胺盐、三丙基胺盐、三乙醇胺盐、二乙醇胺盐、乙醇胺盐、二甲基乙醇胺盐、二环己基胺盐、咖啡碱盐、普鲁卡因盐、胆碱盐、甜菜碱盐、苯明青霉素盐、葡萄糖胺盐、N-甲基葡糖胺盐、可可碱盐、氨丁三醇盐、嘌呤盐、哌嗪盐、吗啉盐、哌啶盐、N-乙基哌啶盐、四甲基胺盐、二苄基胺盐和苯基甘氨酸烷基酯盐)和无机铵盐。
术语“联合制剂”是指包含至少两种制剂(活性成分)的药物制剂，其中的一种制剂或另一种制剂可以在另外的组分给药之前、之后和/或同时给药(任选可重复)。在本文中，“同时给药”包括在彼此相隔48小时内如24小时内给药。
术语“药学上可接受的载体或赋形剂”是指在药物制剂领域熟知的任何类型的溶剂、分散介质、包衣材料、表面活性剂、抗氧化剂、防腐剂(例如抗真菌剂、抗菌剂)、等渗剂、吸收延迟剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等或它们的组合。除了与活性成分不相容的载体之外，在本发明的药物组合物中可考虑使用任何常规载体或赋形剂。
需要说明的是，本发明提供的化合物、组合物以及联合制剂可根据给药途径配制成各种合适的剂型。使用一种或多种药学上可接受的载体或赋形剂，有利于将活性成分加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径，可以按照本领域熟知的常识进行制备。
还应理解，本发明提供的化合物、组合物以及联合制剂的给药途径可以是口服、非肠道(例如注射给药)或局部给药。可以口服的药物制剂包括胶囊剂和片剂等。病人吞咽有困难时，也可以采用舌下片或者其他非吞咽方式给药。本发明提供的化合物、组合物以及联合制剂也可以配制成用于肠胃外给药或者透皮给药或者经黏膜给药，或者采用栓剂或埋植剂的方式给药。本领域技术人员可以理解，本发明化合物可以采用合适的药物释放系统以得到更有利的效果。
另外需要说明的是，本发明提供的化合物、组合物以及联合制剂的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医生的主观判断。
有益效果
发明人出乎意料地发现，本发明所述的式(I)化合物、其异构体、水合物、溶剂化物、前药或其混合物，以及它们的药学上可接受的盐，以及含有所述化合物的药物组合物具有优异的凝血酶抑制活性。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外，应理解，在阅读了本发明所记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本发明所限定的范围。
实施例
所有化合物的结构均经核磁共振( 1HNMR)和/或质谱(MS)鉴定。核磁共振化学位移(δ)以ppm(10 -6)记录。
化合物简写：
TBSCl：叔丁基二甲基氯硅烷；LDA：二异丙基胺基锂；DCC：二环己基碳二亚胺；DMSO：二甲基亚砜；CDI：N,N-羰基-二咪唑；DMF：二甲基甲酰胺；DIEA：N,N-二异丙基乙胺；DMAP：4-二甲氨基吡啶；CDCl 3：氘代氯仿；PE/EA：石油醚/乙酸乙酯；HATU：2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；TFA：三氟乙酸；DCM：二氯甲烷；EDCI：1-乙基-(3-二甲基氨基丙基)碳酰二亚胺；THF：四氢呋喃；Boc：叔丁氧羰基；HOBT：1-羟基苯并三唑；Xantphos：4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；Pd(amphos) 2Cl 2：双[二叔丁基-(4-二甲基氨基苯基)膦]二氯化钯(II)。
中间体A的制备
Figure PCTCN2019080549-appb-000017
按照以下反应式和方法制备中间体A。
Figure PCTCN2019080549-appb-000018
步骤1)：在室温下，将Boc 2O(88.0g)加入到化合物A1(50.0g)的叔丁醇溶液(1000ml)中，60℃下搅拌过夜。反应液冷却至室温，所得悬浊液过滤。滤饼以乙酸乙酯(250ml)洗涤三次。滤饼经真空干燥，得白色固体70g(即化合物A2)。
步骤2)：化合物A2(16.3g)的DMF溶液(100ml)以冰水浴冷却。氮气保护下，将钠氢(3.88g)缓慢加入到体系中。反应液在0℃下搅拌1小时后，将对甲氧基苄氯(15.2g)缓慢加入。反应液升温至室温后，搅拌过夜。反应液浓缩，得粗产品化合物A3(51.0g)。重复上述反应过程。两批所得粗产品合并，经硅胶柱层析(石油醚/乙酸乙酯＝50:1)纯化得白色固体42g(即化合物A3)。
步骤3)：将化合物A3(42.0g)溶于四氢呋喃和甲醇的混合溶剂(250ml/250ml)中，冰水浴冷却。在氮气保护下，将硼氢化钠(13.0g)缓慢加入到体系中。室温搅拌过夜后，在反应液中加入丙酮(40ml)淬灭反应。浓缩得粗产品，经硅胶柱层析(石油醚/二氯甲烷/乙酸乙酯＝5:5:1)纯化，得白色固体37g(即化合物A4)。
步骤4)：在0℃下，将甲烷磺酰氯(24.5g)缓慢滴加入到化合物A4(37.0g)和三乙胺(21.7g)的二氯甲烷(500ml)溶液中。反应液在氮气保护下，室温搅拌1小时。反应液浓缩后，加入丙酮，所得悬浊液过滤，滤液直接应用于下一步反应。
步骤5)：将上述反应所得滤液稀释至500ml，加入溴化锂(14g)。混合液室温搅拌过夜。反应液过滤。滤液减压浓缩，所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝10:1)纯化，得白色固体40g(即化合物A6)。
步骤6)：氮气保护下，将化合物A7(50.0g)溶于二氯甲烷(500ml)中。依次滴加DIEA(62.9g)和叔丁基二甲基氯硅烷(51.6g)，反应液在室温下搅拌过夜。反应液浓缩后，加入饱和氯化铵水溶液(200ml)，并以乙酸乙酯萃取(400ml)三次。有机相合并，经无水硫酸钠干燥后，过滤浓缩。粗产品经硅胶柱层析(石油醚/乙酸乙酯＝15:1～7/1)纯化，得黄色油状物76g(即化合物A8)。
步骤7)：将10wt％的钯碳(7.2g)加入到化合物A8(35g)的四氢呋喃溶液(150ml)中。加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌过夜。反应完全后抽滤。滤液浓缩，得白色固体23.6g(即化合物A9)。
步骤8)：将二异丙胺(24.7g)的四氢呋喃溶液(120ml)冷却到-78℃后，加入2.5M的正丁基锂正己烷溶液(98ml)。反应液缓慢升温到0℃，继续搅拌1小时。将此溶液再度冷却到-78℃，加入化合物A9(20.0g)的四氢呋喃溶液(100ml)，滴加于45分钟内完成。反应液在-65℃下搅拌30分钟，升温至-20℃继续搅拌反应30分钟。在此温度下，将化合物A6(46.1g)的四氢呋喃溶液(100ml)缓慢加入，并于-10～-15℃下搅拌1小时。反应完全后，加入饱和氯化铵水溶液淬灭反应，并用乙酸乙酯萃取三次。有机相合并，经饱和食盐水洗涤，无水硫酸钠干燥、过滤后浓缩，得粗产品60.7g(即化合物A10)，此粗产品直接应用于下一步反应。
步骤9)：将化合物A10(58.8g，粗品)溶于二氯甲烷(500ml)中，室温下依次加入EDCI(21.0g)和DMAP(1.03g)和苄醇(11.0g)。反应液在氮气保护下，室温搅拌过夜。加水淬灭后，浓缩反应液。粗产品经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化，得黄色油状物26.1g(即化合物A11)，此粗产品直接用于下一步反应。
步骤10)：将氟化铵(1.54g)和醋酸(7.48g)分别加入到化合物A11(26.8g)的甲醇溶液中，室温搅拌1小时。浓缩反应液后，加入乙酸乙酯(200ml)稀释，并依次用饱和碳酸氢钠水溶液和食盐水洗涤。有机相经无水硫酸钠干燥、过滤后浓缩。粗产品经硅胶柱层析(石油醚/乙酸乙酯＝4/1～二氯甲烷/甲醇＝50/1)纯化，得白色固体17.1g(即中间体A)。
1HNMR(400MHz,CDCl 3)：δ8.25(d,J＝4.8Hz,1H),7.55(s,1H),7.36–7.33(m,3H),7.23–7.22(m,2H),7.20(d,J＝8.8Hz,2H),6.91(d,J＝3.6Hz,1H),6.78(d,J＝8.8Hz,2H),6.02(brs,1H),5.12(s,2H),5.09(s,2H),3.91(d,J＝2.4Hz,1H),3.75(s,3H),3.58(m,1H),3.15(J＝14.8,5.6Hz,1H),3.03(J＝14.8,8.0Hz,1H),1.41(s,9H)。
LCMS:Rt＝1.939min，[M+H] +＝532.0。
实施例1 化合物I-001的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000019
按照以下反应式和方法制备化合物I-001的三氟乙酸盐。
Figure PCTCN2019080549-appb-000020
步骤1)：化合物1a(400mg)溶于10.0mL二氯甲烷中，加入三乙胺(631mg)。冰盐浴降温至0℃，加入三光气(309mg)，室温反应1h。将反应液倒入冰水中，用二氯甲烷(60mL×3)萃取，合并萃取液用饱和食盐水洗涤，无水硫酸钠干燥，减压旋干，得粗品化合物1b(430mg)。
步骤2)：中间体A(300mg)溶于6mL二氯甲烷，加入三乙胺(171mg)，滴加化合物1b(430mg)的二氯甲烷溶液，室温搅拌反应1h。反应液直接旋干，硅胶柱层析纯化，得到化合物1c(240mg)。
步骤3)：化合物1c(240mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(3.4mg)，氢气氛围下室温反应2h。反应液过滤，用反相制备HPLC纯化，得到化合物1d(120mg)。
步骤4)：化合物1d(120mg)溶于2mL二氯甲烷，降温至0℃，加入3mL三氟乙酸，升至室温搅拌反应过夜。反应液直接旋干，用反相制备HPLC纯化，得到化合物I-001的三氟乙酸盐(28mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.36(s,1H),8.29-8.00(m,3H),7.00-6.73(m,2H),4.94(s,2H),4.53-4.16(m,3H),4.10-4.04(m,1H),3.99-3.85(m,1H),3.80-70(m 1H),3.20-3.10(m,2H)。
LCMS:Rt＝1.105min，[M+H] +＝554.1。
实施例2 化合物I-002的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000021
按照以下反应式和方法制备化合物I-002的三氟乙酸盐。
Figure PCTCN2019080549-appb-000022
步骤1)：化合物2a(2.5g)溶于80.0mL二氯甲烷中，降温至0℃，加入碳酸钠(22.6g)，搅拌10min后，加入化合物2b(5.5g)。氮气保护下，升至室温反应6h。将反应液倒入水中，用二氯甲烷(80mL×3)萃取，合并萃取液用饱和食盐水洗涤，无水硫酸钠干燥，减压旋干，得化合物2c(2.1g)。
步骤2)：化合物2c(2.1g)溶于50mL甲苯中，加入化合物2d(1.15g)，加分水器，升温至130℃回流过夜。反应液旋干，用乙酸乙酯打浆，过滤，得化合物2e(2g)。
步骤3)：化合物2e(2g)溶于20.0mL 30％的氢溴酸乙酸溶液中，氮气保护下，室温反应3h。反应液旋干，乙酸乙酯打浆，得化合物2f(1.6g)。
步骤4)：化合物2f(400mg)溶于3.0mL二氯甲烷中，加入三乙胺(721mg)。冰盐浴降温至0℃，加入三光气(212mg)，室温反应1h。将反应液倒入冰水中，用二氯甲烷(30mL×3)萃取，合并萃取液用饱和食盐水洗涤，无水硫酸钠干燥，减压旋干，得粗品化合物2g(410mg)。
步骤5)：化合物2g(100mg)溶于3mL二氯甲烷，加入三乙胺(57.1mg)，滴加中间体A(410mg)的二氯甲烷溶液，室温搅拌反应1h。反应液直接旋干，硅胶柱层析纯化，得到化合物2h(60mg)。
步骤6)：化合物2h(60mg)溶于3mL甲醇，加入3mL乙酸乙酯。加入钯碳(0.9mg)，氢气氛围下室温反应2h。反应液过滤，得到化合物2i(50mg，94.6％)。
步骤7)：化合物2i(50mg)溶于2mL二氯甲烷，降温至0℃，加入3mL三氟乙酸，升至室温搅拌反应过夜。反应液直接旋干，用反相制备HPLC纯化，得到化合物I-002的三氟乙酸盐(28mg)。
[M+H] +＝448.1。
实施例3 化合物I-003的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000023
按照以下反应式和方法制备化合物I-003的三氟乙酸盐。
Figure PCTCN2019080549-appb-000024
步骤1)：化合物3a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(377mg)。冰盐浴降温至0℃，加入三光气(185mg)，室温反应2h。反应结束后，冰水洗涤，DCM萃取，反应液浓缩，得粗品120mg(即化合物3b)。
步骤2)：将中间体A(100mg)溶于10mL二氯甲烷，加入三乙胺(377mg)，滴加至化合物3b的二氯甲烷溶液，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物3c(120mg)。
步骤3)：化合物3c(120mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物3d(80mg)。
步骤4)：化合物3d(80mg)溶于2mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-003的三氟乙酸盐(10.29mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.50(s,1H),7.86(m,1H),7.41-7.21(m,7H),6.75-6.73(m,2H),4.28-4.23(m,1H),4.07-3.98(m,2H),3.69-3.67(m,1H),3.07-2.77(m,4H),2.67-2.61(m,1H),1.93-1.87(m,4H)。
LCMS:Rt＝0.250min，[M+H] +＝409。
实施例4 化合物I-004的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000025
按照以下反应式和方法制备化合物I-004的三氟乙酸盐。
Figure PCTCN2019080549-appb-000026
步骤1)：化合物4a(100mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步。
步骤2)：将化合物4b(100mg)溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物4c(90mg)。
步骤3)：化合物4c(90mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物4d(70mg)。
步骤4)：化合物4d(70mg)溶于5mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-004的三氟乙酸盐(17.2mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.50(s,1H),7.87(d,1H),7.56(s,2H),7.42(d,1H),7.17-7.01(m,3H),6.78-6.76(m,2H),4.28(d,1H),3.96-3.92(m,1H),3.70-3.66(m,1H),3.47-3.33(m,1H),3.08-3.05(m,2H),2.80-2.65(m,2H),1.97-1.93(m,1H),1.87-1.82(m,1H)。
LCMS:Rt＝1.131min，[M+H] +＝381.1。
实施例5 化合物I-005的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000027
按照以下反应式和方法制备化合物I-005的三氟乙酸盐。
Figure PCTCN2019080549-appb-000028
步骤1)：化合物5a(300mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步。
步骤2)：将化合物5b溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物5c(85mg)。
步骤3)：化合物5c(85mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物5d(67mg)。
步骤4)：化合物5d(67mg)溶于10mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-005的三氟乙酸盐(18.6mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.50(m,1H),7.89(d,1H),7.82(s,1H),7.68(d,1H),7.28(d,1H),7.20(t,1H),7.05(t,1H),6.89(m,2H),4.46-4.39(m,2H),4.14-4.11(m,1H),3.81-3.77(m,1H),3.25-3.13(m,4H)。
LCMS:Rt＝1.167min，[M+H] +＝367.1。
实施例6 化合物I-006的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000029
按照以下反应式和方法制备化合物I-006的三氟乙酸盐。
Figure PCTCN2019080549-appb-000030
步骤1)：化合物6a(300mg)溶于10.0mL二氯甲烷中，加入三乙胺(606mg)。冰盐浴降温至0℃，加入三光气(302mg)，室温反应2h。反应结束后，冰水洗涤，DCM萃取，反应液浓缩可得粗品280mg(即化合物6b)。
步骤2)：将中间体A(324mg)溶于10mL二氯甲烷，加入三乙胺(123mg)，滴加至6b(280mg)的二氯甲烷溶液，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物6c(175mg)。
步骤3)：化合物6c(175mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.2mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物6d(160mg)。
