WO2022122035A1 - 凝血因子XIa抑制剂及其制备方法和应用 - Google Patents

凝血因子XIa抑制剂及其制备方法和应用 Download PDF

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WO2022122035A1
WO2022122035A1 PCT/CN2021/137243 CN2021137243W WO2022122035A1 WO 2022122035 A1 WO2022122035 A1 WO 2022122035A1 CN 2021137243 W CN2021137243 W CN 2021137243W WO 2022122035 A1 WO2022122035 A1 WO 2022122035A1
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membered
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French (fr)
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冯焱
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上海领泰生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a coagulation factor XIa inhibitor, a pharmaceutical composition, a preparation method and the application thereof in preventing or treating thromboembolic diseases.
  • Thrombosis refers to a pathological heterogeneous clot or sediment formed by blood components in the flowing blood in the blood vessel or the intima of the heart, mainly composed of platelets, fibrin or red and white blood cells.
  • Blood clots can occur in blood vessels anywhere in the body, and venous blood clots are four times more common than arterial blood clots.
  • the main cause of venous thrombosis is the slowing of blood flow, which mostly occurs in the lower limbs and pelvic veins, and the upper limbs and liver are also prone to occur, while the occurrence of arterial thrombosis is often related to atherosclerotic lesions, and coronary thrombosis is common. and cerebral thrombosis.
  • thromboembolic diseases have become the first cause of death in the world. bit.
  • anticoagulant drugs such as heparin, warfarin, rivaroxaban, apixaban
  • antiplatelet drugs such as aspirin, ADP clopidogrel
  • thrombolytic drugs Currently widely used clinically used drugs for the treatment of thromboembolic diseases include anticoagulant drugs (such as heparin, warfarin, rivaroxaban, apixaban), antiplatelet drugs (such as aspirin, ADP clopidogrel) and thrombolytic drugs, and these drugs have a good effect on the treatment, prevention or reduction of thrombosis.
  • anticoagulant drugs such as heparin, warfarin, rivaroxaban, apixaban
  • antiplatelet drugs such as aspirin, ADP clopidogrel
  • thrombolytic drugs a good effect on the treatment, prevention or reduction of thrombosis.
  • these clinically used anticoagulants carry a risk of bleeding, especially in predisposed patients. Therefore, it is necessary to
  • FXIa factor XIa knockout models
  • Human blood coagulation consists of intrinsic pathway, extrinsic pathway and common pathway. While FXIa is necessary to maintain the endogenous pathway during blood coagulation, it is a plasma serine protease involved in coagulation regulation and plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin feedback activates FXI, and the activated FXI (FXIa) in turn promotes the massive production of thrombin, thereby further expanding the coagulation process (Gailani, D.
  • FXIa inhibitors in early development include the oral FXIa inhibitor BMS-986177 (a collaboration between Bristol-Myers Squibb and Janssen), which is currently being evaluated in multiple Phase I studies.
  • parenteral drugs such as BMS-962212 (Bristol-Myers Squibb), MAA-868 (Novartis), BAY1213790 (Bayer) and IONIS-FXIRx (Ionis and Bayer) are also currently in Phase II development.
  • the present invention discloses a new class of compounds that can effectively inhibit the activity of FXIa, which not only exhibits good bioinhibitory activity, but also has a good safe therapeutic window width, and can be used for the treatment of various thromboembolic diseases or conditions.
  • the present invention provides compounds of formula I, or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable compounds thereof of salt,
  • R 1 is selected from hydrogen, hydroxyl, halogen, cyano, -OR e , C1-C6 alkyl, C3-8 cycloalkyl, 3-8 membered heteroatoms containing 1-2 heteroatoms selected from N, O or S Cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -NHS(O) 2 R e , NHS(O) 2 OR e , NHS(O) 2 NHR e , -NHS(O)OR e , -NHS(O)R e , -NHS(O)NHR e , -NHC(O)R e , -NHC(O)OR e , - NHC(O)NHR e , -NR e R f , -COR e , -COOR e , or -CONHR e ;
  • Each R 2 is independently selected from hydrogen, hydroxyl, halogen, cyano, -OR e , C1-C6 alkyl, C3-8 cycloalkyl, 3- containing 1-2 heteroatoms selected from N, O or S 8-membered heterocycloalkyl, 6-10-membered aryl, 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -NHS(O) 2 R e , NHS(O) 2 OR e , NHS(O) 2 NHR e , -NHS(O)OR e , -NHS(O)R e , -NHS(O)NHR e , -NHC(O)R e , -NHC(O)OR e , -NHC(O)NHR e , -NR e R f , -COR e , -COOR e , or -CONHR e ;
  • the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are optionally selected from one or more groups selected from halogen, cyano, C1-C6 alkyl, halogenated C1 -C6 alkyl, -COOR e , -OR e , C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, -NHS(O) 2 Re , NHS(O) 2 OR e , NHS(O) 2 NHR e , -NHS(O)OR e , -NHS(O)R e , -NHS(O)NHR e , -NHC(O)R e , -NHC(O)OR e , -NHC(O)NHR e , -NR e R f , or
  • n 1, 2, 3 or 4;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 5 is each independently hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -O-(C3-C8 cycloalkane base), -O-(3-8 membered heterocycloalkyl), C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl;
  • R a , R b , R c and R d are each independently hydrogen or C1-C4 alkyl
  • R a and R b together with the carbon atom to which they are attached form a C3-C8 cycloalkyl
  • p 1, 2, 3 or 4;
  • q 0, 1, 2, 3 or 4;
  • Ring B is C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 6-10 membered aryl, or 1-4 members selected from N, 5-10-membered heteroaryl with O or S heteroatom; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from one or more groups selected from halogen, hydroxyl, cyano, C1- Substituent substitution of C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
  • X 1 is NR 6 or O
  • R 6 is hydrogen or C1-C4 alkyl
  • R 4 is C1-C6 alkyl, -(CH 2 ) r (OCH 2 CH 2 ) s O(C1-C6 alkyl), -(CH 2 ) r (OCH 2 CH 2 ) s N(C1-C6 alkane base) 0-2 , or -(CH2) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), a 3-8 membered heterocycle containing 1-2 heteroatoms selected from N, O or S alkyl; wherein said r is 0, 1, 2, 3, 4, 5, or 6; said s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; said Alkyl or heterocycloalkyl is optionally substituted by 1 or more selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, COOH, COO(C1-C4 alkyl), CONH 2. Substituent substitution of CON(C1-C4 alkyl)
  • R 4 and R 6 together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl;
  • the heterocycloalkyl is optionally surrounded by 1 or more selected from halogen, cyano, hydroxyl, C1-C6 alkyl , C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy substituent;
  • D is -CONRg- , -NRgCO- , 6-10-membered aryl, or 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein Rg is hydrogen Or C1-C4 alkyl; the aryl and heteroaryl are optionally selected from one or more halogen, hydroxyl, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, -(CH2) 0-4 COOH, -(CH2) 0-4 COO(C1-C4 alkyl), - (CH2) 0-4 CONH 2 , -(CH2) 0-4 CON(C1-C4 alkyl) 1-2 , -(CH2) 0-4 S(O) 2 (C1-C4 alkyl), -
  • Q 1 is C1-C6 alkyl, -(CH 2 ) t (C3-C8 cycloalkyl), -(CH 2 ) t (3-8 membered with 1-2 heteroatoms selected from N, O or S Heterocycloalkyl), -(CH 2 ) t (6-10 membered aryl), -(CH 2 ) t (5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S ); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted by R 7 ; the R 7 is selected from halogen, oxo, cyano, C1-6 Alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, containing 1-4 members selected from N, O or 5-10 membered heteroaryl
  • R 1 and R 2 are each independently hydrogen, hydroxyl, halogen, cyano, -OR e , C1-C6 alkyl, C3-8 cycloalkyl, containing 1-2 selected from N , 3-8-membered heterocycloalkyl of O or S heteroatoms, 6-10-membered aryl, 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, -NHS(O ) 2 Re , NHS(O) 2 OR e , NHS(O) 2 NHR e , -NHS(O)OR e , -NHS(O)R e , -NHS(O)NHR e , -NHC(O) R e , -NHC(O)OR e , -NHC(O)NHR e , -NR e R f , -COR e , -COOR e , or -CONHR
  • n 1, 2, 3 or 4;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 5 is each independently hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -O-(C3-C8 cycloalkane base), -O-(3-8 membered heterocycloalkyl), C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl;
  • R a , R b , R c and R d are each independently hydrogen or C1-C4 alkyl
  • R a and R b together with the carbon atom to which they are attached form a C3-C8 cycloalkyl
  • p 1, 2, 3 or 4;
  • q 0, 1, 2, 3 or 4;
  • Ring B is C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, 6-10 membered aryl, or 1-4 members selected from N, 5-10-membered heteroaryl with O or S heteroatom; the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from one or more groups selected from halogen, hydroxyl, cyano, C1- Substituent substitution of C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy;
  • X 1 is NR 6 or O
  • R 6 is hydrogen or C1-C4 alkyl
  • R 4 is C1-C6 alkyl, -(CH 2 ) r (OCH 2 CH 2 ) s O(C1-C6 alkyl), -(CH2) r (OCH 2 CH 2 ) s N(C1-C6 alkyl ) 0-2 , or -(CH2) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), 3-8 membered heterocycloalkane containing 1-2 heteroatoms selected from N, O or S wherein the r is 0, 1, 2, 3, 4, 5 or 6; the s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; the alkane
  • the radical or heterocycloalkyl is optionally substituted by 1 or more selected from hydroxyl, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogen, COOH, COO(C1-C4 alkyl), CONH 2 , the substituent of CON(C1-C4 alkyl)
  • R 4 and R 6 together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl; the heterocycloalkyl is optionally surrounded by 1 or more selected from halogen, cyano, hydroxyl, C1-C6 alkyl , C1-C6 haloalkyl, C1-C6 hydroxyalkyl or C1-C6 alkoxy substituent.
  • D is -CONRg- , -NRgCO- , 6-10-membered aryl, or 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; wherein Rg is hydrogen Or C1-C4 alkyl; the aryl and heteroaryl are optionally selected from one or more halogen, hydroxyl, oxo, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1- C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, -(CH2) 0-4 COOH, -(CH2) 0-4 COO(C1-C4 alkyl), - (CH2) 0-4 CONH 2 , -(CH2) 0-4 CON(C1-C4 alkyl) 1-2 , -(CH2) 0-4 S(O) 2 (C1-C4 alkyl), -
  • Q 1 is C1-C6 alkyl, -(CH 2 ) t (C3-C8 cycloalkyl), -(CH 2 ) t (3-8 membered with 1-2 heteroatoms selected from N, O or S Heterocycloalkyl), -(CH 2 ) t (6-10 membered aryl), -(CH 2 ) t (5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S ); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted by R 7 ; the R 7 is selected from halogen, oxo, cyano, C1-6 Alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, containing 1-4 members selected from N, O or 5-10 membered heteroaryl
  • Ra, Rb, Rc, Rd are each independently hydrogen or methyl.
  • X 1 is NR 6 ; R 6 is hydrogen or methyl.
  • X 1 is NR 6 ; R 6 is hydrogen.
  • R 4 is a C1-C6 alkyl group; the alkyl group is optionally substituted with one or more halogens.
  • R 4 is a C1-C6 alkyl group, the C1-C6 alkyl group is a perhalogenated C1-C6 alkyl group, and all Hs of the C1-C6 alkyl group are substituted by halogen.
  • R 4 is all-F-C1-C6 alkyl, including but not limited to the following: all-F-C1 alkyl, all-F-C2 alkyl, all-F-C3 alkyl, all-F-C4 Alkyl, all-F-C5 alkyl, all-F-C6 alkyl.
  • R 1 is a 5-10-membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S.
  • R 2 is selected from the group consisting of F, Cl, Br, and I.
  • n is 2.
  • R 3 is hydrogen
  • D is -CONH-.
  • Q 1 is a carboxy-substituted phenyl group.
  • ring B is a phenyl group.
  • X 1 is NH
  • R 4 is a C1-C6 alkyl group; the alkyl group is optionally substituted with one or more F.
  • R 4 is -(CH 2 ) r O(C1-C6 alkyl) or -(CH 2 ) r N(C1-C6 alkyl) 0-2 , the r is 0, 1 , 2, 3, or 4.
  • R 4 is -O(C1-C6 alkyl).
  • R 4 is -N(CH 3 ) 2 or -(CH 2 ) 2 N(CH 3 ) 2 .
  • R 4 is morpholinyl
  • R 4 is a 3-8 membered heterocycloalkyl containing 1 N heteroatom; the heterocycloalkyl is optionally selected from hydroxyl, oxo, halogen, C1-C6 alkyl or C1-C6 alkoxy substituents.
  • R 4 is pyrrolidinyl optionally substituted with hydroxy or oxo;
  • R 4 is -(CH 2 ) r (OCH 2 CH 2 ) s O(C1-C6 alkyl), -(CH2) r (OCH 2 CH 2 ) s N(C1-C6 alkane base) 0-2 or -(CH 2 ) r NH(CH 2 CH 2 O) s (C1-C6 alkyl), the r is 0 or 1; the s is 1, 2, 3, 4, 5 , 6, 7, 8, 9, or 10.
  • R 4 is -(OCH 2 CH 2 ) s O(C1-C6 alkyl), -(OCH 2 CH 2 ) s N(C1-C6 alkyl) 0-2 or -NH( CH 2 CH 2 O) s (C1-C6 alkyl); the s is 1, 2, 3, 4, 5, 6, 7, 8 or 9.
  • R 4 is -(OCH 2 CH 2 ) s O(C1-C6 alkyl), -(OCH 2 CH 2 ) s N(C1-C6 alkyl) 0-2 or -NH( CH 2 CH 2 O) s (C1-C6 alkyl); the s is 3, 4, 5, 6 or 7.
  • R 4 is -CH 2 (OCH 2 CH 2 ) s O(C1-C6 alkyl), -CH 2 (OCH 2 CH 2 ) s N(C1-C6 alkyl) 0-2 or -CH 2 NH(CH 2 CH 2 O) s (C1-C6 alkyl), where s is 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • R 4 is -CH 2 (OCH 2 CH 2 ) s O(C1-C6 alkyl), -CH2(OCH 2 CH 2 ) s N(C1-C6 alkyl) 0-2 or -CH 2 NH(CH 2 CH 2 O) s (C1-C6 alkyl), where s is 3, 4, 5, 6 or 7. .
  • R 4 is -(OCH 2 CH 2 ) 5 OCH 3 , -OCH 2 CH 2 OCH 3 , -(OCH 2 CH 2 ) 7 OCH 3 , -NHCH 2 CH 2 OCH 3 , -NH (CH 2 CH 2 O) 5 CH 3 , -NH(CH 2 CH 2 O) 7 CH 3 , -CH 2 OCH 2 CH 2 OCH 3 , -N(CH 3 ) 2 , methyl, methoxy, trifluoro Methyl, perfluoropropyl, perfluorobutyl, -OCH 2 CH 2 N(CH3) 2 , -(OCH 2 CH 2 ) 3 OCH 3 , -(OCH 2 CH 2 ) 2 OCH 3 ,
  • the compound of formula I is a compound of formula IA,
  • R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, Rd, ring B, D, X 1 , p, q, n and Q 1 are as defined above.
  • D is a 5-6-membered heteroaryl group containing 1 or 2 N heteroatoms; the heteroaryl group is optionally composed of 1 or more selected from halogen, hydroxyl, oxo, cyano base, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C4 alkenyl, -(CH 2 ) 0-4 COOH, -(CH 2 ) 0 -4 COO(C1-C4 alkyl), -(CH 2 ) 0-4 CONH 2 , -(CH 2 ) 0-4 CON(C1-C4 alkyl) 1-2 , -(CH 2 ) 0
  • D is imidazolyl, pyridyl, pyridazinyl or pyrimidinyl; the imidazolyl, pyridyl, pyridazinyl or pyrimidinyl is optionally selected by one or more selected from oxo, Cl , methyl, methoxy, ethoxy, -COOH, -CONH 2 , -CONCH 3 , -COOCH 3 , vinyl, cyano, SO 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, Substituents of -CH 2 COOH, -CH 2 COOCH 3 , -CH 2 SO 2 CH 3 , amino, -CH 2 NH 2 , -
  • D is -CONRg-; wherein said Rg is hydrogen or methyl.
  • D is -CONRg-; wherein said Rg is hydrogen.
  • the compound of formula I is a compound of formula IB,
  • R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, Rd, ring B, X 1 , p, q, n and Q 1 are as defined above.
  • ring B is C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1 or 2 N heteroatoms, 5-6 membered heterocycloalkyl containing 1-3 N heteroatoms Aryl or phenyl; the cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl are optionally 1 or more selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkane group, C1-C6 hydroxyalkyl, C1-C6 alkoxy substituent.
  • ring B is a 5-6-membered heteroaryl group containing 1-3 N heteroatoms; the heteroaryl group is optionally composed of 1 or more selected from halogen, hydroxyl, cyano, C1 -C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy substituent.
  • ring B is pyridine, pyrazole or imidazole; the pyridine, pyrazole or imidazole is optionally substituted by one or more selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1- C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy substituents are substituted.
  • ring B is phenyl; the benzene is optionally substituted by one or more selected from halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkane group, C1-C6 alkoxy substituent.
  • the compound of formula I is a compound of formula IC,
  • R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, Rd, X 1 , p, q, n and Q 1 are as defined above.
