WO2019011166A1 - 大环酰胺化合物及其药物组合物和用途 - Google Patents

大环酰胺化合物及其药物组合物和用途 Download PDF

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WO2019011166A1
WO2019011166A1 PCT/CN2018/094428 CN2018094428W WO2019011166A1 WO 2019011166 A1 WO2019011166 A1 WO 2019011166A1 CN 2018094428 W CN2018094428 W CN 2018094428W WO 2019011166 A1 WO2019011166 A1 WO 2019011166A1
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alkyl
group
alkylene
compound
saturated
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PCT/CN2018/094428
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English (en)
French (fr)
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朱加望
宋智泉
宋立强
周林
王波
龙冬
赵近伟
曾宏
钮晓达
宋宏梅
周信
谭玉婷
叶启军
苏东海
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Publication of WO2019011166A1 publication Critical patent/WO2019011166A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a macrocyclic amide compound containing a thiophene group, and a process for the preparation of such a macrocyclic amide compound and an intermediate thereof.
  • the invention further relates to a macrocyclic amide compound containing a thiophene group, and to the use of a pharmaceutical composition comprising the same for the prevention or treatment of a thromboembolic disorder.
  • the diseases that currently cause high mortality mainly include malignant tumors, heart disease and stroke.
  • malignant tumors are more likely to develop heart disease and stroke (N. Engl. J. Med., 2000, 342, 1953-1958; J. Cancer. Res. Clin. Oncol, 2012 , 138(1), 141-1151), and many cancer patients eventually die of heart disease and stroke.
  • Medical research suggests that many cardiovascular and cerebrovascular diseases (such as heart disease and stroke) are associated with high blood viscosity. Therefore, drugs that can exert blood thinning effects are very important for the prevention and treatment of major diseases such as malignant tumors, heart diseases and strokes.
  • anticoagulants can be used (such as warfarin) Heparin, low molecular weight heparin (LMWH) and synthetic pentasaccharides) and antiplatelet agents (such as aspirin and clopidogrel) Treatment, but thromboembolic disorders remain the leading cause of death in developed countries.
  • Oral anticoagulant warfarin inhibits post-translational maturation of coagulation factors VII, IX, X and prothrombin and has been shown to be effective against both venous and arterial thrombosis.
  • its use is limited due to its narrow therapeutic window, slow onset of treatment, large interactions between food and drugs, and the need for monitoring and dose adjustment. Therefore, it has become increasingly important to research and develop safe and effective oral anticoagulants to prevent and treat a wide range of thromboembolic disorders.
  • Hemostasis is a beneficial process for maintaining blood in a fluid state and protecting the integrity of the blood vessels.
  • Thrombosis is an unfavorable process that causes vascular occlusion, which is a major cause of the onset and death of cardiovascular and cerebrovascular diseases. It is desirable to reduce thrombin to a level sufficient to prevent thrombus formation while retaining sufficient levels of thrombin to maintain the necessary hemostatic function (Schumacher, Luettgen et al., 2010, Arterioscler Thromb Vasc Biol, 30, 388- 392).
  • the normal coagulation process is a tightly regulated balancing process that maintains the fluid in a fluid state under normal physiological conditions and also provides a mechanism for the rapid formation of a tampon at the site of injury to prevent blood loss and life-threatening.
  • the coagulation cascade comprises a cascade formed by multiple plasma serine protease zymogen tissues that amplify signals generated by an priming event, such as vessel wall damage, to form a tampon under normal physiology. Under pathophysiological conditions, the coagulation cascade can form intra-arterial thrombi at the site of a ruptured atherosclerotic plaque.
  • the cascade can be divided into three interdependent pathways: extrinsic, intrinsic, and common.
  • coagulation factor XIa is located near the source of the intrinsic coagulation pathway, and transforms factor XI into activated coagulation factor XIa by thrombin, which then catalyzes the production of activated IX (IXa) and further produces more Xa.
  • XIa can be formed by self-activation independent of thrombin, or by activated XII (XIIa) or plasma kallikrein.
  • Activated XIa thrombin promotes sustained thrombin generation and inhibition of fibrinolysis.
  • XIa plays a key role in stabilizing thrombus formation, but is not essential for normal hemostasis (Gai Lani, D.
  • factor XIa limits the expansion of thrombin generation by endogenous cascades and has only a limited effect on the coagulation cascade of tissue factor activation (von dem Borne, Cox et al. 2006, Blood Coagul Fibrinolysis, 17, 251-257).
  • factor XI also acts to prevent fibrinolysis.
  • Amplification of factor XI-dependent thrombin generation can also result in activation of thrombin-activated plasmin inhibitors, which can cause blood clots to resist plasmin.
  • inhibition factor XI may directly enhance the dissolution of blood clots (Bouma, Marx et al, 2001, Thromb Res, 101, 329-354).
  • the potential of factor XI as a safe therapeutic target is strongly demonstrated in animal models and hemophilia C patients (Gomez and Bolton-Maggs, Haemophilia, 2008, 14, 1183-1189).
  • the present invention provides a thiophene group-containing macrocyclic amide compound for use as a factor XIa inhibitor, which has excellent inhibitory activity against factor XIa (high affinity for factor XIa) and high selectivity (relative to blood coagulation factor) Xa and VIIa, with higher selectivity for XIa), better physicochemical properties (eg solubility, physical and/or chemical stability), improved pharmacokinetic properties (eg improved bioavailability, suitable More excellent properties such as half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window).
  • inhibitory activity against factor XIa high affinity for factor XIa
  • high selectivity relative to blood coagulation factor
  • Xa and VIIa with higher selectivity for XIa
  • better physicochemical properties eg solubility, physical and/or chemical stability
  • improved pharmacokinetic properties eg improved bioavailability, suitable More excellent properties such as half-life and duration of
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug wherein the compound has the structure of formula (I):
  • R 1 is selected from the group consisting of H, halogen, hydroxy, C 1-6 alkyl, -O-(C 1-6 alkyl), and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, -O- (C 1-6 alkyl) and C 3-6 cycloalkyl are each independently optionally one or more selected from the group consisting of halogen, -OH, cyano, C 1-3 alkyl, -NH- (C 1 Substituted with a substituent of -6 alkyl), -N(C 1-6 alkyl) 2 and -O-(C 1-3 alkyl);
  • a saturated or unsaturated C 3-10 cycloalkylene, saturated or unsaturated 3-10 membered heterocyclic ring which is absent or selected from one or more of R 7 , R 8 and R 9 a C 6-14 arylene group, a 5-14 membered heteroarylene group, a saturated or unsaturated C 5-14 yttrium ring hydrocarbon group, a saturated or unsaturated C 5-14 sirocycloalkyl group, saturated or not a saturated 5-14 membered diaza bridged ring group and a saturated or unsaturated 5-14 membered arylene spiro ring group;
  • R 4 is selected from the group consisting of H, C 1-5 alkyl and C 2-5 alkenyl, wherein said C 1-5 alkyl and C 2-5 alkenyl are each independently optionally one or more selected from halogen , -OH, cyano, C 1-5 alkyl, -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -O-(C 1-3 alkyl) and Substituted with a halogenated C 1-6 alkyl group;
  • R 7 and/or R 8 optionally substituted with R 7 and/or R 8 and which is attached to the remainder of the molecule via a single or double bond through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, said 3-10
  • the nitrogen-containing heterocyclic ring is optionally benzo-fused, and is preferably attached to the remainder of the molecule by a nitrogen atom in the nitrogen-containing heterocyclic ring and any carbon atom in the fused benzene ring;
  • Y is selected from C, CH, CH2, N, NH and O;
  • Y is selected from the group consisting of CH, CH 2 , N, NH and O;
  • R 5 ' is selected from the group consisting of H, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, -OH, -(C 1-4 alkylene)-OH, -O-(C 1 -4 alkyl), -(C 1-3 alkylene)-O-(C 1-3 alkyl), -O-(halogenated C 1-4 alkyl), -NH 2 , -NH-( C 1-6 alkyl) and -N(C 1-6 alkyl) 2 ;
  • R 6 and R 6' together with the carbon atom to which they are attached form a saturated or unsaturated C 5-6 cycloalkyl, optionally saturated or unsaturated 5-6 membered, optionally substituted by halogen and/or -NH 2 .
  • R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, halogen, cyano, oxo, -OH, -(C 1-4 alkylene)-OH, - NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkylene)-NH 2 , -(halogenated C 1-6 Alkyl)-NH 2 , -CONH 2 , -COOH, C 1-6 alkyl, halo C 1-6 alkyl, -O-(C 1-4 alkyl), -(C 1-3 alkylene ))-O-(C 1-3 alkyl), -O-(halogenated C 1-4 alkyl), saturated or unsaturated C 3-6 cycloalkyl, saturated or unsaturated 3-10 membered a cyclic group, a C 6-14 aryl group, a 5-14 membered heteroary
  • W is CH or N.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotope-labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semi-solid formulation, a liquid formulation or a gaseous state preparation.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled
  • a compound, metabolite or prodrug or a pharmaceutical composition of the invention in the manufacture of a medicament for use as a factor XIa inhibitor.
  • the medicament is for preventing or treating a thromboembolic disorder.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled A compound, metabolite or prodrug or a pharmaceutical composition of the invention for use as a factor XIa inhibitor.
  • the blood coagulation factor XIa inhibitor is used to prevent or treat a thromboembolic disorder.
  • Another aspect of the invention provides a method of preventing or treating a thromboembolic disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester or stereoisomer thereof , tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • Another aspect of the invention provides a method of preparing a compound of the invention.
  • alkylene denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), optionally substituted by one or more (such as 1 to 3) suitable substituents Substituted by halogen (in this case the group is referred to as "haloalkyl”) (eg CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl).
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical comprising one double bond and having from 2 to 5 carbon atoms (“C 2-5 alkenyl”).
  • the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compounds of the invention may exist in pure E (enthafen) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl means a linear or branched monovalent hydrocarbon radical comprising one triple bond and having from 2 to 5 carbon atoms (“C 2-5 alkynyl”).
  • the alkynyl group is, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-2-propynyl and 4-methyl-3-pentynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl).
  • cyclooctyl cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl Or bicyclo [5.2.0] anthracenyl, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • the cycloalkyl has 3 to 15 carbons Atom.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl). Or cyclohexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • cycloalkylene and cycloalkyl mean saturated with, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring carbon atoms (ie, , "cycloalkylene” and “cycloalkyl”) or unsaturated (ie having one or more double and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings including, but not limited to Sub)cyclopropyl, (i)cyclobutyl, (sub)cyclopentyl, (sub)cyclohexyl, (sub)cycloheptyl, (sub)cyclooctyl, (sub)cyclodecyl, (sub) Cyclohexenyl and the like.
  • heterocyclyl and “heterocyclylene” mean, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) ring atoms, at least One ring atom is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie having one or more double bonds in the ring and/or A triple bond) cyclic group.
  • “3-10 membered (sub)heterocyclyl” has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and is independently selected from N, O.
  • heterocyclylene group and the heterocyclic group include, but are not limited to, (meth)oxiranyl, (i)aziridine, (a) azetidinyl, (a)oxyheterocycle Oxetanyl, (i)tetrahydrofuranyl, (i)dioxolinyl, (py)pyrrolidinyl, (i)pyrrolidone, (im)imidazolidinyl, (sub)pyridyl Azoliyl, (i)pyrroline, (i)tetrahydropyranyl, (i)piperidinyl, (y)morpholinyl, (di)dithianyl, (sub)sulfur Orolinyl, (i)piperazinyl or (tri)trithianyl.
  • the heterocyclylene group and the heterocyclic group may be optionally substitute
  • (sub)aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-14 (sub)aryl means an aromatic group containing from 6 to 14 carbon atoms, such as (phenylene) or (methylene)naphthyl.
  • the (i)aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • (sub)heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms. , in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which comprise at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen or sulfur), In addition, in each case, it may be benzo-fused.
  • the (sub)heteroaryl group is selected from the group consisting of (i)thienyl, (i)furanyl, (sub)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (sub)imidazolyl, (Asia) Pyrazolyl, (i)isoxazolyl, (i)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl, etc., and their benzo derivative Or (i)pyridinyl, (i)pyridazinyl, (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, and the like, and their benzo derivatives.
  • (sub) bridged cyclic hydrocarbon group means a bicyclic form of carbocyclic group having 5 to 14 ring carbon atoms (C 5-14 ), wherein two carbon rings share more than two ( For example, 3, 4 or 5) carbon atoms, the carbon chain formed by these common carbon atoms acts as a bridge, and the two carbon atoms at both ends of the bridge are called bridgehead carbon.
  • Such (sub) bridged cyclic hydrocarbon groups may have 5 to 11 ring carbon atoms (C 5-11 ), especially 6 to 10 ring carbon atoms (C 6-10 ), for example 7, 8, or 9 ring carbon atoms .
  • Examples of such (sub) bridged cyclic hydrocarbon groups include, but are not limited to, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2. 2.2] octyl, and Bicyclo [3.2.2] fluorenyl, and the divalent group thus obtained (subbridged cyclic hydrocarbon group).
  • the (sub) bridged cyclic hydrocarbon group may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • (sub)spirohydrocarbyl means a bicyclic ring carbocyclic group having 5 to 14 ring carbon atoms (C5-14) wherein two carbon rings share 1 carbon atom (referred to as As a "spiral atom").
  • the (sub)spirocyclic hydrocarbon group may have, for example, 5 to 11 ring carbon atoms (C 5-11 ), particularly 6 to 10 ring carbon atoms (C 6-10 ), for example 7, 8, or 9 ring carbons. atom.
  • Examples of (sub)spirohydrocarbyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.4] Octyl, spiro[3.5]decyl, spiro[4.4]decyl, spiro[4.5]decyl and spiro[5.5]undecyl, and the divalent group thus obtained (spirocycloalkyl).
  • the (sub)spirocyclic hydrocarbon group may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • (a)aza bridged group means a (sub) bridged cyclic hydrocarbon group as described above, wherein at least one (eg 1, 2 or 3) ring carbon atoms other than the bridgehead carbon are Nitrogen atoms are substituted.
  • (a)azaspirocyclo means a (sub)spirocyclic hydrocarbon group as described above, wherein at least one (eg 1, 2 or 3) ring carbon atoms other than a spiro atom are Nitrogen atoms are substituted.
  • the (a)azide bridged or (a)aza spiro group may have 5 to 14 ring members, especially 5 to 10 ring members, for example 6, 7, 8, or 9 ring members.
  • Examples of (sub)azide bridged ring groups include, but are not limited to, monovalent or divalent groups derived from 3-azabicyclo[3.1.1]heptane and 3-azabicyclo[3.2.1]octane.
  • Examples of (sub)aza spirocyclic groups include, but are not limited to, one derived from 2-azaspiro[3.3]heptane, 2-azaspiro[4.4]nonane, and 8-azaspiro[4.5]decane. Valence or divalent group.
  • the (a)azide bridged ring or (a)aza spirocyclic group optionally additionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, provided that said (sub) The bridgehead carbon of the aza bridged ring group or the spiro atom of the (sub)azaspirocyclic group is not a hetero atom.
  • the (sub)azide bridged or (sub)aza spiro group can be attached to the remainder of the molecule through a heteroatom (eg, N) and/or a carbon atom.
  • the (a)azide bridged ring or (a)azaspirocyclyl can be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present.
  • the normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • the term "precursor group” refers to a group that can be converted to a target group by one or more steps known to those skilled in the art.
  • the precursor group when the target group is -COCH 3 , the precursor group may be H; when the target group is C 2-5 alkenyl, the precursor group may be halogen (preferably Br);
  • the target group is -CH(OH)-C 1-3 alkylene-OH, -C(C 1-3 alkyl)(OH)-C 1-3 alkyl or -C(C 1-3 alkane
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); isotopes of carbon (e.g.
  • Chlorine isotope eg 36 Cl
  • fluorine isotopes eg 18 F
  • iodine isotopes eg 123 I and 125 I
  • nitrogen isotopes eg 13 N and 15 N
  • oxygen isotopes eg 15 O
  • phosphorus isotope eg 32 P
  • sulfur isotope eg 35 S
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the carbon-carbon bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof
  • the compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug.
  • a “compound of the invention” it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • N-oxides are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference.
  • the protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein the compound has the structure of formula (I):
  • R 1 is selected from the group consisting of H, halogen, hydroxy, C 1-6 alkyl, -O-(C 1-6 alkyl), and C 3-6 cycloalkyl, wherein the C 1-6 alkyl, -O- (C 1-6 alkyl) and C 3-6 cycloalkyl are each independently optionally one or more selected from the group consisting of halogen, -OH, cyano, C 1-3 alkyl, -NH- (C 1 Substituted with a substituent of -6 alkyl), -N(C 1-6 alkyl) 2 and -O-(C 1-3 alkyl);
  • a saturated or unsaturated C 3-10 cycloalkylene, saturated or unsaturated 3-10 membered heterocyclic ring which is absent or selected from one or more of R 7 , R 8 and R 9 a C 6-14 arylene group, a 5-14 membered heteroarylene group, a saturated or unsaturated C 5-14 yttrium ring hydrocarbon group, a saturated or unsaturated C 5-14 sirocycloalkyl group, saturated or not a saturated 5-14 membered diaza bridged ring group and a saturated or unsaturated 5-14 membered arylene spiro ring group;
  • R 4 is selected from the group consisting of H, C 1-5 alkyl and C 2-5 alkenyl, wherein said C 1-5 alkyl and C 2-5 alkenyl are each independently optionally one or more selected from halogen , -OH, cyano, C 1-5 alkyl, -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -O-(C 1-3 alkyl) and Substituted with a halogenated C 1-6 alkyl group;
  • R 7 and/or R 8 optionally substituted with R 7 and/or R 8 and which is attached to the remainder of the molecule via a single or double bond through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, said 3-10
  • the nitrogen-containing heterocyclic ring is optionally benzo-fused, and is preferably attached to the remainder of the molecule by a nitrogen atom in the nitrogen-containing heterocyclic ring and any carbon atom in the fused benzene ring;
  • Y is selected from C, CH, CH 2 , N, NH and O;
  • Y is selected from the group consisting of CH, CH 2 , N, NH and O;
  • R 5 ' is selected from the group consisting of H, halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, -OH, -(C 1-4 alkylene)-OH, -O-(C 1 -4 alkyl), -(C 1-3 alkylene)-O-(C 1-3 alkyl), -O-(halogenated C 1-4 alkyl), -NH 2 , -NH-( C 1-6 alkyl) and -N(C 1-6 alkyl) 2 ;
  • R 6 and R 6' together with the carbon atom to which they are attached form a saturated or unsaturated C 5-6 cycloalkyl, optionally saturated or unsaturated 5-6 membered, optionally substituted by halogen and/or -NH 2 .