步骤4)：化合物6d(160mg)溶于2mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-006的三氟乙酸盐(60mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.41(s,1H),8.08(s,2H),7.95-7.88m,1H),7.33-7.14(m,7H),6.87-6.85 (m,2H),4.97-4.92(m,1H),4.27(s,1H),3.99-3.92(m,1H),3.90-3.89(m,2H),3.12(m,2H),2.40-2.25(m,1H),1.99-1.65(m,4H)。
LCMS:Rt＝0.892min，[M+H] +＝395.25。
实施例7 化合物I-007的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000031
按照以下反应式和方法制备化合物I-007的三氟乙酸盐。
Figure PCTCN2019080549-appb-000032
步骤1)：化合物7a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(377mg)。冰盐浴降温至0℃，加入三光气(185mg)，室温反应2h。反应结束后，冰水洗涤，DCM萃取，反应液浓缩，得粗品100mg(即化合物7b)。
步骤2)：将中间体A(100mg)溶于10mL二氯甲烷，加入三乙胺(377mg)，滴加至化合物7b的二氯甲烷溶液，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物7c(90mg)。
步骤3)：化合物7c(90mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物7d(70mg)。
步骤4)：化合物7d(70mg)溶于2mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-007的三氟乙酸盐(9.53mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.40(s,1H),7.84(d,1H),7.39-7.24(m,5H),6.72-6.69(m,2H),5.47(m,1H),4.34-4.30(m,1H),3.92(m,1H),3.82(m,1H),3.07(m,2H),2.48-2.40(m,1H),1.98-1.80(m,2H),1.71-1.41(m,4H)。
LCMS:Rt＝1.158min，[M+H] +＝409.2。
实施例8 化合物I-008的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000033
按照以下反应式和方法制备化合物I-008的三氟乙酸盐。
Figure PCTCN2019080549-appb-000034
步骤1)：化合物8a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(377mg)。冰盐浴降温至0℃，加入三光气(185mg)，室温反应2h。反应结束后，冰水洗涤，DCM萃取，反应液浓缩可得粗品150mg(即化合物8b)。
步骤2)：将中间体A(100mg)溶于10mL二氯甲烷，加入三乙胺(377mg)滴加至化合物8b的二氯甲烷溶液，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物8c(150mg)。
步骤3)：化合物8c(150mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物8d(120mg)。
步骤4)：化合物8d(120mg)溶于2mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-008的三氟乙酸盐(23.98mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.15(s,1H),7.87(d,1H),7.56(s,2H),7.20(d,1H),6.84-6.81(m,1H),6.75(s,2H),6.58(d,1H),6.44-6.40(m,2H),6.14(s,1H),4.25(d,1H),4.10-4.07(m,1H),3.71-3.67(m,1H),3.42-3.16(m,3H),3.06(m,2H)。
LCMS:Rt＝1.099min，[M+H] +＝482.1。
实施例9 化合物I-009的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000035
按照以下反应式和方法制备化合物I-009的三氟乙酸盐。
Figure PCTCN2019080549-appb-000036
步骤1)：化合物9a(250mg)溶于10.0mL二氯甲烷中，加入三乙胺(377mg)。冰盐浴降温至0℃，加入三光气(185mg)，室温反应2h。反应结束后，冰水洗涤，DCM萃取，反应液浓缩可得粗品250mg(即化合物9b)。
步骤2)：将中间体A(150mg)溶于10mL二氯甲烷，加入三乙胺(377mg，)滴加至化合物9b的二氯甲烷溶液，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物9c(350mg)。
步骤3)：化合物9c(350mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物9d(280mg)。
步骤4)：化合物9d(280mg)溶于2mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-009的三氟乙酸盐(50mg)。
1H-NMR(400MHz,MeOD):δ7.76(d,1H),7.34-7.21(m,5H),6.98(s,1H),6.89(d,1H),4.37-4.33(m,1H),3.69-3.60(m,2H),3.48-3.42(m,2H),3.24-3.18(m,2H),2.33(m,1H),2.15-2.05(m,1H)。
MS:m/z＝395.2[M+1]。
实施例10 化合物I-010的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000037
按照以下反应式和方法制备化合物I-010的三氟乙酸盐。
Figure PCTCN2019080549-appb-000038
步骤1)：化合物10a(200mg)溶于10mL THF中，降温至0℃，加入叔丁基异氰酸酯(122.22mg)。室温搅拌2h，纯化后用于下一步(化合物10b)。
步骤2)：化合物10b(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步(化合物10c)。
步骤3)：将化合物10c溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物10d(102mg)。
步骤4)：化合物10d(112mg)溶于10mL乙酸乙酯和甲醇的混合溶液中。加入钯碳(0.8mg)，氢气氛围下室温反应0.5h。反应液过滤，得到化合物10e(85mg)。
步骤5)：化合物10e(86mg)溶于5mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-010的三氟乙酸盐(2.5mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.50(s,1H),7.95-7.88(m,3H),7.37-7.26(m,5H),6.91-6.88(m,2H),5.76(d,1H),5.32(s,1H),4.39-4.38(m,1H),3.88-3.76(m,3H),3.21-3.16(m,2H),2.99-2.87(m,2H),2.67-2.50(m,2H),1.25-1.20(m,9H)。
MS:m/z＝509.3[M+1]。
实施例11 化合物I-011的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000039
按照以下反应式和方法制备化合物I-011的三氟乙酸盐。
Figure PCTCN2019080549-appb-000040
步骤1)：化合物11a(600mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步(含化合物11b)。
步骤2)：将化合物11b溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物11c(180mg)。
步骤3)：化合物11c(180mg)溶于10mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应0.5h。反应液过滤，得到化合物11d(150mg)。
步骤4)：化合物11d(150mg)溶于10mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-011的三氟乙酸盐(40mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.20(s,1H),7.88(d,1H),7.69-7.68(m,3H),7.30(d,1H),7.10(m,1H),6.86-6.84(m,2H),4.51-4.39(m,1H),4.38-4.37(m,1H),4.18-4.17(d,1H),3.80-3.79(m,1H),3.20-3.15(m,4H)。
MS:m/z＝401.3[M+1]。
实施例12 化合物I-012的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000041
按照以下反应式和方法制备化合物I-012的三氟乙酸盐。
Figure PCTCN2019080549-appb-000042
步骤1)：化合物12a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(396mg)。冰盐浴降温至0℃，加入三光气(194mg)，室温反应2h。反应结束后，冰水洗涤，DCM萃取，反应液浓缩得粗品240mg(即化合物12b)。
步骤2)：将中间体A(176mg)溶于10mL二氯甲烷，加入三乙胺(101mg)滴加至化合物12b(240mg)的二氯甲烷溶液，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物12c(220mg)。
步骤3)：化合物12c(170mg)溶于5mL甲醇，加入5mL乙酸乙酯。加入钯碳(0.2mg)，氢气氛围下室温反应1h。反应液过滤，得到化合物12d(120mg)。
步骤4)：化合物12d(120mg)溶于2mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-012的三氟乙酸盐(20mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.50(s，1H),8.23-8.22(m,2H),8.17(d,1H),7.91-7.90(d,1H),7.67-7.65(m,1H),7.36-7.24(m,1H),6.97-6.85(m,2H),4.51-4.39(m,2H),4.23-4.22(m,1H),3.92(m,1H),3.61-3.20(m,4H)。
MS:m/z＝401.3[M+1]。
实施例13 化合物I-013的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000043
按照以下反应式和方法制备化合物I-013的三氟乙酸盐。
Figure PCTCN2019080549-appb-000044
步骤1)：化合物13a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃， 加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步(含化合物13b)。
步骤2)：将化合物13b溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物13c(130mg)。
步骤3)：化合物13c(130mg)溶于10mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应0.5h。反应液过滤，得到化合物13d(90mg)。
步骤4)：化合物13d(70mg)溶于5mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-013的三氟乙酸盐(18mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.20(m,1H),7.88(d,1H),7.86-7.78(m,2H),7.76-7.69(m,1H),7.45(s,2H),6.78-6.76(m,2H),4.50-4.43(m,1H),4.39-4.38(d,1H),4.18-4.17(m,1H),3.82-3.78(m,1H),3.25-3.23(m,2H),3.15-3.13(m,2H)。
MS:m/z＝392.2[M+1]。
实施例14 化合物I-014的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000045
按照以下反应式和方法制备化合物I-014的三氟乙酸盐。
Figure PCTCN2019080549-appb-000046
步骤1)：化合物14a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步(含化合物14b)。
步骤2)：将化合物14b溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物14c(98mg)。
步骤3)：化合物14c(98mg)溶于10mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应0.5h。反应液过滤，得到化合物14d(70mg)。
步骤4)：化合物14d(70mg)溶于5mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-014的三氟乙酸盐(8mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.20(m,1H),7.88(s,1H),7.81(d,1H),7.65(s,1H),7.59-7.53(m,4H),6.81-6.79(m,2H),4.52(m,1H),4.39(d,1H),4.18(m,1H),3.80(m,1H),3.25-3.23(m,2H),3.15-3.13(m,2H)。
MS:m/z＝435.2[M+1]。
实施例15 化合物I-015的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000047
按照以下反应式和方法制备化合物I-015的三氟乙酸盐。
Figure PCTCN2019080549-appb-000048
步骤1)：化合物15a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步(含化合物15b)。
步骤2)：将化合物15b溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物15c(106mg)。
步骤3)：化合物15c(106mg)溶于10mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应0.5h。反应液过滤，得到化合物15d(85mg)。
步骤4)：化合物15d(85mg)溶于5mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-015的三氟乙酸盐(17mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.20(s.1H),8.02(s,2H),7.87(d,1H),7.35-7.24(m,5H),6.88-6.85(m,2H),4.28(d,1H),4.07-4.01(m,2H),3.74-3.69(m,1H),3.13-3.11(d,2H),3.05-2.85(m,2H),2.64(m,1H),1.95-1.90(m,1H),1.79-1.74(m,2H),1.54-1.42(m,1H)。
MS:m/z 409.3[M+1]。
实施例16 化合物I-016的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000049
按照以下反应式和方法制备化合物I-016的三氟乙酸盐。
Figure PCTCN2019080549-appb-000050
步骤1)：化合物16a(200mg)溶于10.0mL二氯甲烷中，加入三乙胺(239mg)。冰盐浴降温至0℃，加入三光气(87.9mg)，室温反应2h，反应液直接用于下一步(含化合物16b)。
步骤2)：将化合物16b溶于10mL二氯甲烷，加入三乙胺(57.1mg)滴加至中间体A的二氯甲烷溶液，室温搅拌反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物16c(106mg)。
步骤3)：化合物16c(106mg)溶于10mL乙酸乙酯。加入钯碳(0.8mg)，氢气氛围下室温反应0.5h。反应液过滤，得到化合物16d(85mg)。
步骤4)：化合物16d(85mg)溶于5mL二氯甲烷中，降温至0℃。加入3mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-016的三氟乙酸盐(15mg)。
1H-NMR(400MHz,DMSO-d 6):δ13.50(s.1H),7.85(d,1H),7.56(brs,2H),7.35-7.24(m,5H),6.78(d,2H),4.25(d,1H),4.04(t,2H),3.70(m,1H),3.08(d,2H),3.08-2.90(m,1H),2.67-2.61(m,2H),1.91(d,1H),1.80-1.73(m,2H),1.70-1.54(m,1H)。
MS:m/z＝409.2[M+1]。
实施例17 化合物I-017的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000051
按照以下反应式和方法制备化合物I-017的三氟乙酸盐。
Figure PCTCN2019080549-appb-000052