  • R 1 is hydrogen, cyano, halogen, C1-C6 alkyl optionally substituted by halogen or hydroxy, C3-C6 cycloalkyl or -C(O)Re; said Re is C1 -C6 alkyl, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N or O; the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from halogen, hydroxy or amino; or R 1 is -OR; the Re is C1-C6 alkyl; the alkyl is optionally substituted with halogen.
  • R 1 is hydrogen, cyano, F, Cl, Br, trifluoromethyl, difluoromethyl, cyclopropyl, formyl, acetyl, cyclopropyl acyl, difluoromethoxy group or trifluoromethoxy.
  • R 1 is a 5-6 heteroaryl group containing 1-4 heteroatoms selected from N or O; Substituents of C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 hydroxyalkyl.
  • R 1 is a 5-6 heteroaryl group containing 1-4 N heteroatoms, the heteroaryl group is optionally selected from one or more of F, Cl, methyl, trifluoromethane group, trifluoroethyl or methoxy group.
  • R 1 is pyrazolyl, imidazolyl, triazole or tetrazolium.
  • R 1 is tetrazolium.
  • the compound of formula I is a compound of formula ID,
  • R 2 , R 3 , R 4 , Ra, Rb, Rc, Rd, X 1 , p, q, n and Q 1 are as defined above.
  • R 2 is hydrogen, halogen, C1-C6 alkyl optionally substituted by halogen or hydroxy, or -ORe; said Re is C1-C6 alkyl, and said alkyl is optionally replaced by a or multiple halogen or hydroxy substitutions.
  • R 2 is hydrogen, trifluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, F or Cl.
  • n is 2.
  • the compound of formula I is a compound of formula IE,
  • R 3 , R 4 , Ra, Rb, Rc, Rd, X 1 , p, q and Q 1 are as defined above.
  • Q 1 is a 5-6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S or Q 1 is a 6-10-membered aryl group; Aryl is optionally substituted with one or more R7 .
  • Q 1 is pyridine, indolyl, benzofuranyl, benzimidazolyl, quinoline or phenyl; the pyridyl, indolyl, benzofuranyl, benzimidazolyl , quinoline or phenyl are optionally substituted with one or more R 7 .
  • the compound of formula I is a compound of formula IF,
  • R 3 , R 4 , Ra, Rb, Rc, Rd, X 1 , p, q and R 7 are as defined above; said u is 1, 2 or 3;
  • R 7 is F, Cl, oxo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 5-6 membered heteroatoms containing 1-4 N heteroatoms Aryl, -COR e , -COOR e , -OR e , -NHS(O) 2 R e , NHS(O) 2 OR e , NHS(O) 2 NHR e , -NHS(O)OR e , -NHS (O)R e , -NHS(O)NHR e , -NHC(O)R e , -NHC(O)OR e , -NHC(O)NHR e , -NR e R
  • R 7 is F, Cl, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 5-6 membered heteroaryl containing 1-4 N heteroatoms, -COR e , -COOR e , -OR e , -NHC(O)R e , -NHC(O)OR e , -NR e R f , -CONHR e ;
  • the R e are each independently hydrogen, C1- C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N or O; the alkyl, cycloalkyl and heterocycloalkyl are optionally One or more selected from
  • R 7 is F, Cl, tetrazolium, -COOH, -COOC(CH 3 ) 3 , -NHC(O)OCH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 or -NH 2.
  • R 7 is -COOH.
  • the present invention provides compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, Processes for the preparation of hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof,
  • R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, Rd, X 1 , p, q, n and Q 1 are as defined above.
  • SM-1 and SM-2 undergo condensation reaction under alkaline conditions to obtain SM-3;
  • the base is an organic base or an inorganic base, including but not limited to triethylamine, N,N-diisopropyl Ethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate;
  • the condensing agents include but are not limited to DCC, DIC, EDC, HATU, HBTU, TBTU;
  • Step 2 SM-3 undergoes a hydrolysis reaction under acidic conditions to obtain the target product; the acid is an organic acid or an inorganic acid, including but not limited to hydrochloric acid and trifluoroacetic acid.
  • R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, Rd, X 1 , p, q, n and Q 1 are as defined above.
  • Step 1 SM-4 is hydrolyzed under acidic conditions to obtain SM-5; the acid is an organic acid or an inorganic acid, including but not limited to trifluoroacetic acid;
  • Step 2 SM-5 and SM-6 undergo a substitution reaction under alkaline conditions to obtain the target compound;
  • the base is an organic base or an inorganic base, including but not limited to triethylamine, N,N-diisopropylethyl Amine, potassium carbonate, sodium carbonate, sodium bicarbonate.
  • the present invention provides compounds of formula II, or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable forms thereof. Salt,
  • R 9 is hydrogen or amino protecting group, preferably hydrogen or BOC;
  • R 10 is hydrogen or C1-C4 alkyl, preferably tert-butyl;
  • R 8 is halogen or -NR 6 (CR c R d ) q C ( O) R 4 ; the R 6 , R c , R d , q, R 4 are as defined above.
  • the present invention provides compounds of formula II, or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable forms thereof.
  • Preferred embodiments of the salt are selected from
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, non- Enantiomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention provides compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds thereof Use of , hydrate, solvate, metabolite, prodrug and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with FXIa activity.
  • the present invention provides compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds thereof , hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment or prevention of thromboembolic diseases.
  • the present invention provides a method for inhibiting the activity of FXIa, comprising: compound of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and/or stereoisomers, enantiomers, non- Enantiomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs, and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are effectively contacted with the FXIa protein.
  • the present invention provides a method of treating or preventing a disease or condition associated with FXIa activity, comprising administering to a patient in need thereof a therapeutically effective amount of Formula I, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, or Formula IF Compounds, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof pharmaceutical composition.
  • the present invention provides a method of treating or preventing thromboembolic disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF, and /Stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof .
  • the compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF of the present invention, and/or their stereoisomers, enantiomers, diastereomers, and deuterated compounds , hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts or pharmaceutical compositions thereof can be used as drugs for inhibiting the activity of FXIa.
  • the compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF of the present invention, and/or their stereoisomers, enantiomers, diastereomers, and deuterated compounds , hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts or pharmaceutical compositions thereof can be used as medicaments for the treatment or prevention of diseases or conditions associated with FXIa activity.
  • the compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF of the present invention, and/or their stereoisomers, enantiomers, diastereomers, and deuterated compounds , hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts or pharmaceutical compositions thereof can be used as drugs for the treatment or prevention of thromboembolic diseases.
  • the thromboembolic diseases described in the present invention include arterial cardiovascular and cerebrovascular thromboembolic disorders, and venous cardiovascular and cerebrovascular thromboembolic disorders.
  • Thromboembolic diseases described in the present invention include but are not limited to unstable angina, acute coronary syndrome, atrial fibrillation, primary myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, Joint replacement surgery thrombosis, hemodialysis thrombosis, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis , cerebral embolism, renal embolism, pulmonary embolism.
  • the compounds of formula I, formula IA, formula IB, formula IC, formula ID, formula IE or formula IF of the present invention, and/or their stereoisomers, enantiomers, diastereomers, and deuterated compounds , hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts or pharmaceutical compositions thereof may be administered alone, or (if desired) in combination with other pharmaceutically acceptable therapeutic agents, Such as in combination with other therapeutic agents for the treatment or prevention of thromboembolic disorders.
  • the ingredients to be combined may be administered simultaneously or sequentially, in a single formulation or in separate formulations.
  • the combination may include not only a combination of a compound of the present invention and one other active agent, but also a combination of a compound of the present invention and two or more other active agents.
  • the other therapeutic agent for treating or preventing thromboembolic diseases according to the present invention is at least one drug selected from the following: warfarin, unfractionated heparin, low molecular weight heparin, synthetic heparin Sugar, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate ), droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, etidron eptifibatide, abciximab, melagatran, desulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator , anistrepla
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight or branched chain alkyl groups; C1-C8 refers to alkyl groups containing 1-8 carbon atoms, such as methyl, ethyl, n-propyl, iso- Propyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethyl propyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl , 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2- Methylpentyl, 3-methylpentyl, 4-methylpenty
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-12 cycloalkyl” refers to a cycloalkyl group comprising 3 to 12 carbon atoms; “C3-C8 membered ring” "Alkyl” refers to a cycloalkyl group comprising 3 to 8 carbon atoms; “C5-C10 membered cycloalkyl” refers to a cycloalkyl group comprising 5 to 10 carbon atoms;
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8 membered cycloalkyl; more preferably C3-C6 cycloalkyl.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings. They may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Spirocycloalkyl groups are classified as mono-spirocycloalkyl, double-spirocycloalkyl, or polyspirocycloalkyl according to the number of spiro atoms shared between the rings.
  • Non-limiting examples of spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but None of the rings have a fully conjugated pi electron system. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, they may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , according to the number of rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl.
  • Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydro Naphthyl, benzocycloheptyl, etc.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is the integer 0, 1 or 2), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • “3-12 membered heterocycloalkyl” refers to a ring group containing 3 to 12 ring atoms
  • “5-10 membered heterocycloalkyl” refers to a ring group containing 5 to 10 ring atoms
  • Cycloalkyl refers to a ring group containing 3 to 8 ring atoms, preferably "3-8 membered heterocycloalkyl” containing 1-3 heteroatoms selected from N, O or S, more preferably containing 1 or 2 3-6 membered heterocycloalkyl with N atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.
  • Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups.
  • “Spiroheterocycloalkyl” refers to a polycyclic heterocycloalkyl group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r are integers 0, 1, 2) and the remaining ring atoms are carbon. They can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
  • the spirocycloalkyl group is divided into single spiroheterocycloalkyl, double spiroheterocycloalkyl or polyspiroheterocycloalkyl, preferably containing 1-3 atoms selected from N, O or a saturated "3-12-membered bis-spiroheterocycloalkyl" of an S heteroatom; more preferably a saturated "3-12-membered bis-spiroheterocycloalkyl" containing 1 or 2 N atoms.
  • spiroheterocycloalkyl include:
  • “Fused heterocycloalkyl” refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but None of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon.
  • the number of rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkanes, preferably "3-12-membered bicyclic fused heterocycloalkanes containing 1-3 heteroatoms selected from N, O or S" group"; more preferably a saturated "3-12 membered bicyclic fused heterocycloalkyl" containing 1 or 2 N atoms.
  • fused heterocycloalkyl include:
  • Bridged heterocycloalkyl refers to polycyclic heterocycloalkyl groups in which any two rings share two atoms that are not directly connected, they may contain one or more double bonds, but none of the rings have fully conjugated pi electrons System wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon.
  • Bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic according to the number of constituent rings, non-limiting examples of bridged heterocycloalkyl include:
  • heterocycloalkyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples include:
  • the heterocycloalkyl group can be optionally substituted or unsubstituted.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic group (that is, rings that share adjacent pairs of carbon atoms) and a polycyclic group with a conjugated pi-electron system
  • 6-10 membered aryl refers to a group containing 6 to 10 members.
  • -10 carbon percarbon aryl groups such as phenyl and naphthyl; preferably phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include:
  • the aryl group can be optionally substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen or S(O)r (where r is an integer 0, 1, 2), 5-6 membered heteroatoms
  • Aryl refers to a heteroaromatic system containing 5-6 ring atoms
  • 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, preferably containing 1-4 selected from N, O or S 5-6 membered heteroaryl with heteroatoms; more preferably 5-6 membered heteroaryl containing 1-4 N atoms; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocycloalkyl
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • C2-8 alkenyl refers to a straight or branched chain alkene containing 2 to 8 carbons group, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C2-6 alkenyl", more preferably "C2-4 alkenyl”.
  • the alkenyl group may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched chain alkynyl group containing 2-8 carbons, Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C2-6 alkynyl", more preferably "C2-4 alkynyl”.
  • the alkynyl group may be substituted or unsubstituted.
  • Alkoxy refers to -O-(alkyl), wherein said alkyl is as defined above.
  • C1-C8 alkoxy refers to an alkyloxy group containing 1-8 carbons, non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group can be optionally substituted or unsubstituted.
  • Haloalkyl refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkyl group is as defined above, non-limiting examples include difluoromethyl, dichloromethyl , dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Hydroxyalkyl refers to an alkyl group optionally substituted with one or more -OH, wherein the alkyl group is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl base.
  • Haloalkoxy refers to a group in which the hydrogen on an alkyl group is optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkoxy group is as defined above.
  • alkoxy group is as defined above.
  • Aminoalkyl refers to an alkyl group optionally substituted with one or more -NH 2 , wherein the alkyl group is as defined above, non-limiting examples include aminomethyl, aminoethyl, aminopropyl, aminoiso propyl.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Halogen means F, Cl, Br or I, preferably F, Cl.
  • HATU refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • DPPA diphenylphosphoryl azide
  • DIAD diisopropyl azodicarboxylate
  • PPh3 refers to triphenylphosphine.
  • DMEDA refers to N,N'-dimethylethylenediamine.
  • DMF refers to N,N'-dimethylformamide
  • DIEA refers to N,N-diisopropylethylamine.
  • DCC refers to dicyclohexylcarbodiimide.
  • EDC refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • DIC refers to N,N-diisopropylcarbodiimide.
  • HBTU refers to O-benzotriazole-tetramethylurea hexafluorophosphate.
  • TBTU refers to O-(IH-benzotriazol-1-yl)-N,N,N',N'-tetramethylisourea boron tetrafluoride.
  • Optional means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not occur.
  • a heterocycloalkyl group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification includes the case where the heterocycloalkyl group is substituted with an alkyl group and the case where the heterocycloalkyl group is not substituted with an alkyl group replaced situation.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are independently of one another substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the present invention also provides pharmaceutically acceptable salts of the compounds of formula (I).
  • pharmaceutically acceptable salts refers to relatively nontoxic acid or base addition salts of compounds of the present invention.
  • the acid addition salts are salts of the compounds of formula (I) of the present invention with suitable inorganic or organic acids. These salts can be prepared during the final isolation and purification of the compounds, or the purified compounds of formula (I) can be used as It is prepared by reacting its free base form with a suitable organic or inorganic acid.
  • the compounds of the present invention can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (in powders, ointments or drops) , or intratumoral administration.
  • the compounds of the present invention may be administered at a dose of approximately 0.05-300 mg/kg body weight/day, preferably 1-300 mg/kg body weight/day, more preferably 1-150 mg/kg body weight/day.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules, and the like.
  • the compounds of formula (I) of the present invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (1 ) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabino glue, etc.; (3) humectants, such as glycerin, etc.; (4) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, some complex silicates and sodium carbonate, etc.; (5) slow Sol
  • the solid dosage forms such as tablets, dragees, capsules, pills and granules can be coated or microencapsulated with coatings and shell materials such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.
  • liquid dosage forms may contain inert diluents conventionally employed in the art such as water and other solvents, solubilizers and emulsifiers such as ethanol, isopropanol , ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or the like mixture, etc.
  • the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening
  • Such suspending agents include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan only, microcrystalline cellulose, aluminum methoxide and agar, and the like or mixtures of these substances.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof can be formulated in dosage forms for parenteral injection including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and for reconstitution Sterile powder for sterile injectable solution or dispersion.
  • Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof may also be formulated for topical administration in dosage forms including, for example, ointments, powders, suppositories, drops, propellants, inhalants, and the like.
  • dosage forms including, for example, ointments, powders, suppositories, drops, propellants, inhalants, and the like.
  • the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, as the active ingredient is under sterile conditions together with a physiologically acceptable carrier and optionally a preservative, buffer, or propellant which may be required if necessary mix.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof is usually admixed with a pharmaceutically acceptable carrier, excipient or diluent.
  • compositions of the present invention can be formulated into conventional pharmaceutical preparations according to conventional preparation methods. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, propellants, and the like.
  • the present invention proves that the compound of the present invention can effectively and significantly reduce the activity of FXIa through the coagulation factor XIa enzyme activity inhibition test.
  • reducing the risk of extrinsic bleeding and increasing the width of the safe treatment window are critical.
  • the maximum therapeutic effect under risk conditions and the present invention proves that the compound of the present invention has a wide safe therapeutic window through activated partial thromboplastin time (APTT) assay, and within a safe and effective dosage range, both effective It inhibits the formation of blood clots and reduces the risk of bleeding.
  • APTT activated partial thromboplastin time
  • Fig. 1 is the compound content spectrum detected by LC-MS after the compound of Example 9 is dissolved in dimethyl sulfoxide solution
  • Fig. 2 is the compound content spectrum of the compound of Example 9 detected by LC-MS after ultrasonication for 5 minutes in a buffer solution with a pH of 7.4
  • Figure 3 is the compound content spectrum detected by LC-MS after the compound of Example 9 was ultrasonicated in a buffer solution with a pH of 8.0 for 5 minutes
  • Fig. 4 is the compound content spectrum detected by LC-MS after the compound of control group 1 is dissolved in dimethyl sulfoxide solution
  • Figure 5 is the chromatogram of compound content detected by LC-MS after the compound of control group 1 was sonicated for 30 seconds in a buffer solution with a pH of 7.4
  • Figure 6 is the chromatogram of compound content detected by LC-MS after the compound of control group 1 was sonicated for 30 seconds in a buffer solution with a pH of 8.0
  • Figure 7 is the chromatogram of compound content detected by LC-MS after the compound of control group 1 was ultrasonicated for 5 minutes in a buffer solution with a pH of 7.4
  • Fig. 8 is the chromatogram of compound content detected by LC-MS after the compound of control group 1 was ultrasonicated for 5 minutes in a buffer solution with a pH of 8.0
  • Step 1 Preparation of (S)-tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-nitrophenyl)propionamido)benzoate
  • Step 2 Preparation of (S)-tert-butyl 4-(3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propionamido)benzoate
  • N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (60.0 g, 0.249 mol) in tetrahydrofuran (600 mL) at -78 °C under nitrogen
  • n-butyllithium After stirring for 30 minutes, N,N-dimethylformamide (54.2 g, 0.742 mol) was added and the reaction was stirred at -78°C for 10 minutes.