  • R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from H, halogen, cyano, oxo, -OH, -(C 1-4 alkylene)-OH, - NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -(C 1-6 alkylene)-NH 2 , -(halogenated C 1-6 Alkyl)-NH 2 , -CONH 2 , -COOH, C 1-6 alkyl, halo C 1-6 alkyl, -O-(C 1-4 alkyl), -(C 1-3 alkylene ))-O-(C 1-3 alkyl), -O-(halogenated C 1-4 alkyl), saturated or unsaturated C 3-6 cycloalkyl, saturated or unsaturated 3-10 membered a cyclic group, a C 6-14 aryl group, a 5-14 membered heteroary
  • W is CH or N.
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, -O-(C 1-6 alkyl), and C 3-6 cycloalkyl. In a more preferred embodiment, R 1 is H or methyl.
  • R 2 is selected from the group consisting of H and -OH.
  • R 2 and R 3 are on the opposite side of the double bond.
  • Y is selected from the group consisting of CH, O and N. In a more preferred embodiment, Y is attached to a double bond and at this point Y is selected from the group consisting of CH and N.
  • R 4 is selected from the group consisting of H, C 1-5 alkyl and C 2-5 alkenyl. In a more preferred embodiment, R 4 is selected from the group consisting of H and methyl.
  • R 5 ' is selected from the group consisting of H, halogen, cyano, -OH, -O-(C 1-4 alkyl), and -NH 2 . In a more preferred embodiment, R 5 ' is H.
  • B when When it does not exist, B is not H.
  • Selected from It is optionally substituted by one or more of R 7 , R 8 and R 9 .
  • the compound of the invention has formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX) ), the structure of formula (X), formula (XI) or formula (XII):
  • R 13 is selected from the group consisting of H, halogen, C 1-5 alkyl, and halogenated C 1-5 alkyl;
  • the compound of the invention has the structure of formula (II'), formula (IV'), formula (VI'), formula (IX') or formula (XII'):
  • R 4 , R 5 , R 5' , R 6 , R 10 , R 11 and R 12 are as defined for formula (I);
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled a compound, metabolite or prodrug, wherein the compound is selected from the group consisting of:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug, and one or more pharmaceutically acceptable carriers, preferably a solid formulation, a semisolid formulation, a liquid formulation Or a gaseous preparation.
  • the pharmaceutical composition comprises from 0.01 to 1000 mg, suitably from 0.5 to 800 mg, preferably from 1 to 400 mg, more preferably from 5 to 200 mg, particularly preferably from 10 to 100 mg, most preferably from 15 to 50 mg of the invention
  • the invention provides a pharmaceutical composition additionally comprising one or more additional therapeutic agents.
  • the invention provides a pharmaceutical composition wherein the one or more additional therapeutic agents are antiplatelet agents or a combination thereof.
  • the anti-platelet agent is clopidogrel and/or aspirin or a combination thereof.
  • the compounds of the present invention can be administered, for example, in the form of tablets, capsules, each of which comprises a sustained release or a sustained release formulation, pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. . They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms known to those skilled in the medical arts. They can be administered alone, but will generally be administered with a pharmaceutically acceptable carrier selected based on the chosen route of administration and standard pharmaceutical practice.
  • composition means a composition comprising a compound of the invention in combination with at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a generally accepted medium for delivery of a biologically active agent to an animal, particularly a mammal, which includes an adjuvant, excipient or carrier, such as a diluent, preservative, Fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungals, lubricants and dispersing agents.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors that are well within the skill of one of ordinary skill in the art.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid vehicles, as well as a wide variety of solid and semi-solid dosage forms. Such carriers may include, in addition to the active agent, a variety of different ingredients and additives, such other ingredients being included in the formulation for a variety of reasons well known to those of ordinary skill in the art, such as stabilizers, binders and the like. The description of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 18th Ed. (1990).
  • the dosage regimen of the compounds of the invention will vary depending on known factors, such as the pharmacokinetic profile of the particular agent and its mode of administration and route; the recipient's species, age, sex, health, medical condition, and Weight; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the kidney and liver function of the patient; and the desired effect.
  • the physician or veterinarian can determine and specify an effective amount of the drug required to prevent, reverse or prevent the development of a thromboembolic disorder.
  • the daily oral dose of each active ingredient will be from about 0.001 to about 1000 mg/kg body weight, preferably from about 0.01 to about 100 mg/kg body weight/day, and most preferably about 0.1. Up to about 20 mg / kg / day.
  • the most preferred dosage will be in the range of from about 0.001 to about 10 mg/kg/min during a constant rate infusion.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds of the invention may also be administered parenterally (e.g., intravenously, intraarterially, intramuscularly, or subcutaneously).
  • parenterally e.g., intravenously, intraarterially, intramuscularly, or subcutaneously.
  • the dose can be administered continuously or intermittently.
  • the formulations can be developed for intramuscular and subcutaneous delivery to ensure gradual release of the active pharmaceutical ingredient.
  • the compounds of the invention may be administered in intranasal form via topical use of a suitable intranasal vehicle or via a transdermal route using a transdermal skin patch.
  • the dosage administration will of course be continuous rather than intermittent throughout the dosage regimen.
  • the compound is usually suitably combined with a suitable pharmaceutical diluent, excipient or carrier (collectively referred to herein as a carrier) with respect to the intended mode of administration (for example, oral administration of tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.
  • a suitable pharmaceutical diluent, excipient or carrier collectively referred to herein as a carrier
  • the active drug component can be combined with, for example, the following oral, non-toxic, pharmaceutically acceptable inert carriers: lactose, starch, sucrose, glucose, methylcellulose, hard Magnesium citrate, dicalcium phosphate, calcium sulphate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical component can be combined with any of the following oral, non-toxic, pharmaceutically acceptable inert carriers. : Ethanol, glycerin, water, etc.
  • suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture, where desired or necessary.
  • Suitable binders include starch; gelatin; natural sugars such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth or sodium alginate; Polysaccharide; wax; wax; Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium oxide, and the like.
  • Disintegrators include, but are not limited to, starch, methyl cellulose, agar, swell, xanthan gum, and the like.
  • the compounds of the invention may also be administered in the form of liposome delivery systems, such as unilamellar vesicles, monolayer vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.
  • the compounds of the invention may also be coupled to soluble polymers as targetable drug carriers.
  • soluble polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyethylene oxide-polylyl substituted with palmitoyl residues Amino acid.
  • the compounds of the invention may be coupled to, for example, the following types of biodegradable polymers suitable for drug controlled release: polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly ⁇ -caprolactone Crosslinked or amphoteric block copolymers of polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.
  • biodegradable polymers suitable for drug controlled release polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly ⁇ -caprolactone Crosslinked or amphoteric block copolymers of polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.
  • Dosage forms suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient per dosage unit.
  • the active ingredient is typically present in an amount of from about 0.1% to about 95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • Compressed tablets can be made using, for example, a diluent. Both tablets and capsules can be prepared as sustained release products to provide continuous release of the drug over a period of hours.
  • Compressed tablets may be coated with a sugar coating or film to mask any unpleasant taste and protect the tablet from the atmosphere, or coated with an enteric coating to selectively disintegrate in the gastrointestinal tract.
  • Liquid dosage forms for oral administration may contain coloring and flavoring to increase patient acceptance.
  • water a suitable oil, physiological saline, dextrose (glucose) and related sugar solutions and glycols (such as propylene glycol or polyethylene glycol) are suitable carriers for solutions for parenteral administration.
  • the solution for parenteral administration preferably contains a water-soluble salt of the active ingredient, a suitable stabilizer, and if necessary, a buffer substance.
  • Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizers.
  • Citric acid and its salts and sodium EDTA salts are also used.
  • the parenteral solution may contain a preservative such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol.
  • Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference work in the art.
  • a daily dose may range from about 0.1 to about 100 mg of the compound of the invention and from about 0.1 to about 100 mg of anticoagulant per kg of patient body weight.
  • the compounds of the invention will generally be present in amounts of from about 5 to about 100 mg per dosage unit, and the amount of the second anticoagulant will be from about 1 to about 50 mg per dosage unit.
  • the usual daily dose may be from about 0.01 to about 25 mg of the compound of the invention and from about 50 to about 150 mg of the antiplatelet agent per kg of the patient's body weight, preferably From about 0.1 to about 1 mg of the compound of the invention and from about 1 to about 3 mg of the antiplatelet agent.
  • the usual daily dose may be from about 0.1 to about 1 mg of the compound of the present invention per kg of the patient's body weight, and in the case of a thrombolytic agent, as in the case of the present invention
  • the usual dosage of the thrombolytic agent when administered alone can be reduced by about 50-80%.
  • the compounds of the invention when provided in the form of a single dosage unit, there is a possibility of chemical interaction between the combined active ingredients. For this reason, when the compounds of the invention are combined with a second therapeutic agent in a single dosage unit, they are formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (ie, reduce).
  • an active ingredient can be coated with a casing. By coating one of the active ingredients in the casing, it is possible to minimize not only the contact between the combined active ingredients, but also to control the release of one of these components in the gastrointestinal tract so that one of these components is not in the stomach. Released in the intestines.
  • One of the active ingredients may also be coated with a material that affects sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained release component may additionally be coated with an enteric coating such that release of this component occurs only in the intestine.
  • Yet another method would involve a formulation of a combination product in which one component is coated with a sustained and/or enteric release polymer and the other components are also polymerized (eg, low viscosity grade hydroxypropyl methylcellulose (HPMC). Or other suitable materials known in the art to coat to further separate the active components. The polymer coating is used to form an additional barrier to interaction with other components.
  • the invention provides a pharmaceutical composition further comprising one or more additional therapeutic agents selected from the group consisting of antiplatelet agents, thrombin inhibitors, thrombolytic agents, fibrinolytic agents, sera Lipid reducing agent, anti-ischemic agent, potassium channel opener, potassium channel blocker, calcium channel blocker, sodium hydrogen exchanger inhibitor, antiarrhythmia, anti-atherosclerosis, anticoagulation Agent, antithrombotic agent, prothrombin solubilizer, fibrinogen antagonist, diuretic, antihypertensive agent, adenosine triphosphatase (ATPase) inhibitor, mineralocorticoid receptor antagonist, phosphodiesterase inhibition Agents, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis regulators, anti-osteoporosis agents, hormone replacement therapy agents, hormone receptor modulators, oral contraceptives, anti-obesity agents, antidepressants, anti-anxiety agents, Antipsychotics, anti-proliferative agents, anti-
  • the invention provides a pharmaceutical composition further comprising one or more additional therapeutic agents selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, alizarin, A Calcium, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, dipyridamole, dimethoate, diclofenac, sulfinpyrazone, piroxicam, Ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue plasminogen activator, modified sexual tissue plasminogen activator, anipase, urokinase, and streptokinase, or a combination thereof.
  • additional therapeutic agents selected from the group consisting of warfarin, unfractionated heparin, low molecular weight he
  • the compounds of the invention may be administered alone or in combination with one or more other therapeutic agents.
  • “Combination administration” or “combination therapy” means a mammal treated by co-administering a compound of the invention and one or more additional therapeutic agents.
  • the components can be administered sequentially, simultaneously or in any order, at different points in time. Thus, the components can be administered separately but in close proximity to provide the desired therapeutic effect.
  • a preferred example is a triple combination of a compound of the invention, aspirin and another anti-platelet agent.
  • the antiplatelet agent is clopidogrel or prasugrel, more preferably clopidogrel.
  • the compounds of the invention are also useful as standard or reference compounds, for example as a quality standard or control in tests or assays involving inhibition of thrombin, Factor Vila, IXa, Xa, XIa and/or plasma kallikrein.
  • Such compounds are available in commercial kits, for example, for pharmaceutical research involving thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein.
  • a compound of the invention can be used as a reference in assays to compare its known activity to a compound having an unknown activity. Especially when the test compound is a derivative of a reference compound, this will allow the experimenter to ensure that the test is performed properly and provides a basis for comparison.
  • the compounds of the invention can be used to test their efficacy.
  • the compounds of the invention are also useful in diagnostic assays involving thrombin, Factor Vila, IXa, Xa, XIa and/or plasma kallikrein.
  • thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein in an unknown sample can be added to a series of containing chromogenic substrates (eg, using S2366 for Factor XIa)
  • the test sample and optionally a solution of one of the compounds of the invention are tested. If pNA production is observed in a solution containing the test sample, but is not observed in the presence of the compound of the present invention, it is inferred that factor XIa is present.
  • the invention also encompasses articles of manufacture.
  • an article is intended to include, but is not limited to, a kit and a package.
  • the article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable compound thereof Accepted salt forms; and (c) a pharmaceutical insert stating that the pharmaceutical composition can be used to treat thromboembolism and/or inflammatory conditions.
  • the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a thromboembolic and/or inflammatory condition.
  • the article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located inside or outside the second container. Located within the first and second containers means that the separate containers contain the items within their boundaries.
  • the first container is a container for holding a pharmaceutical composition. This container can be used for manufacturing, storage, shipping, and/or single/batch sales.
  • the first container is intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for use in cream formulations) or any other container for making, containing, storing, or dispensing a medicinal product.
  • the second container is a container for holding the first container and the optional package insert.
  • second containers include, but are not limited to, boxes (eg, cardboard or plastic), crates, cartons, bags (eg, paper or plastic bags), pouches, and sacks.
  • the package insert may be physically attached to the exterior of the first container via tape, glue, nails or other attachment means, or it may be placed inside the second container without being attached to the first container by any physical means.
  • the package insert is located outside of the second container.
  • the preferred instructions for the drug are physically attached via tape, glue, nails or other attachment means. Alternatively, it may be adjacent or in contact with the exterior of the second container rather than being physically attached.
  • the package insert is a label, label, logo, etc. that states information relating to the pharmaceutical composition located within the first container.
  • the information presented will typically be determined by the regulatory agency that manages the area in which the product is intended to be sold (eg, the State Food and Drug Administration of the People's Republic of China or the United States Food and Drug Administration).
  • the package insert specifically states that the pharmaceutical composition has approved the available indications.
  • the drug insert can be made of any material that one can read or contain.
  • the package insert is a printable material (eg, paper, plastic, cardboard, foil, back tack paper or plastic, etc.) on which the desired information has been formed (eg, printed or applied).
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof
  • a labeled compound, metabolite or prodrug or a pharmaceutical composition of the invention in the manufacture of a medicament for use as a factor XIa inhibitor.
  • the medicament is for preventing or treating a thromboembolic disorder.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof
  • the blood coagulation factor XIa inhibitor is used to prevent or treat a thromboembolic disorder.
  • the invention provides a method of providing a prophylactic and/or therapeutic thromboembolic disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester thereof, , stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • the thromboembolic disorder comprises an arterial cardiovascular thromboembolic disorder, an intravenous cardiovascular thromboembolic disorder, an arterial cerebrovascular thromboembolic disorder, a venous cerebrovascular thromboembolic disorder, and a cardiac chamber thromboembolism Sexual illness.
  • the thromboembolic disorder comprises unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack , 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, And due to (a) prosthetic valves, indwelling catheters, stents or other implants; (b) extracorporeal circulation; (c) hemodialysis or (d) exposure of the blood to thrombosis caused by artificial surfaces that are prone to thrombosis.
  • the invention provides a method of treating and/or preventing a thromboembolic disorder, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein said first A therapeutic agent is a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug, and the second therapeutic agent is at least one agent selected from the group consisting of a second factor Xa inhibitor, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, and a fibrinolytic agent.
  • a second factor Xa inhibitor an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, and a fibrinolytic agent.
  • the second therapeutic agent is at least one agent selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, alizarin, argatroban, aspirin, ibuprofen, naproxen , sulindac, indomethacin, mefenamate, dimethoate, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide , abciximab, melagatran, desulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anipase, urokinase, and streptokinase.
  • the second therapeutic agent is at least one anti-platelet agent.
  • the one or more anti-platelet agents are clopidogrel and/or aspirin, or a combination thereof.
  • the invention provides a method of treating and/or preventing an inflammatory condition, the method comprising: administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs.
  • inflammatory conditions include, but are not limited to, sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.
  • the invention provides a combined preparation of a compound of the invention in combination with one or more other therapeutic agents, simultaneously, separately or sequentially in therapy.
  • the invention provides a combined preparation of a compound of the invention and one or more additional therapeutic agents for simultaneous, separate or sequential use in the treatment and/or prevention of a thromboembolic disorder.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • treatment encompasses the treatment of a disease condition in a mammal, particularly a human, and includes: (a) inhibiting the disease condition, ie, preventing its progression; and/or (b) reducing the disease condition, ie causing the disease condition to subside.
  • control encompasses the prophylactic treatment of a subclinical disease condition in a mammal, particularly a human, with the aim of reducing the likelihood of developing a clinical disease condition.