氮气保护下，将二异丙基乙基胺(128mg)和HATU(250mg)加入到化合物16d(220mg粗产品)的二氯甲烷溶液(5ml)中。0℃下，搅拌1小时后，加入氯化铵(53mg)。反应液在0℃下继续搅拌2小时。加入饱和碳酸氢钠水溶液(10ml)淬灭反应，有机相分离，干燥并浓缩。粗产品经硅胶柱层析(石油醚/乙酸乙酯＝1/2)分离纯化，得白色固体140毫克(化合物17a)。
将化合物17a(140mg)加入到TFA/DCM(3ml/1.5ml)溶液中，25℃下搅拌6小时。LCMS检测反应完全后，室温浓缩。反应液浓缩，用反相制备HPLC分离纯化，得白色固体45.9mg(化合物I-017的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.45(brs,1H),7.98(brs,2H),7.86(d,J＝7.6Hz,1H),7.72(brs,1H),7.35-7.23(m,6H),6.87-6.86(m,2H),4.19(d,J＝3.2Hz,1H),4.08-4.01(m,2H),3.53-3.48(m,1H),3.13-3.11(m,2H),3.03-2.86(m,2H),2.69-2.61(m,1H),1.94-1.88(m,1H),1.79-1.69(m,2H),1.64-1.55(m,1H)。
LCMS:Rt＝3.198min，[M+H] +＝408.3。
实施例18 化合物I-018的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000053
按照以下反应式和方法制备化合物I-018的三氟乙酸盐。
Figure PCTCN2019080549-appb-000054
步骤1)：化合物7d(220mg)溶于2mL二氯甲烷中，降温至0℃。依次加入甲基磺酰胺(48mg)、HATU(190mg)、DIEA(68mg)室温反应过夜。反应液旋干，纯化，得到化合物18a(170mg)。
步骤2)：化合物18a(170mg)溶于2mL二氯甲烷中，降温至0℃。加入三氟乙酸2mL室温反应过夜。反应液直接旋干，硅胶柱层析纯化，得到化合物I-018的三氟乙酸盐(10mg)。
1H-NMR(400MHz,CD 3OD):δ7.78-7.77(m,1H),7.37-7.23(m,5H),6.97-6.89(m,2H),5.36-5.47(m,1H),4.39-4.32(m,1H),4.04-4.01(m,1H),3.75-3.72(m,1H),3.31-3.24(m,3H),3.22-3.20(m,2H),3.03-2.97(m,1H),2.48-2.45(m,1H),2.03-1.99(m,1H),1.65-1.51(m,4H),1.29(m,1H)。
MS:m/z＝486.17[M+1]。
实施例19 化合物I-019的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000055
按照以下反应式和方法制备化合物I-019的三氟乙酸盐。
Figure PCTCN2019080549-appb-000056
步骤1)：化合物7d(70mg)溶于5mL二氯甲烷，依次加入甲胺盐酸盐(10.6mg)、DIEA(20.0mg)、HATU(50.0mg)。室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物19a(80mg)。
步骤2)：化合物19a(75mg)溶于1mL二氯甲烷中，降温至0℃。加入1mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-019的三氟乙酸盐(6.8mg)。
1H-NMR(400MHz,CD 3OD):δ8.21(m,1H),8.09(s,2H),7.89-7.88(m,1H),7.40-7.24(m,5H),6.87-6.83(m,2H),5.47(s,1H),4.28-4.27(m,1H),3.94-3.91(m,1H),3.58-3.53(m,2H)3.17-3.15(m,2H),2.62(m,3H)，2.40(d,1H),1.87(m,1H),1.60-1.58(m,2H),1.46-1.23(m,2H)。
MS:m/z＝422.20[M+1]。
实施例20 化合物I-020的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000057
按照以下反应式和方法制备化合物I-020的三氟乙酸盐。
Figure PCTCN2019080549-appb-000058
步骤1)：化合物7d(70mg)溶于5mL二氯甲烷，依次加入二甲胺盐酸盐(10.6mg)，DIEA(20.0mg)，HATU(50.0mg)，室温搅拌1h。反应液直接旋干，硅胶柱层析纯化，得到化合物20a(75mg)。
步骤2)：化合物20a(75mg)溶于1mL二氯甲烷中，降温至0℃。加入1mL三氟乙酸，室温反应过夜。反应液旋干，用反相制备HPLC纯化，得到化合物I-020的三氟乙酸盐(5.0mg)。
1H-NMR(400MHz,DMSO-d 6):δ8.17(brs,2H),7.91(d,1H),7.40-7.24(m,5H),6.93-6.87(m,2H),5.47(m,1H),4.90-4.88(m,1H),3.92-3.88(m,1H),3.28-3.17(m,2H),2.99(s,3H),2.90(m,1H),2.87(m,3H),2.42-2.38(m,1H),1.87(m,1H),1.59-1.46(m,2H),1.35-1.24(m,2H)。
MS:m/z 436.3[M+1]。
实施例21 化合物I-021的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000059
按照以下反应式和方法制备化合物I-021的三氟乙酸盐。
Figure PCTCN2019080549-appb-000060
步骤1)：室温下将化合物21a(7.05g)、化合物21b(4.8g)、Pd(dppf)Cl 2(249mg)、碳酸铯(22.4g)加入到1,4-二氧六环(140ml)中。加入完毕后，置换氩气三次并在氩气保护下90℃搅拌过夜。待冷却后加水淬灭，乙酸乙酯萃取，有机相干燥浓缩，硅胶色谱柱纯化得到黄色液体，经无水硫酸镁干燥处理得黄色固体5.1g(即化合物21c)。
步骤2)：将化合物21c(5.3g)、PtO 2(0.70g)、浓HCl(9.2mL)加入到装有甲醇(77mL)的氢化反应釜中，加入完毕后封闭反应釜，氢气置换3次然后在氢气(400psi)氛围下室温搅拌6小时。硅藻土过滤PtO 2，减压浓缩，加入乙酸乙酯溶解后水洗3次，无水硫酸镁干燥，得到黄色固体3.7g(即化合物21d)。
步骤3)：将三乙胺(508mg)加入到化合物21d(300mg)的二氯甲烷(10mL)溶液中，降温到0℃加入三光气(249mg)，氩气保护下室温搅拌1小时左右(LCMS检测反应完全)，然后用冰水洗涤反应液(10mL)三次，无水硫酸镁干燥后再加入三乙胺(79mg)，催化量DMAP以及中间体A(150mg)，加完后在氩气保护下室温搅拌约4小时。LCMS检测反应完全后将20ml水加入到反应体系中并用乙酸乙酯(20mL)萃取三次，混合有机相用水洗涤三次和无水硫酸钠干燥，浓缩后得到的残留物用制备硅胶色谱板(石油醚/乙酸乙酯＝10:1)纯化，得到白色固体90mg(即化合物21f)。
步骤4)：将Pd/C(58mg，w/w＝50％，10％)加入到化合物21f(105mg)的乙酸乙酯/甲醇(3/3mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌2小时。反应完全后抽滤、浓缩，得到白色固体88mg(即化合物21g)。
步骤5)：将化合物21g(100mg)加入到TFA/DCM(3/3mL)溶液中室温搅拌3小时左右，LCMS检测反应完全后，室温浓缩反应液经用反相制备HPLC纯化，得到白色固体26mg(即化合物I-021的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ7.87-7.86(d,J＝6.4,1H),7.52(s,2H),7.38-7.36(s,1H),7.16-7.14(d,J＝7.6,2H),7.09-7.06(t,J＝8.8,1H),6.79-6.78(m,2H),4.29-4.24(m,1H),4.06-3.98(m,2H),3.71-3.67(m,1H),3.10-3.08(d,J＝8.4,2H),3.03-2.93(m,2H),2.84(m,1H),2.68-2.61(m,1H),1.95-1.92(m,1H),1.79-1.73(m,2H),1.50-1.47(m,1H)。
LCMS:Rt＝1.315min，[M+H] +＝427.2。
实施例22 化合物I-022的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000061
按照实施例21的方法，使用化合物22b替换化合物21b，制备得到白色固体23mg(即化合物I-022的三氟乙酸盐)。
Figure PCTCN2019080549-appb-000062
1H NMR(400MHz,DMSO-d 6):δ7.97(s,2H),7.90-7.89(d,J＝6,1H),7.36-7.30(m,2H),7.18-7.14(m,2H),6.89-6.87(m,2H),4.32-4.28(m,1H),4.06-3.97(m,2H),3.74-3.70(m,1H),3.17-3.13(d,J＝8.4,2H),2.99-2.93(m,2H),2.81(s,1H),1.93-1.92(m,1H),1.80-1.72(m,2H),1.50-1.47(m,1H)。
LCMS:Rt＝1.318min，[M+H] +＝427.2。
实施例23 化合物I-023的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000063
按照以下反应式和方法制备化合物I-023的三氟乙酸盐。
Figure PCTCN2019080549-appb-000064
氮气保护下，将二异丙基乙基胺(1.48g)和HATU(2.72g)加入到化合物16d(1.78g)的二氯甲烷溶液(20mL)中。冰水浴下搅拌10min后，加入2M的甲胺四氢呋喃溶液(2.86mL)。在此温度下搅拌2小时。加水淬灭反应后，用二氯甲烷萃取。有机相浓缩后，经正相硅胶柱层析纯化(甲醇/二氯甲烷＝1:100～1/50)后，所得产品再以反相C-18硅胶柱纯化(乙腈/水＝30-95％)，得白色固体1.51g(化合物23a)。
将化合物23a(1.5g)加入到TFA/DCM(30mL/15mL)溶液中，于25℃下搅拌5小时，LCMS检测反应完全，室温浓缩。粗产品经C-18反相柱纯化(5-95％乙腈/水(含0.1％TFA))得白色固体1.17(化合物I-023的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.51(brs,1H),8.27-8.23(m,1H),8.00(brs,2H)7.87-7.85(m,1H),7.35-7.31(m,2H),7.29-7.22(m,3H),6.84-6.83(m,2H),4.19(d,J＝3.2Hz,1H),4.07-4.00(m,2H),3.54-3.49(m,1H),3.13-3.11(m,2H),3.02-2.95(m,1H),2.93-2.88(m,1H),2.67-2.64(m,1H),2.62(d,J＝4.4Hz,3H),1.95-1.87(m,1H),1.79-1.68(m,2H),1.64-1.54(m,1H)。
LCMS:Rt＝3.018min，[M+H] +＝422.1。
实施例24 化合物I-024的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000065
按照以下反应式和方法制备I-024化合物的三氟乙酸盐。
Figure PCTCN2019080549-appb-000066
步骤1)：将DIEA(54mg)，HATU(82mg)加入到化合物16d(90mg)的二氯甲烷溶液(20mL)中，搅拌10min加入二甲胺盐酸盐，在室温下搅拌1小时后浓缩上硅胶制备板纯化，得到无色固体73mg(即化合物24a)。
步骤4)：将化合物24a(73mg)加入到TFA/DCM(3/3mL)溶液中室温搅拌3小时左右，LCMS检测反应完全后室温浓缩反应液，用反相制备HPLC纯化，得到白色固体35mg(即化合物I-024的三氟乙酸盐)。
1H NMR(400MHz,CD 3OD):δ7.79-7.77(d,J＝6.8,1H),7.29-7.28(m,4H),7.27-7.20(m,1H),6.95(s,1H),6.90-6.88(d,J＝6.8,1H),4.21-4.16(m,2H),3.65-3.61(m,1H),3.31-3.30(m,2H),3.19(s,3H),3.00-2.91(m,7H),2.03-2.00(m,1H),1.90-1.78(m,2H),1.65(m,1H)。
LCMS:Rt＝1.137min，[M+H] +＝436.3。
实施例25 化合物I-025的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000067
按照以下反应式和方法制备化合物I-025的三氟乙酸盐。
Figure PCTCN2019080549-appb-000068
步骤1)：将DIEA(54mg)，HATU(82mg)加入到化合物16d(90mg)的二氯甲烷溶液(20mL)中，搅拌10min加入甲基磺酰胺，在室温下搅拌1小时后浓缩上硅胶制备板纯化，得到无色固体60mg(即化合物25a)。
步骤4)：将化合物25a(60mg)加入到TFA/DCM(3/3mL)溶液中室温搅拌3小时左右，LCMS检测反应完全后室温浓缩反应液，用反相制备HPLC纯化，得到白色固体27mg(即化合物I-025的三氟乙酸盐)。
1H NMR(400MHz,CD 3OD):δ7.78-7.76(d,J＝6.8,1H),7.29-7.28(m,4H),7.23-7.20(m,1H),6.95(s,1H),6.90-6.88(d,J＝6.8,1H),4.34-4.33(d,J＝3.2,1H),4.23-4.17(m,2H),3.72-3.70(m,1H),3.30-3.22(m,5H),3.00-2.85(m,4H),2.00(m,1H),1.86-1.80(m,2H),1.66(m,1H)。
LCMS:Rt＝1.229min，[M+H] +＝486.2。
实施例26 化合物I-026的盐酸盐的制备
Figure PCTCN2019080549-appb-000069
按照以下反应式和方法制备化合物I-026的盐酸盐。
Figure PCTCN2019080549-appb-000070
步骤1)：将化合物26a(1.46g)，化合物26b(2.0g)和碳酸钾(1.70g)溶于20mL二氧六环和水的混合溶剂中(10/1)，氮气保护下加入Pd(dppf)Cl 2(450mg)。油浴80℃下搅拌90分钟。反应液减压浓缩。所得粗产品经硅胶柱层析纯化(石油醚/乙酸乙酯＝30:1～20:1)，得黄色油状物1.86g(化合物26c)。
步骤2)：将Pd/C(1g，10％wet)加入到化合物26c(1.86g)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，反应液在氢气氛围下，室温搅拌过夜。反应完全后抽滤，浓缩得白色固体1.76g(化合物26d)。
步骤3)：化合物26d溶于5mL HCl二氧六环溶液中。室温下搅拌2小时，减压浓缩。所得固体加入20mL乙酸乙酯稀释，依次用饱和碳酸氢钠水溶液(3mL)、食盐水(3mL)洗涤。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩，得白色固体1.2g(化合物26e)。
步骤4)：将二异丙基乙基胺(642mg)加入到化合物26e(400mg)的二氯甲烷(20mL)溶液中，降温到0℃后一次性加入三光气(197mg)。氮气保护下，室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(5mL)洗涤三次，无水硫酸钠干燥后直接应用于下一步反应。
步骤5)：在上述后处理得到的反应液中再加入二异丙基乙基胺(146mg)，DMAP(46mg)以及中间体A(200mg)。加完后在氩气保护下，室温搅拌3小时。LCMS检测反应完全后将40ml水加入到反应体系中，有机相分离，水相用二氯甲烷(30mL)萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用硅胶柱层析纯化(石油醚/乙酸乙酯＝2:1)，得白色固体280mg(化合物26g)。
步骤6)：将Pd/C(90mg，10％wet)加入到化合物26g(280mg)的乙酸乙酯/甲醇(10mL/10mL)溶液中，加入完毕后抽换气三次并充入氢气，反应液在氢气氛围下搅拌1小时。反应完全后，抽滤。滤液浓缩，得白色固体240mg(化合物26h)。
步骤7)：将化合物26h(50mg)加入到TFA/DCM(2mL/2mL)溶液中，25℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。所得粗产品经C-18反相柱层析(5-95％乙腈/水(含0.02％HCl))纯化得白色固体14.8mg(即化合物I-026的盐酸盐)。
1H NMR(400MHz,DMSO-d 6)δ7.90-7.87(m,3H),7.39-7.34(m,2H),7.15-7.09(m,1H),6.90–6.80(m,2H),4.29(dd,J＝15.1,3.4Hz,1H),4.05–3.98(m,2H),3.71(d,J＝2.9Hz,1H),3.12(dd,J＝7.7,4.0Hz,1H),2.99-2.76(m,4H),2.68-2.66(m,1H),1.90-1.88(m,1H),1.78-1.72(m,1H),1.64–1.36(m,1H)。
LCMS:Rt＝3.761min，[M+H] +＝488.9。
实施例27 化合物I-027的制备
Figure PCTCN2019080549-appb-000071
按照以下反应式和方法制备化合物I-027。
Figure PCTCN2019080549-appb-000072
步骤1)：将化合物27a(3.44g)溶于25mL干燥的二氯甲烷中。氮气保护下于0℃下滴加氯甲酸甲酯(2.46g)的二氯甲烷溶液(5mL)。反应液室温搅拌1.5小时。加水(30mL)淬灭反应，二氯甲烷(20mL)萃取。有机相用食盐水(30mL)洗涤，经无水硫酸钠干燥，过滤后，减压浓缩，得淡黄色固体6.01g(粗品，化合物27b)。
步骤2)：将Boc 2O(6.56g)和DMAP(3.63g)依次加到化合物27b(5.77g，粗品)的四氢呋喃(125mL)溶液中。氮气保护下加下，于78℃搅拌2小时。反应液减压浓缩，粗产品经硅胶柱层析纯化(石油醚/乙酸乙酯＝100:1～20：1)，得淡黄色固体4.4g(化合物27c)。