  • the reaction mixture was diluted with saturated ammonium chloride solution (1000 mL) and extracted with ethyl acetate (3 x 300 mL).
  • the organic layer was collected, washed with water (2 x 200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated.
  • the concentrate was purified by silica gel column to obtain 29.5 g of the target product as a yellow solid.
  • the organic phase was collected and washed with water (2 x 150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the concentrate was purified by silica gel column to obtain 12.2 g of the target product as a yellow solid.
  • Step 1 Preparation of (S)-3-(4-acetamidophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid
  • Step 2 Preparation of (S)-tert-butyl 4-(3-(4-acetamidophenyl)-2-((tert-butoxycarbonyl)amino)propionamido)benzoate
  • Step 4 (S,E)-4-(3-(4-acetamidophenyl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)) Preparation of phenyl)acrylamido)propionamide)tert-butyl benzoate
  • Step 5 (S,E)-4-(3-(4-Acetylaminophenyl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzene) Preparation of (acrylamido)acrylamido)propionamido)benzoic acid
  • Step 1 (S)-tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-((methoxycarbonyl)amino)phenyl)propionamido)benzoate preparation
  • Step 2 Preparation of (S)-tert-butyl 4-(2-amino-3-(4-((methoxycarbonyl)amino)phenyl)propionamido)benzoate
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of tert-butyl -((methoxycarbonyl)amino)phenyl)propionamido)benzoate
  • Step 4 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -((methoxycarbonyl)amino)phenyl)propionamido)benzoic acid
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(2,2,3,3,4,4,4,4-heptafluorobutyramido) ) Preparation of phenyl) propionamido) tert-butyl benzoate
  • Step 2 (S)-4-(2-amino-3-(4-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)propionamido)benzoic acid preparation
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)propionamido)benzoic acid
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(2,2,3,3,4,4,5,5,5-nonafluoropentane) Preparation of amido) phenyl) propionamide) tert-butyl benzoate
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 - Preparation of (2,2,3,3,4,4,5,5,5-nonafluoropentamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(2,2,2-trifluoroacetamido)phenyl)propionamido)benzoic acid Preparation of tert-butyl ester
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(2,2,2-trifluoroacetamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(2,2,2-trifluoroacetamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(3-(4-((2,5,8,11,14,17,20,23-octaoxatricosyl)amino)phenyl)-2- Preparation of tert-butyl ((tert-butoxycarbonyl)amino)benzoate
  • Heptaethylene glycol monomethyl ether (CAS No.: 4437-01-8) (170 mg, 0.5 mmol) and triethylamine (0.1 mL) were added to the above dichloromethane reaction solution. The reaction was stirred at room temperature overnight. Water (10 mL) and dichloromethane (50 mL) were added. The aqueous layer was separated and extracted with dichloromethane (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a yellow solid. The crude product was purified by preparative HPLC to obtain 125 mg of the title compound.
  • Step 2 (S)-4-(3-(4-((2,5,8,11,14,17,20,23-octaoxatricosyl)amino)phenyl)-2- Preparation of aminopropionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(3-(4-((2,5,8,11,14,17,20,23-octaoxatricosyl)amino)phenyl)- Preparation of 2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(((2-methoxyethoxy)carbonyl)amino)phenyl)propionamido ) Preparation of tert-butyl benzoate
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(((2-methoxyethoxy)carbonyl)amino)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(((2-methoxyethoxy)carbonyl)amino)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(3-(2-methoxyethyl)ureido)phenyl)propionamido) Preparation of tert-butyl benzoate
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(3-(2-methoxyethyl)ureido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(3-(2-methoxyethyl)ureido)phenyl)propionamido)benzoic acid
  • the target compound was obtained.
  • Step 1 (S)-tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(morpholine-4-amido)phenyl)propionamido)benzoate preparation
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(morpholine-4-amido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 Preparation of 22-azido-2,5,8,11,14,17,20-heptoxadocosane
  • Step 3 (S)-4-(3-(4-(3-(2,5,8,11,14,17,20-heptaoxadodocan-22-yl)ureido)phenyl
  • Step 3 (S)-4-(3-(4-(3-(2,5,8,11,14,17,20-heptaoxadodocan-22-yl)ureido)phenyl
  • Step 4 (S)-4-(3-(4-(3-(2,5,8,11,14,17,20-heptaoxadodocan-22-yl)ureido)phenyl )-2-aminopropionamido) preparation of benzoic acid
  • the target product was obtained.
  • Step 5 (S,E)-4-(3-(4-(3-(2,5,8,11,14,17,20-heptaoxadocosane-22-yl)ureido) Preparation of phenyl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-tert-4-(2-((tert-butoxycarbonyl)amino)-3-(3-(2-oxopyrrolidin-1-yl)phenyl)propionamido)benzoic acid Preparation of butyl ester
  • Step 2 Preparation of (S)-4-(2-amino-3-(3-(2-oxopyrrolidin-1-yl)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(3 Preparation of -(2-oxopyrrolidin-1-yl)phenyl)propionamido)benzoic acid
  • the target product was obtained as a yellow solid.
  • Step 2 (S)-4-(2-Amino-3-(3-(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(3 Preparation of -(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(2-(2-methoxyethoxy)acetamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(2-(2-methoxyethoxy)acetamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-((2-(dimethylamino)-2-oxoethyl)amino)benzene Preparation of tert-butyl)propionamido)benzoate
  • Step 2 (S)-4-(2-amino-3-(4-((2-(dimethylamino)-2-oxoethyl)amino)phenyl)propionamido)benzoic acid preparation
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -((2-(dimethylamino)-2-oxoethyl)amino)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(((2-(dimethylamino)ethoxy)carbonyl)amino)phenyl) Preparation of propionamido) tert-butyl benzoate
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(((2-(dimethylamino)ethoxy)carbonyl)amino)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(((dimethylamino)ethoxy)carbonyl)amino)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(((2-(2-methoxyethoxy)ethoxy)carbonyl)amino ) Preparation of phenyl) propionamido) tert-butyl benzoate
  • Step 2 (S)-4-(2-Amino-3-(4-(((2-(2-methoxyethoxy)ethoxy)carbonyl)amino)phenyl)propionamido)benzene
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(((2-methoxyethoxy)ethoxy)carbonyl)amino)phenylpropionamido)benzoic acid
  • the target product was obtained.
  • Example 17 (S,E)-4-(3-(4-((2,5,8,11-tetraoxadodecanoyl)amino)phenyl)-2-(3-(3- Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)propionamido)benzoic acid
  • Step 1 (S)-4-(3-(4-((2,5,8,11-tetraoxadodecanoyl)amino)phenyl)-2-((tert-butoxycarbonyl)amino ) Preparation of propionamido) tert-butyl benzoate
  • Step 2 Preparation of (S)-4-(3-(4-((2,5,8,11-tetraoxadodecanoyl)amino)phenyl)-2-aminopropionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(3-(4-((2,5,8,11-tetraoxadodecanoyl)amino)phenyl)-2-(3-(3-chloro) - Preparation of 2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(3-(dimethylamino)propionamido)phenyl)propionamido)benzoic acid Preparation of tert-butyl ester
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(3-(dimethylamino)propionamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(3-(dimethylamino)propionamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 Preparation of tert-butyl 2-(2-(2-methoxyethoxy)ethoxy)acetate
  • Step 3 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(2-(2-(2-methoxyethoxy)ethoxy)acetamide Preparation of tert-butyl)phenyl)propionamido)benzoate
  • the aqueous layer was separated and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by a silica gel column to obtain 120 mg of the title compound.
  • Step 4 (S)-4-(2-Amino-3-(4-(2-(2-(2-(2-methoxyethoxy)ethoxy)acetamido)phenyl)propionamido)benzene
  • the target product was obtained.
  • Step 5 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(2-(2-(2-methoxyethoxy)ethoxy)acetamido)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 1 (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)propane Preparation of amido) tert-butyl benzoate
  • Step 2 Preparation of (S)-4-(2-amino-3-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Step 3 (S,E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-(4 Preparation of -(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • the target product was obtained.
  • Example 21 4-((S)-2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3 -(4-((R)-3-Hydroxypyrrolidine-1-amido)phenylpropionamido)benzoic acid
  • Control 1 (S,E)-4-(2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylamido)-3-( 4-(4-Methylpiperazine-1-amido)phenyl)propionamido)benzoic acid
  • Test Example 1 Coagulation factor 11a activity inhibition test
  • test compounds in the present invention were first dissolved in dimethyl sulfoxide, and the final concentration was 20 mM. Test compounds were then isocratically diluted in dimethyl sulfoxide. It was then diluted twice with 50mM hydroxyethylpiperazine ethanethiosulfonic acid buffer (pH7.4, containing 145mM sodium chloride, 5mM calcium chloride, 0.05% polyethylene glycol 8000) to make the test compound in the reaction system. The final concentration ranged from 1000 nM to 0.004 nM, and the final concentration of dimethyl sulfoxide was 0.5%.
  • Test compounds were added to a 384-well plate (Greiner) with a final concentration of 0.1 nM of activated human coagulation factor 11 protein (Abeam) and 75 ⁇ M of 6-amino-1-naphthalenesulfonamide-based fluorescent substrate (Haematologic Technologies) at 37°C Incubate for 30 minutes. After the incubation, the fluorescence signal value was read on a microplate reader EnVision with an excitation wavelength of 335 nm and an emission wavelength of 460 nm.
  • Test Example 2 Activated partial thromboplastin time (APTT) assay
  • test compounds in the present invention were first dissolved in dimethyl sulfoxide, and the final concentration was 20 mM. Test compounds were then isocratically diluted in dimethyl sulfoxide. It is then diluted twice with ultrapure water to make the final concentration of the test compound in the reaction system range from 60 ⁇ M to 0.03 ⁇ M and the final concentration of dimethyl sulfoxide to be 0.5%.
  • TECO activated partial thrombin time assay kit
  • the method is described as follows: the test compound and the resuspended lyophilized standard human plasma (SIEMENS) were mixed, and 100 ⁇ L was added to the hemagglutination cup, and incubated at 37°C for 2 minutes.
  • the compound of the present invention has better solubility, and the solubility of the compound of Example 9 is improved compared with that of the compound of the control group 1, especially when the pH is 8.0.
  • the compound of the present invention has better stability.
  • the compound of Example 9 is more stable than the compound of the control group 1, and is more favorable for preservation and application in pharmaceutical production.

Abstract

提供凝血因子XIa抑制剂、制备方法、药物组合物及其在预防或治疗FXIa活性相关疾病的应用。具体而言，提供式Ⅰ所示的酰胺类衍生物、其制备方法、含有该衍生物的药物组合物及其作为治疗剂在制备预防或治疗血栓栓塞性疾病的药物的应用。所述的式Ⅰ化合物能够显著地抑制FXIa的活性，且具有较大的治疗安全窗。所述式Ⅰ中的各取代基如说明书中所定义。

Description

凝血因子XIa抑制剂及其制备方法和应用 技术领域
本发明属于医药领域，具体的本发明涉及凝血因子XIa抑制剂、药物组合物、制备方法及其在预防或治疗血栓栓塞性疾病的应用。
技术背景
血栓是指流动血液中的血液成分在血管或心脏内膜形成的一种病理性的非匀质性的凝块或沉淀物，主要由血小板、纤维蛋白或者红白细胞构成。血栓可发生于身体任何部位的血管内，且静脉血栓的发生率为动脉血栓的4倍。静脉血栓形成的主要原因是血流减慢，多发生于下肢和盆腔静脉，上肢和肝脏等脏器也易发生，而动脉血栓的发生常与动脉粥样硬化病变有关，常见的是冠状动脉血栓和脑血栓形成。易栓症、恶性肿瘤、系统性红斑狼疮、心脑血管疾病、糖尿病、肝肾疾病、高脂血症以及药物等都可引起血栓栓塞性疾病，血栓栓塞性疾病已成为全球疾病死亡的第一位。
目前临床上广泛应用的用于治疗血栓栓塞性疾病的药物有抗凝药物(如肝素、华法林、利伐沙班、阿哌沙班)，抗血小板药物(如阿司匹林、ADP氯吡格雷)和溶栓药物，且这些药物对治疗、预防或减少血栓的形成都具有很好的效果。但是这些临床上使用的抗凝类药物存在出血风险，特别是在易患病患者中。因此找到一类即能够有效的抑制或减少血栓的形成，又能够降低出血风险的药物是有必要的。在一项针对血友病C患者(无凝血因子XIa)的研究中发现，这些血友病C患者不但中风的风险极低，且在没有重大伤害或手术的情况下，几乎不会出现不良出血。在通过使用抗体作为凝血因子XIa(FXIa)抑制剂的各种体内外模型或是凝血因子XIa敲除模型也证实了其抗血栓的作用，并且少量或是没有延长出血时间或是扩大出血量，因此，FXIa被认为可能是预防或治疗血栓的有效靶点。