  • Patients selected for prophylactic therapy are selected based on factors known to increase the risk of clinical disease conditions compared to the general population.
  • Control therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treating an individual who has not yet presented a clinical disease condition, while secondary prevention is defined as preventing a secondary occurrence of the same or similar clinical disease condition.
  • disk reduction as used herein encompasses a therapy that reduces the incidence of developing a clinical disease condition.
  • primary and secondary prevention therapies are examples of reduced risk.
  • “Therapeutically effective amount” is intended to include an amount of a compound of the invention effective to inhibit Factor XIa, either alone or in combination, to prevent or treat the conditions listed herein. When applied to a combination, the term refers to a combined amount of the active ingredient which produces a prophylactic or therapeutic effect, whether administered continuously or simultaneously.
  • thrombosis refers to the formation or presence of a thrombus; an intravascular coagulation that may cause ischemia or an infarction of tissue supplied by a blood vessel.
  • symbolization refers to a sudden blockage of an artery caused by a clot or foreign matter carried by a bloodstream to a deposition site.
  • thromboembolic refers to a vascular occlusion caused by a thrombotic substance that is carried by a bloodstream from an initial location to block another blood vessel.
  • thromboembolic disorders refers to "thrombosis” and “embolic” disorders.
  • thromboembolic disorders includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart or peripheral circulation.
  • thromboembolic disorder also includes a particular condition selected from, but not limited to, unstable angina or other acute coronary syndrome, atrial fibrillation, primary or recurrent Myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, brain Arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or procedures that are exposed to blood by an artificial surface that promotes thrombosis.
  • Medical implants or devices include, but are not limited to, prosthetic valves, prosthetic valves, indwelling catheters, stents, blood oxygenators, shunts, vascular interfaces, ventricular assist devices, and artificial hearts or hearts Chamber and vascular grafts.
  • Surgical procedures include, but are not limited to, cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis.
  • thromboembolic disorders includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.
  • stroke refers to embolic stroke or arteriosclerotic thrombosis caused by occlusive thrombosis in the carotid communis, carotid interna, or intracranial arteries. Stroke (atherothrombotic stroke).
  • thrombosis includes vascular occlusion (eg, after a bypass) and reocclusion (eg, during or after percutaneous transluminal coronary angioplasty).
  • Thromboembolic disorders can be caused by conditions including, but not limited to, atherosclerosis, surgical or surgical complications, long-term fixation, arterial fibrillation, congenital thrombophilia, cancer, diabetes The effects of drugs or hormones and pregnancy complications.
  • Thromboembolic disorders are often associated with patients with atherosclerosis.
  • Risk factors for atherosclerosis include, but are not limited to, male gender, age, hypertension, lipid disorders, and diabetes. Risk factors for atherosclerosis are also risk factors for atherosclerotic complications (ie, thromboembolic disorders).
  • arterial fibrillation is often associated with thromboembolic disorders.
  • Risk factors for arterial fibrillation and secondary thromboembolic disorders include cardiovascular disease, rheumatic heart disease, non-rheumatic mitral valve disease, hypertensive cardiovascular disease, chronic lung disease, and a variety of mixed cardiac abnormalities and thyrotoxicosis disease.
  • Diabetes is often associated with atherosclerosis and thromboembolic disorders. More common types 2 risk factors include (but are not limited to) family history, obesity, physical inactivity, race/ethnicity, previously fasting glucose or glucose tolerance test, pregnancy A history of diabetes or childbirth "big baby", high blood pressure, low HDL cholesterol and polycystic ovarian syndrome.
  • Risk factors for congenital thrombotic tendency include increased coagulation factor function mutations or loss of functional mutations in the anticoagulant or fibrinolytic pathway.
  • Thrombosis has been found to be associated with a variety of tumor types, such as pancreatic cancer, breast cancer, brain tumors, lung cancer, ovarian cancer, prostate cancer, gastrointestinal malignancies, and Hodgkins or non-Hodgkin's (non -Hodgkins) Lymphoma.
  • tumor types such as pancreatic cancer, breast cancer, brain tumors, lung cancer, ovarian cancer, prostate cancer, gastrointestinal malignancies, and Hodgkins or non-Hodgkin's (non -Hodgkins) Lymphoma.
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Thin layer chromatography was performed using a GF 254 (0.4-0.5 nm) silica gel plate from Yantai.
  • the reaction was monitored by thin layer chromatography (TLC) or LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, solvents.
  • TLC thin layer chromatography
  • LC-MS LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, solvents.
  • the volume ratio is adjusted depending on the polarity of the compound, or is adjusted by adding triethylamine or the like.
  • the eluent system includes, but is not limited to, a dichloromethane and methanol system, and a n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine or the like.
  • the temperature of the reaction is room temperature (20 ° C to 30 ° C) unless otherwise specified in the examples.
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
  • the compounds of the invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials employed and suitable for effecting the conversion.
  • Those skilled in the art of organic synthesis should be aware that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the following determination: modify the order of the synthetic steps or route another specific method route relative to one method to obtain the desired compound of the invention.
  • X represents halogen or a C 1-3 alkyl sulfonate group optionally substituted by halogen (for example, a triflate group); and R 5a and R 5a' with R 5 and R 5 ' Identical, or R 5a and R 5a' are groups which can be converted to R 5 and R 5 ' by one or more steps known to those skilled in the art, in which case R 5a can be H (for example, when R 5 When -COCH 3 is, R 5a is H, or when R 5' is -NH-(C 1-6 alkyl), R 5a' is -NO 2 ); R 6a and R 6a' and R 6 and R 6' identical, or R 6a and R 6a' are groups which can be converted to R 6 and R 6 ' by one or more steps known to those skilled in the art (for example, when R 6 and/or R 6' are -COOH, R 6a and / or R 6a ' is -COO (C 1-3 alkyl
  • the conversion of the protecting group can be accomplished in the next two steps. For example, a 4 M hydrochloric acid dioxane solution is slowly dropped into the reaction system, and after completion of the reaction, Compound 1-4 is obtained. The amino group in compound 1-4 is protected with Boc to give compound 1-5. Suzuki-Miyaura coupling of compound 1-5 and Int-1a (in a solvent such as dimethyl sulfoxide or a mixed solvent of dimethyl sulfoxide and water or dimethylformamide) in a base such as phosphoric acid In the presence of potassium), a catalyst (for example, Pd(dppf)Cl 2 .CH 2 Cl 2 complex) is used to obtain a compound 1-6.
  • a catalyst for example, Pd(dppf)Cl 2 .CH 2 Cl 2 complex
  • Boron pinacolate can be used (boronpinacolate
  • the intermediate is substituted for boric acid for coupling to an aryl/heteroaryl halide or triflate, or the boron pinacol ester intermediate can be converted to boric acid.
  • it can be substituted for aryl/heteroaryl
  • the base halide undergoes metal-halogen exchange, quenched with a trialkoxy boronate reagent and water After treatment to prepare corresponding boronic acid to give (Miyaura, N et al., Chem.Rev, 95:.. 2457 (1995)).
  • one or more steps in Route 1 may be omitted depending on the desired product structure (eg, when the bond between R 2 and R 3 is a double bond, the eighth step may be omitted).
  • the eighth step may be omitted.
  • art may be (for example, R 6a and R 6a after the fifth step 'is converted to R 6 and R 6' one or more steps of the conversion reaction) it needs to be adjusted according to the respective order of the steps.
  • Triethylamine (3.9 mL) was added to a mixed solution of 3-amino-4-bromobenzoic acid (SM-1-1) (5.0 g, 23.1 mmol) in DMF (100 mL) and MeOH (10 mL). , 27.8 mmol).
  • SM-1-1 3-amino-4-bromobenzoic acid
  • the reaction solution was heated to 100 ° C, and DPPA (6.0 mL, 27.8 mmol) was added dropwise. After stirring at the same temperature for 3 hours, it was cooled to room temperature. Diethyl acetate and water were added, and the mixture was combined with EtOAc. -2 (4.5 g, 80%).
  • Step 6 ((S)-1-(4-(4-((methoxycarbonyl))amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)thiophene Preparation of 2-butyl)but-3-en-1-yl)carbamic acid tert-butyl ester (A-7)
  • Step 7 tert-Butylmethyl ((1 2 Z,5R,6E,9S)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2 (1,2 Preparation of benzo-indolyl-6-ene-2 4 ,9-diyl)dicarbamate (A-8)
  • Step 8 tert-Butylmethyl((5R,9S,Z)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2(1,2)-benzene Preparation of Cyclohexyl-2 4 ,9-diyl)dicarbamate (Int-A)
  • the compound A-8 (500 mg, 1.05 mmol) was dissolved in 20 mL of methanol, and then Pd/C (200 mg, 10%) was added, and the mixture was heated to 40 ° C for 48 hours under a hydrogen atmosphere. After the reaction was completed by TLC, the reaction mixture was filtered, and the filtrate was concentrated to afford tod-A (401 mg, 80%).
  • Example D ((5R,9S,Z)-1 5 -acetyl-9-amino-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2 ( ) 1,2 - preparation yl) carbamate hydrochloride (Int-B) - a benzene aromatic heterocyclic nonyl -24
  • Second step ((5R,9S,Z)-1 5 -acetyl-9-amino-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2 ) 1,2 - preparation yl) carbamate hydrochloride (Int-B) - a benzene aromatic heterocyclic nonyl -24
  • Example F ((5R,9S,Z)-9-Amino-1 5 -((dimethylamino)methyl)-5-methyl-4-oxo-3-aza-1 (4, 2) - thiophene-heteroaryl-2 (1,2) - preparation yl) carbamate dihydrochloride (Int-C) - a benzene aromatic heterocyclic nonyl -24
  • Second step ((5R,9S,Z)-9-amino-1 5 -((dimethylamino)methyl)-5-methyl-4-oxo-3-aza-1 (4, 2) - thiophene-heteroaryl-2 (1,2) - preparation yl) carbamate dihydrochloride (Int-C) - a benzene aromatic heterocyclic nonyl -24
  • SM-4-1 The compound 3-amino-4-bromobenzoic acid (SM-4-1) (10.8 g, 50 mmol) was dissolved in MeOH (50 mL), chlorosulfone (11.9 g, 100 mmol) The reaction was carried out at ° C for 2 hours, and the reaction was monitored by LC-MS. The reaction mixture was concentrated, saturated NaHCO 3 adjusted pH> 7, and extracted with EA, dried over anhydrous sodium sulfate, and concentrated to give the desired product SM-4-2 (tan solid, 10.5g, 91%).
  • Example 1 ((5R,9S,Z)-9-((1r,4S)-4-(Aminomethyl)cyclohexane-1-carboxamido)-5-methyl-4-oxo- 1 5 -(prop-1-en-2-yl)-3-aza-1(4,2)-thiophene-2(1,2)-benzeneheteroline aryl-2 4 -yl)carbamic acid Preparation of methyl ester (1)
  • the second step tert-butylmethyl ((5R,9S,Z)-5-methyl-4-oxo-1 5 -(prop-1-en-2-yl)-3-aza-1 (4, 2) - thiophene-heteroaryl-2 (1,2) - benzene aromatic heterocyclic -24 nonyl, 9-yl) dicarbamate (T1-2) preparation of
  • the third step ((5R,9S,Z)-9-amino-5-methyl-4-oxo-1 5 -(prop-1-en-2-yl)-3-aza-1 (4 ) thiophene-heteroaryl-2 (1,2 - - carbamic acid methyl ester hydrochloride (T1-3) the base) -, 2) a heterocyclic non aromatic benzene -24
  • Step 4 ((5R,9S,Z)-9-((1r,4S)-4-((((9H- ⁇ -9-yl)methoxy)carbonyl)amino)methyl)methyl)cyclohexane Alkyl-1-formylamino)-5-methyl-4-oxo-1 5 -(prop-1-en-2-yl)-3-aza-1(4,2)-thiophene-2 preparation yl) carbamate (T1 - 4) - a (1,2) - benzene aromatic heterocyclic nonyl -24
  • Step 5 ((5R,9S,Z)-9-((1r,4S)-4-(aminomethyl)cyclohexane-1-carboxamido)-5-methyl-4-oxo- 1 5 -(prop-1-en-2-yl)-3-aza-1(4,2)-thiophene-2(1,2)-benzeneheteroline aryl-2 4 -yl)carbamic acid
  • Example 2 ((5R,9S,Z)-9-((1r,4S)-4-(aminomethyl)cyclohexane-1-carboxamido)-5-methyl-4-oxo- preparation yl) carbamate (2) --15-- vinyl-3-aza-1 (4,2) - thiophene-heteroaryl-2 (1,2) - benzene aromatic heterocyclic nonyl -24
  • Example 3 ((5R,9S,Z)-1 5 -acetyl-9-((1r,4S)-4-(aminomethyl)cyclohexane-1-carboxamido)-5-methyl Methyl 4-oxo-3-aza-1(4,2)-thiophene-2(1,2)-phenylheteroline-aryl-2 4 -yl)carbamate hydrochloride (TM3) preparation
  • T3-2 was dissolved in 20 mL of methanol, and then 4N hydrogen chloride/dioxane solution (10 mL) was added thereto, and after stirring at room temperature for 4 hours, it was directly concentrated, and then the residue was dissolved with a small amount of methanol, and dropped therein. Ethyl acetate was added until the solid was completely precipitated, and the title compound (0.87 g, yield: 67%) was obtained by filtration.
  • Example 4 ((5R,9S,Z)-1 5 -acetyl-9-(4-(aminomethyl)-3-cyclopropylbenzoylamino)-5-methyl-4-oxo 3-aza-1 (4,2) - thiophene-heteroaryl-2 (1,2) - carbamic acid methyl ester hydrochloride (TM4) of yl) - benzene aromatic heterocyclic nonyl -24
  • Step 5 (4-((5R,9S,Z)-1 5 -acetyl-2 4 -((methoxycarbonyl)amino)-5-methyl-4-oxo-3-aza) -1(4,2)-thiophene-2(1,2)-phenylheteroaryl-9-yl)carbamoyl)-2-cyclopropylbenzyl)(tert-butoxycarbonyl)carbamic acid
  • T4-6 butyl ester
  • T4-6 was synthesized in a manner similar to that described in the first step of Example 3 except that T4-5 was used instead of T3-1 in the first step of Example 3.
  • Step 6 ((5R,9S,Z)-1 5 -acetyl-9-(4-(aminomethyl)-3-cyclopropylbenzoyl)-5-methyl-4-oxo- 3-aza-1 (4,2) - thiophene-heteroaryl-2 (1,2) - preparation yl) carbamate hydrochloride (TM4) - a benzene aromatic heterocyclic nonyl -24
  • TM4 was synthesized in a manner similar to that described in the second step of Example 3.
  • the total yield of the fifth and sixth steps was 60%.
  • Example 5 ((5R,9S,Z)-1 5 -acetyl-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) Phenyl)-6-oxo-3,6-dihydropyridine-1(2H)-yl)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene preparation yl) carbamate (5) - nonyl benzene aromatic heterocyclic -24---2 (1,2)
  • Acetonitrile (200 mL) and T5-1 (2.00 g, 12.86 mmol) were sequentially added to a 500 mL one-necked flask, and the mixture was stirred for 20 minutes in an ice bath. Then isoamyl nitrite (3.01 g, 25.71 mmol) and TMSN 3 (2.96 g, 25.71 mmol) were added sequentially and stirring was continued for 20 min. The ice bath was removed, the temperature was raised to 30 ° C for 2 hours, and TLC was monitored until the starting material was completely reacted.
  • the second step preparation of 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde (T5-3)
  • Step 5 ((5R,9S,Z)-1 5 -acetyl-9-(N-(3-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-) 1-yl)phenyl)-3-oxopropyl)-2-(diethoxyphosphoryl)acetamido)-5-methyl-4-oxo-3-aza-1 (4,2 ) - thiophene-heteroaryl-2 (1,2) - preparation yl) carbamate (T5-6) - a benzene aromatic heterocyclic nonyl -24
  • Step 6 ((5R,9S,Z)-1 5 -acetyl-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) Phenyl)-6-oxo-3,6-dihydropyridine-1(2H)-yl)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene preparation yl) carbamate (5) - nonyl benzene aromatic heterocyclic -24---2 (1,2)
  • Example 6 ((5R,9S,Z)-1 5 -acetyl-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) Phenyl)-6-oxopyrimidine-1(6H)-yl)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2(1,2) - preparation yl) carbamate (6) - benzene aromatic heterocyclic nonyl -24
  • the third step 4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine Preparation of (T6-4)
  • Step 5 6-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)-one (T6-6) preparation
  • Step 6 ((5R,9S,Z)-1 5 -acetyl-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) Phenyl)-6-oxopyrimidine-1(6H)-yl)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2(1,2) - preparation yl) carbamate (6) - benzene aromatic heterocyclic nonyl -24
  • Example 7 ((5R,9S,Z)-1 5 -acetyl-5-methyl-4-oxo-9-((1r,4S)-4-(((Z)-4-oxo) Depent-2-en-2-yl)amino)methyl)cyclohexane-1-carboxamido)-3-aza-1(4,2)-thiophene-2(1,2)-benzene Preparation of Methyl Heterocyclic Indolyl-2 4 -yl)carbamate (7)
  • Example 8 ((5R,9S,Z)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6 -oxo-3,6-dihydropyridine-1(2H)-yl)-5-methyl-4-oxo-1 5 -(prop-1-en-2-yl)-3-aza- 1 (4,2) - thiophene-heteroaryl-2 (1,2) - nonyl benzene aromatic heterocyclic -24-- yl) carbamate (9) preparation of
  • Compound 9 was synthesized in a manner similar to that described in the first step to the sixth step of Example 5, except that in the fifth step of Example 8, T1-3 was used instead of the Int-B of the fifth step of Example 5.