步骤3)：将化合物27c(5.0g)、化合物吡啶-3-硼酸(2.24g)和碳酸钾(3.13g)溶于二氧六环和水的混合溶剂(30mL/3mL)中，氮气保护下加入Pd(dppf)Cl 2(260g)。油浴110℃下搅拌过夜。反应液过滤，滤液减压浓缩。粗产品经硅胶柱层析纯化(石油醚/乙酸乙酯＝20:1～3/1)，得褐色油状物4.85g(化合物27d)。
步骤4)：将化合物27d(3.2g)溶于10mL干燥二氯甲烷中，氮气保护下，加入苄溴(4.16g)，室温下搅拌过夜。反应液减压浓缩，所得固体溶于二氯甲烷(20mL)中。有机相用水(50mL)洗涤两次，水相冷冻干燥，得黄色固体880mg(化合物27e)。
步骤5)：将硼氢化钠(160mg)加入到化合物27e(880mg，粗品)的甲醇(16mL)溶液中。氮气保护下室温搅拌2小时。反应液浓缩，加入水稀释，用二氯甲烷(30mL)萃取三次，有机相合并，经食盐水(50mL)洗涤，无水硫酸钠干燥后过滤，滤液浓缩的黄色油状物586mg。此油状物溶于10mL四氢呋喃中，依次加入Boc 2O(384mg)和DMAP(215mg)。反应液于78℃下搅拌2.5小时。反应液浓缩，加水稀释，用二氯甲烷(50mL)萃取。有机相经食盐水洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩。粗产品经硅胶柱层析纯化(二氯甲烷/甲醇＝50:1～20:1)，得黄色固体620mg(化合物27f)。
步骤6)：将Pd/C(350mg，10％wet)加入到化合物27f(720mg)的甲醇(15mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下，于30℃搅拌1.5小时。反应完全后抽滤，滤液浓缩，得黄色油状物550mg(化合物27g)。
步骤7)：将二异丙基乙基胺(139mg)加入到化合物27g(120mg)的二氯甲烷(7mL)溶液中，降温到0℃后一次性加入三光气(51mg)。氮气保护下室温搅拌3小时。反应液用冰水冷却过的饱和碳酸氢钠水溶液(4mL)洗涤一次，无水硫酸钠干燥后过滤，滤液直接应用于下一步反应。
步骤8)：在上述后处理得到的反应液中再加入二异丙基乙基胺(28mg)，DMAP(9mg)以及中间体A(74mg)。加完后在氩气保护下室温搅拌过夜。LCMS检测反应完全后，加水(3mL)淬灭反应，二氯甲烷(4mL)萃取三次。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。使用中间体A(149mg)重复上述两步反应。两批次所得粗产品合并，用硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化，得到白色固体570mg(化合物27i)。
步骤9)：将Pd/C(115mg,10％wet)加入到化合物27i(330mg)的乙酸乙酯/甲醇(5mL/5mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌3小时。反应完全后抽滤，浓缩得到白色固体270mg(化合物27j)。
步骤10)：将化合物27j(250mg)加入到TFA/DCM(5mL/2.5mL)溶液中，25℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品用反相(5-95％乙腈/水)制备HPLC纯化，得白色固体58.1mg(即化合物I-027)。
1H NMR(400MHz,DMSO-d 6):δ9.59(s,1H),7.79-7.76(m,1H),7.38(d,J＝8.0Hz,2H),7.20-7.16(m,2H),6.44-6.41(m,1H),6.34(s,1H),5.95(s,2H),4.13(d,J＝18.4Hz,1H),4.03-3.94(m,2H),3.65(s,3H),3.55-3.50(m,1H),2.88-2.84(m,4H),2.72-2.59(m,1H),1.88-1.86(m,1H),1.76-1.67(m,2H),1.57-1.46(m,1H)。
LCMS:Rt＝2.779min，[M+H] +＝482.0。
实施例28 化合物I-028的盐酸盐的制备
Figure PCTCN2019080549-appb-000073
按照以下反应式和方法制备化合物I-028的盐酸盐。
Figure PCTCN2019080549-appb-000074
步骤1)：将化合物28a(868mg)，化合物26b(2.0g)和碳酸钾(1.08g)溶于11mL二氧六环和水的混合溶剂(10/1)中。加入Pd(dppf)Cl 2(120mg),反应液在氮气保护下，于110℃搅拌过夜。反应液减压浓缩，所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝4:1)纯化，得淡黄色油状物1.26g(化合物28b)。
步骤2)：将Pd/C(1.0g,10％wet)加入到化合物28b(1.59g)的甲醇(20mL)溶液中。加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下，室温搅拌过夜。反应完全后抽滤，滤液浓缩，得淡黄色油状物1.41g(化合物28c)。
步骤3)：将化合物28c(1.41g)溶于HCl二氧六环溶液(2N，5mL)中。室温下搅拌3小时，减压浓缩。固体用乙酸乙酯稀释，用稀氨水溶液洗涤至pH>8。有机相用无水硫酸钠干燥，过滤。滤液减压浓缩，得淡黄色油状物800mg(化合物28d)。
步骤4)：将二异丙基乙基胺(469mg)加入到化合物28d(200mg)的二氯甲烷(10mL)溶液中，降温到0℃后加入三光气(180mg)。氮气保护下，室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤四次，经水硫酸钠干燥后过滤。滤液直接应用于下一步反应。
步骤5)：在上述后处理得到的反应液中再加入二异丙基乙基胺(155mg)，DMAP(44mg)以及中间体A(191mg)。加完后在氮气保护下室温搅拌2小时。LCMS检测反应完全，将10毫升水加入到反应体系中。有机相分离，水相用二氯甲烷萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化得到白色固体199mg(化合物28f)。
步骤6)：将Pd/C(60mg，10％wet)加入到化合物28f(199mg)的乙酸乙酯/甲醇(4mL/4mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下，室温搅拌1小时。反应完全后抽滤，滤液浓缩，得白色固体135mg(化合物28g)。
步骤7)：将化合物28g(65mg)加入到TFA/DCM(8mL/2mL)溶液中，30℃下搅拌2小时，LCMS检测反应完全后，室温浓缩反应液。经C-18反相柱纯化(5-95％乙腈/水(含0.02％HCl))，得白色固体40mg(即化合物I-028的盐酸盐)。
1H NMR(400MHz,DMSO-d 6):δ14.04(s,1H),8.19(s,2H),7.92(d,J＝5.6Hz,1H),7.56(s,1H),7.33(s,1H),6.94(s,1H),6.88(d,J＝6.4Hz,1H),4.32-4.27(m,1H),4.05(s,2H),3.78(s,3H),3.71(d,J＝9.2Hz,1H),3.14(d,J＝7.2Hz,2H),2.97-2.68(m,2H),2.57(s,1H),1.99-1.96(m,1H),1.76-1.73(m,1H),1.58-1.56(m,2H)。
LCMS:Rt＝2.475min。[M+H] +＝413。
实施例29 化合物I-029的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000075
按照以下反应式和方法制备化合物I-029的三氟乙酸盐。
Figure PCTCN2019080549-appb-000076
步骤1)：将DIEA(174mg)，HATU(215mg)加入到化合物21g(290mg，粗品)的二氯甲烷溶液(3mL)中，0℃下搅拌20min，加入甲胺四氢呋喃溶液(0.45mL)。反应液在0℃下，继续搅拌6小时。加二氯甲烷(20mL)稀释后，依次用饱和氯化铵水溶液(10mL)和饱和食盐水(10mL)洗涤。有机相用无水硫酸钠干燥并过滤。滤液减压浓缩，所得粗产品用硅胶柱层析(甲醇/二氯甲烷＝1:25)纯化，得白色固体149mg(化合物29a)。
步骤2)：将化合物29a(149mg)加入到TFA/DCM(3mL/1.5mL)溶液中。室温搅拌2时左右，LCMS检测反应完全。室温浓缩反应液，所得粗产品用反相制备HPLC纯化，得白色固体78mg(即化合物I-029的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.41(brs,1H),8.26–8.20(m,1H),7.98(s,2H),7.88–7.85(m,1H),7.40–7.35(m,1H),7.16–7.14(m,2H),7.09–7.05(m,1H),6.86–6.84(m,2H),4.21–4.19(m,1H),4.19–4.01(m,2H),3.54–3.50(m,1H),3.14–3.11(m,2H),2.98–2.87(m,2.6H),2.86–2.73(m,0.4H),2.61(dd,J＝12.8,4.8Hz,3H),1.94–1.91(m,1H),1.82–1.69(m,2H),1.64–1.42(m,1H)。
LCMS:Rt＝3.196min，[M+H] +＝440.2。
实施例30 化合物I-030的制备
Figure PCTCN2019080549-appb-000077
按照以下反应式和方法制备化合物I-030。
Figure PCTCN2019080549-appb-000078
步骤1)：将DIEA(81mg),HATU(120mg)加入到化合物22g(136mg)的二氯甲烷溶液(3mL)中，0℃下搅拌30min。加入甲胺四氢呋喃溶液(0.21mL)。0℃下，搅拌2小时，反应液加水淬灭。有机相分离，用无水硫酸钠干燥并过滤，滤液减压浓缩。所得粗产品用硅胶柱层析(甲醇/二氯甲烷＝1:20)纯化，得白色固体106mg(化合物30a)。
步骤2)：将化合物30a(106mg)加入到TFA/DCM(6mL/2mL)溶液中室温搅拌2时左右。LCMS检测反应完全后，室温浓缩。反应液经C-18反相柱(5-95％乙腈/水)纯化，得白色固体31.4mg(即化合物I-030)。
1H NMR(400MHz,DMSO-d 6):δ8.26-8.21(m,1H),7.81(t,J＝6.0Hz,1H),7.35-7.31(m,2H),7.15(t,J＝8.8Hz,2H),6.57(t,J＝5.6Hz,3H),6.49(d,J＝4.4Hz,1H),4.19-4.16(m,1H),4.05-3.97(m,2H),3.42-3.40(m,1H),2.97-2.80(m,4H),2.66(s,1H),2.63-2.58(m,3H),1.89-1.87(m,1H),1.81-1.69(m,2H),1.57-1.46(m,1H)。
LCMS:Rt＝2.772min，[M+H] +＝440。
实施例31 化合物I-031的制备
Figure PCTCN2019080549-appb-000079
按照以下反应式和方法制备化合物I-031。
Figure PCTCN2019080549-appb-000080
步骤1)：氮气保护下，将二异丙基乙基胺(69.7mg)和HATU(90.7mg)加入到化合物15d(100mg)的二氯甲烷溶液(10mL)中。0℃下搅拌10min，加入氯化铵(17.0mg)。反应液在0℃下继续搅拌2小时。加入2mL水淬灭反应，用二氯甲烷(4mL)萃取三次。有机相合并浓缩后，经C-18反相柱(50-90％乙腈/水)纯化，得白色固体62mg(化合物31e)。
步骤2)：将化合物31e(62mg)加入到TFA/DCM(2mL/1mL)溶液中，25℃下搅拌2小时。LCMS检测反应完全后，室温浓缩。反应液浓缩后溶于1mL DMF中，经C-18反相柱(5-95％乙腈/水)纯化，得白色固体13.1mg(即化合物I-031)。
1H NMR(400MHz,DMSO-d 6):δ7.79(d,J＝5.2Hz,1H),7.67(s,1H),7.35-7.29(m,5H),7.25-7.20(m,1H),6.45(d,J＝5.2Hz,1H),6.35(s,1H),5.89(s,2H),4.18(d,J＝3.2Hz,1H),4.03(t,2H),3.37-3.35(m,1H),2.94-2.87(m,4H),2.83-2.74(m,1H),1.92-1.89(m,1H),1.81-1.68(m,2H),1.53-1.43(m,1H)。
LCMS:Rt＝3.835min，[M+H] +＝408.1。
实施例32 化合物I-032的盐酸盐的制备
Figure PCTCN2019080549-appb-000081
按照以下反应式和方法制备化合物I-032的盐酸盐。
Figure PCTCN2019080549-appb-000082
步骤1)：氮气保护下，将二异丙基乙基胺(51.9mg)和HATU(76.4mg)加入到化合物26h(95mg)的二氯甲烷溶液(5mL)中。0℃下搅拌10min后，加入氯化铵(14.3mg)。在0℃下搅拌2小时。饱和碳酸氢钠水溶液淬灭反应后，加入水，用二氯甲烷萃取。有机相合并浓缩后，经硅胶柱层析(甲醇/二氯甲烷＝1/20)纯化，得白色固体90mg(化合物32a)。
步骤2)：将化合物32a(90mg)加入到TFA/DCM(4mL/2mL)溶液中，20℃下，搅拌3小时左右。LCMS检测反应完全后，室温浓缩。反应液经C-18反相柱纯化(5-95％乙腈/0.02％盐酸水溶液)得白色固体59mg(即化合物I-032的盐酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.63–13.46(m,1H),8.01(s,2H),7.88(d,J＝3.8Hz,1H),7.80–7.68(m,1H),7.40(d,J＝1.6Hz,1H),7.36(d,J＝8.3Hz,1H),7.31(d,J＝12.5Hz,1H),7.18–7.07(m,1H),6.87(dd,J＝6.1,1.8Hz,2H),4.20(t,J＝3.1Hz,1H),4.04-3.98(m,2H),3.50(d,J＝3.4Hz,1H),3.13(dd,J＝7.6,3.2Hz,2H),3.02–2.81(m,2H),2.77–2.60(m,1H),1.98–1.83(m,1H),1.79-1.71(m,2H),1.62–1.38(m,1H)。
LCMS:Rt＝2.985，[M+H] +＝487.9。
实施例33 化合物I-033的制备
Figure PCTCN2019080549-appb-000083
按照以下反应式和方法制备化合物I-033。
Figure PCTCN2019080549-appb-000084
步骤1)：氮气保护下，将二异丙基乙基胺(51.9mg)和HATU(76.4mg)加入到化合物26h(95mg)的二氯甲烷溶液(5mL)中，0℃下搅拌10min。甲胺四氢呋喃溶液(0.134mL)用0.5mL干燥二氯甲烷稀释，于0℃下加入到反应体系，在此温度下搅拌2小时。饱和碳酸氢钠水溶液淬灭反应后，加入水，用二氯甲烷萃取。有机相合并，浓缩后，经硅胶柱层析纯化(甲醇/二氯甲烷＝1/20)得到无色透明固体60mg(化合物33a)。
步骤8)：将化合物33a(60mg)加入到TFA/DCM(4mL/2mL)溶液中，20℃下搅拌3小时。LCMS检测反应完全后，室温浓缩。反应液浓缩后溶于1mL DMF中，经C18反相柱纯化(5-95％乙腈/水)得到白色固体28.1mg(即化合物I-033)。
1H NMR(400MHz,DMSO-d 6)δ8.31–8.17(m,1H),7.85–7.71(m,1H),7.39-7.34(m,2H),7.19–7.06(m,1H),6.53–6.42(m,1H),6.43(d,J＝1.6Hz,1H),6.6.18(brs,2H),4.23–4.15(m,1H),4.09–3.89(m,2H),3.44–3.36(m,1H),3.03–2.75(m,4H),2.78-2.754(m,1H),2.61(dd,J＝11.7,4.5Hz,3H),2.00–1.82(m,1H),1.88-1.78(m,2H),1.62–1.37(m,1H)。
LCMS:Rt＝3.050min，[M+H] +＝502.0。
实施例34 化合物I-034的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000085
按照以下反应式和方法制备化合物I-034的三氟乙酸盐。
Figure PCTCN2019080549-appb-000086
步骤1)：将化合物34a(2.5g),化合物26b(3.53g)和碳酸钾(2.86g)溶于二氧六环和水的混合溶剂(50mL/5mL)中。氮气保护下，加入Pd(dppf)Cl 2(1.27g)，油浴80℃下搅拌3小时。反应液减压浓缩，所得粗产品经硅胶柱层析(石油醚/乙酸乙酯＝20:1)纯化，得黄色油状物3.32g(化合物34b)。
步骤2)：将Pd/C(660mg,10％wet)加入到化合物34b(3.32g)的甲醇(40mL)溶液中。加入完毕后 抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌过夜。反应完全后抽滤，滤液浓缩，得无色油状物3.21g(化合物34c)。
步骤3)：化合物34c(3.21g)溶于30mL HCl甲醇溶液。室温下搅拌过夜，反应液减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(20mL)，用乙酸乙酯(50mL)萃取。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩，得褐色固体2g(化合物34d)。
步骤4)：将二异丙基乙基胺(1.22g)加入到化合物34d(770mg)的二氯甲烷(16mL)溶液中，降温到0℃后一次性加入三光气(466mg)。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤，无水硫酸钠干燥后过滤。滤液浓缩，得黄色油状物1.1g(粗产品，化合物34e)，直接应用于下一步反应。
步骤5)：将上述反应的化合物34e(964mg，粗品)溶于二氯甲烷(16mL)。依次加入中间体A(500mg),二异丙基乙基胺(365mg)和DMAP(115mg)。加完后在氩气保护下，室温搅拌两小时。LCMS检测反应完全后，加入饱和食盐水(20mL)洗涤。有机相合分离，经无水硫酸钠干燥，过滤后，减压浓缩。所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝6:1)纯化，得白色固体885mg(粗品，化合物34f)。