人体血液凝固由内源性途径、外源性途径和共同通路组成。而FXIa是血液凝固过程中维持内源性途径所必须的，是一种涉及凝血调节的血浆丝氨酸蛋白酶，在凝血级联反应放大过程中发挥关键作用。在凝血级联反应中，凝血酶反馈激活FXI，活化的FXI(FXIa)又促使凝血酶的大量产生，从而使凝血过程进一步扩展(Gailani，D.等人，Arterioscler.Thromb.Vasc.Biol.,2007,27:2507-2513)，这一过程所引起的凝血酶爆发使纤维蛋白原转化成纤维蛋白，纤维蛋白聚合形成血液凝块的结构构架，且活化作为凝血的关键细胞组分的血小板(Hoffman，M.,Blood Reviews,2003,17:S1-S5)。因此，FXIa在整个凝血过程中至关重要，且与FXa抑制剂相比，进一步降低了出血风险，已成为各大公司及研究机构的研究热点。早期研发中的FXIa抑制剂包括口服FXIa抑制剂BMS-986177(百时美施贵宝公司与杨森公司合作)，目前正在多个Ⅰ期研究中进行评估。除口服药物外，胃肠外给药如BMS-962212(Bristol-Myers Squibb)，MAA-868(Novartis)，BAY1213790(Bayer)和IONIS-FXIRx(Ionis和Bayer)目前也处于Ⅱ期开发阶段。本发明公开了一类新的能够有效抑制FXIa活性的化合物，其不仅表现出良好的生物抑制活性，还具有很好的安全治疗窗口宽度，可用于各种血栓栓塞性疾病或病症的治疗。
发明内容
本发明提供了式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，
Figure PCTCN2021137243-appb-000001
其中：
R 1选自氢、羟基、卤素、氰基、-OR e、C1-C6烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-COR e、-COOR e、或-CONHR e；
各R 2独立地选自氢、羟基、卤素、氰基、-OR e、C1-C6烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-COR e、-COOR e、或-CONHR e；
R 1和R 2中，所述烷基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、-COOR e、-OR e、C3-C8环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、或-CONHR e的取代基取代；所述R e和R f各自独立的为氢、C1-C6烷基、卤代C1-C6烷基、C1-C6羟基烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；
n为1、2、3或4；
A为-CH 2CH 2-、-CH＝CH-、-C≡C-、-CH 2NH-或-NHCH 2-；
R 3为氢或C1-C4烷基；
或者R 3和A以及所连接的原子一起形成
Figure PCTCN2021137243-appb-000002
Figure PCTCN2021137243-appb-000003
R 5各自独立的为氢、羟基、卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、C3-C8环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基；
R a、R b、R c和R d各自独立为氢或C1-C4烷基；
或者R a和R b与其所连接的碳原子一起形成C3-C8环烷基；
或者R c和R d与其所连接的碳原子一起形成C3-C8环烷基；
p为1、2、3或4；
q为0、1、2、3或4；
环B为C3-C8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基或含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述环烷基、杂环烷基、芳基和杂芳基任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或C1-C6烷氧基的取代基取代；
X 1为NR 6或O；
R 6为氢或者C1-C4烷基；
R 4为C1-C6烷基、-(CH 2) r(OCH 2CH 2) sO(C1-C6烷基)、-(CH 2) r(OCH 2CH 2) sN(C1-C6烷基) 0-2、或-(CH2) rNH(CH 2CH 2O) s(C1-C6烷基)、含有1-2个选自N、O或S杂原子的3-8元杂环烷基；其中所述r为0、1、2、3、4、5或者6；所述s为0、1、2、3、4、5、6、7、8、9或者10；所述烷基或杂环烷基任选被1个或多个选自羟基、氧代基、C1-C6烷基、C1-C6烷氧基、卤素、COOH、COO(C1-C4烷基)、CONH 2、CON(C1-C4烷基) 1-2的取代基取代；条件是当R 4为杂环烷基时，不包括哌嗪基；
或者R 4和R 6与其所连接的原子一起形成5-6元杂环烷基；所述杂环烷基任选被1个或多个选自卤素、氰基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或C1-C6烷氧基的取代基取代；
D为-CONR g-、-NR gCO-、6-10元芳基、或含有1-4个选自N、O或S杂原子的5-10元杂芳基；其中所述Rg为氢或者C1-C4烷基；所述芳基、杂芳基任选的被1个或多个选自卤素、羟基、氧代、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4羟基烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、-(CH2) 0-4COOH、-(CH2) 0-4COO(C1-C4烷基)、-(CH2) 0-4CONH 2、-(CH2) 0-4CON(C1-C4烷基) 1-2、-(CH2) 0-4S(O) 2(C1-C4烷基)、-(CH2) 0-4NH 2、-(CH2) 0-4N(C1-C4烷基) 1-2、-(CH2) 0-4S(C1-C4烷基)的取代基取代；
Q 1为C1-C6烷基、-(CH 2) t(C3-C8环烷基)、-(CH 2) t(含有1-2个选自N、O或S杂原子的3-8元杂环烷基)、-(CH 2) t(6-10元芳基)、-(CH 2) t(含有1-4个选自N、O或S杂原子的5-10元杂芳基)；其中所述烷基、环烷基、杂环烷基、芳基、杂芳基各自独立的任选被R 7取代；所述R 7选自卤素、氧代、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C3-8环烷基、3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-COR e、-COOR e、-OR e、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-CONHS(O) 2R e或-CONHR e；所述R e和R f各自独立的为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C3-C8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述烷基、环烷基、杂环烷基、 芳基、杂芳基任选的被选自-OC(O)(C1-C4烷基)、-COOH、-C(O)O(C1-C4烷基)、-C(O)NH 2、-C(O)N(C1-C4烷基) 1-2、氨基、-C(O)(C1-C4烷基)、-O(C1-C4烷基)的取代基取代；所述t为0、1、2、3或4。
在另一优选例中，R 1和R 2各自独立的为氢、羟基、卤素、氰基、-OR e、C1-C6烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-COR e、-COOR e、或-CONHR e；其中所述烷基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个选自卤素、氰基、C1-6烷基、卤代C1-6烷基、-COOR e、-OR e、C3-C8环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、或-CONHR e的取代基取代；所述R e和R f各自独立的为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；
n为1、2、3或4；
A为-CH 2CH 2-、-CH＝CH-、-C≡C-、-CH 2NH-或-NHCH 2-；
R 3为氢或C1-C4烷基；
或者R 3和A以及所连接的原子一起形成
Figure PCTCN2021137243-appb-000004
Figure PCTCN2021137243-appb-000005
R 5各自独立的为氢、羟基、卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、C3-C8环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基；
R a、R b、R c和R d各自独立为氢或C1-C4烷基；
或者R a和R b与其所连接的碳原子一起形成C3-C8环烷基；
或者R c和R d与其所连接的碳原子一起形成C3-C8环烷基；
p为1、2、3或4；
q为0、1、2、3或4；
环B为C3-C8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基或含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述环烷基、杂环烷基、芳基和杂芳基任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或C1-C6烷氧基的取代基取代；
X 1为NR 6或O；
R 6为氢或者C1-C4烷基；
R 4为C1-C6烷基、-(CH 2) r(OCH 2CH 2) sO(C1-C6烷基)、 -(CH2) r(OCH 2CH 2) sN(C1-C6烷基) 0-2、或-(CH2) rNH(CH 2CH 2O) s(C1-C6烷基)、含有1-2个选自N、O或S杂原子的3-8元杂环烷基；其中所述r为0、1、2、3、4、5或者6；所述s为0、1、2、3、4、5、6、7、8、9或者10；所述烷基或杂环烷基任选被1个或多个选自羟基、氧代基、C1-C6烷基、C1-C6烷氧基、卤素、COOH、COO(C1-C4烷基)、CONH 2、CON(C1-C4烷基) 1-2的取代基取代；条件是当R 4为杂环烷基时，不包括哌嗪基；
或者R 4和R 6与其所连接的原子一起形成5-6元杂环烷基；所述杂环烷基任选被1个或多个选自卤素、氰基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或C1-C6烷氧基的取代基取代。
D为-CONR g-、-NR gCO-、6-10元芳基、或含有1-4个选自N、O或S杂原子的5-10元杂芳基；其中所述Rg为氢或者C1-C4烷基；所述芳基、杂芳基任选的被1个或多个选自卤素、羟基、氧代、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4羟基烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、-(CH2) 0-4COOH、-(CH2) 0-4COO(C1-C4烷基)、-(CH2) 0-4CONH 2、-(CH2) 0-4CON(C1-C4烷基) 1-2、-(CH2) 0-4S(O) 2(C1-C4烷基)、-(CH2) 0-4NH 2、-(CH2) 0-4N(C1-C4烷基) 1-2、-(CH2) 0-4S(C1-C4烷基)的取代基取代；
Q 1为C1-C6烷基、-(CH 2) t(C3-C8环烷基)、-(CH 2) t(含有1-2个选自N、O或S杂原子的3-8元杂环烷基)、-(CH 2) t(6-10元芳基)、-(CH 2) t(含有1-4个选自N、O或S杂原子的5-10元杂芳基)；其中所述烷基、环烷基、杂环烷基、芳基、杂芳基各自独立的任选被R 7取代；所述R 7选自卤素、氧代、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C3-8环烷基、3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-COR e、-COOR e、-OR e、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-CONHS(O) 2R e或-CONHR e；所述R e和R f各自独立的为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C3-C8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述烷基、环烷基、杂环烷基、芳基、杂芳基任选的被选自-OC(O)(C1-C4烷基)、-COOH、-C(O)O(C1-C4烷基)、-C(O)NH 2、-C(O)N(C1-C4烷基) 1-2、氨基、-C(O)(C1-C4烷基)、-O(C1-C4烷基)的取代基取代；所述t为0、1、2、3或4。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，Ra、Rb、Rc、Rd各自独立的为氢或甲基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，Ra、Rb、Rc、Rd各自独立的为氢。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，p为1，q为0。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，X 1为NR 6；R 6为氢或是甲基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，X 1为NR 6；R 6为氢。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为C1-C6烷基；所述烷基任选被1个或多个卤素取代。
在另一优选例中，R 4为C1-C6烷基，所述C1-C6烷基为全卤代C1-C6烷基，所述C1-C6烷基的全部H均被卤素取代。
在另一优选例中，R 4为全F代C1-C6烷基，包括但不限于以下：全F代C1烷基、全F代C2烷基、全F代C3烷基、全F代C4烷基、全F代C5烷基、全F代C6烷基。
在另一优选例中，R 1为含有1-4个选自N、O或S杂原子的5-10元杂芳基。
在另一优选例中，R 2选自下组：F、Cl、Br、I。
在另一优选例中，n为2。
在另一优选例中，A为-CH＝CH-。
在另一优选例中，R 3为氢。
在另一优选例中，D为-CONH-。
在另一优选例中，Q 1为羧基取代的苯基。
在另一优选例中，环B为苯基。
在另一优选例中，X 1为NH。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为C1-C6烷基；所述烷基任选被1个或多个F取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-(CH 2) rO(C1-C6烷基)或-(CH 2) rN(C1-C6烷基) 0-2，所述r为0、1、2、3或者4。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-O(C1-C6烷基)。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为甲氧基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-N(CH 3) 2或-(CH 2) 2N(CH 3) 2。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为吗啉基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为含有1个N杂原子的3-8元杂环烷基；所述杂环烷基任选被选自羟 基、氧代基、卤素、C1-C6烷基或C1-C6烷氧基的取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为任选被羟基或氧代基取代的吡咯烷基；
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-(CH 2) r(OCH 2CH 2) sO(C1-C6烷基)、-(CH2) r(OCH 2CH 2) sN(C1-C6烷基) 0-2或-(CH 2) rNH(CH 2CH 2O) s(C1-C6烷基)，所述r为0或者1；所述s为1、2、3、4、5、6、7、8、9或者10。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-(OCH 2CH 2) sO(C1-C6烷基)、-(OCH 2CH 2) sN(C1-C6烷基) 0-2或-NH(CH 2CH 2O) s(C1-C6烷基)；所述s为1、2、3、4、5、6、7、8或者9。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-(OCH 2CH 2) sO(C1-C6烷基)、-(OCH 2CH 2) sN(C1-C6烷基) 0-2或-NH(CH 2CH 2O) s(C1-C6烷基)；所述s为3、4、5、6或7。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-CH 2(OCH 2CH 2) sO(C1-C6烷基)、-CH 2(OCH 2CH 2) sN(C1-C6烷基) 0-2或-CH 2NH(CH 2CH 2O) s(C1-C6烷基)，所述s为1、2、3、4、5、6、7、8或者9。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-CH 2(OCH 2CH 2) sO(C1-C6烷基)、-CH2(OCH 2CH 2) sN(C1-C6烷基) 0-2或-CH 2NH(CH 2CH 2O) s(C1-C6烷基)，所述s为3、4、5、6或7。。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4为-(OCH 2CH 2) 5OCH 3、-OCH 2CH 2OCH 3、-(OCH 2CH 2) 7OCH 3、-NHCH 2CH 2OCH 3、-NH(CH 2CH 2O) 5CH 3、-NH(CH 2CH 2O) 7CH 3、-CH 2OCH 2CH 2OCH 3、-N(CH3) 2、甲基、甲氧基、三氟甲基、全氟丙基、全氟丁基、-OCH 2CH 2N(CH3) 2、-(OCH 2CH 2) 3OCH 3、-(OCH 2CH 2) 2OCH 3、-CH 2CH 2N(CH3) 2或-CH 2(OCH 2CH 2) 2OCH 3。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 4和R 6与其所连接的原子一起形成
Figure PCTCN2021137243-appb-000006
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，所述式Ⅰ化合物为式ⅠA化合物，
Figure PCTCN2021137243-appb-000007
其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、环B、D、X 1、p、q、n和Q 1如上述所定义。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，D为含有1个或2个N杂原子的5-6元杂芳基；所述杂芳基任选被1个或多个选自卤素、羟基、氧代、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4羟基烷基、C1-C4烷氧基、C2-C4烯基、-(CH 2) 0-4COOH、-(CH 2) 0-4COO(C1-C4烷基)、-(CH 2) 0-4CONH 2、-(CH 2) 0-4CON(C1-C4烷基) 1-2、-(CH 2) 0-4S(O) 2(C1-C4烷基)、-(CH 2) 0-4NH 2、-(CH 2) 0-4N(C1-C4烷基) 1-2、-(CH 2) 0-4S(C1-C4烷基)的取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，D为咪唑基、吡啶基、哒嗪基或嘧啶基；所述咪唑基、吡啶基、哒嗪基或嘧啶基任选被1个或多个选自氧代、Cl、甲基、甲氧基、乙氧基、-COOH、-CONH 2、-CONCH 3、-COOCH 3、乙烯基、氰基、SO 2CH 3、-CH 2OH、-CH 2CH 2OH、-CH 2COOH、-CH 2COOCH 3、-CH 2SO 2CH 3、氨基、-CH 2NH 2、-CH 2N(CH 3) 1-2的取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，D为-CONR g-；其中所述Rg为氢或者甲基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，D为-CONR g-；其中所述Rg为氢。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，所述式Ⅰ化合物为式ⅠB化合物，
Figure PCTCN2021137243-appb-000008
其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、环B、X 1、p、q、n和Q 1上 述所定义。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，环B为C3-C6环烷基、含有1个或2个N杂原子的3-6元杂环烷基、含有1-3个N杂原子的5-6元杂芳基或苯基；所述环烷基、杂环烷基、苯基、杂芳基任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，环B为含有1-3个N杂原子的5-6元杂芳基；所述杂芳基任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，环B为吡啶、吡唑或咪唑；所述吡啶、吡唑或咪唑任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，环B为苯基；所述苯任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个更优选实施方案中，所述式Ⅰ化合物为式ⅠC化合物，
Figure PCTCN2021137243-appb-000009
其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q、n和Q 1上述所定义。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 1为氢、氰基、卤素、任选被卤素或羟基取代的C1-C6烷基、C3-C6环烷基或-C(O)Re；所述Re为C1-C6烷基、C3-C8环烷基或含有1-2个选自N或者O杂原子的3-8元杂环烷基；所述烷基、环烷基、杂环烷基任选被一个或多个选自卤素、羟基或氨基的基团取代；或者R 1为-OR；所述Re为C1-C6烷基；所述烷基任选被卤素取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化 物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 1为氢、氰基、F、Cl、Br、三氟甲基、二氟甲基、环丙基、甲酰基、乙酰基、环丙基酰基、二氟甲氧基或三氟甲氧基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 1为含有1-4个选自N或O杂原子的5-6杂芳基；所述杂芳基任选被一个或多个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4羟基烷基的取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 1为含有1-4个N杂原子的5-6杂芳基，所述杂芳基任选被一个或多个选自F、Cl、甲基、三氟甲基、三氟乙基或甲氧基的取代基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 1为吡唑基、咪唑基、三氮唑或四氮唑。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 1为四氮唑。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，所述式Ⅰ化合物为式ⅠD化合物，
Figure PCTCN2021137243-appb-000010
其中所述R 2、R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q、n和Q 1上述所定义。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 2为氢、卤素、任选被卤素或是羟基取代的C1-C6烷基或者-ORe；所述Re为C1-C6烷基，所述烷基任选被一个或多个卤素或羟基取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 2为氢、三氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、F或者Cl。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，n为2。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施 方案中，所述式Ⅰ化合物为式ⅠE化合物，
Figure PCTCN2021137243-appb-000011
其中所述R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q和Q 1如上述所定义。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，Q 1为含有1个或2个选自N、O或S杂原子的5-6元杂芳基或Q 1为6-10元芳基；所述芳基和杂芳基任选被一个或多个R 7取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，Q 1为吡啶、吲哚基、苯并呋喃基、苯并咪唑基、喹啉或苯基；所述吡啶基、吲哚基、苯并呋喃基、苯并咪唑基、喹啉或苯基任选被一个或多个R 7取代。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，所述式Ⅰ化合物为式ⅠF化合物，
Figure PCTCN2021137243-appb-000012
其中所述R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q和R 7如上述所定义；所述u为1、2或者3；
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 7为F、Cl、氧代、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、含有1-4个N杂原子的5-6元杂芳基、-COR e、-COOR e、-OR e、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-CONHS(O) 2R e或-CONHR e；所述R e各自独立的为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C3-C8环烷基、含有1-2个选自N或O杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述烷基、环烷基、杂环烷基、芳基和杂芳基任选的被一个 或多个选自-OC(O)(C1-C4烷基)、-COOH、-C(O)O(C1-C4烷基)、-C(O)NH 2、-C(O)N(C1-C4烷基) 1-2、氨基、-C(O)(C1-C4烷基)、-O(C1-C4烷基)的取代基取代；所述R f为氢或C1-C6烷基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 7为F、Cl、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、含有1-4个N杂原子的5-6元杂芳基、-COR e、-COOR e、-OR e、-NHC(O)R e、-NHC(O)OR e、-NR eR f、-CONHR e；所述R e各自独立的为氢、C1-C6烷基、C3-C8环烷基、含有1-2个选自N或O杂原子的3-8元杂环烷基；所述烷基、环烷基和杂环烷基任选的被一个或多个选自-OC(O)(C1-C4烷基)、-COOH、-C(O)O(C1-C4烷基)、-C(O)NH 2、-C(O)N(C1-C4烷基) 1-2、氨基、-C(O)(C1-C4烷基)、-O(C1-C4烷基)的取代基取代；所述R f为氢或C1-C6烷基。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 7为F、Cl、四氮唑、-COOH、-COOC(CH 3) 3、-NHC(O)OCH 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2或-NH 2。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，R 7为-COOH。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的一个优选实施方案中，u为1。