  • Compound TM41 was synthesized in a manner similar to that described in the first step to the sixth step of Example 4 except that in the fifth step of Example 9, substituting T1-3 for Int-B of the fifth step of Example 4.
  • Example 10 ((5R,9S,Z)-9-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6 -oxo-3,6-dihydropyridine-1(2H)-yl)-1 5 -(1,2-dihydroxypropan-2-yl)-5-methyl-4-oxo-3-nitrogen preparation yl) carbamate (73) - heteroaryl 1 (4,2) - thiophene-heteroaryl-2 (1,2) - benzene aromatic heterocyclic nonyl -24
  • TM75 was synthesized in a similar manner to that described in Example 10 except that the compound of Example 10 was replaced with TM41 in Example 11.
  • T76-1 (330 mg, 0.49 mmol) was dissolved in 20 mL of methanol, and then 10 mL of a dioxane hydrochloride solution was added thereto, and stirred at room temperature for 3 to 4 hours, and then directly concentrated to dryness to give a title compound. (213 mg, 71%).
  • Example 13 (5R,9S,Z)-1 5 -acetyl-9-((1r,4S)-4-(aminomethyl)cyclohexane-1-carboxamido)-5-methyl- Preparation of 4-oxo-3-aza-1(4,2)-thiophene-2(1,2)-benzeneheterocyclic aryl-2 4 -formate hydrochloride (TM47)
  • Second step 4-(5-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)thiophen-3-yl)-3-((R)-2 Synthesis of methyl-methylbut-3-enoylamino)benzoate (47-2)
  • the intermediate SM-2 (388 mg, 3.9 mmol) was dissolved in DCM (10 mL) under nitrogen, and a few drops of DMF was added, and oxalyl chloride (655 mg, 5.1 mmol) was slowly added dropwise in an ice bath, and the conditions in the ice bath were continued. Stir for 30 minutes, then warm to room temperature and stir for 1 hour until use.
  • Step 5 ((5R,9S,Z)-1 5 -bromo-9-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-3-aza-1 (4,2 Synthesis of thiophene-2(1,2)-benzene heterocyclic aryl- 2-4 -carboxylate (47-5)
  • Step 6 ((5R,9S,Z)-1 5 -acetyl-9-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-3-aza-1 (4, Synthesis of 2)-Thiophene-2(1,2)-benzene Heterocyclic Amino-2 4 -carboxylate (47-6)
  • reaction mixture was cooled to room temperature, then 1 mL of 3N hydrochloric acid was added, and water was added thereto, and the mixture was extracted with EA, dried over anhydrous sodium sulfate, and then concentrated and purified by column chromatography to give the desired product 47-6 (yellow oil, 130 mg) , 76%).
  • Step 7 ((5R,9S,Z)-1 5 -acetyl-9-amino-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2 ( Synthesis of 1,2)-Benzene Heterocyclic Amino-2 4 -carboxylate (47-7)
  • Step 8 ((5R,9S,Z)-1 5 -acetyl-9-((1r,4S)-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-methyl Amido)-5-methyl-4-oxo-3-aza-1(4,2)-thiophene-2(1,2)-benzeneheteroline aryl-2 4 -carboxylate (47 -8) Synthesis
  • Step 9 (5R, 9S, Z)-1 5 -acetyl-9-((1r,4S)-4-(aminomethyl)cyclohexane-1-carboxamido)-5-methyl- 4-oxo-3-aza-1 (4,2) - thiophene-heteroaryl-2 (1,2) ---24 non aromatic heterocycle benzene - carboxylic acid hydrochloride (TM47) of
  • Test Example 1 Detection of inhibitory factor XIa activity
  • Enzyme Human Factor XIa, purchased from Haemtech.
  • Substrate Boc-Ile-Glu-Gly-Arg-AMC acetate, available from Bachem.
  • test compound was dissolved in assay buffer (50 mM HEPES, 145 mM NaCl, 5 mM KCl, 0.1% BSA, pH 7.4) at various concentrations.
  • Factor XIa and the test compound were added to a 384-well plate, mixed and incubated for 10 minutes at room temperature. The reaction was initiated by the addition of a substrate (Boc-Ile-Glu-Gly-Arg-AMC acetate).
  • substrate Boc-Ile-Glu-Gly-Arg-AMC acetate
  • the 384-well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value. Read once every 30 seconds and continuously read 20 cycles. The inhibition rate of the enzyme activity of each test group was calculated during the linear reaction period.
  • concentration-inhibition rate signal curve of the test compound was prepared using the mapping software Prism 5, and the IC 50 value
  • Example 5 1.07 ⁇ 0.10 Example 6 0.82 ⁇ 0.07 Example 8 3.63 ⁇ 0.56 Example 9 0.51 ⁇ 0.05 Example 10 0.57 ⁇ 0.03 Example 11 1.98 ⁇ 0.15 Example 12 1.49 ⁇ 0.15
  • the compound of the present invention has an IC 50 of the factor XIa of the order of nM.
  • IC 50 of the compound is less than 4.0nM, IC 50 less than the preferred compounds 1.0nM, IC 50 less than the most preferred compounds 0.5nM.
  • Test Example 2 Detection of inhibitory factor VIIa activity
  • Enzyme Human Factor VIIa; purchased from Haematologic Technologies.
  • Substrate Boc-VPR-AMC; purchased from R&D.
  • Tissue factor Tissue factor F3, purchased from Sino Biological.
  • Detection method The test compound was dissolved in a detection buffer (50 mM Hepes, 150 mM NaCl, 5 mM CaCl 2 , pH 7.4). Factor VIIa and tissue factor were mixed at an equimolar concentration, and after incubation at 37 ° C for 15 minutes, the test compound was added, incubated at room temperature for 10 minutes, and finally the substrate (Boc-VPR-AMC) was added to initiate the reaction.
  • the plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value. Read once every 30 seconds and continuously read 20 cycles. The inhibition rate of the enzyme activity of each test group was calculated during the linear reaction period. The range of IC 50 was judged based on the inhibition rate at different concentrations.
  • Test Example 3 Detection of inhibitory factor Xa activity
  • Enzyme Human Factor Xa, purchased from R&D.
  • test compound was first dissolved in assay buffer (50 mM Tris, 150 mM NaCl, 10 mM CaCl 2 , 0.05% Brij 35, pH 7.5).
  • Factor Xa and the test compound were added to a 384-well plate, mixed and incubated for 10 minutes at room temperature.
  • the reaction was initiated by the addition of substrate (Mca-RPKPVE-Nval-WRK (Dnp)-NH2).
  • substrate Mca-RPKPVE-Nval-WRK (Dnp)-NH2
  • the plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was 320 nm, and the emission light wavelength was 405 nm to read the fluorescence value. Read once every 30 seconds and continuously read 20 cycles.
  • the inhibition rate of the enzyme activity of each test group was calculated during the linear reaction period. The range of IC 50 was judged based on the inhibition rate at different concentrations.
  • Example 1 >20
  • Example 2 >20
  • Example 3 >20
  • Example 4 >20
  • Example 6 >20
  • Test Example 4 Effect of compound on coagulated APTT (activated partial thromboplastin time) and PT (prothrombin time) in vitro
  • APTT reagent was purchased from Sysmex.
  • PT reagent was purchased from Sysmex.
  • the upper layer of plasma is collected by centrifugation, and the same amount is divided into multiple portions, and different test compounds are added thereto, so that the final concentration of the test compound is 10 ⁇ M, and the mixture is mixed at 37 ° C. Incubate for 3 minutes, then place the sample in the Sysmexcon Automated Coagulation Analyzer CA1500 for APTT and PT detection.
  • the blank group plasma (without compound) was used as a control, and the ratio of APTT and PT of all test groups to blank plasma was calculated.
  • the endogenous coagulation pathway is initiated to activate XIa.
  • the APTT is prolonged (the ratio of plasma APTT to the blank group is greater than 1); while the PT reagent is activated
  • the source of the coagulation pathway is not associated with XIa, and the addition of XIa inhibitor does not prolong PT (a ratio of plasma PT to the blank group is approximately 1).
  • the compounds of the present invention prolong APTT in the blood of dogs and humans, indicating that the compounds of the present invention inhibit endogenous coagulation pathways in dogs and humans.
  • the compounds of the invention have similar effects on APTT and PT in mouse, rat, and monkey plasma.
  • Test Example 5 In vitro safety test
  • Example 1 >10
  • Example 2 >10
  • Example 3 >10
  • Example 4 >10
  • Example 5 >10
  • Example 6 >10
  • Example 9 >10
  • Example 10 >10
  • Example 11 >10
  • Example 12 >10
  • the compounds of the present invention have an IC 50 for hERG of more than 10 ⁇ M. Therefore, the compound of the present invention has no inhibitory effect on hERG and has no safety hazard leading to prolongation of the QT interval of the heart.
  • arteriovenous shunt thrombosis model tests were performed on rats, mice, dogs and monkeys. The test results showed that thrombus formation was effectively inhibited after administration of the compounds of the respective examples.

Abstract

本发明涉及含噻吩基团的大环酰胺化合物，以及该类大环酰胺化合物及其中间体的制备方法。本发明还涉及含噻吩基团的大环酰胺化合物，以及包含该类化合物的药物组合物用于预防或治疗血栓栓塞性病症的用途。

Description

大环酰胺化合物及其药物组合物和用途 发明领域
本发明涉及含噻吩基团的大环酰胺化合物，以及该类大环酰胺化合物及其中间体的制备方法。本发明还涉及含噻吩基团的大环酰胺化合物，以及包含该类化合物的药物组合物用于预防或治疗血栓栓塞性病症的用途。
发明背景
当前导致高死亡率的疾病主要包括恶性肿瘤、心脏病和中风等。同时，临床上也发现，患有恶性肿瘤的患者往往更易患上心脏病和中风(N.Engl.J.Med.，2000，342，1953-1958；J.Cancer.Res.Clin.Oncol，2012，138(1)，141-151)，并且许多癌症患者最终死于心脏病和中风。医学研究认为，许多心脑血管疾病(诸如心脏病和中风等)与血液粘度过高有关。因此，可发挥血液稀释作用的药物对于恶性肿瘤、心脏病和中风等重大疾病的预防和治疗是非常重要。
尽管可使用抗凝血药(诸如华法林
Figure PCTCN2018094428-appb-000001
肝素、低分子量肝素(LMWH)和合成五糖)以及抗血小板药(诸如阿司匹林和氯吡格雷
Figure PCTCN2018094428-appb-000002
)进行治疗，但血栓栓塞性病症仍然是发达国家中死亡的主要原因。口服抗凝血药华法林抑制凝血因子VII、IX、X和凝血酶原的转译后成熟，并已证明其对静脉和动脉血栓二者有效。然而，由于其狭窄的治疗窗口、治疗作用起效慢、食物和药物间相互作用大及需要监测和剂量调整，其用途受到限制。因此，研究和开发安全和有效的口服抗凝血药以预防和治疗广泛的血栓栓塞性病症已经变得日益重要。
止血是维持血液呈液体状态并保护血管完整性的有利过程。血栓形成则是造成血管阻塞的不利过程，其为造成心脑血管疾病发病和致死的主要因素。可将凝血酶减少到足以阻止血栓形成的水平，同时又能保留足够水平的凝血酶维持必要的止血功能的药物是理想的(Schumacher，Luettgen等人，2010，Arterioscler Thromb Vasc Biol，30，388-392)。