步骤6)：将Pd/C(310mg，10％wet)加入到化合物34f(885mg，粗品)的乙酸乙酯/甲醇(5mL/5mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤。滤液浓缩，得白色固体827mg(粗品，化合物34g)。
步骤7)：将化合物34g(150mg，粗品)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌2小时。LCMS检测反应完全后，室温浓缩反应液。粗产品用反相制备HPLC纯化，得白色固体56mg(即化合物I-034的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.4(brs,1H),7.95(s,2H),7.90–7.87(m,1H),7.45–7.40(m,2H),7.34–7.32(m,2H),6.88–6.86(m,2H),4.30(dd,J＝16.0,3.2Hz,1H),4.07–3.96(m,2H),3.75–3.70(m,1H),3.15–3.07(m,2H),2.97–2.83(m,2.5H),2.75–2.67(m,0.5H),1.96–1.84(m,1H),1.76–1.69(m,2H),1.66–1.57(m,1H)。
LCMS:Rt＝2.881min，[M+H] +＝493.1。
实施例35 化合物I-035的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000087
按照以下反应式和方法制备化合物I-035的三氟乙酸盐。
Figure PCTCN2019080549-appb-000088
步骤1)：氮气保护下，将二异丙基乙基胺(109mg)和HATU(213mg)加入到化合物34g(200mg，粗品)的二氯甲烷溶液(4mL)中。0℃下搅拌30min后，加入氯化铵(45mg)。在0℃下搅拌2小时。加入氯化铵水溶液(10mL)淬灭反应，有机相用二氯甲烷萃取。有机相合并浓缩，经硅胶柱层析(甲醇/二氯甲烷＝1/20)纯化，得白色固体228mg(粗品，化合物35a)。
步骤2)：将化合物35a(228mg，粗品)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品用反相制备HPLC纯化，得白色固体40.3mg(即化合物I-035的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.38(brs,1H),7.98(s,2H),7.88–7.85(m,1H),7.70(d,J＝16.8Hz,1H),7.44–7.41(m,2H),7.34–7.29(m,3H),6.88–6.86(m,2H),4.21–4.19(m,1H),4.08–4.01(m,2H),3.53–3.48(m,1H),3.14–3.11(m,2H),2.97–2.86(m,3H),2.75–2.66(m,1H),1.95–1.83(m,1H),1.83–1.69(m,2H),1.64–1.45(m,1H)。
LCMS:Rt＝3.356min，[M+H] +＝492.0。
实施例36 化合物I-036的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000089
按照以下反应式和方法制备化合物I-036的三氟乙酸盐。
Figure PCTCN2019080549-appb-000090
步骤1)：氮气保护下，将二异丙基乙基胺(108mg)和HATU(202mg)加入到化合物34g(200mg，粗品)的二氯甲烷溶液(4mL)中。0℃下搅拌30min后，加入甲胺四氢呋喃溶液(2.0M，0.28mL)。在0℃下继续搅拌3小时。加入氯化铵水溶液(10mL)淬灭反应，用二氯甲烷萃取。有机相合并浓缩后，经硅胶柱层析(甲醇/二氯甲烷＝1/25)纯化，得白色固体247mg(粗品，化合物36a)。
步骤2)：将化合物36a(247mg，粗品)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品用反相制备HPLC纯化，得白色固体58.2mg(即化合物I-036的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.39(brs,1H),8.27–8.18(m,1H),7.97(s,2H),7.88–7.85(m,1H),7.44–7.41(m,2H),7.34–7.32(m,2H),6.85–6.83(m,2H),4.21–4.19(m,1H),4.07–4.00(m,2H),3.54–3.49(m,1H),3.14–3.11(m,2H),3.01–2.85(m,3H),2.73–2.66(m,1H),2.61(dd,J＝14,4.4Hz,3H),1.95–1.83(m,1H),1.69–1.57(m,2H),1.54–1.43(m,1H)。
LCMS:Rt＝3.480min，[M+H] +＝506.0。
实施例37 化合物I-037的制备
Figure PCTCN2019080549-appb-000091
按照以下反应式和方法制备化合物I-037。
Figure PCTCN2019080549-appb-000092
步骤1)：将化合物37a(2.0g)溶于15mL四氢呋喃中，氮气保护下，于-78℃加入KHMDS的四氢呋 喃溶液(19mL)。在此温度下搅拌30分钟后，加入化合物PhN(Tf) 2(6.8g)的四氢呋喃(20mL)溶液。缓慢升温至室温，并搅拌过夜。加入水淬灭反应后，乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤后减压浓缩。粗产品经硅胶柱层析纯化(石油醚/乙酸乙酯＝50:1)得无色油状物2.9g(化合物37b)。
步骤2)：将化合物37b(2.0g)，化合物26b(2.39g)和碳酸钾(2.13g)溶于二氧六环和水的混合溶剂中(20mL/3mL)，氮气保护下加入Pd(dppf)Cl 2·DCM(566mg)。油浴85℃下搅拌3小时。反应液减压浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝50:1～30:1)得无色油状物1.9g(化合物37c)。
步骤3)：将Pd/C(300mg，10％)加入到化合物37c(1.9g)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌过夜。反应完全后抽滤，浓缩得到白色油状物1.8g(化合物37d)。
步骤4)：化合物37d(1.8g)溶于15mL HCl二氧六环溶液。室温下搅拌3小时后减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(5mL)，用乙酸乙酯(20mL)萃取三次，有机相合并，用食盐水(3mL)洗涤。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩得黄色油状物1.2g(化合物37e)。
步骤5)：将二异丙基乙基胺(1.79g)加入到化合物37e(900mg)的二氯甲烷(20mL)溶液中，降温到0℃后一次性加入三光气(548mg)的二氯甲烷(20mL)溶液。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(20mL)洗涤三次，无水硫酸钠干燥后过滤，滤液直接应用于下一步反应。
步骤6)：在上述后处理得到的反应液(～50mL)中再加入二异丙基乙基胺(327mg)，DMAP(103mg)以及中间体A(450mg)。加完后在氩气保护下室温搅拌过夜。LCMS检测反应完全后，加水淬灭反应，二氯甲烷萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝1:3)纯化得到白色固体570mg(化合物37g)。
步骤7)：将Pd/C(250mg，10％)加入到化合物37g(570mg)的乙酸乙酯/甲醇(20mL/20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤，浓缩得到白色固体500mg(化合物37h)。
步骤8)：将化合物37h(150mg)加入到TFA/DCM(4mL/2mL)溶液中，25℃下搅拌4小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经C-18反相柱层析纯化，得白色固体68.1mg(即化合物I-037)。
1H NMR(400MHz,DMSO-d 6):δ7.79(d,J＝5.6Hz,1H),6.43(s,1H),6.34(s,1H),5.93(s,2H),4.13(d,J＝11.6Hz,1H),4.00-3.90(m,2H),3.57-3.51(m,1H),2.88(d,J＝6.8Hz,2H),2.76-2.63(m,1H),2.58-2.51(m,2H),1.77-1.73(m,1H),1.65-1.53(m,8H),1.44-1.19(m,10H)。
LCMS:Rt＝3.453min，[M+H] +＝443.1。
实施例38 化合物I-038的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000093
按照以下反应式和方法制备化合物I-038的三氟乙酸盐。
Figure PCTCN2019080549-appb-000094
步骤1)：氮气保护下，将二异丙基乙基胺(93mg)和HATU(137mg)加入到化合物15d(150mg)的二氯甲烷溶液(3mL)中。0℃下搅拌20min后，加入正丙胺(29mg)。在0℃下继续搅拌4小时。反应液经二氯甲烷稀释后，依次用氯化铵水溶液(10mL)，饱和食盐水(10mL)洗涤。有机相经干燥，过滤并浓缩。粗产品经硅胶柱层析(二氯甲烷/甲醇＝25/1)纯化，得白色固体150mg(化合物38a)。
步骤2)：将化合物38a(150mg)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌2小时。LCMS检测反应完全后，室温浓缩。粗产品经反相制备HPLC纯化，得白色固体67mg(即化合物I-038的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.43(brs,13.43),8.23–8.21(m,1H),7.97(s,2H),7.87–7.85(m,1H),7.35–7.29(m,4H),7.25–7.21(m,1H),6.86–6.85(m,2H),4.23(d,J＝3.6Hz,1H),4.07–4.00(m,2H),3.52–3.47(m,1H),3.13–3.11(m,2H),3.08–3.01(m,1H),2.98–2.89(m,3H),2.84–2.74(m,1H),1.95–1.88(m,1H),1.84–1.69(m,2H),1.54–1.43(m,1H),1.37–1.31(m,2H),0.76(t,J＝7.2Hz,3H)。
LCMS:Rt＝2.901min，[M+H] +＝450.1。
实施例39 化合物I-039的制备
Figure PCTCN2019080549-appb-000095
按照以下反应式和方法制备化合物I-039。
Figure PCTCN2019080549-appb-000096
步骤1)：氮气保护下，将二异丙基乙基胺(98mg)和HATU(127mg)加入到化合物15d(140mg)的二氯甲烷溶液(6mL)中。0℃下搅拌10min后，加入化合物39a(58mg)。反应液在0℃下搅拌3小时。加入饱和氯化铵水溶液(4mL)淬灭反应，用二氯甲烷(4mL)萃取三次。有机相合并，用水(2mL)洗涤，经无水硫酸钠干燥，过滤。滤液浓缩后，经薄层层析制备板(甲醇/二氯甲烷＝1/16)纯化，得白色固体140mg(化合物39b)。
步骤5)：将化合物39b(140mg)加入到TFA/DCM(4mL/2mL)溶液中，25℃下搅拌2小时。LCMS检测反应完全后，室温浓缩。反应液浓缩后，用反相制备HPLC纯化，得白色固体31.8mg(即化合物I-039)。
1H NMR(400MHz,DMSO-d 6):δ8.13(t,1H),7.78(d,J＝5.2Hz,1H),7.34-7.28(m,4H),7.25-7.21(m,1H),6.43(d,J＝6.4Hz,1H),6.32(s,1H),5.84(s,2H),4.23(d,J＝3.2Hz,1H),4.02(t,2H),3.52(t,4H),3.31(s,1H),3.25-3.20(m,1H),3.16-3.09(m,1H),2.93-2.86(m,4H),2.81-2.76(m,1H),2.33-2.30(m,4H),2.28-2.26(m,2H),1.93-1.89(m,1H),1.81-1.72(m,2H),1.53-1.43(m,1H)。
LCMS:Rt＝3.135min，[M+H] +＝521.2。
实施例40化合物I-040的制备
Figure PCTCN2019080549-appb-000097
按照以下反应式和方法制备化合物I-040。
Figure PCTCN2019080549-appb-000098
步骤1)：将化合物40a(1.00g)，化合物26b(1.49g)和碳酸钾(1.33g)溶于15mL二氧六环和水的混合溶剂中(5/1)。氮气保护下，加入Pd(dppf)Cl 2(353mg)。油浴80℃下搅拌2小时。反应液减压浓缩，经硅胶柱层析(石油醚/乙酸乙酯＝20:1)纯化，得黄色油状物1.4g(化合物40b)。
步骤2)：将Pd/C(300mg，10％wet)加入到化合物40b(1.4g)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下，室温搅拌过夜。反应完全后抽滤，滤液浓缩，得白色固体1.3g(化合物40c)。
步骤3)：化合物40c(1.3g)溶于10mL HCl二氧六环溶液。室温下搅拌3小时后，减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(5mL)中，乙酸乙酯(100mL)萃取三次。有机相用食盐水(5mL)洗涤。经无水硫酸钠干燥后过滤，减压浓缩得到白色固体860mg(化合物40d)。
步骤4)：化合物40d用甲苯共沸带干，除尽水分后备用。将二异丙基乙基胺(550mg)加入到化合物40d(300mg)的二氯甲烷(10mL)溶液中，降温到0℃后，一次性加入三光气(168mg)的二氯甲烷溶液(10mL)。氮气保护下，室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤三次，经无水硫酸钠干燥后直接应用于下一步反应。
步骤5)：在上述后处理得到的反应液(含40e)(～25mL)中再加入二异丙基乙基胺(109mg),DMAP(34.5mg)以及中间体A(150mg)。加完后在氮气保护下，室温搅拌5小时。LCMS检测反应完全后，将20毫升水加入到反应体系中。有机相分离，水相用二氯甲烷(30mL)萃取。有机相合并后，用无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝3:1～2:1)纯化，得白色固体140mg(化合物40f)。
步骤6)：将Pd/C(100mg，10％wet)加入到化合物40f(140mg)的乙酸乙酯/甲醇(10mL/10mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下，室温搅拌1小时。反应完全后抽滤，滤液浓缩，得白色固体160mg(化合物40g)。
步骤7)：将化合物40g(160mg)加入到TFA/DCM(4mL/2mL)溶液中，25℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。所得固体溶于1mL DMF中，经C-18反相柱(5-95％乙腈/水)纯化，得白色固体67.2mg(即化合物I-040)。
1H NMR(400MHz,DMSO-d 6)δ7.88(d,J＝8.0Hz,3H),7.78(dd,J＝11.0,5.1Hz,2H),7.54–7.40(m,3H),6.44(dd,J＝9.5,4.0Hz,1H),6.35(d,J＝4.3Hz,1H),5.97(s,2H),4.18(dd,J＝22.2,3.3Hz,1H),4.15-4.08(m,2H),3.63–3.54(m,1H),3.11-3.06(m,1H),2.98-2.91(m,1H),2.90(t,J＝6.9Hz,3H),2.08-1.98(m,1H),1.88-180(m,2H),1.72–1.48(m,1H)。
LCMS:Rt＝3.030，[M+H] +＝459.0。
实施例41 化合物I-041的制备
Figure PCTCN2019080549-appb-000099
按照以下反应式和方法制备化合物I-041的三氟乙酸盐。
Figure PCTCN2019080549-appb-000100
步骤1)：将DIEA(14mg)，HATU(18mg)加入到化合物15d(20mg)的二氯甲烷溶液(5mL)中，搅拌10min加入甲胺盐酸盐，在室温下搅拌1小时后上硅胶制备板纯化，得到无色固体18mg(即化合物41a)。
步骤4)：将化合物41a(37mg)加入到TFA/DCM(1.5/1.5mL)溶液中室温搅拌3小时左右，LCMS检测反应完全后室温浓缩反应液，用反相制备HPLC纯化，得到白色固体13mg(即化合物I-041的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ8.19(m,1H),7.91(brs,2H),7.86(d,1H),7.34-7.21(m,5H),6.84-6.82(m,2H),4.21(d,2H),4.07-4.00(m,2H),3.53-3.48(m,1H),3.11(d,J＝7.2,2H),2.95-2.76(m,3H),2.58(d,3H),1.93-1.90(m,1H),1.82-1.71(m,2H),1.53-1.47(m,1H)。
LCMS:Rt＝1.273min，[M+H] +＝422.0。
实施例42 化合物I-042的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000101
按照以下反应式和方法制备化合物I-042的三氟乙酸盐。
Figure PCTCN2019080549-appb-000102
1)将化合物42a(1.5g)，化合物26b(2.5g)和碳酸钾(2.1g)溶于二氧六环和水的混合溶剂中(11mL,10/1),氮气保护下加入Pd(dppf)Cl 2(910mg)。油浴80℃下搅拌2小时。反应液减压浓缩。经硅胶柱层析纯化(石油醚/乙酸乙酯＝10:1)得黄色油状物2.2g(化合物42b)。