本发明式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐为以下具体化合物
Figure PCTCN2021137243-appb-000013
Figure PCTCN2021137243-appb-000014
Figure PCTCN2021137243-appb-000015
本发明提供式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐的制备方法，
当A为-CH＝CH-，且Q1被羧酸取代时；
方法一：
Figure PCTCN2021137243-appb-000016
其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q、n和Q 1上述所定义。
包括步骤1：SM-1和SM-2在碱性条件下发生缩合反应得到SM-3；其中所述 碱为有机碱或无机碱，包括但不限于三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸氢钠；所述缩合剂包括但不限于DCC、DIC、EDC、HATU、HBTU、TBTU；
步骤2：SM-3在酸性条件下发生水解反应，得到目标产物；所述酸为有机酸或无机酸，包括但不限于盐酸、三氟乙酸。
方法二：
Figure PCTCN2021137243-appb-000017
其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q、n和Q 1上述所定义。
步骤1：SM-4在酸性条件下发生水解反应得到SM-5；所述酸为有机酸或无机酸，包括但不限于三氟乙酸；
步骤2：SM-5和SM-6在碱性条件下发生取代反应，得到目标化合物；所述碱为有机碱或无机碱，包括但不限于三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸氢钠。
本发明提供式Ⅱ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，
Figure PCTCN2021137243-appb-000018
其中R 9为氢或氨基保护基团，优选为氢或BOC；R 10为氢或C1-C4烷基，优选为叔丁基；R8为卤素或-NR 6(CR cR d) qC(O)R 4；所述R 6、R c、R d、q、R 4如上述所定义。
本发明提供式Ⅱ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐的优选实施例选自
Figure PCTCN2021137243-appb-000019
Figure PCTCN2021137243-appb-000020
Figure PCTCN2021137243-appb-000021
Figure PCTCN2021137243-appb-000022
Figure PCTCN2021137243-appb-000023
本发明提供了药物组合物，包括治疗有效量的式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，以及药学上可接受的载体、稀释剂或赋形剂。
本发明提供了式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐制备治疗或预防与FXIa活性相关的疾病或病症的药物的应用。
本发明提供了式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐制备治疗或预防血栓栓塞性疾病的药物的应用。
本发明提供给了抑制FXIa活性的方法，包括使式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物与FXIa蛋白有效接触。
本发明提供给了治疗或预防与FXIa活性相关的疾病或病症方法，包括向有需要的患者给与治疗有效量的式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物。
本发明提供给了治疗或预防血栓栓塞性疾病的方法，包括向有需要的患者给与治疗有效量的式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物。
本发明所述式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物可用作抑制FXIa活性的药物使用。
本发明所述式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物可用作治疗或预防与FXIa活性相关的疾病或病症的药物使用。
本发明所述式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物可用作治疗或预防血栓栓塞性疾病的药物使用。
本发明所述血栓栓塞性疾病包括动脉心脑血管血栓栓塞性病症、静脉心脑血管血栓栓塞性病症。
本发明所述血栓栓塞性疾病包括但不限于不稳定型心绞痛、急性冠状动脉综合征、心房纤维性颤动、初发性心肌梗塞、复发性心肌梗塞、缺血性猝死、短暂性缺血发作、关节置换手术血栓形成、血液透析血栓形成、中风、动脉粥样硬化、外周闭塞性动脉病、静脉血栓形成、深部静脉血栓形成、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。
本发明所述式Ⅰ、式ⅠA、式ⅠB、式ⅠC、式ⅠD、式ⅠE或式ⅠF化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐或其药物组合物可以单独给药，或者(如果需要)与其他药学上可接受的治疗剂联合给药，如与其他的用于治疗或预防血栓栓塞性治病的治疗剂组合。待组合的各成分可同时或顺序的给予，以单一制剂形式或以不同制剂的形式给予。所述组合不仅可包括本发明化合物和一种其他活性剂的组合，也可包括本发明化合物和两种或更多种其他活性剂的组合。
本发明所述的其他的用于治疗或预防血栓栓塞性治病的治疗剂为抗凝血剂、抗血小板剂、凝血酶抑制剂、血栓溶解剂或纤维蛋白溶解剂。优选地，本发明所述的其他的用于治疗或预防血栓栓塞性治病的治疗剂为至少一种选自以下的药物：华法林、未经分级分离的肝素、低分子量肝素、合成五糖、水蛭素、阿加曲班(argatroban)、阿司匹林、布洛芬(ibuprofen)、萘普生(naproxen)、舒林酸(sulindac)、吲哚美辛(indomethacin)、甲灭酸盐(mefenamate)、屈噁昔康(droxicam)、双氯芬酸(diclofenac)、磺吡酮(sulfinpyrazone)、吡罗昔康(piroxicam)、噻氯匹定(ticlopidine)、氯吡格雷、替罗非班(tirofiban)、依替巴肽(eptifibatide)、阿昔单抗(abciximab)、美拉加群(melagatran)、去硫酸水蛭素(desulfatohirudin)、组织纤维蛋白溶酶原活化剂、经修饰的组织纤维蛋白溶酶原活化剂、阿尼普酶(anistreplase)、替奈普酶、尿激酶(urokinase)或链激酶(streptokinase)。
详细说明：除非有相反陈述、下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”是指饱和的脂肪族烃基团，包括直链或支链烷基；C1-C8是指含有1-8个碳原子的烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1、1-二甲基丙基、1、2-二甲基丙基、2、2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1、1、2-三甲基丙基、1、1-二甲基丁基、1、2-二甲基丁基、2、2-二甲基丁基、1、3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2、3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2、3-二甲基戊基、2、4-二甲基戊基、2、2-二甲基戊基、3、3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2、3-二甲基己基、2、4-二甲基己基、2、5-二甲基己基、2、2-二甲基己基、3、3-二甲基己基、4、4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体；优选C1-C6 烷基；更优选C1-C4烷基。所述烷基可以是取代的或未取代的。
“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基；“C3-12环烷基”指包括3至12个碳原子的环烷基；“C3-C8元环烷基”指包括3至8个碳原子的环烷基；“C5-C10元环烷基”指包括5至10个碳原子的环烷基；
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环丁基、环戊基、环己基；优选C3-C8元环烷基；更优选C3-C6环烷基。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基。螺环烷基的非限制性实施例包含：
Figure PCTCN2021137243-appb-000024
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基。稠环烷基的非限制性实施例包含：
Figure PCTCN2021137243-appb-000025
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，根据组成环的数目可以分为双环、三环、四环或多环桥环烷基。桥环烷基的非限制性实施例包含：
Figure PCTCN2021137243-appb-000026
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。所述环烷基可以是任选取代的或未取代的。
“杂环烷基”指饱和的或部分不饱和的单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1或2)，但不包含-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“3-12元杂环烷基”指包含3至12个环原子的环基，“5-10元杂环烷基”指包含5至10个环原子的环基，“3-8元杂环烷基”指包含3至8个环原子的环基，优选含有1-3个选自N、O或S杂原子的“3-8元杂环烷基”，更优选含有1个或2个N原子的3-6元杂环烷基。
单环杂环烷基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基等。
多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“螺杂环烷基”指单环之间 共用一个原子(称螺原子)的多环杂环烷基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)，其余环原子为碳。他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环烷基、双螺杂环烷基或多螺杂环烷基，优选含有1-3个选自N、O或S杂原子的饱和的“3-12元双螺杂环烷基”；更优选含有1个或2个N原子的饱和的“3-12元双螺杂环烷基”。螺杂环烷基的非限制性实施例包含：
Figure PCTCN2021137243-appb-000027
“稠杂环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环烷基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选含有1-3个选自N、O或S杂原子的“3-12元双环稠杂环烷基”；更优选含有1个或2个N原子的饱和的“3-12元双环稠杂环烷基”。稠杂环烷基的非限制性实施例包含：
Figure PCTCN2021137243-appb-000028
“桥杂环烷基”指任意两个环共用两个不直接连接的原子的多环杂环烷基团，他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥杂环烷基的非限制性实施例包含：
Figure PCTCN2021137243-appb-000029
所述杂环烷基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连 接在一起的环为杂环烷基，非限制性实施例包含：
Figure PCTCN2021137243-appb-000030
所述杂环烷基可以是任选取代的或未取代的。
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)且具有共轭的π电子体系的多环基团，“6-10元芳基”指含有6-10个碳的全碳芳基，例如苯基和萘基；优选苯基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2021137243-appb-000031
Figure PCTCN2021137243-appb-000032
所述芳基可以是任选取代的或未取代的。
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧或S(O)r(其中r是整数0、1、2)，5-6元杂芳基指含有5-6个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，优选含有1-4个选自N、O或S杂原子的5-6元杂芳基；更优选含有1-4个N原子的5-6元杂芳基；非限制实施例包括呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑、咪唑基、三唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2021137243-appb-000033
所述杂芳基可以是任选取代的或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述所定义的烷基，“C2-8烯基”指含有2-8个碳的直链或支链烯基，包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3丁烯基等，优选“C2-6烯基”，更优选“C2-4烯基”。所述烯基可以是取代的或未取代的。
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，“C2-8炔基”指含有2-8个碳的直链或支链炔基，包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基，优选“C2-6炔基”，更优选“C2-4炔基”。所述炔基 可以是取代的或未取代的。
“烷氧基”指-O-(烷基)，其中所述烷基如上所定义。“C1-C8烷氧基”指含1-8个碳的烷基氧基，非限制性实施例包括甲氧基、乙氧基、丙氧基、丁氧基等。所述烷氧基可以是任选取代的或未取代的。
“卤代烷基”指任选的被一个或多个氟、氯、溴或碘原子取代的烷基，其中所述烷基如上所定义，非限制性实施例包括二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“羟基烷基”指任选被一个或多个-OH取代的烷基，其中所述烷基如上所定义，非限制性实施例包括羟甲基、羟乙基、羟基丙基、羟基异丙基。
“卤代烷氧基”指烷基上的氢任选的被一个或多个氟、氯、溴或碘原子取代的基团，其中所述烷氧基如上所定义。例如二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“氨基烷基”指任选被一个或多个-NH 2取代的烷基，其中所述烷基如上所定义，非限制性实施例包括氨基甲基、氨基乙基、氨基丙基、氨基异丙基。
“胺”是本领域公认的，并且指取代的氨。
“氨基”指-NH 2。
“氰基”指-CN。
“氧代”指＝O基团。
“卤素”指F、Cl、Br或I，优选F、Cl。
“HATU”指2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
“DPPA”指叠氮磷酸二苯酯。
“DIAD”指偶氮二甲酸二异丙酯。
“PPh 3”指三苯基膦。
“DMEDA”指N,N'-二甲基乙二胺。
“DMF”指N,N'-二甲基甲酰胺。
“DIEA”指N,N-二异丙基乙胺。
“DCC”指二环己基碳二亚胺。
“EDC”指1-(3-二甲氨基丙基)-3-乙基碳二亚胺。
“DIC”指N,N-二异丙基碳二亚胺。
“HBTU”指O-苯并三氮唑-四甲基脲六氟磷酸酯。
“TBTU”指O-(IH-苯并三唑-1-基)-N,N,N’,N’-四甲基异脲四氟化硼。
“任选”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环烷基团”意味着烷基可以但不必须存在，该说明包括杂环烷基团被烷基取代的情形和杂环烷基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子、优选为最多5个、更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻、取代基仅处在它们的可能的化学位置、本领域技术人员能够在不付出过多努力的情况下确定(通过实验或 理论)可能或不可能的取代。例如、具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物、以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药、利于活性成分的吸收进而发挥生物活性。
本发明还提供式(I)化合物药学上可接受的盐。术语“药学上可接受的盐”是指相对无毒的本发明化合物的酸加成盐或碱加成盐。所述酸加成盐为本发明式(I)化合物与合适的无机酸或者有机酸形成的盐，这些盐可在化合物最后的分离和提纯过程中制备，或者可用纯化的式(I)化合物以其游离碱形式与适宜的有机酸或无机酸进行反应来制备。
本发明的化合物或其药学上可接受的盐可给药于哺乳动物包括人，可口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂或滴剂)、或瘤内给药。
本发明化合物的给药剂量可以大约为0.05-300mg/kg体重/天，优选1-300mg/kg体重/天，更优选1-150mg/kg体重/天。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体剂型，包括但不限于胶囊剂、片剂、丸剂、散剂和颗粒剂等。在这些固体剂型中，本发明式(I)化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合，例如与柠檬酸钠或磷酸二钙，或与下述成分混合：(1)填料或增容剂，如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；(2)粘合剂，如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶等；(3)保湿剂，如甘油等；(4)崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠等；(5)缓溶剂，如石蜡等；(6)吸收加速剂，如季铵化合物等；(7)润湿剂如鲸蜡醇和单硬脂酸甘油酯等；(8)吸附剂，如高岭土等；和(9)润滑剂，如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠等，或其混合物。胶囊剂、片剂和丸剂中也可包含缓冲剂。
所述固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料例如肠溶衣和其他本领域公知的材料进行包衣或微囊化。它们可包含不透明剂，并且这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时、活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型，包括但不限于药学上可接受的乳液、溶液、悬浮液、糖浆和酊剂等。除了作为活性成分的式(I)化合物或其药学上可接受的盐外，液体剂型可包含本领域中常规采用的惰性稀释剂如水和其他溶剂、增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1、3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包含常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇只、 微晶纤维素、甲醇铝和琼脂等或这些物质的混合物。
本发明化合物或其药学上可接受的盐可以配制为用于肠胃外注射的剂型包括但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐也可以配制为用于局部给药的剂型包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明式(I)化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明还提供药物组合物，它含有本发明式(I)化合物或其药学上可接受的盐作为活性成分，以及药学上可接受载体、赋形剂或稀释剂。在制备药物组合物时，通常是将本发明式(I)化合物或其药学上可接受的盐与药学上可接受载体、赋形剂或稀释剂混合。
可以按常规制备方法将所述本发明组合物配制为常规药物制剂。例如片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混浮剂、分散液、溶液剂、糖浆剂、酏剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂等。
本发明通过凝血因子XIa酶活性抑制试验证明本发明所述化合物能够有效的显著降低FXIa的活性。对于抗血栓药物而言，降低外源性出血风险和提高安全治疗窗口宽度至关重要，用于抑制凝血的有效剂量和可能发生出血的剂量之间的剂量范围应该尽可能的大，才能实现最小风险状况下的最大治疗效果，而本发明通过活化部分凝血活酶时间(APTT)测定实验证明本发明所述化合物具有很宽的安全治疗窗口，在安全的有效的用药剂量范围内，既能够有效的抑制血栓的形成，又能够降低出血风险。
附图说明
图1是实施例9化合物在二甲亚砜溶液中溶解后经LC-MS检测的化合物含量图谱
图2是实施例9化合物在PH为7.4的缓冲溶液中超声5分钟后经LC-MS检测的化合物含量图谱
图3是实施例9化合物在PH为8.0的缓冲溶液中超声5分钟后经LC-MS检测的化合物含量图谱
图4是对照组1化合物在二甲亚砜溶液中溶解后经LC-MS检测的化合物含量图谱
图5是对照组1化合物在PH为7.4的缓冲溶液中超声30秒后经LC-MS检测的化合物含量图谱
图6是对照组1化合物在PH为8.0的缓冲溶液中超声30秒后经LC-MS检测的化合物含量图谱
图7是对照组1化合物在PH为7.4的缓冲溶液中超声5分钟后经LC-MS检测的化合物含量图谱
图8是对照组1化合物在PH为8.0的缓冲溶液中超声5分钟后经LC-MS检测的化合物含量图谱
具体实施例
下面将结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。本发明实施例中的起始原料是已知的并且可以在市场上买到、或者可以采用或按照本领域已知的方法来合成。在无特殊说明的情况下，本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。
Ⅰ化合物制备实施例
中间体1：(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-硝基苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000034
在0℃下，向(S)-2-((叔丁氧基羰基)氨基)-3-(4-硝基苯基)丙酸(9.3g，30mmol)在吡啶(1000mL)中的溶液中加入4-氨基苯甲酸叔丁酯(5.8g，30mmol)和三氯氧磷(3.4mL)。将所得溶液在0℃下搅拌2反应小时。加入水(300mL)。分离水层，并用乙酸乙酯(300mL×3)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到粗产物。粗产物经硅胶柱纯化得到目标化合物8.0g。
LC-MS:(ES,m/z):[M+H] +＝486.0
步骤2：(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000035
在0℃下，向(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-硝基苯基)丙酰胺基)苯甲酸叔丁酯(8.0g，16.5mmol)的甲醇(1000mL)溶液中加入钯/碳(800mg)。在氢气氛围下，将所得溶液在室温下搅拌反应16小时。将反应液过滤，浓缩滤液，得到目标粗产物7.4g。粗产物直接用于下一步。
LC-MS:(ES,m/z):[M+H] +＝456.0
中间体2：(S)-4-(3-(4-溴苯基)-2-((叔丁氧羰基)氨基)丙酰胺基)苯甲酸叔丁酯
Figure PCTCN2021137243-appb-000036
在0℃下，向(S)-3-(4-溴苯基)-2-((叔丁氧基羰基)氨基)丙酸(6.8g， 20mmol)的吡啶(300mL)溶液中加入4-氨基苯甲酸叔丁酯(3.8g，20mmol)和三氯氧磷(2.3mL)。将所得溶液在0℃下搅拌反应4小时。加入水(300mL)。分离水层，并用乙酸乙酯(300mL×3)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到粗产物。粗品经硅胶柱纯化，得到目标化合物8.7g。
LC-MS:(ES,m/z):[M+H] +＝519.1
中间体3：(S)-4-(3-(3-溴苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯
Figure PCTCN2021137243-appb-000037
在0℃下，向(S)-3-(3-溴苯基)-2-((叔丁氧基羰基)氨基)丙酸(6.8g，20mmol)的吡啶(300mL)溶液中加入4-氨基苯甲酸叔丁酯(3.8g，20mmol)和三氯氧磷(2.3mL)。将所得溶液在0℃下搅拌4小时。加入水(300mL)。分离水层，并用乙酸乙酯(300mL×3)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到粗产物。粗品经硅胶柱纯化，得到目标化合物8.7g。
LC-MS:(ES,m/z):[M+H] +＝519.1
中间体4：(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸
步骤1：N-(4-氯-3-氟苯基)-2,2,2-三氟乙酰胺的制备
Figure PCTCN2021137243-appb-000038
室温下，将4-氯-3-氟苯胺(50.0g，0.345mol)，2,2-2-三氟乙酸酐(86.6g，0.412mol)在乙醚(1500mL)中的混合物搅拌反应16h。反应混合物用正己烷(1500mL)稀释，并在室温下搅拌30分钟。将混合物过滤，滤液浓缩，得到白色固体目标粗产物72.5g。粗产物直接应用于下一步。
LC-MS:(ESI,m/z):[M+H] +＝241.0.