正常的凝血过程是一个多种因素紧密调节的平衡过程，其保持血液在正常生理条件下为流体状态，同时也提供用于在损伤部位迅速形成止血塞，以防止血液流失而危及生命的机制。凝血级联包含由多个血浆丝氨酸蛋白酶酶原组织形成的级联，其用于放大由一引发事件(如血管壁损伤)产生的信号，从而在正常生理下形成止血塞。在病理生理条件下，凝血级联可在破裂的粥样硬化斑块部位形成动脉内血栓。所述级联可分成三个相互依存的途径：外在(extrinsic)、内在(intrinsic)和共同(common)途径。其中，凝血因子XIa位于内在凝血途径的源头附近，通过凝血酶将凝血因子XI转化为激活的凝血因子XIa，随后催化产生激活的IX(IXa)，并进一步产生更多的Xa。XIa可以通过独立于凝血酶的自我激活形成，也可由活化的XII(XIIa)或血浆激肽释放酶来激活。激活的XIa凝血酶会促使持续不断的凝血酶的生成和纤维蛋白溶解的抑制。XIa对稳定血栓的形成发挥着关键作用，但对正常止血并不是必需的因子(Gai Lani，D.等人，Arterioscler.Thromb.Vasc.Biol.，27：2507-2513(2007))。大量爆发性(burst)生成的凝血酶使纤维蛋白原转化为纤维蛋白，其聚合形成血液凝结的结构骨架，并激活作为凝结的关键细胞组分的血小板(Hoffman，M.，Blood Reviews，17：S1-S5(2003))。因此，凝血因子XIa在传递这种放大环路中起关键作用，并因此成为抗血栓形成治疗中有吸引力的药物靶点。
研究表明，抑制凝血因子XIa能限制通过内源性的级联反应造成的凝血酶产生的扩增，同时对组织因子激活的凝固级联反应仅有有限的影响(von dem Borne，Cox等人，2006，Blood Coagul Fibrinolysis，17，251-257)。除了影响凝血酶的产生，凝血因子XI还发挥抗纤维蛋白溶解的作用。凝血因子XI依赖的凝血酶产生的扩增也会导致凝血酶激活的纤维蛋白溶酶抑制物的激活，该抑制物会使血凝块对纤维蛋白溶酶产生抵抗。也就是说，抑制因子XI可能会直接增强血凝块的溶解(Bouma，Marx等人，2001，Thromb Res，101，329-354)。因子XI作为安全的治疗靶点的潜力在动物模型和血友病C患者中得到有力的证实(Gomez和Bolton-Maggs，Haemophilia，2008，14，1183-1189)。
近年来有许多关于开发凝血因子XIa抑制剂，将其作为血液稀释剂来治疗或阻止血栓形成(静脉及动脉血栓)的报道(Bioorg.Med.Chem.Lett.，26(2016)，472-478；Bioorg.Med.Chem.，24(2016)，2257-2272)。但是已开发的凝血因子XIa抑制剂在体内的吸收或代谢稳定性等方面仍然存在不足，不能令人满意。因此，开发得到对XIa抑制性更强，并且具有改善的稳定性、药物代谢动力学性质和/或毒副作用等性质的新型凝血因子XIa抑制剂是迫切希望的。
发明概述
本发明提供用作凝血因子XIa抑制剂的含有噻吩基团的大环酰胺化合物，其具有优异的对凝血因子XIa的抑制活性(对凝血因子XIa具有高亲和力)、高选择性(相对于凝血因子Xa和VIIa，对XIa具有更高的选择性)、更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性和/或较少的副作用，较宽的治疗窗)等更优异的性质。
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：
Figure PCTCN2018094428-appb-000003
其中：
Figure PCTCN2018094428-appb-000004
表示单键或双键；
R 1选自H、卤素、羟基、C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基，其中所述C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基各自独立地任选地被一个或多个选自卤素、-OH、氰基、C 1-3烷基、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2和-O-(C 1-3烷基)的取代基取代；
R 2和R 3各自独立地选自H、卤素、-OH和氧代基(＝O)；
Figure PCTCN2018094428-appb-000005
不存在或者选自任选地被R 7、R 8和R 9中的一个或多个取代的饱和或不饱和的C 3-10亚环烃基、饱和或不饱和的3-10元亚杂环基、C 6-14亚芳基、5-14元亚杂芳基、饱和或不饱和的C 5-14亚桥环烃基、饱和或不饱和的C 5-14亚螺环烃基、饱和或不饱和的5-14元亚氮杂桥环基和饱和或不饱和的5-14元亚氮杂螺环基；
B选自H、卤素以及任选地被R 10、R 11和R 12中的一个或多个取代的-C(＝NH)NH 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-4亚烷基)-NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)、-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)、饱和或不饱和的C 3-10环烃基、饱和或不饱和的3-10元杂环基、C 6-14芳基、5-14元杂芳基、饱和或不饱和的C 5-14桥环烃基、饱和或不饱和的C 5-14螺环烃基、饱和或不饱和的5-14元氮杂桥环基和饱和或不饱和的5-14元氮杂螺环基；
L 1为-C(＝O)NR 4-或基团
Figure PCTCN2018094428-appb-000006
R 4选自H、C 1-5烷基和C 2-5烯基，其中所述C 1-5烷基和C 2-5烯基各自独立地任选地被一个或多个选自卤素、-OH、氰基、C 1-5烷基、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-O-(C 1-3烷基)和卤代C 1-6烷基的取代基取代；
基团
Figure PCTCN2018094428-appb-000007
表示任选地另外含有独立地选自N、O、C＝O、S、S＝O和S(＝O) 2的1、2或3个环成员的3-10元含氮杂环，其任选地被R 7和/或R 8取代，并且其通过所述含氮杂环中的氮原子以及任一其余环原子经单键或双键与分子的其余部分连接，所述3-10元含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接；
Y选自C、CH、CH2、N、NH和O；
优选地，Y选自CH、CH 2、N、NH和O；
R 5选自-C(＝O)(C 1-3烷基)、-C(＝O)(C 3-6环烷基)、-CH(OH)C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-CH 2NH 2、-CH 2NH(C 1-3烷基)、-CH 2N(C 1-3烷基) 2、-C 2-5烯基和-C 2-5炔基，所述烷基、亚烷基、环烷基、烯基和炔基任选地被一个或多个选自卤素、羟基、-C 1-6亚烷基-OH、-O-(C 1-3烷基)、-C 1-6亚烷基-O-(C 1-3烷基)、氨基、-C 1-6亚烷 基-NH 2、-C 1-6亚烷基-NH-(C 1-6烷基)和-C 1-6亚烷基-N(C 1-3烷基) 2的取代基取代；
R 5’选自H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、-OH、-(C 1-4亚烷基)-OH、-O-(C 1-4烷基)、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(卤代C 1-4烷基)、-NH 2、-NH-(C 1-6烷基)和-N(C 1-6烷基) 2；
R 6和R 6’各自独立地选自H、卤素、氰基、-OH、C 1-4烷基、-COOH、-C(＝O)O(C 1-4烷基)、-(C 1-6亚烷基)-COOH、-(C 1-6亚烷基)-COO(C 1-6烷基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-O-(C 1-4烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-NHC(＝O)(C 1-4烷基)、-NHC(＝O)O(C 1-4烷基)、-NHC(＝O)O(C 3-6环烷基)、-NHC(＝O)O(C 1-4亚烷基)-OH、-NHC(＝O)O(C 1-4亚烷基)-O-(C 1-4烷基)、-NHC(＝O)O(C 1-4亚烷基)-COOH、-(C 1-4亚烷基)NHC(＝O)O(C 1-4烷基)、-NHC(＝O)N(C 1-4烷基) 2和-NHSO 2(C 1-4烷基)，所述烷基或亚烷基任选地被一个或多个选自卤素、氰基、-NH 2和-OH的取代基取代；
或者R 6和R 6’连同其所连接的碳原子共同形成任选被卤素和/或-NH 2取代的饱和或不饱和的C 5-6环烃基、饱和或不饱和的5-6元杂环基、C 6-14芳基或5-14元杂芳基；
R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、卤素、氰基、氧代基、-OH、-(C 1-4亚烷基)-OH、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-6亚烷基)-NH 2、-CONH 2、-COOH、C 1-6烷基、卤代C 1-6烷基、-O-(C 1-4烷基)、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(卤代C 1-4烷基)、饱和或不饱和的C 3-6环烃基、饱和或不饱和的3-10元杂环基、C 6-14芳基、5-14元杂芳基、-C(＝NH)NH 2、-C(＝O)(C 1-4烷基)、-C(＝O)O(C 1-4烷基)、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)和-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)；并且
W为CH或N。
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用作凝血因子XIa抑制剂的药物中的用途。所述药物用于预防或治疗血栓栓塞性病症。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物，其用作凝血因子XIa抑制剂。所述凝血因子XIa抑制剂用于预防或治疗血栓栓塞性病症。
本发明的另一方面提供预防或治疗血栓栓塞性病症的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物。
本发明的另一方面提供制备本发明的化合物的方法。
发明详细描述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-5个碳原子(“C 2-5烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、 3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”意指线性的或支化的单价烃基，其包含一个三键，且具有2-5个碳原子(“C 2-5炔基”)。所述炔基为例如乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、2-戊炔基、3-戊炔基、4-戊炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、2-甲基-2-丙炔基和4-甲基-3-戊炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”和“环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基、(亚)环丁基、(亚)环戊基、(亚)环己基、(亚)环庚基、(亚)环辛基、(亚)环壬基、(亚)环己烯基等。
如本文中所使用，术语“杂环基”和“亚杂环基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环基”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环基。亚杂环基和杂环基的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。亚杂环基和杂环基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-14(亚)芳基”意指含有6至14个碳原子的芳族基团，诸如(亚)苯基或(亚)萘基。(亚)芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语“(亚)杂芳基”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，(亚)杂芳基选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“(亚)桥环烃基”意指具有5-14个环碳原子(C 5-14)的双环形式的碳环基，其中两个碳环共用多于两个(例如3、4或5个)碳原子，这些共用碳原子所形成的碳链作为桥，所述桥两端的两个碳原子称作桥头碳。这样的(亚)桥环烃基可以具有5-11个环碳原子(C 5-11)，特别是6-10个环碳原子(C 6-10)，例如7、8或9个环碳原子。这样的(亚)桥环烃基的实例包括但不限于双环[2.1.1]己基、双环[2.2.1]庚基、双环[2.2.1]庚烯基、双环[2.2.2]辛基和双环[3.2.2]壬基，以及由此得到的二价基团(亚桥环烃基)。所述(亚)桥环烃基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)螺环烃基”意指具有5-14个环碳原子(C5-14)的双环形式的碳环基，其中两个碳环共用1个碳原子(称作“螺原子”)。所述(亚)螺环烃基可以具有例如5-11个环碳原子(C 5-11)，特别是6-10个环碳原子(C 6-10)，例如7、8或9个环碳原子。(亚)螺环烃基的实例包括但不限于螺[2.2]戊基、螺[2.3]己基、螺[2.4]庚基、螺[3.3]庚基、螺[2.5]辛基、螺[3.4]辛基、螺[3.5]壬基、螺[4.4]壬基、螺[4.5]癸基和螺[5.5]十一烷基，以及由此得到的二价基团(亚螺环烃基)。所述(亚)螺环烃基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
本文所用的术语“(亚)氮杂桥环基”意指上文所述的(亚)桥环烃基，其中除桥头碳之外的至少一个(例如1、2或3个)环碳原子被氮原子代替。本文所用的术语“(亚)氮杂螺环基”意指上文所述的(亚)螺环烃基，其中除螺原子之外的至少一个(例如1、2或3个)环碳原子被氮原子代替。所述(亚)氮杂桥环基或(亚)氮杂螺环基可以具有5-14个环成员，特别是5-10个环成员，例如6、7、8或9个环成员。(亚)氮杂桥环基的实例包括但不限于得自3-氮杂双环[3.1.1]庚烷和3-氮杂双环[3.2.1]辛烷的一价或二价基团。(亚)氮杂螺环基的实例包括但不限于得自2-氮杂螺[3.3]庚烷、2-氮杂螺[4.4]壬烷和8-氮杂螺[4.5]癸烷的一价或二价基团。所述(亚)氮杂桥环基或(亚)氮杂螺环基任选地另外含有独立地选自N、O和S的1、2或3个杂原子，条件是所述(亚)氮杂桥环基的桥头碳或所述(亚)氮杂螺环基的螺原子不是杂原子。(亚)氮杂桥环基或(亚)氮杂螺环基可以通过杂原子(例如N)和/或碳原子与分子其余部分连接。所述(亚)氮杂桥环基或(亚)氮杂螺环基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如本文中所使用，术语“前体基团”是指可经过本领域技术人员已知的一步或多步反应转化为目标基团的基团。例如，当目标基团为-COCH 3时，所述前体基团可为H；当目标基团为C 2-5烯基时，所述前体基团可为卤素(优选为Br)；当目标基团为-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基或者-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH时，所述前体基团可为C 2-5烯基；当目标基团为-NH-(C 1-6烷基)或-NHC(＝O)O(C 1-4烷基)时，所述前体基团可为-NO 2；并且当目标基团为-COOH时候，所述前体基团可为-COO(C 1-3烷基)。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2018094428-appb-000008
实楔形
Figure PCTCN2018094428-appb-000009
或虚楔形
Figure PCTCN2018094428-appb-000010
描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括盐酸盐、乙酸盐、天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、葡庚糖酸盐、葡糖酸盐、硝酸盐、乳清酸盐、棕榈酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、镁盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts，Protective Groups in  Organic Synthesis，John Wiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
化合物
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：
Figure PCTCN2018094428-appb-000011
其中：
Figure PCTCN2018094428-appb-000012
表示单键或双键；
R 1选自H、卤素、羟基、C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基，其中所述C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基各自独立地任选地被一个或多个选自卤素、-OH、氰基、C 1-3烷基、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2和-O-(C 1-3烷基)的取代基取代；
R 2和R 3各自独立地选自H、卤素、-OH和氧代基(＝O)；
Figure PCTCN2018094428-appb-000013
不存在或者选自任选地被R 7、R 8和R 9中的一个或多个取代的饱和或不饱和的C 3-10亚环烃基、饱和或不饱和的3-10元亚杂环基、C 6-14亚芳基、5-14元亚杂芳基、饱和或不饱和的C 5-14亚桥环烃基、饱和或不饱和的C 5-14亚螺环烃基、饱和或不饱和的5-14元亚氮杂桥环基和饱和或不饱和的5-14元亚氮杂螺环基；
B选自H、卤素以及任选地被R 10、R 11和R 12中的一个或多个取代的-C(＝NH)NH 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-4亚烷基)-NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)、-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)、饱和或不饱和的C 3-10环烃基、饱和或不饱和的3-10元杂环基、C 6-14芳基、5-14元杂芳基、饱和或不饱和的C 5-14桥环烃基、饱和或不饱和的C 5-14螺环烃基、饱和或不饱和的5-14元氮杂桥环基和饱和或不饱和的5-14元氮杂螺环基；
L 1为-C(＝O)NR 4-或基团
Figure PCTCN2018094428-appb-000014
R 4选自H、C 1-5烷基和C 2-5烯基，其中所述C 1-5烷基和C 2-5烯基各自独立地任选地被一个或多个选自卤素、-OH、氰基、C 1-5烷基、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-O-(C 1-3烷基)和卤代C 1-6烷基的取代基取代；
基团
Figure PCTCN2018094428-appb-000015
表示任选地另外含有独立地选自N、O、C＝O、S、S＝O和S(＝O) 2的1、2或3个环成员的3-10元含氮杂环，其任选地被R 7和/或R 8取代，并且其通过所述含氮杂环中的氮原子以及任一其余环原子经单键或双键与分子的其余部分连接，所述3-10元含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接；
Y选自C、CH、CH 2、N、NH和O；
优选地，Y选自CH、CH 2、N、NH和O；
R 5选自-C(＝O)(C 1-3烷基)、-C(＝O)(C 3-6环烷基)、-CH(OH)C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-CH 2NH 2、-CH 2NH(C 1-3烷基)、 -CH 2N(C 1-3烷基) 2、-C 2-5烯基和-C 2-5炔基，所述烷基、亚烷基、环烷基、烯基和炔基任选地被一个或多个选自卤素、羟基、-C 1-6亚烷基-OH、-O-(C 1-3烷基)、-C 1-6亚烷基-O-(C 1-3烷基)、氨基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NH-(C 1-6烷基)和-C 1-6亚烷基-N(C 1-3烷基) 2的取代基取代；
R 5’选自H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、-OH、-(C 1-4亚烷基)-OH、-O-(C 1-4烷基)、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(卤代C 1-4烷基)、-NH 2、-NH-(C 1-6烷基)和-N(C 1-6烷基) 2；