2)化合物42b(1.2g)溶于10mL HCl二氧六环溶液。室温下搅拌过夜，减压浓缩。所得固体溶于10mL饱和碳酸氢钠水溶液中，乙酸乙酯萃取(20mL×2)。有机相经无水硫酸钠干燥后过滤，减压浓缩得到黄色油状物750mg(化合物42c)。
3)化合物42c用甲苯共沸带干，除尽水分后备用。将二异丙基乙基胺(569mg)加入到化合物42c(300mg)的二氯甲烷(10mL)溶液中，降温到0℃后，一次性加入三光气(218mg)。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(20mL)洗涤三次，无水硫酸钠干燥后直接应用于下一步反应。
4)在上述后处理得到的反应液中再加入二异丙基乙基胺(190mg),DMAP(62mg)以及中间体A(260mg)。加完后在氮气保护下室温搅拌3小时。LCMS检测反应完全后将20毫升水加入到反应体系中，有机相分离，水相用二氯甲烷(30mL)萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品经硅胶柱层析纯化(石油醚/乙酸乙酯＝3:1)纯化，得白色固体200mg(化合物42e)。
5)将Ra-Ni(1.0g)加入到化合物42e(200mg)的四氢呋喃(5mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌3小时。反应完全后抽滤，浓缩得到白色固体168mg(化合物42f)。
6)在冰水浴条件下，将二异丙基乙基胺(148mg),氯甲酸甲酯(86mg)加入到化合物42f(168mg)的二氯甲烷溶液(10mL)中，室温搅拌过夜。反应液加水淬灭。有机相分离，用无水硫酸钠干燥并过滤，滤液减压浓缩。所得粗产品用硅胶柱层析(乙酸乙酯/石油醚＝2:1)纯化，得白色固体153mg(化合物42g)。
7)将Pd/C(50mg,10％wet)加入到化合物42g(153mg)的四氢呋喃(10mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌过夜。反应完全后抽滤，浓缩得到白色固体136mg(化合物42h)。
8)将化合物42h(136mg)加入到TFA/DCM(6mL/2mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩。反应液浓缩后溶于1mL DMF中，经反相制备HPLC纯化的白色固体32mg(即化合物I-042的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.35(brs,1H),9.61(d,J＝4.0Hz,1H),7.97(brs,2H),7.89-7.87(m,1H),7.39-7.38(m,1H),7.32-7.30(m,1H),7.25-7.20(m,1H),6.95-6.87(m,3H),4.31(d,J＝3.6Hz,0.5H),4.28(d,J＝3.2Hz,0.5H),4.07-3.98(m,2H),3.74-3.70(m,1H),3.65(s,3H),3.14-3.12(m,2H),3.04-2.85(m,2H),2.78-2.67(m,0.5H),2.63-2.54(m,0.5H),1.97-1.87(m,1H),1.85-1.77(m,1H),1.73-1.64(m,1H).,1.52-1.42(m,1H)。
LCMS:Rt＝3.562min，[M+H] +＝482.0。
实施例43 化合物I-043的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000103
按照以下反应式和方法制备化合物I-043。
Figure PCTCN2019080549-appb-000104
氮气保护下，依次将吡啶(64mg)和化合物43a(81mg)加入到化合物I-041(90mg)的四氢呋喃溶液(4mL)中。0℃搅拌10分钟后，室温继续搅拌过夜。加入五滴水淬灭反应，反应液经C-18反相柱纯化(40-95％乙腈/水)，得无色固体15.2mg(即化合物I-043)。反应液中的原料I-041回收浓缩得白色固体60mg。
1H NMR(400MHz,DMSO-d 6):δ8.18(d,J＝4.8Hz,1H),7.83(s,1H),7.64(s,1H),7.35-7.30(m,4H),7.24-7.21(m,1H),6.91(d,J＝5.2Hz,1H),6.54(brs,1H),4.37(s,1H),4.36-4.22(m,1H),4.18(t,3H),3.72-3.67(m,1H),3.18-3.13(m,1H),3.02-2.96(m,2H),2.89-2.83(m,2H),2.10-2.06(m,1H),1.90-1.87(m,1H),1.76-1.65(m,4H),1.41-1.37(m,2H),1.34-1.25(m,4H),0.90(t,3H)。
LCMS:Rt＝4.375min，[M+H] +＝550.4。
实施例44 化合物I-044的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000105
按照以下反应式和方法制备化合物I-044的三氟乙酸盐。
Figure PCTCN2019080549-appb-000106
氮气保护下，将二异丙基乙基胺(93.5mg)和HATU(137mg)加入到化合物37h(160mg)的二氯甲烷溶液(5mL)中。0℃下搅拌10min后，加入氯化铵(25.8mg)。在0℃下搅拌2小时。加入饱和碳酸氢钠水溶液淬灭反应，用二氯甲烷萃取。有机相合并浓缩后，经硅胶柱层析(甲醇/二氯甲烷＝1/40)纯化，得白色固体160mg(化合物44a)。
将化合物44a(160mg)加入到TFA/DCM(4mL/2mL)溶液中，25℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经C-18反相柱层析(5-95％乙腈/水(含0.1％TFA))纯化，得白色固体57.2mg(即化合物I-044的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.25(brs,1H),7.87-7.85(m,3H),7.66(s,1H),7.29-7.27(m,1H),6.87-6.84(m,2H),4.17(d,J＝2.8Hz,1H),3.96-3.91(m,2H),3.53-3.50(m,1H),3.11-3.09(m,2H),2.83-2.76(m,0.5H),2.63-2.59(m,2.5H),1.77-1.69(m,4H),1.64-1.54(m,5H),1.44-1.21(m,10H)。
LCMS:Rt＝3.233min，[M+H] +＝442.1。
实施例45 化合物I-045的制备
Figure PCTCN2019080549-appb-000107
按照以下反应式和方法制备化合物I-045。
Figure PCTCN2019080549-appb-000108
氮气保护下，将二异丙基乙基胺(166mg)和HATU(305mg)加入到化合物37h(200mg)的二氯甲烷溶液(8mL)中。0℃下搅拌10min后，加入甲胺四氢呋喃溶液(2.0M,0.33mL)。在0℃下搅拌2小时。加入饱和碳酸氢钠水溶液淬灭反应，用二氯甲烷萃取。有机相合并浓缩后，经硅胶柱层析(甲醇/二氯甲烷＝1/40)纯化，得白色固体180mg(化合物45a)。
将化合物45a(180mg)加入到TFA/DCM(4mL/2mL)溶液中，25℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经C-18反相柱层析(10-95％乙腈/水)纯化，得白色固体34.2mg(即化合物I-045)。
1H NMR(400MHz,DMSO-d 6):δ8.22-21(m,1H),7.79(d,J＝5.2Hz,1H),6.42(d,J＝5.2Hz,1H),6.31(s,1H),5.88(brs,2H),4.14(d,J＝3.2Hz,0.5H),4.12(d,J＝3.2Hz,0.5H),4.02-3.87(m,2H),3.32-3.30(m,1H),2.88-2.84(m,2H),2.80-2.72(m,1H),2.60-2.57(m,3H),2.56-2.51(m,2H),1.65-1.55(m,4H),1.46-1.43(m,5H),1.40-1.21(m,10H)。
LCMS:Rt＝3.328min，[M+H] +＝456.1。
实施例46 化合物I-046的制备
Figure PCTCN2019080549-appb-000109
按照以下反应式和方法制备化合物I-046。
Figure PCTCN2019080549-appb-000110
将化合物46a(1.00g)，化合物26b(1.65g)和碳酸钾(1.3g)溶于20mL二氧六环和水的混合溶剂中 (10/1),氮气保护下加入Pd(dppf)Cl 2(590mg)。油浴80℃下搅拌2小时。反应液减压浓缩。经硅胶柱层析纯化(石油醚/乙酸乙酯＝10:1)得黄色油状物1.18g(化合物46b)。
将Pd/C(200mg,10％wet)加入到化合物46b(1.18g)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌过夜，LCMS显示～50％转换率，反应液在50℃下，在3.5个大气压的氢气氛围下搅拌4小时。反应完全后抽滤，浓缩得到褐色油状物1.2g(化合物46c)。
化合物46c(1.2g)溶于10mL HCl二氧六环溶液。室温下搅拌3小时后，减压浓缩。所得固体溶于10mL饱和碳酸氢钠水溶液中，乙酸乙酯萃取(20mL x 2)。有机相经无水硫酸钠干燥后过滤，减压浓缩得到黄色油状物600mg(化合物46d)。
化合物46d用甲苯共沸带干，除尽水分后备用。将二异丙基乙基胺(734mg)加入到化合物46d(400mg)的二氯甲烷(10mL)溶液中，降温到0℃后，一次性加入三光气(282mg)。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤三次，无水硫酸钠干燥后直接应用于下一步反应。
在上述后处理得到的反应液中再加入二异丙基乙基胺(245mg),DMAP(46mg)以及中间体A(202mg)。加完后在氮气保护下室温搅拌5小时。LCMS检测反应完全后将20毫升水加入到反应体系中，有机相分离，水相用二氯甲烷(30mL)萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用C-18反相柱层析(40-95％乙腈/水)纯化，得白色固体140mg(化合物46f)。
将Pd/C(42mg,10％wet)加入到化合物46f(140mg)的乙酸乙酯/甲醇(3mL/3mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌1小时。反应完全后抽滤，浓缩得到白色固体123mg(化合物46g)。
将化合物46g(123mg)加入到TFA/DCM(6mL/2mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩。反应液浓缩后溶于1mL DMF中，经反相制备HPLC纯化得到白色固体30.9mg(化合物I-046)。
1H NMR(400MHz,DMSO-d 6)δ8.32-8.30(m,1H),7.94-7.92(m,1H),7.82(d,J＝7.6Hz,1H),7.77(d,J＝5.6Hz,1H),7.58-7.46(m,4H),6.41(d,J＝4.8Hz,1H),6.33(s,1H),5.89(brs,2H),4.25-4.08(m,3H),3.57-3.54(m,1H),3.47-3.45(m,2H),3.06-2.95(m,1H),2.91-2.81(m,2H),2.05-1.89(m,2H),1.87-1.81(m,1H),1.76-1.65(m,1H)。
LCMS:Rt＝2.934，[M+H] +＝459.3。
实施例47 化合物I-047的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000111
按照以下反应式和方法制备化合物I-047的三氟乙酸盐。
Figure PCTCN2019080549-appb-000112
将化合物47a(1.0g)，化合物26b(1.32g)和碳酸钾(1.18g)溶于二氧六环和水的混合溶剂中(15mL/3mL)，氮气保护下加入Pd(dppf)Cl 2·DCM(350mg)。油浴90℃下搅拌2小时。反应液减压浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝6:1)得白色固体1.13g(化合物47b)。
将Pd/C(500mg,10％wet)加入到化合物47b(1.13g)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌过夜。反应完全后抽滤，浓缩得到白色固体1.1g(化合物47c)。
化合物47c(1.1g)溶于20mL HCl二氧六环溶液。室温下搅拌3小时后减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(10mL)，用乙酸乙酯(10mL)萃取三次，有机相合并，用食盐水(5mL)洗涤。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩得黄色固体750mg(化合物47d)。
将二异丙基乙基胺(489mg)加入到化合物47d(300mg)的二氯甲烷(10mL)溶液中，降温到0℃后一次性加入三光气(150mg)的二氯甲烷(10mL)溶液。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤三次，无水硫酸钠干燥后过滤，滤液直接应用于下一步反应。
在上述后处理得到的反应液中再加入二异丙基乙基胺(109mg)，DMAP(34.5mg)以及中间体A(150mg)。加完后在氩气保护下室温搅拌过夜。LCMS检测反应完全后，加水淬灭反应，二氯甲烷萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝40:1)纯化得到白色固体200mg(粗品，～80％纯度，化合物47f)。
将Pd/C(100mg,10％wet)加入到化合物47f(200mg,粗品)的乙酸乙酯/甲醇(20mL/20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤，浓缩得黄色油状物200mg(粗品，～80％纯度，化合物47g)。
将化合物47g(200mg,粗品)加入到TFA/DCM(3mL/3mL)溶液中，25℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品溶于DMF(1mL),经C-18反相柱层析(5-95％乙腈/水(含0.1％TFA))纯化，得白色固体111.2mg(即化合物I-047的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.32(brs,2H),7.96(brs,2H),7.90-7.87(m,1H),7.65-7.61(m,4H),7.48-7.44(m,2H),7.41-7.34(m,3H),6.89-6.86(m,2H),4.33(d,J＝3.6Hz,0.5H),4.29(d,J＝3.2Hz,0.5H),4.08-4.02(m,2H),3.76-3.70(m,1H),3.16-3.13(m,2H),3.05-2.92(m,2H),2.90-2.82(m,0.5H),2.73-2.65(m,0.5H),2.00-1.92(m,1H),1.96-1.75(m,2H),1.67-1.59(m,0.5H),1.55-1.46(m,0.5H)。
LCMS:Rt＝3.408min，[M+H] +＝485.0。
实施例48 化合物I-048的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000113
按照以下反应式和方法制备化合物I-048的三氟乙酸盐。
Figure PCTCN2019080549-appb-000114
将化合物48a(1.0g),化合物26b(1.46g)和碳酸钾(1.18g)溶于二氧六环和水的混合溶剂(10mL/1mL)中。氮气保护下加入Pd(dppf)Cl 2(523mg)，油浴80℃下搅拌3小时。反应液减压浓缩，所得粗产品经硅胶柱层析(石油醚/乙酸乙酯＝20:1)纯化，得无色油状物1.21g(化合物48b)。
将Pd/C(240mg,10％wet)加入到化合物48b(1.21g)的甲醇(15mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌过夜。反应完全后抽滤。滤液浓缩，得无色油状物1.22g(粗产品)，直接应用于下一步反应。
化合物48c(1.22g，粗品)溶于10mL HCl二氧六环溶液。室温下搅拌过夜，反应液减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(20mL)，用乙酸乙酯(50mL)萃取。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩，得黄色油状物760mg(化合物48d)。
将二异丙基乙基胺(364mg)加入到化合物48d(230mg)的二氯甲烷(5mL)溶液中，降温到0℃后一次性加入三光气(140mg)。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤，无水硫酸钠干燥后过滤，浓缩得黄色油状物281mg(粗产品)，直接应用于下一步反应。
将上述反应的化合物48e(281mg,粗品)溶于二氯甲烷(5mL)。依次加入中间体A(150mg),二异丙基乙基胺(110mg)和DMAP(35mg)。加完后在氩气保护下室温搅拌三小时。LCMS检测反应完全后，加入饱和食盐水(10mL)洗涤。有机相合分离，经无水硫酸钠干燥，过滤。滤液减压浓缩，所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝4:1)纯化，得白色固体180mg(化合物48f)。
将Pd/C(63mg,10％wet)加入到化合物48f(180mg)的乙酸乙酯/甲醇(2mL/2mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤。滤液浓缩，得白色固体164mg(粗品，化合物48g)。