步骤2：6-氨基-3-氯-2-氟苯甲醛的制备
Figure PCTCN2021137243-appb-000039
在-78℃和氮气保护下，向N-(4-氯-3-氟苯基)-2,2,2-三氟乙酰胺(60.0g，0.249mol)在四氢呋喃(600mL)中的溶液中加入正丁基锂。搅拌30分钟后，加入N，N-二甲基甲酰胺(54.2g，0.742mol)，并在-78℃下搅拌反应10分钟。反应混合物用饱和氯化铵溶液(1000mL)稀释，并用乙酸乙酯(3×300mL)萃取。收集有机层，用水(2×200mL)和饱和食盐水(200mL)洗涤，用无水硫酸钠干 燥，过滤并浓缩滤液。浓缩物经硅胶柱纯化，得到黄色固体目标产物29.5g。
LC-MS:(ES,m/z):[M+H] +＝174.2.
步骤3：(E)-3-(6-氨基-3-氯-2-氟苯基)丙烯酸甲酯
Figure PCTCN2021137243-appb-000040
在0℃下，向2-(二乙氧基磷酰基)乙酸甲酯(52.8g，0.251mol)在四氢呋喃(300mL)中的混合物中加入氢化钠(10.1g，0.252mol，60％含量)，0℃下搅拌反应10分钟后，加入6-氨基-3-氯-2-氟苯甲醛(29.0g，0.168mol)。反应混合物在室温下搅拌反应30分钟。用冰水(500mL)淬灭反应，并用乙酸乙酯(3×200mL)萃取。收集有机相并用水(2×150mL)和饱和食盐水(150mL)洗涤，用无水硫酸钠干燥，过滤并浓缩。浓缩物经硅胶柱纯化，得到黄色固体状目标产物12.2g。
LC-MS:(ESI,m/z):[M+H] +＝230.1.
步骤4：(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸甲酯
Figure PCTCN2021137243-appb-000041
(E)-3-(6-氨基-3-氯-2-氟苯基)丙烯酸甲酯(12.2g，0.533mol)和原甲酸三甲酯(22.6g，0.213mol)在乙酸(500mL)中的混合物室温下搅拌反应30分钟，然后加入叠氮基三甲基硅烷(73.6g，0.640mol)，反应混合物在30℃下搅拌反应16h后，反应混合物用水(1500mL)稀释，并用乙酸乙酯(3×400mL)萃取，收集有机层，并用水(2×300mL)和饱和食盐水(300mL)洗涤，用无水硫酸钠干燥，过滤浓缩。浓缩物经硅胶柱纯化，得到目标产物黄色固体11.0g。
LC-MS:(ESI,m/z):[M+H] +＝283.0.
步骤5：(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸的制备
Figure PCTCN2021137243-appb-000042
(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸甲酯(11.0g，39.0mmol)和氢氧化钠(3.12g，78.0mmol)在水(200mL)和甲醇(200mL)中的混合物在室温下搅拌反应2h。用1M HCl将水层的pH调节至5-6，并用乙酸乙酯(3×200mL)萃取。收集有机层，并用水(2×150mL)和饱和食盐水(150mL)洗涤有机层，用无水硫酸钠干燥，过滤并浓缩，得到浅黄色固体状目标粗产物9.1g。粗产物直接应用于下一步。
LC-MS:(ESI,m/z):[M+H] +＝269.0.
中间体5：(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸-2,5-二氧代基吡咯烷-1-基酯
Figure PCTCN2021137243-appb-000043
向(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸(12.68g，10.0mmol)在四氢呋喃(100ml)和N，N-二甲基甲酰胺(10ml)的溶液中加入1-羟基吡咯烷基-2，5-二酮(1.15g，10mmol)和DIC(1.26g，10mmol)，在氮气氛围下在室温下搅拌反应过夜。反应生成白色沉淀。抽滤收集沉淀物。固体用甲醇和水洗涤，真空干燥，得到目标化合物3.65g。
LC-MS:(ES,m/z):[M+H] +＝366.0
实施例1：(S，E)-4-(3-(4-乙酰胺基苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸
步骤1：(S)-3-(4-乙酰胺基苯基)-2-((叔丁氧基羰基)氨基)丙酸的制备
Figure PCTCN2021137243-appb-000044
向(S)-3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酸(560mg，2mmol)的四氢呋喃(10mL)溶液中加入三乙胺(404mg，4mmol)和乙酰氯(160mg，2mmol)。将反应液在0℃下搅拌反应2小时。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到目标粗产物250mg。粗产物直接用于下一步反应。
LC-MS:(ES,m/z):[M+NH 4] +＝340.2
步骤2：(S)-4-(3-(4-乙酰胺基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000045
在0℃下，向(S)-3-(4-乙酰胺基苯基)-2-((叔丁氧基羰基)氨基)丙酸(250mg，0.78mmol)在吡啶(5mL)中的溶液中加入4-氨基苯甲酸叔丁酯(150mg，0.78mmol)和三氯氧磷(0.2mL)。反应液在0℃下搅拌2反应小时。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤并减压浓缩。浓缩物通过硅胶柱纯化，得到目标产物130mg。
LC-MS:(ES,m/z):[M+H] +＝498.2
步骤3：(S)-4-(3-(4-乙酰胺基苯基)-2-氨基丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000046
将(S)-4-(3-(4-乙酰胺基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(130mg，0.26mmol)溶于乙酸乙酯盐酸溶液(1M，2mL)中，反应液在室温下搅拌反应2小时。减压浓缩反应液，得到目标粗产物80mg。
LC-MS:(ES,m/z):[M+H]+＝398.0
步骤4：(S，E)-4-(3-(4-乙酰胺基苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000047
向(S)-4-(3-(4-乙酰胺基苯基)-2-氨基丙酰胺基)苯甲酸叔丁酯(80mg，0.23mmol)在N，N-二甲基甲酰胺(2mL)中的溶液中加入(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸、HATU(105mg，0.28mmol)和N，N-二异丙基乙胺(60mg，0.46mmol)，反应液室温下搅拌反应16小时。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到目标粗产物100mg。
LC-MS:(ES,m/z):[M+NH 4]+＝665.2
步骤5：(S，E)-4-(3-(4-乙酰氨基苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000048
向(S，E)-4-(3-(4-乙酰氨基苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺)苯甲酸叔丁酯(100mg，0.15mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液室温下搅拌反应16小时。浓缩反应液，得到目标粗产物。用制备型HPLC纯化粗产物，得到目标化合物29.11mg。
LC-MS:(ES,m/z):[M+H]+＝592.2
1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.84(d,J＝8Hz,2H),8.90(d, J＝8Hz,1H)，7.80-8.00(m,3H),7.50-7.60(m,3H),7.40-7.50(m,2H),7.20-7.25(m,2H),6.75-6.80(m,2H),4.60-6.75(m,1H),2.75-3.00(m,2H),2.00(s,3H).
实施例2：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-((甲氧基羰基)氨基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-((甲氧基羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000049
向(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(180mg，0.4mmol)在二氧六环(10mL)和水(1mL)的溶液中加入碳酸氢钠(100mg，1.2mmol)和氯甲酸甲酯(37mg，0.4mmol)。反应液在室温下搅拌反应16h。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤并减压浓缩。浓缩物通过硅胶柱纯化，得到目标产物120mg。粗产物直接用于下一步反应。
LC-MS:(ES,m/z):[M+H]+＝514.2
步骤2：(S)-4-(2-氨基-3-(4-((甲氧基羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000050
(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-((甲氧基羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯(120mg，0.23mmol)溶于乙酸乙酯盐酸溶液(1M，2mL)中，反应液在室温下搅拌2小时。减压浓缩反应液，得到目标粗产物60mg。
LC-MS:(ES,m/z):[M+H]+＝414.2
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-((甲氧基羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000051
参照实施例1步骤4的合成方法，得到目标粗产物。
LC-MS:(ES,m/z):[M+H +] +＝664.0
步骤4：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-((甲氧基羰基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000052
参照实施例1步骤5的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+NH 4 +] +＝625.0
1H NMR(400MHz,DMSO-d 6)δ12.70(s,1H),10.48(s,1H),9.83(s,1H),9.54(s,1H),8.85(d,J＝4Hz,1H),8.25(s,0.06H)，7.80-8.00(m,3H),7.50-7.60(m,3H),7.40-7.50(m,2H),7.20-7.25(m,2H),7.00-7.15(m,2H),6.80-7.00(m,2H),4.60-4.65(m,1H),3.63(s,1H),3.00-3.10(m,1H),2.60-2.70(m,1H).
实施例3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2,2,3,3,4,4,4-七氟丁酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(2,2,3,3,4,4,4,4-七氟丁酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000053
向(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(455mg，1mmol)的二氯甲烷(4mL)溶液中加入2,2,3,3,4,4,4-七氟丁酰氯(232mg，1mmol)和三乙胺(760mg，2mmol)和N，N-二异丙基乙胺(303mg，3mmol)，反应液室温下搅拌反应16小时。加入水(10mL)和二氯甲烷(50mL)。分离水层，用二氯甲烷(30mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到目标粗产物150mg。
LC-MS:(ES,m/z):[M+H +]＝652.1
步骤2：(S)-4-(2-氨基-3-(4-(2,2,3,3,4,4,4-七氟丁酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000054
向(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(2,2,3,3,4,4,4-七氟丁酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯(150mg，0.23mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌反应16小时。减压浓缩反应物，得到目标粗产物100mg。
LC-MS:(ES,m/z):[M+H +]＝496.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯 酰胺基)-3-(4-(2,2,3,3,4,4,4-七氟丁酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000055
向(S)-4-(2-氨基-3-(4-(2,2,3,3,4,4,4-七氟丁酰胺基)苯基)丙酰胺基)苯甲酸溶液(100mg，0.20mmol)的二甲基亚砜(2mL)溶液中加入(E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酸-2,5-二氧代基吡咯烷-1-基酯(73mg，0.20mmol)和N，N-二异丙基乙胺(0.2mL)。将反应液在室温下搅拌反应16h。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到目标粗产物。用制备型HPLC纯化粗产物，得到目标化合物29.39mg。
LC-MS:(ES,m/z):[M+H +]＝746.1
1H NMR(400MHz,DMSO-d 6)δ12.73(s,1H),11.21(s,1H),10.52(s,1H),9.83(s,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),3.00-3.05(m,1H),1.80-1.90(m,1H).
实施例4：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2,2,3，3,4,4,5,5,5-九氟戊酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(2,2,3,3,4,4,5,5,5-九氟戊酰胺基)苯基)丙酰胺)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000056
在0℃时，向(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(455mg，1mmol)在吡啶(10mL)中的溶液中加入2,2,3,3,4,4,5,5,5-九氟戊酸(264mg，1mmol)和三氯氧磷(0.2mL)。反应液在室温下温搅拌反应4小时。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到目标粗产物150mg。
LC-MS:(ES,m/z):[M+H +]＝702.1
步骤2：(S)-4-(2-氨基-3-(4-(2,2,3,3,4,4,5,5,5-九氟戊酰胺)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000057
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝546.0
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2,2,3，3,4,4,5,5,5-九氟戊酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000058
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝795.9
1H NMR(400MHz,DMSO-d 6)δ12.70(s,1H),11.21(s,1H),10.52(s,1H),9.83(s,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),3.00-3.05(m,1H),1.80-1.90(m,1H).
实施例5：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2,2,2-三氟乙酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(2,2,2-三氟乙酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000059
参照实施例4步骤1的合成方法，得到目标粗产物。
LC-MS:(ES,m/z):[M+H +]＝552.5
步骤2：(S)-4-(2-氨基-3-(4-(2,2,2-三氟乙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000060
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝396.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2,2,2-三氟乙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000061
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝646.1
1H NMR(400MHz,DMSO-d 6)δ12.71(s,1H),11.17(s,1H),10.52(s,1H),9.83(s,1H),8.88(d,J＝8.0,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),3.00-3.05(m,1H),1.80-1.90(m,1H).
实施例6：(S，E)-4-(3-(4-((2,5,8,11,14,17,20,23-八氧杂二十三烷酰基)氨基)苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸
步骤1：(S)-4-(3-(4-((2,5,8,11,14,17,20,23-八氧杂二十三烷酰基)氨基)苯基)-2-((叔丁氧基羰基)氨基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000062
在0℃，向(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(228mg，0.5mmol)的二氯甲烷(5mL)溶液中加入饱和碳酸氢钠水溶液(5mL)和三光气(53mg，0.18mmol)。反应液在室温下搅拌反应4小时。分离水层，并用二氯甲烷(5mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤。将七甘醇单甲醚(CAS号：4437-01-8)(170mg，0.5mmol)和三乙胺(0.1mL)加入到上述二氯甲烷的反应液中。将反应液在室温搅拌过夜。加入水(10mL)和二氯甲烷(50mL)。分离水层，并用二氯甲烷(30mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到黄色固体状粗产物。将粗产物通过制备型HPLC纯化，得到目标化合物125mg。
LC-MS:(ES,m/z):[M+H +]＝722.1
步骤2：(S)-4-(3-(4-((2,5,8,11,14,17,20,23-八氧杂二十三烷酰基)氨基)苯基)-2-氨基丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000063
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝666.4
步骤3：(S，E)-4-(3-(4-((2,5,8,11,14,17,20,23-八氧杂二十三烷酰基)氨基)苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000064
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝916.2.
1H NMR(400MHz,DMSO-d 6)δ12.50(s,1H),10.51(s,1H),9.82(s,1H),9.66(s,1H),8.85(d,J＝8.0,1H),7.20-8.00(m,10H),6.80-6.90(m,2H),4.60-4.70(m,1H),4.20(s,2H),3.80(s,2H),3.65(s,2H),3.30(s,3H),3.00-3.05(m,1H),2.80-2.90(m,1H).
实施例7：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(((2-甲氧基乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(((2-甲氧基乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000065
以2-甲氧基乙基-1-醇为原料，参照实施例6步骤1的合成方法合成。得到目标产物。
LC-MS:(ES,m/z):[M+Na] +＝580.0
步骤2：(S)-4-(2-氨基-3-(4-(((2-甲氧基乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000066
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝402.0
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(((2-甲氧基乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000067
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝652.0
1H NMR(400MHz,DMSO-d 6)δ12.67(s,1H),10.49(s,1H),9.83(s,1H),9.64(s,1H),8.83(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.354(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),7.76(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),6.14(t,J＝8.0Hz,1H),4.60-4.70(m,1H),4.19-4.15(m,2H),3.57-3.53(m,2H),3.30-3.20(m,3H),3.05-3.00(m,1H),2.90-2.80(m,1H).
实施例8：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(3-(2-甲氧基乙基)脲基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(3-(2-甲氧基乙基)脲基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000068
参照实施例6步骤1的合成方法合成，得到目标化合物。
LC-MS:(ES,m/z):[M+Na] +＝557.2
步骤2：(S)-4-(2-氨基-3-(4-(3-(2-甲氧基乙基)脲基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000069
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝401.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(3-(2-甲氧基乙基)脲基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000070
参照实施例3步骤3的合成方法，得到目标物。
LC-MS:(ES,m/z):[M+H] +＝651.0
1H NMR(400MHz,DMSO-d 6)δ12.70(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0,1H),8.43(s,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.26(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),7.76(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),6.14(t,J＝8.0Hz,1H),4.70-4.60(m,1H),3.50-3.20(m,2H),3.30-3.25(m,3H),3.00-2.80(m,1H),2.90-2.80(m,1H).
实施例9：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(吗啉-4-酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(吗啉-4-酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000071
参照实施例6步骤1的合成方法，得到目标化合物。
LC-MS:(ES,m/z):[M+H] +＝569.3
步骤2：(S)-4-(2-氨基-3-(4-(吗啉-4-酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000072
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝413.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(吗啉-4-酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000073
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝663.2
1H NMR(400MHz,DMSO-d 6)δ12.60(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0Hz,1H),8.44(s,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.34(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),7.76(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),4.70-4.60(m,1H),3.60-3.50(m,4H),3.40-3.30(m,4H),3.05-3.00(m,1H),2.90-2.80(m,1H).
实施例10：(S，E)-4-(3-(4-(3-(2,5,8,11,14,17,20-七氧杂二十二烷-22-基)脲基)苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸
步骤1：22-叠氮基-2,5,8,11,14,17,20-七氧杂二十二烷的制备
Figure PCTCN2021137243-appb-000074
在0℃下，向七甘醇单甲醚(340mg，1mmol)的四氢呋喃(5mL)溶液中加入DPPA(275mg，1mmol)，DIAD(404mg，2mmol)和PPh 3(524mg，2mmol)。反应液在室温下搅拌反应16小时。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL x 2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到粗产物。用制备型HPLC纯化粗产物，得到目标化合物40mg。
LC-MS:(ES,m/z):[M+H 2O] +＝383.1
步骤2：2,5,8,11,14,17,20-七氧杂二十二烷基-22-胺的制备
Figure PCTCN2021137243-appb-000075
向22-叠氮基-2,5,8,11,14,17,20-七氧杂二十二烷(40mg，0.1mmol)的四氢呋喃(4mL)溶液中加入PPh3(60mg，0.2mmol)。反应液在室温下搅拌反应16小时。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到目标粗产物35mg。粗产物直接用于下一步反应。
LC-MS:(ES,m/z):[M+H 2O] +＝357.2
步骤3：(S)-4-(3-(4-(3-(2,5,8,11,14,17,20-七氧杂二十二烷-22-基)脲基)苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000076
以2,5,8,11,14,17,20-七氧杂二十二烷基-22-胺为原料，参照参照实施例6步骤1的合成方法合成，得到目标化合物。
LC-MS:(ES,m/z):[M+H] +＝821.2
步骤4：(S)-4-(3-(4-(3-(2,5,8,11,14,17,20-七氧杂二十二烷-22-基)脲基)苯基)-2-氨基丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000077
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝665.1
步骤5：(S，E)-4-(3-(4-(3-(2,5,8,11,14,17,20-七氧杂二十二烷-22-基)脲基)苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000078
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝915.1
1H NMR(400MHz,DMSO-d 6)δ12.62(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0Hz,1H),8.45(s,1H),8.26(s,1.47H),8.00-7.80(m,3H),7.70-7.58(m,3H),7.34(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),7.76(dd,J 1＝16.0Hz andJ 2＝16.0Hz,2H),6.90-6.80(m,2H),4.70-4.60(m,1H),3.80-3.50(m,26H),3.35-3.25(m,5H),3.00-3.05(m,1H),2.80-2.90(m,1H).