R 6和R 6’各自独立地选自H、卤素、氰基、-OH、C 1-4烷基、-COOH、-C(＝O)O(C 1-4烷基)、-(C 1-6亚烷基)-COOH、-(C 1-6亚烷基)-COO(C 1-6烷基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-O-(C 1-4烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-NHC(＝O)(C 1-4烷基)、-NHC(＝O)O(C 1-4烷基)、-NHC(＝O)O(C 3-6环烷基)、-NHC(＝O)O(C 1-4亚烷基)-OH、-NHC(＝O)O(C 1-4亚烷基)-O-(C 1-4烷基)、-NHC(＝O)O(C 1-4亚烷基)-COOH、-(C 1-4亚烷基)NHC(＝O)O(C 1-4烷基)、-NHC(＝O)N(C 1-4烷基) 2和-NHSO 2(C 1-4烷基)，所述烷基或亚烷基任选地被一个或多个选自卤素、氰基、-NH 2和-OH的取代基取代；
或者R 6和R 6’连同其所连接的碳原子共同形成任选被卤素和/或-NH 2取代的饱和或不饱和的C 5-6环烃基、饱和或不饱和的5-6元杂环基、C 6-14芳基或5-14元杂芳基；
R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、卤素、氰基、氧代基、-OH、-(C 1-4亚烷基)-OH、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-6亚烷基)-NH 2、-CONH 2、-COOH、C 1-6烷基、卤代C 1-6烷基、-O-(C 1-4烷基)、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(卤代C 1-4烷基)、饱和或不饱和的C 3-6环烃基、饱和或不饱和的3-10元杂环基、C 6-14芳基、5-14元杂芳基、-C(＝NH)NH 2、-C(＝O)(C 1-4烷基)、-C(＝O)O(C 1-4烷基)、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)和-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)；并且
W为CH或N。
在优选的实施方案中，R 1选自H、C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基。在更优选的实施方案中，R 1为H或甲基。
在优选的实施方案中，R 2和R 3各自独立地选自H、-OH和氧代基(＝O)。
在优选的实施方案中，R 2选自H和-OH。
在优选的实施方案中，R 3选自H、-OH和氧代基(＝O)。
在优选的实施方案中，当
Figure PCTCN2018094428-appb-000016
表示双键时，R 2和R 3处于双键的异侧。
在优选的实施方案中，Y选自CH、O和N。在更优选的实施方案中，Y与一个双键连接，并且此时Y选自CH和N。
在优选的实施方案中，L 1选自-C(＝O)NH-、-C(＝O)N(CH 3)-、
Figure PCTCN2018094428-appb-000017
Figure PCTCN2018094428-appb-000018
在更优选的实施方案中，L 1选自-C(＝O)NH-、
Figure PCTCN2018094428-appb-000019
Figure PCTCN2018094428-appb-000020
在优选的实施方案中，R 4选自H、C 1-5烷基和C 2-5烯基。在更优选的实施方案中，R 4选自H和甲基。
在优选的实施方案中，R 5选自-CH(OH)C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-CH 2N(C 1-3烷基) 2、-C 2-5烯基、-C 2-5炔基和-C(＝O)(C 1-3烷基)；优选地，R 5选自-CH(OH)C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-C 2-5烯基、-C 2-5炔基和-C(＝O)(C 1-3烷基)；所述烷基、亚烷基、烯基和 炔基任选地被一个或多个选自卤素、-NH 2、-OH、-CH 2OH、-OCH 3和-CH 2OCH 3的取代基取代。
在更优选的实施方案中，R 5选自-C(＝O)CH 3、-CH＝CH 2、-C(＝CH 2)CH 3、-CH(OH)CH 3、-CH(OH)CH 2OH、-C(CH 3)(OH)-CH 2OH、-CH 2N(CH 3) 2、-C≡CH、-C≡CCH 2OCH 3和-C≡CCH 2OH；优选地，R 5选自-C(＝O)CH 3、-CH＝CH 2、-C(＝CH 2)CH 3、-CH(OH)CH 3、-CH(OH)CH 2OH、-C(CH 3)(OH)-CH 2OH、-C≡CH、-C≡CCH 2OCH 3和-C≡CCH 2OH。
在优选的实施方案中，R 5’选自H、卤素、氰基、-OH、-O-(C 1-4烷基)和-NH 2。在更优选的实施方案中，R 5’为H。
在优选的实施方案中，R 6和R 6’各自独立地选自H、-COOH、-C(＝O)O(C 1-4烷基)、-NHC(＝O)O(C 1-4烷基)和-NHC(＝O)O(C 1-4亚烷基)-OH，所述烷基任选地被一个或多个选自卤素、氰基、-NH 2和-OH的取代基取代；或者R 6和R 6’连同其所连接的碳原子共同形成被-NH 2取代的5-6元杂芳基。在更优选的实施方案中，R 6和R 6’各自独立地选自H、-COOH、-NHC(＝O)OCH 3和-NHC(＝O)OCH 2CH 2OH；或者R 6和R 6’连同其所连接的碳原子共同形成
Figure PCTCN2018094428-appb-000021
在优选的实施方案中，当
Figure PCTCN2018094428-appb-000022
不存在时，B不为H。
在优选的实施方案中，
Figure PCTCN2018094428-appb-000023
选自任选地被R 7、R 8和R 9中的一个或多个取代的饱和或不饱和的C 5-6亚环烃基、饱和或不饱和的5-6元亚杂环基、C 6-10亚芳基、5-10元亚杂芳基、饱和或不饱和的C 5-14亚桥环烃基和饱和或不饱和的5-14元亚氮杂螺环基。在更优选的实施方案中，
Figure PCTCN2018094428-appb-000024
选自
Figure PCTCN2018094428-appb-000025
Figure PCTCN2018094428-appb-000026
Figure PCTCN2018094428-appb-000027
其任选地被R 7、R 8和R 9中的一个或多个取代。
在优选的实施方案中，B选自H、卤素以及任选地被R 10、R 11和R 12中的一个或多个取代的-C(＝NH)NH 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-4亚烷基)-NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)、-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)、饱和或不饱和的C 3-10环烃基、饱和或不饱和的5-6元杂环基、C 6-10芳基、5-10元杂芳基、饱和或不饱和的C 5-14桥环烃基和饱和或不饱和的5-14元氮杂螺环基。在更优选的实施方案中，B选自H、F、Cl、Br、I、-CH 2NH 2、-C(＝NH)NH 2、-CH 2NHC(CH 3)＝CHC(＝O)CH 3、-CH 2NHC(＝O)O-CH(CH 3)-OC(＝O)CH 2CH 3、
Figure PCTCN2018094428-appb-000028
Figure PCTCN2018094428-appb-000029
其任选地被R 10、R 11和R 12中的一个或多个取代。
在优选的实施方案中，R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、卤素、-(C 1-4亚烷基)-OH、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-(C 1-6亚烷基)-NH 2、C 1-6烷基、卤代C 1-6烷基、饱和或不饱和的C 3-6环烃基、饱和或不饱和的3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C(＝NH)NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)和-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)。在更优选的实施方案中，R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、F、Cl、Br、-NH 2、-CH 2OH、-CH 2NH 2、-CF 3、-CH 2NHC(CH 3)＝CHC(＝O)CH 3、-CH 2NHC(＝O)O-CH(CH 3)-OC(＝O)CH 2CH 3、
Figure PCTCN2018094428-appb-000030
在优选的实施方案中，本发明的化合物具有式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)或式(XII)的结构：
Figure PCTCN2018094428-appb-000031
Figure PCTCN2018094428-appb-000032
其中
B、R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 10、R 11、R 12和W如对于式(I)所定义；
R 13选自H、卤素、C 1-5烷基和卤代C 1-5烷基；并且
Figure PCTCN2018094428-appb-000033
选自：
Figure PCTCN2018094428-appb-000034
在更优选的实施方案中，本发明的化合物具有式(II’)、式(IV’)、式(VI’)、式(IX’)或式(XII’)结构：
Figure PCTCN2018094428-appb-000035
其中
B、R 4、R 5、R 5’、R 6、R 10、R 11和R 12如对于式(I)所定义；
优选地，R 6选自-COOH和-NHC(＝O)OCH 3；并且B、R 4、R 5、R 5’、R 10、R 11和R 12如对于式(I)所定义。
本发明涵盖对各个实施方案进行任意组合所得的化合物。
在优选的实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
Figure PCTCN2018094428-appb-000036
Figure PCTCN2018094428-appb-000037
Figure PCTCN2018094428-appb-000038
Figure PCTCN2018094428-appb-000039
Figure PCTCN2018094428-appb-000040
Figure PCTCN2018094428-appb-000041
药物组合物、制剂和组合
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
在优选的实施方案中，所述药物组合物包含0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药。
在优选实施方案中，本发明提供另外包含一种或多种其它治疗剂的药物组合物。在一些优选的实施方案中，本发明提供药物组合物，其中所述一种或多种其它治疗剂为抗血小板剂或其组合。优选地，所述抗血小板剂为氯吡格雷和/或阿司匹林或其组合。
本发明的化合物可以例如片剂、胶囊剂(其各自包括持续释放或按时释放的制剂)、丸剂、散剂、颗粒剂、酏剂、酊剂、混悬剂、糖浆剂和乳剂的口服剂型来给药。它们还可以静脉内(大丸剂(bolus)或输注)、腹膜内、皮下或肌肉内形式来给药，其所有均使用医药领域技术人员所已知的剂型。它们可单独给药，但一般将连同基于所选给药途径和标准医药实践所选择的药学上可接受的载体一起给药。
术语″药物组合物″表示包含本发明的化合物与至少一种其它药学上可接受的载体组合的组合物。″药学上可接受的载体″是指用于将生物活性剂传递至动物(尤其哺乳动物)的本领域普遍接受的介质，其包括佐剂、赋形剂或载体，例如稀释剂、防腐剂、填充剂、流量调节剂、崩解剂、润湿剂、乳化剂、助悬剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂。根据完全处于本领域普通技术人员的技能范围内的许多因素来配制药学上可接受的载体。这些因素包括(但不限于)：所配制活性剂的类型和性质；含药剂的组合物所给药的个体；组合物的预定给药途径和所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质二者，以及多种固体和半固体剂型。此类载体除活性剂以外还可包括多种不同成分和添加剂，此类其它成分出于本领域普通技术人员所公知的多种原因而包括在制剂中，例如使稳定剂、粘合剂等。适合的药学上可接受的载体的描述及其选择中所涉及的因素参见多种可容易获得的资源中，例如Remington′s Pharmaceutical Sciences，第18版(1990)。
当然，本发明的化合物的给药方案将视已知因素而变，例如特定药剂的药物代谢动力学特征及其给药模式和途径；接受者的物种、年龄、性别、健康情况、医学状况和体重；症状的性质和程度；并行治疗的种类；治疗频率；给药途径；患者的肾脏和肝脏功能；以及所需效果。医师或兽医可确定和规定预防、逆转或阻止血栓栓塞性病症发展所需的药物的有效量。
作为一般指导，当用于指定效果时，各活性成分的日口服剂量将为约0.001至约1000毫克/千克体重、优选为约0.01至约100毫克/千克体重/日，且最优选为约0.1至约20毫克/千克/日的范围内。静脉内给药时，在恒定速率输注期间，最优选剂量将在约0.001至约10毫克/千克/分钟的范围内。本发明的化合物可以单次日剂量来给药，或总日剂量可以每日两次、三次或四次的分剂量给药。
本发明的化合物还可通过肠胃外给药(例如静脉内、动脉内、肌肉内或皮下)给药。当静脉内或动 脉内给药时，剂量可连续或间歇给药。此外，制剂可经开发用于肌肉内和皮下递送以便确保活性医药成分逐渐释放。
本发明的化合物可以鼻内形式经由局部使用适当的鼻内载体或经由经皮途径使用经皮皮肤贴片来给药。当以经皮递送系统的形式给药时，剂量给药在整个给药方案中当然将为连续而非间歇性的。
化合物通常与关于预定给药形式(例如口服片剂、胶囊、酏剂和糖浆)和与常规医药实践相一致而适当选择的适合医药稀释剂、赋形剂或载体(在本文中总称为载体)混合给药。
例如，对于以片剂或胶囊剂形式口服给药，活性药物组分可与例如以下口服、无毒、药学上可接受的惰性载体组合：乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露糖醇、山梨糖醇等；对于以液体形式口服给药，口服药物组分可与例如以下任何口服、无毒、药学上可接受的惰性载体组合：乙醇、甘油、水等。此外，在合意或必要时，还可将适合的粘合剂、润滑剂、崩解剂和着色剂掺入混合物中。适当粘合剂包括淀粉；明胶；天然糖，例如葡萄糖或β-乳糖；玉米甜味剂；天然和合成胶，例如阿拉伯胶(acacia)、黄芪胶(tragacanth)或海藻酸钠；羧甲基纤维素；聚乙二醇；蜡；等等。这些剂型中所使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氧化钠等。崩解剂包括(但不限于)淀粉、甲基纤维素、琼脂、膨润士、黄原胶等。
本发明的化合物还可以脂质体递送系统的形式来给药，例如单层小囊泡、单层大囊泡和多层囊泡。脂质体可由多种磷脂例如胆固醇、硬脂酰胺或磷脂酰胆碱形成。
本发明的化合物还可与作为可靶向药物载体的可溶性聚合物偶合。此类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或聚环氧乙烷-经棕榈酰基残基取代的聚赖氨酸。此外，本发明的化合物可与例如以下适用于实现药物控制释放的一类可生物降解的聚合物偶合：聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两性嵌段共聚物。
适于给药的剂型(药物组合物)每剂量单位可含有约1毫克至约1000毫克活性成分。在这些药物组合物中，活性成分的存在量一般为以组合物的总重量计约0.1-95重量％。
明胶胶囊可含有活性成分和粉状载体，例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。可使用例如稀释剂来制造压制片剂。片剂和胶囊剂都可制备为持续释放产品以提供药物在数小时时期内的连续释放。压制片剂可经糖衣包覆或薄膜包覆以掩盖任何令人不快的味道且保护片剂免受大气影响，或经肠溶衣包覆以使其在胃肠道中选择性崩解。
用于口服给药的液体剂型可含有着色剂和调味剂以增加患者接受度。
一般而言，水、适当的油、生理盐水、右旋糖(葡萄糖)和相关糖溶液和二醇(例如丙二醇或聚乙二醇)为用于肠胃外给药溶液剂的适合载体。用于肠胃外给药的溶液剂优选含有活性成分的水溶性盐、适当稳定剂，且必要时含有缓冲物质。单独或组合的抗氧化剂，例如亚硫酸氢钠、亚硫酸钠或抗坏血酸为适合的稳定剂。还使用柠檬酸及其盐和EDTA钠盐。另外，肠胃外给药溶液剂可含有防腐剂，例如苯扎氯胺、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯和氯丁醇。
适合的药学上可接受的载体描述于Remington′s Pharmaceutical Sciences，Mack Publishing Company(本领域中的标准参考著作)中。
在将本发明的化合物与其它抗凝血剂组合的情况中，例如日剂量可为约0.1至约100毫克本发明的化合物和约0.1至约100毫克抗凝血剂每千克患者体重。对于片剂剂型，本发明的化合物的存在量一般可为每剂量单位约5至约100毫克，且第二抗凝血剂的量为每剂量单位约1至约50毫克。
在本发明的化合物与抗血小板剂组合给药的情况中，作为一般指导，通常日剂量可为每千克患者体重约0.01至约25毫克本发明的化合物和约50至约150毫克抗血小板剂，优选为约0.1至约1毫克本发明的化合物和约1至约3毫克抗血小板剂。
在本发明的化合物与血栓溶解剂组合给药的情况中，通常日剂量可为每千克患者体重约0.1至约1毫克本发明的化合物，且在血栓溶解剂的情况下，当和本发明的化合物一起给药时，单独给药时的血栓溶解剂的常用剂量可减少约50-80％。
特别地，当以单一剂量单位的形式提供时，组合的活性成分之间存在化学相互作用的可能性。出于此原因，当本发明的化合物与第二治疗剂组合在单一剂量单位中时，它们经配制以使得尽管将活性成分组合在单一剂量单位中，但活性成分之间的物理接触被最小化(即，减少)。例如，一种活性成分可用肠衣包覆。通过使活性成分之一经肠衣包覆，有可能不仅使组合的活性成分之间的接触最小化，而且还可能控制这些组分之一在胃肠道中的释放，以使得这些组分之一不在胃中释放而是在肠中释放。活性成分之一还可用影响整个胃肠道中的持续释放的材料包覆且还用来使组合的活性成分之间的物理接触最小。此外，持续释放的组分可另外经肠衣包覆以使得此组分的释放仅在肠中发 生。又一方法将涉及组合产品的制剂，其中一种组分用持续和/或肠内释放聚合物包覆，且其它组分还用聚合物(例如低粘度级羟丙基甲基纤维素(HPMC)或本领域中已知的其它适当物质)包覆以进一步隔开活性组分。聚合物包覆用来形成与其它组分的相互作用的另外的屏障。
使本发明的组合产品的组分(无论是以单一剂型给药或以分开形式但以相同方式同时给药)之间的接触最小化的这些以及其它方式对本领域技术人员而言根据本发明公开将显而易见。
在另一些实施方案中，本发明提供药物组合物，其进一步包含选自以下的一种或多种其它治疗剂：抗血小板剂、凝血酶抑制剂、血栓溶解剂、纤维蛋白溶解剂、促使血清脂质减少剂、抗缺血剂、钾通道开启剂、钾通道阻断剂、钙通道阻断剂、钠氢交换器抑制剂、抗心律不齐剂、抗动脉粥样硬化剂、抗凝血剂、抗血栓剂、凝血酶原溶解剂、纤维蛋白原拮抗剂、利尿剂、抗高血压剂、腺苷三磷酸酶(ATPase)抑制剂、盐皮质激素受体拮抗剂、磷酸二酯酶抑制剂、抗糖尿病剂、消炎剂、抗氧化剂、血管生成调节剂、抗骨质疏松剂、激素替代治疗剂、激素受体调节剂、口服避孕剂、抗肥胖剂、抗抑郁剂、抗焦虑剂、抗精神病剂、抗增生剂、抗肿瘤剂、抗溃疡和胃食道逆流病剂、生长激素剂和/或生长激素促分泌素、甲状腺模拟剂、抗感染剂、抗病毒剂、抗菌剂、抗真菌剂、胆固醇/脂质降低剂和脂质分布治疗剂，以及模拟缺血预处理和/或心肌顿抑(myocardial stunning)的药剂，或其组合。
在另一些实施方案中，本发明提供药物组合物，其进一步包含选自以下的一种或多种其它治疗剂：华法林、未分级肝素、低分子量肝素、合成五糖、蛭素、阿加曲班、阿司匹林、布洛芬、萘普生、舒林酸、吲哚美辛、甲灭酸盐(mefenamate)、双嘧达莫、屈噁昔康、双氯芬酸、磺吡酮、吡罗昔康、噻氯匹定、氯吡格雷、替罗非班、依替巴肽、阿昔单抗、美拉加群、希美加群、二硫酸蛭素(disulfatohirudin)、组织纤溶酶原活化剂、改性的组织纤溶酶原活化剂、阿尼普酶、尿激酶和链激酶，或其组合。
本发明的化合物可单独给药或与一种或多种其它治疗剂组合给药。″组合给药″或″组合疗法″表示将本发明的化合物和一种或多种其它治疗剂共同给药所治疗的哺乳动物。当组合给药时，各组分可同时或以任意次序在不同时间点相继给药。因此，各组分可分开但在时间上充分接近地给药以提供所需的治疗效果。
优选实例为本发明的化合物、阿司匹林和另一抗血小板剂的三重组合。优选，所述抗血小板剂为氯吡格雷或普拉格雷，更优选为氯吡格雷。