将化合物48h(164mg,粗品)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经反相制备HPLC纯化，得白色固体80.0mg(化合物I-048的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.39(brs,1H),7.96(brs,2H),7.89–7.86(m,1H),7.66(d,J＝8.4Hz,2H),7.58–7.52(m,2H),7.47(t,J＝8.0Hz,2H),7.42(t,J＝7.6Hz,1H),7.39–7.35(m,1H),7.31–7.26(m,1H),6.89–6.86(m,2H),4.32(d,J＝3.6Hz,0.5H),4.29(d,J＝3.6Hz,0.5H),4.09–4.01(m,2H),3.75–3.70(m,1H),3.15–3.12(m,2H),3.05–3.00(m,1H),3.00–2.82(m,1.5H),2.78–2.68(m,0.5H),2.02–1.93(m,1H),1.89–1.79(m,2H),1.70–1.60(m,0.5H),1.56–1.45(m,0.5H)。
LCMS:Rt＝2.610min，[M+H] +＝485.3。
实施例49 化合物I-049的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000115
按照以下反应式和方法制备化合物I-049的三氟乙酸盐。
Figure PCTCN2019080549-appb-000116
将化合物49a(1.0g)，化合物26b(1.24g)和碳酸钾(1.11g)溶于二氧六环和水的混合溶剂中(15mL/3mL),氮气保护下加入Pd(dppf)Cl 2·DCM(327mg)。油浴90℃下搅拌3小时。反应液减压浓缩。硅胶柱层析纯化(石油醚/乙酸乙酯＝20:1)得无色油状物1.3g(化合物49b)。
将Pd/C(350mg,10％wet)加入到化合物49b(1.3g)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌过夜。反应完全后抽滤，浓缩得到白色油状物1.2g(化合物49c)。
化合物49c(1.2g)溶于20mL HCl二氧六环溶液。室温下搅拌3小时后减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(5mL),用乙酸乙酯(20mL)萃取三次，有机相合并，用食盐水(3mL)洗涤。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩得无色油状物850mg(化合物49d)。
将二异丙基乙基胺(611mg)加入到化合物49d(400mg)的二氯甲烷(20mL)溶液中，降温到0℃后一次性加入三光气(187mg)的二氯甲烷(20mL)溶液。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤三次，无水硫酸钠干燥后过滤，滤液直接应用于下一步反应。
在上述后处理得到的反应液中再加入二异丙基乙基胺(131mg)，DMAP(41.3mg)以及中间体A(180mg)。加完后在氩气保护下室温搅拌过夜。LCMS检测反应完全后，加水淬灭反应，二氯甲烷萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝2.5:1)纯化，得白色固体220mg(粗品，～70％纯度，化合物49f)。
将Pd/C(100mg,10％wet)加入到化合物49f(220mg,粗品)的乙酸乙酯/甲醇(20mL/20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤，浓缩得白色固体200mg(粗品，～70％纯度，化合物49g)。
将化合物49g(200mg,粗品)加入到TFA/DCM(4mL/2mL)溶液中，25℃下搅拌4小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经C-18反相柱层析(5-95％乙腈/水(含0.1％TFA))纯化，得白色固体58.3mg(化合物I-049的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6):δ13.30(brs,1H),7.97(brs,2H),7.88(d,J＝11.2Hz,1H),7.41-7.37(m,2H),7.33-7.27(m,2H),7.15-7.11(m,1H),7.00-6.96(m,4H),6.89-6.87(m,2H),4.32(d,J＝3.6Hz,0.5H),4.29(d,J＝3.2Hz,0.5H),4.07-3.98(m,2H),3.76-3.71(m,1H),3.15-3.13(m,2H),3.02-2.88(m,2H),2.86-2.74(m,0.5H),2.69-2.61(m,0.5H),1.96-1.89(m,1H),1.84-1.68(m,2H),1.65-1.56(m,0.5H),1.53-1.44(m,0.5H)。
LCMS:Rt＝3.372min，[M+H] +＝501.0。
实施例50 化合物I-050的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000117
参考化合物I-049的合成方法，用原料50a替换原料49a，制备得到化合物I-050的三氟乙酸盐。
Figure PCTCN2019080549-appb-000118
1H NMR(400MHz,DMSO-d 6)δ13.37(brs,1H),8.00(brs,2H),7.90–7.88(m,1H),7.42–7.31(m,3H),7.16–6.97(m,5H),6.88–6.82(m,3H),4.31(d,J＝3.6Hz,0.5H),4.27(d,J＝3.2Hz,0.5H),4.03–3.98(m,2H),3.73–3.70(m,1H),3.13(d,J＝8.0Hz,2H),3.01–2.88(m,2H),2.85–2.77(m,0.5H),2.69–2.60(m,0.5H),1.95–1.89(m,1H),1.82–1.68(m,2H),1.64–1.55(m,0.5H),1.51–1.42(m,0.5H)。
LCMS：Rt＝3.108min，[M+H] +＝501.3。
实施例51 化合物I-051的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000119
按照以下反应式和方法制备化合物I-051的三氟乙酸盐。
Figure PCTCN2019080549-appb-000120
将化合物51a(1.0g),化合物26b(1.77g)和碳酸钾(1.44g)溶于二氧六环和水的混合溶剂(11mL,10/1)中。氮气保护下加入Pd(dppf)Cl 2(637mg)，油浴80℃下搅拌3小时。反应液减压浓缩，所得粗产品经硅胶柱层析(石油醚/乙酸乙酯＝10:1)纯化，得无色油状物1.57g(粗品，化合物51b)，此粗产品直接应用于下一步反应。
将Pd/C(314mg,10％wet)加入到化合物51b(1.57g,粗品)和1,2-二氯苯(2.36g)的甲醇(30mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌三小时。反应完全后抽滤。滤液浓缩，所得粗产品用反相柱(乙腈/水＝20-95％)纯化，得黄色油状物523mg(化合物51c)。
化合物51c(523mg)溶于5mL HCl二氧六环溶液。室温下搅拌过夜，反应液减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(10mL)，用乙酸乙酯(25mL)萃取。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩，得白色固体321mg(化合物51d)。
将二异丙基乙基胺(639mg)加入到化合物51d(321mg)的二氯甲烷(8mL)溶液中，降温到0℃后一次性加入三光气(247mg)。氮气保护下，室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤，无水硫酸钠干燥后过滤。浓缩得黄色油状物486mg(粗品，化合物51e)，此粗产品直接应用于下一步反应。
将上述反应的化合物51e(486mg,粗品)溶于二氯甲烷(10mL)。依次加入中间体A(350mg),二异丙基乙基胺(255mg)和DMAP(81mg)。加完后在氩气保护下室温搅拌三小时。LCMS检测反应完全后，加入饱和食盐水(10mL)洗涤。有机相分离，经无水硫酸钠干燥，过滤。滤液减压浓缩，所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化，得白色固体450mg(化合物51f)。
将Pd/C(158mg，10％wet)加入到化合物51f(450mg)和1,2-二氯苯(265mg)的乙酸乙酯/甲醇(5mL/5mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤。滤液浓缩，所得粗产品用反相柱(乙腈/水＝20％-95％)纯化，得白色固体290mg(化合物51g)。
氮气保护下，将二异丙基乙基胺(135.5mg)和HATU(266mg)加入到化合物51g(230mg)的二氯甲烷溶液(5mL)中。0℃下搅拌50min后，加入甲胺四氢呋喃溶液(0.35mL)。反应液在0℃下继续搅拌3小时。加入5mL氯化铵水溶液淬灭反应，用二氯甲烷萃取。有机相合并，经无水硫酸钠干燥，过滤浓缩。粗产品经硅胶柱层析纯化(二氯甲烷/甲醇＝100/1)，得黄色油状物324mg(粗品，化合物51i)，此粗产品直接应用于下一步反应。
将化合物51i(324mg，粗品)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经反相制备HPLC纯化，得白色固体32.0mg(化合物I-051的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.47(brs,1H),8.25(d,J＝4.8Hz,0.5H),8.21(d,J＝4.8Hz,0.5H),7.98(brs,2H),7.88–7.85(m,1H),7.40–7.38(m,2H),7.34–7.31(m,2H),6.85–6.83(m,2H),4.21(d,J＝2.8Hz,0.5H),4.19(d,J＝2.8Hz,0.5H),4.06–3.98(m,2H),3.52–3.49(m,1H),3.14-3.11(m,2H),2.95–2.82(m,2H),2.82-2.77(m,0.5H),2.70–2.66(m,0.5H),2.62(d,J＝4.8Hz,1.5H),2.59(d,J＝4.8Hz,1.5H)1.93–1.86(m,1H),1.82–1.67(m,2H),1.63–1.56(m,0.5H),1.53–1.43(m,0.5H)。
LCMS:Rt＝3.324min，[M+H] +＝456.0。
实施例52 化合物I-052的制备
Figure PCTCN2019080549-appb-000121
按照以下反应式和方法制备化合物I-052。
Figure PCTCN2019080549-appb-000122
将化合物52a(1.5g)，化合物52b(1.57g)，Xantphos(681mg)和碳酸铯(7.7g)混合于20mL二氧六环中，氮气保护下加入Pd(OAc) 2(264mg)。油浴90℃下搅拌4小时。反应液减压浓缩。经硅胶柱层析纯化(石油醚/乙酸乙酯＝1:1)得黄色固体420mg(化合物52c)。
化合物52c(660mg)溶于20mL HCl二氧六环溶液。室温下搅拌过夜，减压浓缩。所得固体溶于10mL饱和碳酸氢钠水溶液中，乙酸乙酯萃取(20mL x 5)。有机相经无水硫酸钠干燥后过滤，减压浓缩得到黄色油状物440mg(化合物52d)。
冰水浴下，将37wt％的甲醛水溶液(314mg)加入到化合物52d(440mg)的甲醇(10mL)溶液中，搅拌30分钟后加入氰基硼氢化钠(198mg),继续搅拌过夜。反应液经C18反相柱纯化(5-95％乙腈/水)，得白色固体343mg(化合物52e)。
将化合物52e(343mg)，化合物26b(520mg)和碳酸钾(423mg)溶于二氧六环和水的混合溶剂中(22mL,10/1),氮气保护下加入Pd(amphos) 2Cl 2(217mg)。油浴100℃下搅拌3小时。反应液减压浓缩。经硅胶柱层析纯化(二氯甲烷/甲醇＝30:1)得黄色油状物600mg(粗品)，此产品直接用于下一步反应。
将Pd/C(200mg,10％wet)加入到化合物52f(600mg,粗品)的甲醇(20mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下25℃搅拌3小时，LCMS显示～80％转换率，反应液在室温(15℃)下继续搅拌过夜，抽滤，浓缩得到褐色油状物603mg(粗品)，此产品直接用于下一步反应。
化合物52g(603mg,粗品)溶于20mL HCl二氧六环溶液。室温下搅拌3小时后，减压浓缩，得到白色固体粗品620mg(粗品)，此产品直接用于下一步反应。
化合物52h用甲苯共沸带干，除尽水分后备用。将二异丙基乙基胺(1.9g)加入到化合物52h(620mg，粗品)的二氯甲烷(10mL)溶液中，降温到0℃后，一次性加入三光气(223mg)。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤一次，无水硫酸钠干燥后直接应用于下一步反应。
在上述后处理得到的反应液中再加入二异丙基乙基胺(194mg),DMAP(92mg)以及中间体A(400mg)。加完后在氮气保护下室温搅拌过夜。LCMS检测反应完全后将20毫升水加入到反应体系中，有机相分离，水相用二氯甲烷(30mL)萃取。有机相合并后，用无水硫酸钠干燥，过滤，减压浓缩。所得粗产品用C-18反相柱层析(10-95％乙腈/水)纯化，得白色固体450mg(化合物52j)。
将Pd/C(80mg,10％wet)加入到化合物52j(230mg)的乙酸乙酯/甲醇(3mL/3mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌1小时。反应完全后抽滤，浓缩得到白色固体205mg(化合物52k)。
将化合物52k(205mg)加入到TFA/DCM(6mL/2mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩。反应液浓缩后溶于1mL DMF中，经反相制备HPLC纯化的白色固体54.8mg(化合物I-052)。
1H NMR(400MHz,DMSO-d 6)δ7.79-7.76(m,1H),7.34(t,J＝7.6Hz,1H),7.25-7.24(m,1H),7.18(t,J＝8.0Hz,2H),6.42(t,J＝5.2Hz,1H),6.34(d,J＝3.6Hz,1H),5.97(brs,2H),4.18(d,J＝2.8Hz,0.5H),4.12(d,J＝2.8Hz,0.5H),4.04-3.95(m,2H),3.65-3.62(m,2H),3.56-3.52(m,1H),3.11(d,J＝4.8Hz,2H),3.05-2.95(m,2H),2.89-2.87(m,2H),2.74-2.68(m,3H),2.29(d,J＝2.8Hz,3H),1.92-1.85(m,1H),1.80-1.68(m,2H),1.62-1.43(m,1H)。
LCMS:Rt＝3.064，[M+H] +＝521.1。
实施例53 化合物I-053的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000123
按照以下反应式和方法制备化合物I-053的三氟乙酸盐。
Figure PCTCN2019080549-appb-000124
将化合物53a(1.0g)，化合物26b(1.5g)和碳酸钾(1.23g)溶于二氧六环和水的混合溶剂(10mL/1mL)中。氮气保护下加入Pd(dppf)Cl 2(547mg)，油浴80℃下搅拌3小时。反应液减压浓缩，所得粗产品经硅胶柱层析(石油醚/乙酸乙酯＝10:1)纯化，得黄色油状物1.18g(化合物53b)。
将Pd/C(240mg,10％wet)加入到化合物53b(1.18g)的甲醇(10mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下室温搅拌3小时。反应完全后抽滤。滤液浓缩，得黄色油状物1.16mg(化合物53c)。
化合物53c(1.16g)溶于10mL HCl二氧六环溶液。室温下搅拌过夜，反应液减压浓缩。所得固体溶于饱和碳酸氢钠水溶液(10mL)，用乙酸乙酯(50mL)萃取。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩，得棕色固体496mg(化合物53d)。
将二异丙基乙基胺(491mg)加入到化合物53d(291mg)的二氯甲烷(5mL)溶液中，降温到0℃后一次性加入三光气(190mg)。氮气保护下室温搅拌过夜。反应液用饱和碳酸氢钠水溶液(10mL)洗涤，无水 硫酸钠干燥后过滤，浓缩得黄色油状物450mg(化合物53e，粗产品)，此粗产品直接应用于下一步反应。
将上述反应的化合物53e(450mg，粗品)溶于二氯甲烷(5mL)。依次加入中间体A(200mg)，二异丙基乙基胺(147mg)和DMAP(46mg)。加完后在氩气保护下室温搅拌3小时。LCMS检测反应完全后，加入饱和食盐水(10mL)洗涤。有机相合分离，经无水硫酸钠干燥，过滤。滤液减压浓缩，所得粗产品用硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化，得白色固体297mg(化合物53f，粗产品)，此粗产品直接应用于下一步反应。
将Pd/C(104mg,10％wet)加入到化合物53f(297mg,粗产品)的乙酸乙酯/甲醇(3mL/3mL)溶液中，加入完毕后抽换气三次并充入氢气，混合体系在氢气氛围下搅拌1小时。反应完全后抽滤。滤液浓缩，得白色固体259mg(化合物53g)。
氮气保护下，将二异丙基乙基胺(143mg)和HATU(281mg)加入到化合物53g(259mg)的二氯甲烷溶液(5mL)中。0℃下搅拌50min后，加入甲胺四氢呋喃溶液(0.37mL)。反应液在0℃下继续搅拌3小时。加入5mL氯化铵水溶液淬灭反应，用二氯甲烷萃取。有机相合并，经无水硫酸钠干燥，过滤浓缩。粗产品经硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)，得黄色油状物216mg(化合物53h)。