实施例11：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(3-(2-氧代基吡咯烷-1-基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧羰基)氨基)-3-(3-(2-氧代基吡咯烷-1-基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000079
向(S)-4-(3-(3-溴苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(259mg，0.5mmol)的甲苯(10mL)溶液中加入吡咯烷-2-酮(43mg，0.5mmol)和碘化亚铜(95mg，0.5mmol)和DMEDA(44mg，0.5mmol)。反应液在100℃搅拌反应过夜。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(20mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到粗产物。粗产物硅胶柱纯化得到黄色固体状目标化合物180mg。
LC-MS:(ES,m/z):[M+Na] +＝546.2
步骤2：(S)-4-(2-氨基-3-(3-(2-氧代基吡咯烷-1-基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000080
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝368.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(3-(2-氧代基吡咯烷-1-基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000081
参照实施例3步骤3的合成方法，得到黄色固体状目标产物。
LC-MS:(ES,m/z):[M+H] +＝618.1
1H NMR(400MHz,DMSO-d 6)δ12.71(s,1H),10.52(s,1H),9.83(s,1H),8.87(d,J＝8Hz,1H),8.17(s,0.45H),8.00-7.80(m,3H),7.60-7.50(m,3H),7.29(t,J＝8.0Hz,1H),7.23(s,1H),7.20-7.10(m,2H),6.76(dd,J 1＝16.0Hz and J 2＝16.0Hz,2H),4.60-4.70(m,1H),3.60-3.70(m,2H),3.00-3.05(m,1H),1.80-1.90(m,1H),2.40-2.50(m,2H),2.00-2.10(m,2H).
实施例12：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(3-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(3-(4-甲基-2-氧代哌嗪-1-基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000082
以4-甲基哌嗪-2-酮为原料，参照实施例11步骤1的合成方法合成。得到目标化合物。
LC-MS:(ES,m/z):[M+Na] +＝553.2
步骤2：(S)-4-(2-氨基-3-(3-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸
Figure PCTCN2021137243-appb-000083
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝397.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(3-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000084
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H +]＝647.1
1H NMR(400MHz,DMSO-d 6)δ12.50(s,1H),10.50(s,1H),9.84(s,1H),8.87(d,J＝8Hz,1H),8.00-7.80(m,3H),7.75-7.60(m,3H),7.35-7.25(t,J＝8.0Hz,1H),7.23(s,1H),7.20-7.10(m,2H),7.76(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),4.60-4.70(m,1H),3.60-3.70(m,1H),3.40-3.50(m,1H),3.00-3.05(m,3H),2.70-2.80(m,1H),2.50-2.60(m,2H),2.27(s,3H).
实施例13：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2-(2-甲氧基乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(2-(2-甲氧基乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000085
向2-(2-甲氧基乙氧基)乙酸(55mg，0.41mmol)的DMF(2mL)溶液中加入HATU(233mg，0.61mmol)和DIEA(158mg，1.22mmol)。在室温下搅拌反应10分钟后，加入(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(205mg，0.45mmol)。反应液在室温下搅拌反应16h。用水(30mL)稀释反应混合物，并用乙酸乙酯(3×10mL)萃取。合并有机层，并用水(2×10ml)和饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤并浓缩。浓缩物通过硅胶柱纯化，得到目标产物144mg。
LC-MS:(ESI,m/z):[M+NH 4] +＝589.3
步骤2：(S)-4-(2-氨基-3-(4-(2-(2-甲氧基乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000086
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ESI,m/z):[M+H] +＝416.0
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2-(2-甲氧基乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000087
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ESI,m/z):[M+H] +＝666.2
1H NMR(400MHz,DMSO-d 6)δ12.68(s,1H),10.50(s,1H),9.83(s,1H),9.55(s,1H),8.85(d,J＝8.0Hz,1H),7.91(dd,J＝18.1,8.6Hz,3H),7.70–7.61(m,3H),7.52(d,J＝8.5Hz,2H),7.22(d,J＝8.5Hz,2H),6.81–6.72(m,2H),4.74–4.70(m,1H),4.04(s,2H),3.65(dd,J＝5.6,3.6Hz,2H),3.51(dd,J＝5.6,3.6Hz,2H),3.28(s,3H),3.04(dd,J＝13.8,5.0Hz,1H),2.85(dd,J＝13.7,9.5Hz,1H).
实施例14：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-((2-(二甲基氨基)-2-氧代基乙基)氨基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-((2-(二甲基氨基)-2-氧代基乙基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000088
向(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(200mg，0.44mmol)的DMF(2mL)溶液中加入2-溴-N，N-二甲基乙酰胺(145mg，0.88mmol)和三乙胺(113mg，0.13mmol)。反应液在室温下搅拌反应16h。用水(30mL)稀释反应混合物，并用乙酸乙酯(3×10mL)萃取。合并有机层，用水(2×10ml)和饱和食盐水(10mL)洗涤，经无水硫酸钠干燥，过滤并浓缩。浓缩物经硅胶柱纯化，得到目标产物130mg。
LC-MS:[M+H] +＝541.3
步骤2：(S)-4-(2-氨基-3-(4-((2-(二甲基氨基)-2-氧代基乙基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000089
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ESI,m/z):[M+H] +＝385.2
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-((2-(二甲基氨基)-2-氧代基乙基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000090
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ESI,m/z):[M+H] +＝635.0
1H NMR(400MHz,DMSO-d 6)δ12.69(s,1H),10.47(s,1H),9.84(s,1H),8.78(d,J＝7.9Hz,1H),7.94–7.87(m,4H),7.69(d,J＝8.8Hz,2H),7.63–7.61(m,1H),7.00(d,J＝8.5Hz,2H),6.80(s,1H),6.76–6.75(m,1H),6.55(d,J＝8.5Hz,2H),5.35–5.33(m,1H),3.82(d,J＝4.4Hz,2H),2.99(s,3H),2.95–2.90(m,2H),2.86(s,3H).
实施例15：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(((二甲基氨基)乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(((2-(二甲基氨基)乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000091
以2-(二甲氨基)乙基-1-醇为原料，参照实施例6步骤1的合成方法合成。得到目标化合物。
LC-MS:(ES,m/z):[M+H] +＝571.3
步骤2：(S)-4-(2-氨基-3-(4-(((2-(二甲基氨基)乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000092
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝415.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(((二甲基氨基)乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲 酸的制备
Figure PCTCN2021137243-appb-000093
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝665.0
1H NMR(400MHz,DMSO-d 6)δ10.47(s,1H),9.83(s,1H),9.58(s,1H),8.85(d,J＝8.0Hz,1H),8.26(s,1.47H),8.00-7.80(m,3H),7.70-7.58(m,3H),7.35(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),7.76(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),6.90-6.80(m,2H),4.70-4.60(m,1H),4.13(t,J＝8.0Hz,2H),3.00-2.90(m,2H),2.70-2.80(m,2H)2.18(s,6H).
实施例16：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(((2-甲氧基乙氧基)乙氧基)羰基)氨基)苯基丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(((2-(2-甲氧基乙氧基)乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000094
以2-(2-甲氧基乙氧基)乙基-1-醇为原料，参照实施例6步骤1的合成方法合成。得到目标化合物
LC-MS:(ES,m/z):[M+H 2O] +＝619.3
步骤2:(S)-4-(2-氨基-3-(4-(((2-(2-甲氧基乙氧基)乙氧基)羰基)氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000095
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝446.0
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(((2-甲氧基乙氧基)乙氧基)羰基)氨基)苯基丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000096
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝696.0
1H NMR(400MHz,DMSO-d 6)δ10.50(s,1H),9.84(s,1H),9.66(s,1H),8.87(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.70-7.58(m,3H),7.35(d,J＝8.0Hz,2H),7.17(d,J＝8.0Hz,2H),6.76(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),4.70-4.60(m,1H),4.20–4.15(m,2H),3.73-2.60(m,2H),2.60-2.50(m,2H)3.24(s,3H),3.10-3.00(m,1H),2.80-2.75(m,1H).
实施例17：(S，E)-4-(3-(4-((2,5,8,11-四氧杂十二烷酰基)氨基)苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸
步骤1：(S)-4-(3-(4-((2,5,8,11-四氧杂十二烷酰基)氨基)苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000097
以2-(2-(2-甲氧基乙氧基)乙氧基)乙基-1-醇为原料，参照参照实施例6步骤1的合成方法合成。得到目标化合物。
LC-MS:(ES,m/z):[M+H] +＝645.9
步骤2：(S)-4-(3-(4-((2,5,8,11-四氧杂十二烷酰基)氨基)苯基)-2-氨基丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000098
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝490.1
步骤3：(S，E)-4-(3-(4-((2,5,8,11-四氧杂十二烷酰基)氨基)苯基)-2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000099
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H 2O] +＝757.0
1H NMR(400MHz,DMSO-d 6)δ12.72(s,1H),10.50(s,1H),9.83(s,1H),9.61(s,1H),8.84(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.69(d,J＝8.0Hz,2H),7.62(dd,J＝8.0,1.2Hz,1H),7.35(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),6.77(q,J＝16.0Hz,2H),4.80-4.60(m,1H),4.22–4.11(m,2H),3.68–3.59(m,2H),3.59–3.46(m,6H),3.44–3.39(m,2H),3.21(s,3H),3.10-2.90(m,1H),2.90-2.70(m,1H).
实施例18：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(3-(二甲基氨基)丙酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(3-(二甲基氨基)丙酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000100
向(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(259mg，0.5mmol)的吡啶(10mL)溶液中加入3-(二甲基氨基)丙酸(59mg，0.5mmol)和三氯氧磷(0.2mL)。将反应液在0℃下搅拌反应2h。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到粗产物。粗产物经硅胶柱纯化得到目标化合物150mg。
LC-MS:(ES,m/z):[M+H] +＝555.2
步骤2：(S)-4-(2-氨基-3-(4-(3-(二甲氨基)丙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000101
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝399.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰 胺基)-3-(4-(3-(二甲基氨基)丙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000102
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝649.0
1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.97(s,1H),9.83(s,1H),8.88(d,J＝8Hz,1H),8.33(s,1H),8.00-7.80(m,3H),7.60-7.50(m,3H),7.46(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),6.78(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),4.60-4.70(m,1H),3.10-3.00(m,1H),2.80-2.75(m,1H),2.60-2.50(m,2H),2.50-2.40(m,2H),2.46(s,6H).
实施例19：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2-(2-(2-甲氧基乙氧基)乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸
步骤1：2-(2-(2-甲氧基乙氧基)乙氧基)乙酸叔丁酯的制备
Figure PCTCN2021137243-appb-000103
在0℃下，向2-(2-甲氧基乙氧基)乙基-1-醇(480mg，4mmol)在四氢呋喃(20mL)中的溶液中加入60％氢化钠(192mg，4.8mmol)。将所得溶液在0℃下搅拌反应2小时。加入2-溴乙酸叔丁酯(451mg，4.8mmol)，将反应液在室温下搅拌反应16h。反应液倒入冰水中。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到粗产物600mg。粗产物直接用于下一步。
步骤2：2-(2-(2-甲氧基乙氧基)乙氧基)乙酸的制备
Figure PCTCN2021137243-appb-000104
向2-(2-(2-甲氧基乙氧基)乙氧基)乙酸叔丁酯(300mg，1.28mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌反应16小时。浓缩反应液，得到粗产物200mg。粗产物直接用于下一步。
步骤3：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(2-(2-(2-甲氧基乙氧基)乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000105
向2-(2-(2-甲氧基乙氧基)乙氧基)乙酸(100mg，0.55mmol)的DMF(5mL)溶液中加入(S)-4-(3-(4-氨基苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(250mg，0.55mmol)，N，N-二异丙基乙胺(0.2mL)和HATU(418mg，1.1mmol)。将所得溶液在室温下搅拌反应16h。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，无水硫酸钠干燥，过滤并浓缩，得到粗产物。将粗制物用硅胶柱纯化得到目标化合物120mg。
LC-MS:(ES,m/z):[M+H 2O] +＝633.1
步骤4：(S)-4-(2-氨基-3-(4-(2-(2-(2-甲氧基乙氧基)乙氧基)乙酰氨基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000106
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝460.0
步骤5：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(2-(2-(2-甲氧基乙氧基)乙氧基)乙酰胺基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000107
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝710.1
1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.83(s,1H),9.49(s,1H),8.86(d,J＝8.0Hz,1H),8.00-7.80(m,3H),7.70-7.65(m,3H),7.53(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),6.75(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),4.70-4.60(m,1H),4.06–4.02(m,2H),3.70-3.50(m,6H),2.60-2.40(m,2H)3.21(s,3H),3.10-3.00(m,1H),2.80-2.75(m,1H).
实施例20：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸
步骤1：(S)-4-(2-((叔丁氧基羰基)氨基)-3-(4-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸叔丁酯的制备
Figure PCTCN2021137243-appb-000108
向(S)-4-(3-(4-溴苯基)-2-((叔丁氧基羰基)氨基)丙酰胺基)苯甲酸叔丁酯(259mg，0.5mmol)的甲苯(10mL)溶液中加入4-甲基哌嗪-2-酮(77mg，0.5mmol)和碘化亚铜(95mg，0.5mmol)和DMEDA(44mg，0.5mmol)。将所得溶液在100℃下搅拌反应过夜。加入水(10mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(30mL×2)萃取。合并有机层，用无水硫酸钠干燥，过滤并浓缩，得到粗产物。粗产物经硅胶柱纯化得到目标化合物80mg。
LC-MS:(ES,m/z):[M+Na] +＝553.2
步骤2：(S)-4-(2-氨基-3-(4-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000109
参照实施例3步骤2的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝397.1
步骤3：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(4-甲基-2-氧代基哌嗪-1-基)苯基)丙酰胺基)苯甲酸的制备
Figure PCTCN2021137243-appb-000110
参照实施例3步骤3的合成方法，得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝647.2
1H NMR(400MHz,DMSO-d 6)δ12.50(s,1H),10.51(s,1H),9.84(s,1H),8.87(d,J＝8Hz,1H),8.00-7.80(m,3H),7.70-7.55(m,3H),7.30(d,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),7.77(dd,J 1＝16.0Hz,J 2＝16.0Hz,2H),4.70-4.60(m,1H),3.70-3.60(m,2H),3.30-3.20(m,3H),3.00-2.90(m,1H),2.80-2.70(m,2H),2.30-2.20(m,3H).
实施例21：4-((S)-2-((E)-3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-((R)-3-羟基吡咯烷-1-酰胺基)苯基丙酰胺基)苯甲酸
Figure PCTCN2021137243-appb-000111
参照实施例6的方法合成。
LC-MS:(ES,m/z):[M+H] +＝663.4.
1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.84(s,1H),8.86(d,J＝8.0Hz,1H),8.31(s,1H),8.01(s,1H),7.96–7.85(m,3H),7.67(d,J＝8.7Hz,2H),7.62(dd,J＝8.6,1.3Hz,1H),7.38(d,J＝8.5Hz,2H),7.13(d,J＝8.5Hz,2H),6.77(q,J＝16.1Hz,2H),4.93(br,1H),4.75-4.65(m,1H),4.30–4.25(m,1H),3.43–3.40(m,2H),3.26-3.23(m,1H),3.06–2.95(m,1H),2.88–2.76(m,1H),1.95-1.85(m,1H),1.83–1.71(m,1H).
对照组1：(S，E)-4-(2-(3-(3-氯-2-氟-6-(1H-四唑-1-基)苯基)丙烯酰胺基)-3-(4-(4-甲基哌嗪-1-酰胺基)苯基)丙酰胺基)苯甲酸
Figure PCTCN2021137243-appb-000112
参照实施例6的方法合成。
LC-MS：(ES,m/z):[M+H] +＝676.1.
1H NMR(400MHz,DMSO-d 6)δ12.64(s,1H),10.49(s,1H),9.83(s,1H),8.83(d,J＝8.0Hz,1H),8.41(s,1H),8.00-7.95(m,3H),7.69(d,J＝8.7Hz,2H),7.62(d,J＝8.7Hz,1H),7.34(d,J＝8.5Hz,2H),7.13(d,J＝8.5Hz,2H),6.77(q,J＝16.1Hz,2H),4.80-4.65(m,1H),3.50-3.40(m,4H),3.05-2.95(m,1H),2.90-2.75(m,1H),2.36–2.24(m,4H),2.18(s,3H).