本发明的化合物还适用作标准或参考化合物，例如作为在涉及抑制凝血酶、因子VIIa、IXa、Xa、XIa和/或血浆激肽释放酶的测试或检验中的质量标准或对照。此类化合物可在商业试剂盒中提供，例如用于涉及凝血酶、因子VIIa、IXa、Xa、XIa和/或血浆激肽释放酶的医药研究。例如，本发明的化合物可在检验中用作参考物以将其已知活性与具有未知活性的化合物作比较。尤其当测试化合物是参考化合物的衍生物时，这将使实验者确保检验适当进行且提供用于比较的基础。当开发新的检验或方案时，可使用本发明的化合物以测试其功效。
本发明的化合物还可用于涉及凝血酶、因子VIIa、IXa、Xa、XIa和/或血浆激肽释放酶的诊断检验中。例如，在未知样品中凝血酶、因子VIIa、IXa、Xa、XIa和/或血浆激肽释放酶的存在可通过将相关发色底物(例如对于因子XIa而言使用S2366)添加至一系列含有测试样品和任选地本发明的化合物之一的溶液中来测定。若在含有测试样品的溶液中观测到pNA产生，但在本发明的化合物存在下未观测到，则推断存在因子XIa。
本发明还涵盖制品。如本文中所使用，制品意欲包括(但不限于)试剂盒和包装。本发明的制品包含：(a)第一容器；(b)位于该第一容器内的药物组合物，其中该组合物包含：第一治疗剂，其包含：本发明的化合物或其药学上可接受的盐形式；和(c)声明该药物组合物可用于治疗血栓栓塞和/或炎性病症的药品说明书。在另一些实施方案中，药品说明书声明药物组合物可与第二治疗剂组合使用以治疗血栓栓塞和/或炎性病症。制品可进一步包含：(d)第二容器，其中组分(a)和(b)位于该第二容器内且组分(c)位于该第二容器内部或外部。位于第一和第二容器内表示分开的容器将物品容纳在其边界内。
第一容器为用于容纳药物组合物的容器。此容器可用于制造、储存、运送和/或单个/成批出售。第一容器意欲包括瓶、广口瓶、小瓶、烧瓶、注射器、管(例如用于乳膏制剂)或任何其它用于制造、容纳、储存或分配医药产品的容器。
第二容器为用于容纳第一容器和任选药品说明书的容器。第二容器的实例包括(但不限于)盒子(例如纸板或塑料的)、板条箱、纸板箱、袋子(例如纸袋或塑料袋)、小袋(pouch)和包(sack)。药品说明书可经由胶带、胶水、钉或其它附着方法实体附着于第一容器外部，或可将其放置于第二容器内 部而不借助于任何实体方式附着于第一容器。或者，药品说明书位于第二容器外部。当位于第二容器外部时，优选药品说明书经由胶带、胶水、钉或其它附着方法实体附着。或者，其可与第二容器外部相邻或接触而非物理附着。
药品说明书为陈述与位于第一容器内的药物组合物相关的信息的标记、卷标、标志等。所陈述的信息将通常由管理制品欲出售地区的管理机构(例如中华人民共和国国家食品药品监督管理总局或美国食品和药物管理局(United States Food and Drug Administration))来确定。优选地，药品说明书具体陈述药物组合物已经批准可用的适应症。药品说明书可由任何材料制成，人可读取其中或其上所含的信息。优选地，药品说明书为上面已形成(例如打印或施涂)所需信息的可打印材料(例如纸张、塑料、纸板、箔片、背粘性纸张或塑料等)。
治疗方法和生物学
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用作凝血因子XIa抑制剂的药物中的用途。所述药物用于预防或治疗血栓栓塞性病症。
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物，其用作凝血因子XIa抑制剂。所述凝血因子XIa抑制剂用于预防或治疗血栓栓塞性病症。
在一些实施方案中，本发明提供提供预防和/或治疗血栓栓塞性病症的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物。
在一些实施方案中，所述血栓栓塞性病症包括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、静脉脑血管血栓栓塞性病症和心脏腔室血栓栓塞性病症。
在另一些实施方案中，所述血栓栓塞性病症包括不稳定型心绞痛、急性冠状动脉综合症、心房纤维性颤动、首次心肌梗塞、复发性心肌梗塞、缺血性猝死、短暂性脑缺血发作、中风、动脉粥样硬化、外周闭塞性动脉疾病、静脉血栓形成、深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞，以及由于(a)人工瓣膜、留置导管、支架或其它植入物；(b)体外循环；(c)血液透析或(d)血液暴露于易引发血栓形成的人造表面而导致的血栓形成。
在另一些实施方案中，本发明提供治疗和/或预防血栓栓塞性病症的方法，该方法包括：向有需要的个体给药治疗有效量的第一和第二治疗剂，其中所述第一治疗剂为本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，并且所述第二治疗剂为至少一种选自第二因子Xa抑制剂、抗凝血剂、抗血小板剂、凝血酶抑制剂、溶血栓剂和纤维蛋白溶解剂的药剂。优选所述第二治疗剂为至少一种选自以下的药剂：华法林、未分级肝素、低分子量肝素、合成五糖、蛭素、阿加曲班、阿司匹林、布洛芬、萘普生、舒林酸、吲哚美辛、美芬纳特(mefenamate)、屈噁昔康、双氯芬酸、磺吡酮、吡罗昔康、噻氯匹定、氯吡格雷、替罗非班、依替巴肽、阿昔单抗、美拉加群、去硫酸蛭素(desulfatohirudin)、组织纤溶酶原活化剂、改性的组织纤溶酶原活化剂、阿尼普酶、尿激酶和链激酶。优选所述第二治疗剂为至少一种抗血小板剂。优选所述一种或多种抗血小板剂为氯吡格雷和/或阿司匹林，或其组合。
在另一些实施方案中，本发明提供治疗和/或预防炎性病症的方法，该方法包括：向有需要的个体给药治疗有效量的至少一种本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药。所述炎性病症的实例包括(但不限于)败血症、急性呼吸窘迫综合征和全身性炎性反应综合征。
在另一些实施方案中，本发明提供本发明的化合物与一种或多种其它治疗剂在疗法中同时、分开或相继使用的联合制剂。
在另一些实施方案中，本发明提供本发明的化合物与一种或多种其它治疗剂在治疗和/或预防血栓栓塞性病症中同时、分开或相继使用的联合制剂。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
如本文所使用的″治疗″涵盖治疗哺乳动物、尤其人类的疾病病况，且包括：(a)抑制疾病病况， 即阻止其发展；和/或(b)减轻疾病病况，即引起疾病病况消退。
如本文所使用的″防治″或″预防″涵盖预防性治疗哺乳动物、尤其人类的亚临床疾病病况，旨在降低发生临床疾病病况的可能性。基于已知与一般群体相比患临床疾病病况的风险增加的因素，选择用于预防性疗法的患者。″防治″疗法可分为(a)初级预防(primary prevention)和(b)二级预防(secondary prevention)。初级预防定义为治疗尚未呈现临床疾病病况的个体，而二级预防定义为预防相同或类似临床疾病病况的二次发生。
如本文所使用的″风险降低″涵盖降低发展临床疾病病况的发病率的疗法。因而，初级和二级预防疗法为风险降低的实例。
″治疗有效量″意欲包括本发明的化合物在单独或组合给药时有效抑制因子XIa以预防或治疗本文所列的病症的量。当应用于组合时，该术语是指产生预防性或治疗性效果的活性成分的组合量，无论是连续或同时组合给药。
如本文中所使用，术语″血栓形成″是指血栓的形成或存在；可能引起缺血的血管内凝固或由血管供给的组织的梗塞。如本文中所使用，术语″栓塞″是指由被血流带至沉积位置的凝块或外来物质所引起的动脉突发性阻塞。如本文中所使用，术语″血栓栓塞″是指由被血流自初始位置运载而堵塞另一血管的血栓性物质所引起的血管阻塞。术语″血栓栓塞性病症″指″血栓″和″栓塞″病症。
如本文所使用，术语″血栓栓塞性病症″包括动脉心血管血栓栓塞性病症、静脉心血管或脑血管血栓栓塞性病症和心脏腔室或周围循环中的血栓栓塞性病症。如本文中所使用，术语″血栓栓塞性病症″还包括选自(但不限于)以下的特定病症：不稳定型心绞痛或其它急性冠状动脉综合征、心房纤维性颤动、初发性或复发性心肌梗塞、缺血性猝死、短暂缺血性发作、中风、动脉粥样硬化、周围闭塞性动脉疾病、静脉血栓形成、深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞和由血液暴露于促进血栓形成的人工表面的医学植入物、装置或手术所引起的血栓形成。医学植入物或装置包括(但不限于)：修复瓣膜、人工瓣膜、留置导管(indwelling catheter)、支架、血液充氧器、支路(shunts)、血管接口、心室辅助装置和人工心脏或心脏腔室和血管移植物。手术程序包括(但不限于)：心肺绕道、经皮冠状动脉介入术(percutaneous coronary intervention)和血液透析。在另一些实施方案中，术语″血栓栓塞性病症″包括急性冠状动脉综合征、中风、深静脉血栓形成和肺栓塞。
如本文中所使用，术语″中风″是指由颈总动脉(carotid communis)、颈内动脉(carotid interna)或脑内动脉中的闭塞性血栓形成所引起的栓塞性中风或动脉硬化性血栓形成中风(atherothrombotic stroke)。
应注意，血栓形成包括血管闭塞(例如在绕道后)和再闭塞(例如在经皮经腔冠状动脉血管成形术期间或之后)。血栓栓塞性病症可由包括(但不限于)以下的病状引起：动脉粥样硬化、外科手术或外科手术并发症、长期固定、动脉纤维性颤动、先天性血栓形成倾向(congenital thrombophilia)、癌症、糖尿病、药物或激素的作用和妊娠并发症。
血栓栓塞性病症通常与患有动脉粥样硬化的患者相关联。动脉粥样硬化的风险因素包括(但不限于)男性性别、年龄、高血压、脂质病症和糖尿病。动脉粥样硬化的风险因素同时为动脉粥样硬化并发症(即血栓栓塞性病症)的风险因素。
类似地，动脉纤维性颤动通常与血栓栓塞性病症相关联。动脉纤维性颤动和继发的血栓栓塞性病症的风险因素包括心血管疾病、风湿性心脏病、非风湿性二尖瓣病、高血压心血管疾病、慢性肺病和多种混杂心脏异常以及甲状腺毒症。
糖尿病通常与动脉粥样硬化和血栓栓塞性病症相关联。更常见的2型的风险因素包括(但不限于)家族史、肥胖症、身体不活动性、种族/人种、先前空腹血糖或葡糖耐量测试异常(impaired fasting glucose or glucose tolerance test)、妊娠期糖尿病病史或分娩“巨型儿(big baby)”、高血压、低HDL胆固醇和多囊泡性卵巢综合征。
先天性血栓形成倾向的风险因素包括凝血因子功能突变增进或抗凝血剂或纤维蛋白溶解路径中的功能突变损失。
已发现血栓形成与多种肿瘤类型相关联，例如胰腺癌、乳腺癌、脑肿瘤、肺癌、卵巢癌、前列腺癌、胃肠恶性疾病和何杰金氏(Hodgkins)或非何杰金氏(non-Hodgkins)淋巴瘤。
实施例
以下列举实施例和试验例，进而详细地说明本发明，但它们不限制本发明的范围，另外在不脱离本发明的范围下可进行变化。
MS的测定使用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。
制备高效液相色谱法使用岛津LC-8A制备液相色谱仪(YMC，ODS，250×20mm色谱柱)。
薄层色谱法纯化采用的是烟台产GF 254(0.4～0.5nm)硅胶板。
反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系包括但不限于：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系和石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，或者加入三乙胺等进行调节。
柱色谱法一般使用青岛海洋200～300目硅胶为固定相。洗脱剂体系包括但不限于二氯甲烷和甲醇体系以及正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺等进行调节。
如实施例中无特殊说明，则反应的温度为室温(20℃～30℃)。
实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company或者特伯化学等公司。
如本文中所使用的缩写具有以下含义：
Figure PCTCN2018094428-appb-000042
Figure PCTCN2018094428-appb-000043
本发明的化合物可以有机合成领域的技术人员已知的多种方式制备。本发明的化合物可使用下文描述的方法以及合成有机化学领域中已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选方法包括(但不限于)下文所述那些。反应可在适于所使用的试剂和材料且适合于实现转化的溶剂或溶剂混合物中进行。有机合成领域的技术人员应了解，分子上存在的官能团应与所提出的转化一致。这有时将需要以下判断：修改合成步骤的顺序或相对于一种方法路线选择另一特定方法路线以获得本发明的所需化合物。
还应认识到，本领域中设计任何合成途径的另一主要考虑因素是正确选择用于保护本发明中所述化合物中存在的反应性官能团的保护基团。向受过训练的相关人士描述许多替代方案的权威说明为Greene等人(Protective Groups in Organic Synthesis，第4版，Wiley-Interscience(2006))。
除非另外说明，以下路线中化合物的取代基如上文所定义。本领域技术人员会明白，根据期望获得的产物结构，可省略以下路线中的一个或多个步骤。本领域技术人员也可根据需要适当地调整反应步骤的顺序。
路线1
在路线1中，X表示卤素或任选地被卤素取代的C 1-3烷基磺酸酯基(例如三氟甲磺酸酯基)；并且R 5a和R 5a’与R 5和R 5’相同，或者R 5a和R 5a’为可经过本领域技术人员已知的一步或多步反应转化为R 5和R 5’的基团，此时R 5a可以为H(例如，当R 5为-COCH 3时，R 5a为H，或者当R 5’为-NH-(C 1-6烷基)时，R 5a’为-NO 2)；R 6a和R 6a’与R 6和R 6’相同，或者R 6a和R 6a’为可经过本领域技术人员已知的一步或多步反应转化为R 6和R 6’的基团(例如，当R 6和/或R 6’为-COOH时，R 6a和/或R 6a’为-COO(C 1-3烷基)，或者当R 6和/或R 6’为-NHC(＝O)O(C 1-4烷基)时，R 6a和/或R 6a’为-NO 2)。
根据Negi(Synthesis，991(1996))所述的修改步骤制备的醛1-1和(S)-2-甲基丙烷-2-亚磺酰胺在碳酸铯或者无水硫酸铜存在下在溶剂(例如二氯甲烷)中缩合，得到化合物1-2(Ellman，J.，J.Org.Chem.，64：1278(1999))。使用Kuduk(Tetrahedron Letters，45，6641(2004))所述的修改步骤，可使适当取代的格氏试剂(Grignard reagent)(例如溴化烯丙基镁)与化合物1-2反应，得到化合物1-3。
保护基的转化可在随后的两个步骤完成。例如将4M的盐酸二氧六环溶液缓慢滴入反应体系中，反应完全后，得到化合物1-4。将化合物1-4中的氨基用Boc保护得到化合物1-5。化合物1-5和Int-1a的Suzuki-Miyaura偶联(在溶剂(例如二甲基亚砜，或者二甲基亚砜与水或二甲基甲酰胺的混合溶剂)中，于碱(例如磷酸钾)存在下，利用催化剂(例如Pd(dppf)Cl 2.CH 2Cl 2络合物)进行)，得到化合物1-6。
在Int-1a不可商购获得的情况下，可采用Ishiyama，T.等人的方法(J.Org.Chem.，60(23)：7508-7510(1995)；Miyaura，N.；Suzuki，A.；Chem.Rev.，1995，2457-2483；Oster，A.，J.Med.Chem.，2010，53，8176-8186)，使芳基/杂芳基卤化物经历用二硼物质(例如双(频那醇根合)二硼或双(新戊二醇根合(neopentyl glycolato))二硼进行的钯介导的偶联，得到相应的4，4，5，5-四甲基-[1，3，2]二氧杂环戊硼烷或5，5-二甲基-[1，3，2]二氧杂环己硼烷中间体。或者，该相同中间体可如Murata等人(J.Org.Chem.，62(19)：6458-6459(1997))所述通过使中间体卤化物和相应二烷氧基氢硼烷反应来制备。可用硼频那醇酯(boronpinacolate)中间体替代硼酸进行对芳基/杂芳基卤化物或三氟甲磺酸酯的偶联，或可使硼频那醇酯中间体转化成硼酸。或者，可通过对芳基/杂芳基卤化物进行金属-卤素交换，用三烷氧基硼酸酯试剂猝灭且进行水性后处理得到硼酸来制备相应硼酸(Miyaura，N.等人，Chem.Rev.，95：2457(1995))。
还认识到，中间体合成的范围可进一步扩展超出使用Suzuki-Miyaura偶联方法的范围，因为上述前驱体芳基/杂芳基卤化物或三氟甲磺酸酯还为Stille、Negishi、Hiyama和Kumada型交叉偶联方法的前驱体(Tsuji，J.，Transition Metal Reagents and Catalysts：Innovations in Organic Synthesis，John Wiley&Sons(2000)；Tsuji，J.，Palladium Reagents and Catalysts：Innovations in Organic Synthesis，John Wiley&Sons(1996))。
将化合物1-6与中间体Int2反应得化合物1-7。进行环闭合复分解反应Grubbs成环(Rao，V，Euro.J.Medi.Chem.，2012，57，344-361)，得到化合物1-8。将化合物1-8进行还原反应(例如Pd/C还原氢 化)，得到化合物1-9。将化合物1-9进行适当的官能团转化得到化合物1-10。将化合物1-10脱除保护基得到化合物1-11。将化合物1-11通过多种方式与另一片段连接，如缩合反应和成环反应等，得到式(I)中化合物。
本领域技术人员会明白，根据期望得到的产物结构，可以省略路线1中的一步或多步(例如当R 2和R 3之间的键为双键时，可省略第八步)。本领域技术人员还会明白，可根据需要调整各个步骤的顺序(例如可在第五步后进行R 6a和R 6a’转化为R 6和R 6’的一步或多步转化反应)。
Figure PCTCN2018094428-appb-000044
在路线2中，X、R 5a、R 5a’、R 6a和R 6a’如在路线1中所定义。
如路线1中所述得到化合物2-4。添加Boc保护基，随后马上进行硼酸化反应得到化合物2-5，将其与适当的芳基/杂芳基卤化物进行Suzuki-Miyaura偶联得到化合物2-6。与路线1中化合物1-6至化合物1-11的转化类似地，将化合物2-6转化为化合物2-11。将化合物2-11通过多种方式与另一片段连接，如缩合反应和成环反应等，得到式(I)中化合物。
Figure PCTCN2018094428-appb-000045
实施例A：(3-氨基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸甲酯(SM-1)的制备
Figure PCTCN2018094428-appb-000046
第一步：(3-氨基-4-溴苯基)氨基甲酸甲酯(SM-1-2)的制备
在氮气保护下，向3-氨基-4-溴苯甲酸(SM-1-1)(5.0g，23.1mmol)在DMF(100mL)和MeOH(10mL)中的混合溶液加入三乙胺(3.9mL，27.8mmol)。将反应液加热至100℃，滴加DPPA(6.0mL，27.8mmol)。在相同温度下搅拌3小时后降至室温。加入乙酸乙酯和水稀释，分层，将水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤并浓缩滤液，将粗产品经硅胶柱层析纯化得标题化合物SM-1-2(4.5g，80％)。
第二步：(3-氨基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸甲酯(SM-1)的制备
在氮气保护下，向250mL的圆底烧瓶中依次加入SM-1-2(5.9g，24.2mmol)、联硼酸频那醇酯(12.3g，48.4mmol)、KOAc(7.12g，72.6mmol)、Pd(dppf)Cl 2.CH 2Cl 2(1.96g，2.4mmol)和DMSO(120mL)。将反应液加热至90℃，搅拌3小时之后降至室温。加乙酸乙酯和水稀释，分层，将水相用乙酸乙酯萃取，合并有机相，加无水硫酸钠干燥，过滤并浓缩滤液，将粗产品经硅胶柱层析纯化得标题化合物SM-1(5.8g，82％)。
实施例B：(R)-2-甲基丁-3-烯酸(SM-2)的制备
Figure PCTCN2018094428-appb-000047
第一步：(4R)-4-苄基-3-((R)-2-甲基丁-3-烯酰基)噁唑烷-2-酮(SM-2-4)的制备
在氮气保护和冰浴条件下将化合物SM-2-1(20.0g，200mmol)和N-甲基吗啉(20.3g，200mmol)溶于300mL四氢呋喃中，然后滴入特戊酰氯(24.1g，200mmol)。滴加完毕后，将反应液继续在冰浴条件搅拌40分钟，然后冷却至-78℃待用。
在氮气保护下将化合物SM-2-2(32.2g，182mmol)溶于四氢呋喃(400mL)中，冷却至-78℃，缓慢滴加正丁基锂(200mmol，2.2M，91mL)，然后继续在-78℃下搅拌30分钟。将上述待用溶液加入反应液中，继续反应4小时。TLC监测反应完毕后，将反应液用饱和氯化铵淬灭，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，浓缩后得到粗产品SM-2-3，将粗品经硅胶柱层析纯化(石油醚∶乙酸乙酯＝40∶1)，得到SM-2-4(23g，45％)。
第二步：(R)-2-甲基丁-3-烯酸(SM-2)的制备
将化合物SM-2-4(7.0g，27mmol)溶于四氢呋喃(100mL)中，在冰浴条件下向反应体系中缓慢滴入30％的双氧水(12.2g，108mmol)，继续搅拌5分钟，然后向反应体系中再加入2N氢氧化锂溶液(27mL，54mmol)。TLC监测反应完毕后，将反应液用饱和硫代硫酸钠和碳酸氢钠溶液淬灭，旋转蒸发移除四氢呋喃，将水相用氯仿萃取三次，保留水相，将其用浓盐酸酸化至pH＜3，再用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩后得到SM-2(2.5g，91％)。