将化合物53h(216mg)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经反相制备HPLC纯化，得白色固体108.8mg(化合物I-053的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.34(brs,1H),8.26(m,0.5H),8.21(m,0.5H),7.97(brs,2H),7.88–7.85(m,1H),7.71–7.69(m,2H),7.55–7.52(m,2H),6.86–6.83(m,2H),4.21(d,J＝3.2Hz,0.5H),4.19(d,J＝3.2Hz,0.5H),4.07–4.01(m,2H),3.54–3.49(m,1H),3.14–3.11(m,2H),3.08–2.85(m,2.5H),2.81–2.71(m,0.5H),2.62(d,J＝4.4Hz,1.5H),2.59(d,J＝4.4Hz,1.5H),1.96–1.93(m,1H),1.91–1.75(m,2H),1.66–1.58(m,0.5H),1.54–1.44(m,0.5H)。
LCMS:Rt＝3.460min，[M+H] +＝490.0。
实施例54～55 化合物I-054和I-055的三氟乙酸盐的制备
Figure PCTCN2019080549-appb-000125
按照以下反应式和方法制备得到化合物I-054和I-054的三氟乙酸盐。
Figure PCTCN2019080549-appb-000126
将化合物30a(277mg，～90％纯度)以手性SFC拆分，得Peak 1:80mg(30a-1)，Peak 2:60mg(30a-2)。
将化合物30a-1(80mg)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经反相制备HPLC纯化，得白色固体50.1mg(化合物I-054的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.39(brs,1H),8.21–8.20(m,1H),7.98(brs,2H),7.87(d,J＝6.8Hz,1H),7.35–7.32(m,2H),7.15(m,2H),6.86–6.84(m,2H),4.21(d,J＝3.2Hz,1H),4.07–3.98(m,2H),3.54–3.49(m,1H),3.13(d,J＝8.0Hz,2H),2.93–2.81(m,3H),2.59(d,J＝4.8Hz,3H),1.93–1.88(m,1H),1.83–1.67(m,2H),1.52–1.43(m,1H)。
LCMS:Rt＝3.113min，[M+H] +＝440.1。
将化合物30a-2(60mg)加入到TFA/DCM(3mL/1.5mL)溶液中，30℃下搅拌3小时。LCMS检测反应完全后，室温浓缩反应液。粗产品经反相制备HPLC纯化，得白色固体21.3mg(化合物I-055的三氟乙酸盐)。
1H NMR(400MHz,DMSO-d 6)δ13.40(brs,1H),8.27–8.25(m,1H),7.96(brs,2H),7.86(d,J＝6.4Hz,1H),7.34–7.31(m,2H),7.18–7.14(m,2H),6.84–6.83(m,2H),4.19(d,J＝3.2Hz,1H),4.05–3.98(m,2H),3.53–3.48(m,1H),3.12(d,J＝8.0Hz,2H),3.00–2.85(m,2H),2.71–2.65(m,1H),2.62(d,J＝4.8Hz,3H),1.91–1.88(m,1H),1.78–1.67(m,2H),1.64–1.55(m,1H)。
LCMS:Rt＝3.062min，[M+H] +＝440.1。
药理学评价
一、活化部分凝血活酶时间(APTT)测定
方法：1.制备人血浆：收集人静脉全血置于3.2％的枸橼酸钠抗凝管中(人血:枸橼酸钠＝9:1(V/V))。～1560g离心8min，制备人血浆。
2.制备受试样品：用DMSO溶解受试化合物，梯度稀释得到3000、600、120、24、4.8μM的储备液，各浓度分别按1:49(V/V)与所制备的人血浆混合。
3.阴性对照：将没有受试化合物的DMSO溶剂，梯度稀释得到3000、600、120、24、4.8μM的储备液，各浓度分别按1:49(V/V)与所制备的人血浆混合。
4.测试：将上述受试样品和阴性对照的测试液分别混合3～5分钟后，取30μL测试液上机(MC-2000血凝仪)，37℃预温2min，再加入30μL APTT试剂(MDC Hemostasis，Cat：300025)37℃孵育5min，然后加30μL CaCl 2开始APTT测定。
计算：根据测得的APTT结果，按以下公式计算APTT比。
APTT比＝(APTT 受试化合物/APTT 阴性对照)
用指数方程拟合Lg(浓度)与APTT比(Origin Pro 8.5.1SR2)，计算1.5倍APTT比和2倍APTT比时的药物工作浓度，即EC 150和EC 200。结果见表1。
表1
实施例 EC 150(μM) EC 200(μM)
16 1.41 6.99
23 1.48 4.40
41 2.18 8.22
按照上述相同的方法测试本发明的其它示例化合物的APTT，结果发现，本发明的其它示例化合物或其盐的EC 150基本上均在1.41～30.00μM的范围内，EC 200均在4.4～60.00μM的范围内，表现出非常好的凝血活性。
二、体外酶活性检测试验
方法：用DMSO溶解受试化合物至10mM母液，-80℃保存待用，用时取母液冻存，再用DMSO稀释至2mΜ作为起始反应浓度，用DMSO 4倍梯度稀释成9个浓度作为工作液，1μl/孔；2×缓冲液配制：200mM tris-HCl，400mM NaCl，0.04％TWEEN20，pH7.4；2×人FXIa蛋白(hFXIa)，反应液为2×缓冲液稀释FXIa蛋白(Cat# ab62411)至反应所需浓度0.25ng/μl，10μl/孔；2×S-2366反应液，用去离子水将S-2366反应液配成2mM，10μl/孔；先把酶反应液加入384孔板中，再将稀释好的受试化合物反应液依次加入对应孔；阴性对照为DMSO溶剂；空白用缓冲液替代；1000rpm室温下离心1min，避光反应30min后，最后每孔加入S-2366反应液，震荡混匀30s，37℃反应20min，OD 405nm测其吸光值，prism曲线分析，计算IC 50值。
结果见表2。
表2
实施例 IC 50(nM)
13 23.21
16 1.89
18 10.71
19 5.99
20 10.81
23 1.5
24 3.6
25 3.2
26 11.1
28 23.14
30 2.4
31 2.8
32 4.1
33 3.5
41 4.1
42 9.1
44 3.8
45 5.3
46 7.7
51 3.3
55 1.7
按照上述相同的方法测试本发明的其它示例化合物的酶活性，结果发现，本发明的其它示例化合物或其盐的IC 50基本上均在1.5～50.00nM的范围内，表现出优异的酶活性。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 式(I)所示的化合物，其异构体、溶剂化物、前药或其混合物，以及它们药学上可接受的盐：
    Figure PCTCN2019080549-appb-100001
    其中，R 1选自氢、卤素、C 1-10烷基、C 3-10环烷基、杂环基、芳基、杂芳基、-(CH 2) tNR 6R 7、-COR 5a、-COOR 5b、-C(O) m(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-NHC(O) m(CH 2) nC(O) mC 1-6烷基、-S(O) m(CH 2) tNR 6R 7、-NH(CH 2) tS(O) mR 5a、-NH(CH 2) tS(O) m-OR 5b、-OR 5b、-SR 5b、-(CH 2) tCN、-O(CH 2) nNR 6R 7；
    R 2选自氢、卤素、羟基、C 1-10烷基、C 1-10烷氧基、-(CH 2) tX(CH 2) nNR 6R 7、-(CH 2) tCN、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-(CH 2) tNR 6R 7、-C(O) m(CH 2) tNR 6R 7、-C(O) m(CH 2) t-芳基、-C(O) m(CH 2) t-杂芳基、-CONH(CH 2) t-杂环基、-CONHS(O) mR 5a、-CONHS(O) m-OR 5b；
    X选自O、S；
    A为芳基、杂芳基、C 3-10环烷基或杂环基；
    B为含氮杂环基，其中氮原子与CX相连，其进一步可任选地被1～3个R 3所取代；所述R 3相同或不同，分别独立地选自氢、氧代、卤素、羟基、-(CH 2) tCN、-(CH 2) tNR 6R 7、-(CH 2) tCONR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷基氧基、杂环基、苯并杂环基、芳基或杂芳基；并且当B被R 3取代时，至少一个R 3为C 3-10环烷基、芳基、苯并杂环基或杂芳基；所述R 3进一步可任选地被1～3个R 4a所取代；
    或者，B为含氮稠合二环基，其中氮原子与CX相连，其进一步可任选地被1～3个R 4b所取代；
    所述R 4a、R 4b相同或不同，分别独立地选自氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷基氧基、杂环基、杂环基氧基、芳基、氨基、硝基、-(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-(CH 2) tCONR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-SR 5b、-OR 5b；进一步地，所述R 4a、R 4b任选地被如下的一个或多个基团取代：氢、＝O、卤素、C 1-10烷基、C 1-10烷氧基或芳基；
    上述基团中，R 5a相同或不同，各自独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷基、C 3-10环烷基、杂环基、芳基、杂芳基；
    上述基团中，R 5b、R 6、R 7相同或不同，各自独立地选自氢、C 1-10烷基、卤代C 1-10烷基、C 3-10环烷基、杂环基、芳基、杂芳基；
    上述基团中，n相同或不同，各自独立地选自1～10的整数；
    上述基团中，m相同或不同，各自独立地选自1或2的整数；
    上述基团中，t相同或不同，各自独立地选自0～10的整数。
  2. 根据权利要求1所述的化合物，其特征在于，B为3-10元含氮杂环基，其可任选地被1～3个R 3所取代；
    优选地，B为可任选地被1-3个R 3所取代的如下基团：
    Figure PCTCN2019080549-appb-100002
    或者，B为5-12元含氮稠合二环基(例如5、6、7、8、9、10、11或12元的含氮稠合二环基)，其进一步可任选地被1～3个R 4b所取代，所述含氮稠合二环基例如为苯并吡咯烷基、苯并哌啶基、苯并哌嗪基、三唑并哌嗪基；
    优选地，B为可任选地被1-3个R 4b所取代的如下基团：
    Figure PCTCN2019080549-appb-100003
    优选地，B为
    Figure PCTCN2019080549-appb-100004
    其中，Y为C、S、O或N，
    Figure PCTCN2019080549-appb-100005
    代表3-10元杂环基，R 8为C 3-10 环烷基、芳基、杂芳基、或苯并杂环基，所述R 8可任选地被1-3个R 10所取代，所述R 10为氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、芳基、氨基、硝基、-(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-(CH 2) tCONR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-SR 5b、-OR 5b；进一步地，所述取代基R 10可任选地被如下一个或多个基团取代：氢、＝O、卤素、C 1-10烷基、C 1-10烷氧基或芳基；R 9相同或不同，各自独立地选自氢、氧代、卤素、羟基、-(CH 2) tCN、-(CH 2) tNR 6R 7、-(CH 2) tCONR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、芳基、杂芳基；上述R 9可任选地被1-3个如下基团R 11所取代：氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、芳基、氨基、硝基、-(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-(CH 2) tCONR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-SR 5b、-OR 5b；w为1或2；
    还优选地，R 8选自C 3-10环烷基、芳基、杂芳基、苯并杂环基；所述R 8可任选地被如下基团取代：氢、氧代、卤素、-(CH 2) tCN、C 1-10烷基、C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、杂环基、杂环基氧基、氧代杂环基、C 1-10烷基氧代杂环基、芳基、芳基氧基、氨基、硝基、-(CH 2) tNR 6R 7、-NHCOOC 1-10烷基、-NHCOC 1-10烷基、CONR 6R 7、-COR 5a、-COOR 5b、-SR 5b、-OH。
  3. 根据权利要求1或2所述的化合物，其特征在于，R 1选自氢、卤素、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷基氧基、芳基、-(CH 2) tNR 6R 7、-COR 5a、-COOR 5b、-C(O)(CH 2) tNR 6R 7、-(CH 2) tNHC(O) mC 1-10烷基、-NHC(O) m(CH 2) nC(O) mC 1-6烷基、-S(O) m(CH 2) tNR 6R 7、-NH(CH 2) tS(O) mR 5a、-SR 5b、-(CH 2) tCN、-O(CH 2) nNR 6R 7；
    优选地，A为芳基或杂芳基；
    优选地，R 2选自-(CH 2) tX(CH 2) nNR 6R 7、-(CH 2) tCN、-(CH 2) tNR 6R 7、-(CH 2) tCOR 5a、-(CH 2) tCOOR 5b、-C(O) m(CH 2) tNR 6R 7、-C(O) m(CH 2) t芳基、-C(O) m(CH 2) t杂芳基、-CONH(CH 2) t杂环基、-CONHS(O) mR 5a；
    优选地，X为O；
    优选地，n相同或不同，各自独立地选自1、2、3、4、5、6、7、8、9或10的整数；
    优选地，m相同或不同，各自独立地选自1或2；
    优选地，t相同或不同，各自独立地选自0、1、2、3、4、5、6、7、8、9或10的整数；
    优选地，R 5a相同或不同，各自独立地选自氢、卤素、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、杂环基、芳基、杂芳基；
    优选地，R 5b、R 6、R 7相同或不同，各自独立地选自氢、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、杂环基、芳基、杂芳基。
  4. 根据权利要求1-3任一项所述的化合物，其特征在于，具有如下结构：
    Figure PCTCN2019080549-appb-100006
    其中，R 1、R 2、A、B、X、n具有权利要求1-3任一项所述定义。
  5. 根据权利要求1-4任一项所述的化合物，其特征在于，选自包括但不限于以下的化合物，其异构体、溶剂化物、前药或其混合物，以及它们药学上可接受的盐：
    Figure PCTCN2019080549-appb-100007
    Figure PCTCN2019080549-appb-100008
    Figure PCTCN2019080549-appb-100009
    Figure PCTCN2019080549-appb-100010
    Figure PCTCN2019080549-appb-100011
  6. 权利要求1-5任一项所述式(I)化合物的制备方法，包括如下：
    Figure PCTCN2019080549-appb-100012
    1)化合物(e)与三光气或二氯化硫在碱性条件下反应得到化合物(f)；
    2)化合物(f)与化合物(A 0)在碱性条件下反应得到式(I)化合物；
    其中，R 1、R 2、A、B、X、n具有权利要求1-5任一项所述定义。
  7. 一种药物组合物，其特征在于，包含权利要求1-5任一项所述的式(I)化合物，其异构体、溶剂化物、前药或其混合物，以及药学上可接受的盐中的至少一种，和任选的药学上可接受的载体和/或赋形剂。
  8. 权利要求1-5任一项所述化合物或权利要求7所述的药物组合物在制备治疗和/或预防血栓形成或血栓栓塞相关病症的药物中的用途；或者在制备凝血酶抑制剂药物中的用途；
    优选地，所述血栓形成或血栓栓塞相关病症包括但不限于，例如动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、心脏腔室或外周循环中的血栓栓塞性病症，不稳定型心绞痛、急性冠状动脉综合征、心房纤维性颤动、心肌梗塞、短暂性缺血发作、中风、动脉粥样硬化、外周闭塞性动脉病、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，以及由于其中血液暴露于促进血栓形成的人造表面的医疗植入物、装置或过程而引起的血栓形成。
  9. 一种药物制剂，其包括权利要求7所述的药物组合物，其中，所述药物制剂包括但不限于片剂、丸剂、颗粒剂、胶囊剂、注射剂、混悬剂、滴剂、浸膏剂、软膏剂、贴剂、乳剂、膜剂、栓剂、糊剂、凝胶剂、或喷雾剂。
  10. 一种联合制剂，其包括将权利要求7所述的药物组合物与其它抗凝血药物、抗血栓药物或抗静脉栓塞药物中的至少一种合用；所述抗凝血药物、抗血栓药物或抗静脉栓塞药物包括但不限于：肝素、低分子量肝素LMWH、依诺肝素、华法林、利伐沙班、阿哌沙班、依度沙班、贝曲沙班、奥米沙班、阿司匹林、噻氯匹啶、氯吡格雷、替罗非班、香豆素、尿激酶、血小板蛋白IIb/IIIa受体拮抗剂。
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WO2023185791A1 (zh) * 2022-03-28 2023-10-05 四川海思科制药有限公司 一种2-氨基吡啶衍生物制备方法

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