Ⅱ生物活性测试实施例
测试实施例1：凝血因子11a活性抑制试验
将本发明中的受试化合物先溶解于二甲基亚砜中，终浓度为20mM。然后用二甲基亚砜将受试化合物等梯度稀释。再用50mM羟乙基哌秦乙硫磺酸缓冲液(pH7.4，包含145mM氯化钠，5mM氯化钙，0.05％聚乙二醇8000)二次稀释，使受试化合物在反应体系中的终浓度范围为1000nM～0.004nM，二甲基亚砜的 终浓度为0.5％。将受试化合物与终浓度为0.1nM活化的人凝血因子11蛋白(Abcam)和75μM的6-氨基-1-萘磺酰胺基荧光底物(Haematologic Technologies)加入384孔板(Greiner)，37℃孵育30分钟。孵育结束后，在酶标仪EnVision上以激发波长为335nm、发射波长为460nm读取荧光信号值。通过与对照组荧光信号值对比，计算受试化合物在各浓度下的抑制率，进而通过GraphPad Prism 8以对数浓度-抑制率进行非线性曲线拟合，计算受试化合物的IC 50值。具体结果见表1。
测试实施例2：活化部分凝血活酶时间(APTT)测定
将本发明中的受试化合物先溶解于二甲基亚砜中，终浓度为20mM。然后用二甲基亚砜将受试化合物等梯度稀释。再用超纯水二次稀释，使受试化合物在反应体系中的终浓度范围为60μM～0.03μM，二甲基亚砜的终浓度为0.5％。按照活化部分凝血酶时间测定试剂盒(TECO)说明书进行测试。方法描述如下：受试化合物和重悬的冻干标准人血浆(SIEMENS)混匀后取100μL加入血凝杯中，37℃孵育2分钟。然后加入100μL预热的APTT试剂，再37℃孵育5分钟。最后加入100μL 25mM预热的氯化钙。用血凝仪(TECO)检测记录凝固形成时间。通过与对照组凝固时间的比值，计算受试化合物在各浓度下的效应倍数，进而通过GraphPad Prism 8以对数浓度-效应倍数进行非线性曲线拟合，计算受试化合物的EC 1.5×和EC 2.0×值。具体结果见表1。
表1：
Figure PCTCN2021137243-appb-000113
Figure PCTCN2021137243-appb-000114
结论：如表1所示，本发明化合物具有较好的FXIa抑制活性，且具有较宽的治疗安全窗。
测试实施例3：溶解度测试实验
分别配置0.1M pH6.5、pH 7.4和pH 8.0的磷酸二氢钠-磷酸氢二钠缓冲溶液(PBS)和0.1M pH 9.0的甘氨酸-氢氧化钠缓冲溶液，将10mg样品分别加入到上述1mL缓冲溶液中，摇床上室温过夜，而后15200rpm速度离心10分钟，取上清液LC-MS(液质色谱连用)常规方法分析溶液中化合物含量，具体结果如表2中所示：
表2：
Figure PCTCN2021137243-appb-000115
结论：本发明化合物溶解性更好，实施例9较对照组1化合物的溶解度有所改善，特别是pH为8.0时。
测试实施例4：稳定性测试实验
分别配置0.1M pH 7.4和pH 8.0的磷酸二氢钠-磷酸氢二钠缓冲溶液(PBS)。分别将1.8mg实施例9化合物和1.8mg对照组1化合物加入到0.5mL的二甲亚砜溶液中溶解后，即刻取样通过LC-MS进行样品含量分析；将2.5mg和5.2mg实施例9化合物分别加入到0.5mL pH 7.4和pH 8.0的磷酸二氢钠-磷酸氢二钠缓冲溶液中，超声5分钟后，取样通过LC-MS进行样品含量分析；将2.6mg和5.4mg对照组1化合物分别加入到0.5mL pH 7.4和pH 8.0的磷酸二氢钠-磷酸氢二钠缓冲溶液中，超声5分钟后，取样通过LC-MS进行样品含量分析；另将2.4mg和5.4mg对照组1化合物分别加入到0.5mL pH 7.4和pH 8.0的磷酸二氢钠-磷酸氢二钠缓冲溶液中，超声30秒后，取样通过LC-MS进行样品含量分析。
表3：
Figure PCTCN2021137243-appb-000116
Figure PCTCN2021137243-appb-000117
注：/表示未超声。
结论：本发明化合物稳定性更好，实施例9化合物较对照组1化合物更稳定，更利于保存和应用于制药生产。

Claims (32)

  1. 式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，
    Figure PCTCN2021137243-appb-100001
    其中：
    R 1选自氢、羟基、卤素、氰基、-OR e、C1-C6烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-COR e、-COOR e、或-CONHR e；
    各R 2独立地选自氢、羟基、卤素、氰基、-OR e、C1-C6烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-COR e、-COOR e、或-CONHR e；
    R 1和R 2中，所述烷基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、-COOR e、-OR e、C3-C8环烷基、3-8元杂环烷基、6-10元芳基、5-10元杂芳基、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、或-CONHR e的取代基取代；所述R e和R f各自独立的为氢、C1-C6烷基、卤代C1-C6烷基、C1-C6羟基烷基、C3-8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；
    n为1、2、3或4；
    A为-CH 2CH 2-、-CH＝CH-、-C≡C-、-CH 2NH-或-NHCH 2-；
    R 3为氢或C1-C4烷基；
    或者R 3和A以及所连接的原子一起形成
    Figure PCTCN2021137243-appb-100002
    Figure PCTCN2021137243-appb-100003
    R 5各自独立的为氢、羟基、卤素、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、C3-C8环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基；
    R a、R b、R c和R d各自独立为氢或C1-C4烷基；
    或者R a和R b与其所连接的碳原子一起形成C3-C8环烷基；
    或者R c和R d与其所连接的碳原子一起形成C3-C8环烷基；
    p为1、2、3或4；
    q为0、1、2、3或4；
    环B为C3-C8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基或含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述环烷基、杂环烷基、芳基和杂芳基任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或C1-C6烷氧基的取代基取代；
    X 1为NR 6或O；
    R 6为氢或者C1-C4烷基；
    R 4为C1-C6烷基、-(CH 2) r(OCH 2CH 2) sO(C1-C6烷基)、-(CH 2) r(OCH 2CH 2) sN(C1-C6烷基) 0-2、或-(CH2) rNH(CH 2CH 2O) s(C1-C6烷基)、含有1-2个选自N、O或S杂原子的3-8元杂环烷基；其中所述r为0、1、2、3、4、5或者6；所述s为0、1、2、3、4、5、6、7、8、9或者10；所述烷基或杂环烷基任选被1个或多个选自羟基、氧代基、C1-C6烷基、C1-C6烷氧基、卤素、COOH、COO(C1-C4烷基)、CONH 2、CON(C1-C4烷基) 1-2的取代基取代；条件是当R 4为杂环烷基时，不包括哌嗪基；
    或者R 4和R 6与其所连接的原子一起形成5-6元杂环烷基；所述杂环烷基任选被1个或多个选自卤素、氰基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或C1-C6烷氧基的取代基取代；
    D为-CONR g-、-NR gCO-、6-10元芳基、或含有1-4个选自N、O或S杂原子的5-10元杂芳基；其中所述Rg为氢或者C1-C4烷基；所述芳基、杂芳基任选的被1个或多个选自卤素、羟基、氧代、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4羟基烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、-(CH2) 0-4COOH、-(CH2) 0-4COO(C1-C4烷基)、-(CH2) 0-4CONH 2、-(CH2) 0-4CON(C1-C4烷基) 1-2、-(CH2) 0-4S(O) 2(C1-C4烷基)、-(CH2) 0-4NH 2、-(CH2) 0-4N(C1-C4烷基) 1-2、-(CH2) 0-4S(C1-C4烷基)的取代基取代；
    Q 1为C1-C6烷基、-(CH 2) t(C3-C8环烷基)、-(CH 2) t(含有1-2个选自N、O或S杂原子的3-8元杂环烷基)、-(CH 2) t(6-10元芳基)、-(CH 2) t(含有1-4个选自N、O或S杂原子的5-10元杂芳基)；其中所述烷基、环烷基、杂环烷基、芳基、杂芳基各自独立的任选被R 7取代；所述R 7选自卤素、氧代、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C3-8环烷基、3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基、-COR e、-COOR e、-OR e、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、 -NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-CONHS(O) 2R e或-CONHR e；所述R e和R f各自独立的为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C3-C8环烷基、含有1-2个选自N、O或S杂原子的3-8元杂环烷基、6-10元芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述烷基、环烷基、杂环烷基、芳基、杂芳基任选的被选自-OC(O)(C1-C4烷基)、-COOH、-C(O)O(C1-C4烷基)、-C(O)NH 2、-C(O)N(C1-C4烷基) 1-2、氨基、-C(O)(C1-C4烷基)、-O(C1-C4烷基)的取代基取代；所述t为0、1、2、3或4。
  2. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R a、R b、R c、R d各自独立的为氢或甲基。
  3. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，p为1，q为0。
  4. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，X 1为NR 6；R 6为氢或是甲基。
  5. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 4为C1-C6烷基；所述烷基任选被1个或多个卤素取代。
  6. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 4为-(CH 2) rO(C1-C6烷基)或-(CH 2) rN(C1-C6烷基) 0-2，所述r为0、1、2、3或者4。
  7. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 4为吗啉基或任选被羟基或氧代取代的吡咯烷基。
  8. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 4为-(CH 2) r(OCH 2CH 2) sO(C1-C6烷基)、-(CH2) r(OCH 2CH 2) sN(C1-C6烷基) 0-2或-(CH 2) rNH(CH 2CH 2O) s(C1-C6烷基)，所述r为0或者1；所述s为1、2、3、4、5、6、7、8、9或者10。
  9. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 4为-(OCH 2CH 2) 5OCH 3、-OCH 2CH 2OCH 3、-(OCH 2CH 2) 7OCH 3、-NHCH 2CH 2OCH 3、-NH(CH 2CH 2O) 5CH 3、-NH(CH 2CH 2O) 7CH 3、-CH 2OCH 2CH 2OCH 3、-N(CH3) 2、甲基、甲氧基、三氟甲基、全氟丙基、全氟丁基、-OCH 2CH 2N(CH3) 2、-(OCH 2CH 2) 3OCH 3、-(OCH 2CH 2) 2OCH 3、-CH 2CH 2N(CH3) 2或-CH 2(OCH 2CH 2) 2OCH 3。
  10. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 4和R 6与其所连接的原子一起形成
    Figure PCTCN2021137243-appb-100004
  11. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，D为含有1个或2个N杂原子的5-6元杂芳基；所述杂芳基任选被1个或多个选自卤素、羟基、氧代、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4羟基烷基、C1-C4烷氧基、C2-C4烯基、-(CH 2) 0-4COOH、-(CH 2) 0-4COO(C1-C4烷基)、-(CH 2) 0-4CONH 2、-(CH 2) 0-4CON(C1-C4烷基) 1-2、-(CH 2) 0-4S(O) 2(C1-C4烷基)、-(CH 2) 0-4NH 2、-(CH 2) 0-4N(C1-C4烷基) 1-2、-(CH 2) 0-4S(C1-C4烷基)的取代基取代；优选的D为咪唑基、吡啶基、哒嗪基或嘧啶基；所述咪唑基、吡啶基、哒嗪基或嘧啶基任选被1个或多个选自氧代、Cl、甲基、甲氧基、乙氧基、-COOH、-CONH 2、-CONCH 3、-COOCH 3、乙烯基、氰基、SO 2CH 3、-CH 2OH、-CH 2CH 2OH、-CH 2COOH、-CH 2COOCH 3、-CH 2SO 2CH 3、氨基、-CH 2NH 2、-CH 2N(CH 3) 1-2的取代基取代。
  12. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述式Ⅰ化合物为式ⅠB化合物，
    Figure PCTCN2021137243-appb-100005
    其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、环B、X 1、p、q、n和Q 1如权利要求1中所定义。
  13. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，环B为C3-C6环烷基、含有1个或2个N杂原子的3-6元杂环烷基、含有1-3个N杂原子的5-6元杂芳基或苯基；所述环烷基、杂环烷基、苯基、杂芳基任选被1个或多个选自卤素、羟基、氰基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C1-C6烷氧基取代基取代。
  14. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述式Ⅰ化合物为式ⅠC化合物，
    Figure PCTCN2021137243-appb-100006
    其中所述R 1、R 2、R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q、n和Q 1上权利要求1中所定义。
  15. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 1为氢、氰基、卤素、任选被卤素或羟基取代的C1-C6烷基、C3-C6环烷基或-C(O)Re；所述Re为C1-C6烷基、C3-C8环烷基或含有1-2个选自N或者O杂原子的3-8元杂环烷基；所述烷基、环烷基、杂环烷基任选被一个或多个选自卤素、羟基或氨基的基团取代；或者R 1为-ORe；所述Re为C1-C6烷基；所述烷基任选被卤素取代。
  16. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 1为氢、氰基、F、Cl、Br、三氟甲基、二氟甲基、环丙基、甲酰基、乙酰基、环丙基酰基、二氟甲氧基或三氟甲氧基。
  17. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 1为含有1-4个选自N或O杂原子的5-6杂芳基；所述杂芳基任选被一个或多个选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4羟基烷基的取代基取代；优选R 1为含有1-4个N杂原子的5-6杂芳基，所述杂芳基任选被选自F、Cl、甲基、三氟甲基、三氟乙基、甲氧基的取代基取代；更优选R 1为吡唑基、咪唑基、三氮唑或四氮唑；最优选R 1为四氮唑。
  18. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述式Ⅰ化合物为式ⅠD化合物，
    Figure PCTCN2021137243-appb-100007
    其中所述R 2、R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q、n和Q 1如权利要求1中所定义。
  19. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 2为氢、卤素、任选被卤素或是羟基取代的C1-C6烷基或者-ORe；所述Re为C1-C6烷基，所述烷基任选被一个或多个卤素或羟基取代。
  20. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，R 2为氢、三氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、F或者Cl。
  21. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的 盐，所述式Ⅰ化合物为式ⅠE化合物，
    Figure PCTCN2021137243-appb-100008
    其中所述R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q和Q 1如权利要求1所定义。
  22. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，Q 1为含有1个或2个选自N、O或S杂原子的5-6元杂芳基或6-10元芳基；所述杂芳基、芳基任选被一个或多个R 7取代。
  23. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，Q 1为吡啶、吲哚基、苯并呋喃基、苯并咪唑基、喹啉或苯基；所述吡啶基、吲哚基、苯并呋喃基、苯并咪唑基、喹啉或苯基任选被一个或多个R 7取代。
  24. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述式Ⅰ化合物为式ⅠF化合物，
    Figure PCTCN2021137243-appb-100009
    其中所述R 3、R 4、Ra、Rb、Rc、Rd、X 1、p、q和R 7如权利要求1中所定义；所述u为1、2或者3；
  25. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述R 7为F、Cl、氧代、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、含有1-4个N杂原子的5-6元杂芳基、-COR e、-COOR e、-OR e、-NHS(O) 2R e、NHS(O) 2OR e、NHS(O) 2NHR e、-NHS(O)OR e、-NHS(O)R e、-NHS(O)NHR e、-NHC(O)R e、-NHC(O)OR e、-NHC(O)NHR e、-NR eR f、-CONHS(O) 2R e或-CONHR e；所述R e各自独立的为氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基、C3-C8环烷基、含有1-2个选自N或O杂原子的3-8元杂环烷基、6-10芳基、含有1-4个选自N、O或S杂原子的5-10元杂芳基；所述烷基、环烷基、杂环烷基、芳基和杂芳基任选的被一个或 多个选自-OC(O)(C1-C4烷基)、-COOH、-C(O)O(C1-C4烷基)、-C(O)NH 2、
    -C(O)N(C1-C4烷基) 1-2、氨基、-C(O)(C1-C4烷基)、-O(C1-C4烷基)的取代基取代；所述R f为氢或C1-C6烷基。
  26. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述R 7为F、Cl、四氮唑、-COOH、-COOC(CH 3) 3、-NHC(O)OCH 3、-CONH 2、-CONHCH 3、-CON(CH 3) 2或-NH 2。
  27. 如权利要求1所述的式Ⅰ化合物，或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药、或其药学上可接受的盐，所述式Ⅰ化合物选自
    Figure PCTCN2021137243-appb-100010
    Figure PCTCN2021137243-appb-100011
    Figure PCTCN2021137243-appb-100012
  28. 一种药物组合物，包括治疗有效量的权利要求1-27任一项所述化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，以及药学上可接受的载体、稀释剂或赋形剂。
  29. 权利要求1-27任一项所述化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐制备治疗或预防与FXIa活性相关的疾病或病症的药物的应用。
  30. 权利要求1-27任一项所述化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐制备治疗或预防血栓栓塞性疾病的药物的应用。
  31. 权利要求1-27任一项所述化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐制备治疗或预防动脉心血管血栓栓塞性病症、静脉心血管血栓栓塞性病症、动脉脑血管血栓栓塞性病症及静脉脑血管血栓栓塞性疾病的药物的应用。
  32. 权利要求1-27任一项所述化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐制备治疗或预防不稳定型心绞痛、急性冠状动脉综合征、心房纤维性颤动、初发性心肌梗塞、复发性心肌梗塞、缺血性猝死、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、深部静脉血栓形成、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、肺栓塞性疾病的药物的应用。
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