实施例C：叔丁基甲基((5R，9S，Z)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂(thiophena)-2(1，2)-苯杂环壬芳(benzenacyclononaphan)-2 4，9-二基)二氨基甲酸酯(Int-A)的制备
Figure PCTCN2018094428-appb-000048
第一步：(R，E)-N-((4-溴噻吩-2-基)亚甲基)-2-甲基丙烷-2-亚磺酰胺(A-2)的制备
在氮气保护下，将化合物4-溴噻吩-2-甲醛(A-1)(50g，0.26mol)和(R)-2-甲基丙烷-2-亚磺酰胺(35g，0.29mol)溶于二氯甲烷(400mL)，加入碳酸铯(171g，0.52mol)，在室温下搅拌4小时。TLC监测反应完毕后，将反应液用饱和氯化铵淬灭，乙酸乙酯萃取，合并有机相，将有机相用饱和食盐水溶液洗一次，无水硫酸钠干燥，过滤，浓缩后得到标题化合物A-2的粗产物(63g，85％)。
第二步：(R)-N-((S)-1-(4-溴噻吩-2-基)丁-3-烯-1-基)-2-甲基丙烷-2-亚磺酰胺(A-3)的制备
在氮气保护下，将化合物A-2(29g，0.10mol)溶于二氯甲烷(300mL)中，然后在室温下将1M的烯丙基溴化镁的乙醚溶液(150mL，0.15mol)缓慢滴入反应液中，滴加完毕后在相同温度下继续反应2～3小时。TLC监测反应完毕后，饱和氯化铵淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤并浓缩滤液得到标题化合物A-3的粗产品，将其直接用于下一步。
第三步：(S)-1-(4-溴噻吩-2-基)丁-3-烯-1-胺盐酸盐(A-4)的制备
在氮气保护下，将A-3的粗产品溶于甲醇(150mL)中，在冰浴下将4N的氯化氢/二氧六环溶液(150mL)缓慢滴入反应体系中，滴加完毕后继续反应2小时。TLC监测反应完毕后，将直接浓缩后得到粗产品用于下一步。
第四步：(S)-(1-(4-溴噻吩-2-基)丁-3-烯-1-基)氨基甲酸叔丁酯(A-5)的制备
在氮气保护下，将上一步骤得到的粗产品溶解在二氯甲烷(150mL)中，然后向其中依次滴入三乙胺(41.2g，0.41mol)和二碳酸二叔丁酯(24g，0.11mol)，滴加完毕后，继续在室温条件下搅拌4小时。TLC监测反应完毕后，将反应用饱和碳酸氢钠溶液淬灭，二氯甲烷萃取，合并有机相，用无水硫酸钠干燥，过滤，将浓缩后的粗产品通过硅胶柱层析分离得到标题化合物A-5(25.2g，第二步至第四步总收率76％)。
第五步：(S)-(1-(4-(2-氨基-4-((甲氧基羰基)氨基)苯基)噻吩-2-基)丁-3-烯-1-基)氨基甲酸叔丁酯(A-6)的制备
将A-5(10.9g，33mmol)、SM-1(8.8g，30mmol)、Pd(dppf)Cl 2·CH 2Cl 2(2.45g，3mmol)和碳酸铯(29.3g，90mmol)加入装有1，4-二氧六环(120mL)和水(30mL)的圆底烧瓶中，在氮气气氛下，升温至90℃反应3小时。TLC监测反应完成后，加水淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤并浓缩滤液，将粗产品经硅胶柱层析纯化得到标题化合物A-6(10.5g，85％)。
第六步：((S)-1-(4-(4-((甲氧基羰基)氨基)-2-((R)-2-甲基丁-3-烯酰氨基)苯基)噻吩-2-基)丁-3-烯-1-基)氨基甲酸叔丁酯(A-7)的制备
在氮气保护下，将中间体SM-2(2.55g，25.5mmol)溶于二氯甲烷(30mL)中，在冰浴下加入数滴DMF，再缓慢滴入草酰氯(3.30g，25.5mmol)，继续在冰浴条件下搅拌30分钟，然后升温至室温搅拌1小时后待用。
将化合物A-6(7.00g，17.0mmol)溶于50mL二氯甲烷中，在0℃下加入吡啶(4.10g，51.03mmol)，搅拌5分钟，然后缓慢滴加入上述待用的溶液，滴加完毕后，升至室温反应2小时。TLC监测反应完毕后，将反应液用饱和碳酸氢钠淬灭，二氯甲烷萃取，无水硫酸钠干燥，过滤，将浓缩后的粗产品经硅胶柱层析纯化得到标题化合物A-7(6.10g，89％)。
第七步：叔丁基甲基((1 2Z，5R，6E，9S)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-6-烯-2 4，9-二基)二氨基甲酸酯(A-8)的制备
在氮气保护下将化合物A-7(900mg，1.8mmol)溶于700mL二氯甲烷中，加入Grubbs II催化剂(460mg，0.54mmol)，在氮气气氛下升温至50℃，回流反应24小时。TLC监测反应完毕后，将反应液直接旋干，粗品经硅胶柱层析纯化得到标题化合物A-8(160mg，19％)。
第八步：叔丁基甲基((5R，9S，Z)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4，9-二基)二氨基甲酸酯(Int-A)的制备
将化合物A-8(500mg，1.05mmol)溶于20mL甲醇中，加入Pd/C(200mg，10％)，在氢气气氛下，升温至40℃反应48小时。TLC监测反应完成后，过滤反应液，浓缩滤液得到Int-A(401mg，80％)。
实施例D：((5R，9S，Z)-1 5-乙酰基-9-氨基-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(Int-B)的制备
Figure PCTCN2018094428-appb-000049
第一步：叔丁基甲基((5R，9S，Z)-1 5-乙酰基-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4，9-二基)二氨基甲酸酯(B-1)的制备
将化合物Int-A(760mg，1.60mmol)溶于80mL的DCE中，室温下加入AlCl 3(7.72g，32mmol)，随后滴加入乙酰氯(2.51g，32mmol)，在室温下反应，LC-MS监测反应完全。将反应液通过加入甲醇淬灭，然后加入饱和碳酸钠溶液调节体系pH至约9，加入二碳酸二叔丁酯(700mg，3.2mmol)，在室温下反应，LC-MS监测反应完全后抽滤，将滤液浓缩后加入乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，将浓缩后的粗品经柱层析纯化得到化合物B-1(560mg，67％)。
第二步：((5R，9S，Z)-1 5-乙酰基-9-氨基-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(Int-B)的制备
在室温下，将化合物B-1(560mg，1.09mmol)溶于12mL甲醇中，滴加入4N氯化氢/二氧六环溶液(6mL)，LC-MS监测反应完全后，将反应液浓缩得到化合物Int-B(466mg，95％)。
实施例E：(1r，4r)-4-(((((9H-芴-9-基)甲氧基)羰基)氨基)甲基)环己烷-1-甲酸(SM-3)的制备
Figure PCTCN2018094428-appb-000050
将(1r，4r)-4-(氨基甲基)环己烷-1-甲酸(1.15g，7.30mmol)溶于12mL的1，4-二氧六环中，然后依次加入10％碳酸钠水溶液(23.2mL)和Fmoc-Cl(2.26g，8.76mmol)，在室温下反应3小时。然后向反应体系中加入1M的盐酸(40mL)，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，将滤液浓缩后的粗品经柱层析纯化得到标题化合物SM-3(1.55g，56％)。
实施例F：((5R，9S，Z)-9-氨基-1 5-((二甲基氨基)甲基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯二盐酸盐(Int-C)的制备
Figure PCTCN2018094428-appb-000051
第一步：叔丁基甲基((5R，9S，Z)-1 5-((二甲基氨基)甲基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4，9-二基)二氨基甲酸酯(C-1)的制备
将化合物Int-A(1.20g，2.50mmol)溶解在MeCN/DMF(1/2，12mL)中，然后向其中加入N，N-二甲基亚甲基碘化胺(1.41g，7.59mmol)。氮气置换三次，加热至80℃搅拌，LC-MS监测反应完全。后处理得到标题化合物的粗产品，将其直接用于下一步。
第二步：((5R，9S，Z)-9-氨基-1 5-((二甲基氨基)甲基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯二盐酸盐(Int-C)的制备
在圆底烧瓶中，向上步反应制备的粗品C-1的甲醇溶液(4mL)中加入4N盐酸/二氧六环溶液(6mL)。在室温下搅拌，LC-MS监测反应完全后，将反应液浓缩得到Int-C(1.00g，两步收率80％)。
实施例G：3-氨基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(SM-4)的制备
Figure PCTCN2018094428-appb-000052
第一步：3-氨基-4-溴苯甲酸甲酯(SM-4-2)的合成
将化合物3-氨基-4-溴苯甲酸(SM-4-1)(10.8g，50mmol)溶于MeOH(50mL)，冰浴下滴加氯化亚砜(11.9g，100mmol)，升温至100℃反应2小时，LC-MS监测反应完毕。将反应液浓缩，加入饱和NaHCO 3调pH＞7，用EA萃取，无水硫酸钠干燥，浓缩得目标产物SM-4-2(黄褐色固体，10.5g，91％)。
第二步：3-氨基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(SM-4)的合成
将化合物SM-4-2(1.48g，6.4mmol)溶于二氧六环(30mL)，依次加入联硼酸频那醇酯(4.91g，19.3mmol)、乙酸钾(1.89g，19.3mmol)和Pd(PPh 3) 2Cl 2(450mg，0.64mmol)，氮气置换5次，并在氮气保护下升温至80℃反应2小时，LC-MS监测反应完毕。向反应液中加入水，用EA萃取，无水硫酸钠干燥，浓缩后经柱层析纯化得目标产物SM-4(白色固体，1.40g，79％)。
实施例1：((5R，9S，Z)-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(1)的制备
Figure PCTCN2018094428-appb-000053
第一步：叔丁基甲基((5R，9S，Z)-1 5-溴-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4，9-二基)二氨基甲酸酯(T1-1)的制备
在室温氮气保护下，将Int-A(200mg，0.42mmol)溶解在CH 3CN/DMF(1∶1，30mL)中，然后向其中加入NBS(186mg，1.05mmol)，搅拌1小时。TLC监测反应完全后，亚硫酸钠淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，浓缩后得到标题化合物(T1-1)，将其在未进一步纯化下直接用于下一步。
第二步：叔丁基甲基((5R，9S，Z)-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4，9-二基)二氨基甲酸酯(T1-2)的制备
向圆底烧瓶中的粗品T1-1的DMSO(5mL)溶液依次加入4，4，5，5-四甲基-2-(丙-1-烯-2-基)-1，3，2-二氧杂硼杂环戊烷(182mg，1.08mmol)、Pd(dppf)Cl 2·CH 2Cl 2(29mg，0.04mmol)和七水合磷酸钾(414mg，1.08mmol)。将反应体系用氮气置换三次后，加热至90℃，搅拌2小时。TLC监测反应完全后，将反应液在冰浴下用水淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤并浓缩，将浓缩后所得的粗产品经柱层析纯化得到标题化合物(T1-2)(140mg，两步收率65％)
第三步：((5R，9S，Z)-9-氨基-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(T1-3)的制备
向圆底烧瓶中的T1-2(80mg，0.16mmol)的MeOH(2mL)溶液加入4M HCl(二氧六环溶液，1mL)。在室温下搅拌2小时，TLC监测反应完全，直接浓缩得粗产品(T1-3)(70mg，97％)。
第四步：((5R，9S，Z)-9-((1r，4S)-4-(((((9H-芴-9-基)甲氧基)羰基)氨基)甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(T1-4)的制备
向圆底烧瓶中的T1-3(40mg，0.09mmol)的DMF(5mL)溶液依次加入DIPEA(35mg，0.27mmol)、SM-3(40mg，0.11mmol)和HATU(37mg，0.10mmol)。在室温下搅拌4小时，LC-MS监测反应完全。加水淬灭，然后乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤并浓缩。将浓缩后的粗品经柱层析纯化得到标题化合物(T1-4)(30mg，44％)。
第五步：((5R，9S，Z)-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(1)的制备
向T1-4(30mg，0.40mmol)的DMF(5mL)溶液中加入哌啶(2mL)，在室温下搅拌12小时，LC-MS监测反应完全，加水淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥并过滤，将滤液浓缩后所得的粗品经柱层析纯化得到标题化合物(1)(23mg，75％)。
MS m/z(ESI)：553[M+H] +.
1H NMR(400MHz，CD 3OD)δ9.78(s，1H)，9.21(s，1H)，8.40(s，2H)，8.23(d，J＝7.6Hz，1H)，7.33(d，J＝8.4Hz，1H)，7.28(s，1H)，7.18(d，J＝8.4Hz，1H)，6.73(s，1H)，5.06(s，1H)，4.95(s，1H)，4.95-4.91(m，1H)，3.67(s，3H)，2.51-2.49(m，2H)，2.10-2.08(m，1H)，1.85(s，3H)，1.82-1.67(m，5H)，1.64-1.50(m，3H)，1.44-1.20(m，7H)，0.94-0.83(m，4H).
实施例2：((5R，9S，Z)-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-1 5-乙烯基-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(2)的制备
Figure PCTCN2018094428-appb-000054
除在实施例2中第一步用4，4，5，5-四甲基-2-乙烯基-1，3，2-二氧杂硼杂环戊烷代替实施例1中第二步的4，4，5，5-四甲基-2-(丙-1-烯-2-基)-1，3，2-二氧杂硼杂环戊烷外，采用与实施例1第二步至第五步所描述的类似方法合成化合物2。
MS m/z(ESI)：539[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.83(s，1H)，9.30(s，1H)，8.41(s，2H)，8.25(d，J＝7.2Hz，1H)，7.42(dd，J＝8.4，2.0Hz，1H)，7.30(s，1H)，7.19(d，J＝8.4Hz，1H)，6.81(s，1H)，6.66(dd，J＝17.2，10.8Hz，1H)，5.39(d，J＝16.8Hz，1H)，5.08(d，J＝11.6Hz，1H)，4.93(q，J＝7.2Hz，1H)，3.68(s，3H)，2.48-2.43(m，3H)，2.16-2.05(m，1H)，1.83-1.61(m，5H)，1.57-1.42(m，2H)，1.40-1.22(m，6H)，0.94-0.82(m，5H).
实施例3：((5R，9S，Z)-1 5-乙酰基-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM3)的制备
Figure PCTCN2018094428-appb-000055
第一步：((5R，9S，Z)-1 5-乙酰基-9-((1r，4S)-4-(((叔丁氧羰基)氨基)甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(T3-2)的制备
将化合物Int-B(2.21mmol，1.0g)在10mL的DMF中溶解，搅拌均匀，然后加入DIPEA(6.63mmol，0.85g)、T3-1(2.65mmol，0.68g)和HATU(2.65mmol，1.01g)。在室温下搅拌4小时，向反应液滴加60mL的蒸馏水直至固体析出完全，过滤得到标题化合物(T3-2)的粗产品，将其直接用于下一步反应。
第二步：((5R，9S，Z)-1 5-乙酰基-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM3)的制备
将T3-2在20mL的甲醇中溶解，然后向其中加入4N氯化氢/二氧六环溶液(10mL)，在室温下搅拌4小时后，直接浓缩，然后将残留物用少量甲醇溶解，向其中滴入乙酸乙酯直至固体完全析出，抽滤得到标题化合物(0.87g，两步收率67％)。
MS m/z(ESI)：555[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.89(s，1H)，9.12(s，1H)，8.39(s，1H)，7.96(s，3H)，7.52-7.30(m， 3H)，6.75(s，1H)，4.88(s，1H)，3.69(s，3H)，2.69-2.58(m，2H)，2.29-2.37(m，1H)，2.20-2.11(m，1H)，2.05(s，3H)，1.89-1.62(m，5H)，1.57-1.44(m，1H)，1.39-1.05(m，6H)，1.01-0.66(m，6H).
实施例4：((5R，9S，Z)-1 5-乙酰基-9-(4-(氨甲基)-3-环丙基苯甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM4)的制备
Figure PCTCN2018094428-appb-000056
第一步：3-溴-4-(溴甲基)苯甲酸甲酯(T4-2)的制备
将3-溴-4-甲基苯甲酸甲酯(10.0g，43.65mmol)在四氯化碳(100mL)中溶解，加入NBS(7.0g，32.29mmol)和过氧化苯甲酰(1.0g，4.37mmol)，回流反应过夜。浓缩反应液，经硅胶柱层析纯化得到标题化合物(T4-2)(5.9g，44％)。
第二步：3-溴-4-(((双叔丁氧羰基)氨基)甲基)苯甲酸甲酯(T4-3)的制备
将叔丁醇钾(1.02g，9.11mmol)溶于DMF(35mL)中，在冰浴下搅拌10分钟，加入Boc2NH(1.94g，8.93mmol)，升至室温搅拌1小时，然后加入T4-2(2.75g，8.93mmol)，继续反应5小时。将反应液倒入1N盐酸(100mL)中，乙酸乙酯萃取，合并有机相。将有机相用饱和食盐水溶液洗涤，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析纯化得到标题化合物(T4-3)(880mg，22％)。
第三步：4-(((双叔丁氧羰基)氨基)甲基)-3-环丙基苯甲酸甲酯(T4-4)的制备
将化合物T4-3(660mg，1.49mmol)在甲苯(5mL)中溶解，依次加入水(5mL)、环丙基三氟硼酸钾(441mg，2.98mmol)、醋酸钯(34mg，0.15mmol)、碳酸钾(618mg，4.47mmol)和2-二环己基磷-2’，6’-二异丙氧基-1，1’-联苯(139mg，0.30mmol)，在95℃下反应过夜。反应完毕后，加入水(50mL)和乙酸乙酯(100mL)，通过硅藻土垫过滤，收集有机相，将其用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩滤液，通过制备TLC纯化得到标题化合物(T4-4)(520mg，86％)。
第四步：4-(((双叔丁氧羰基)氨基)甲基)-3-环丙基苯甲酸(T4-5)的制备
将化合物T4-4(500mg，1.23mmol)在THF(15mL)中溶解，依次加入水(3mL)和氢氧化锂一水合物(413mg，9.84mmol)，在95℃下反应9小时。用1N盐酸将溶液调至pH＝3，乙酸乙酯萃取，合并有机相。用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤后浓缩滤液，通过制备TLC纯化得标题化合物(T4-5)(245mg，51％)。
第五步：(4-(((5R，9S，Z)-1 5-乙酰基-2 4-((甲氧基羰基)氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-9-基)氨基甲酰基)-2-环丙基苄基)(叔丁氧羰基)氨基甲酸叔丁酯(T4-6)的制备
除用T4-5代替实施例3第一步中的T3-1，采用与实施例3中第一步所描述的类似方法合成T4-6。
第六步：((5R，9S，Z)-1 5-乙酰基-9-(4-(氨甲基)-3-环丙基苯甲酰基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM4)的制备
除用T4-6代替实施例3第二步中的T3-2，采用与实施例3中第二步所描述的类似方法合成TM4。第五步和第六步的总收率为60％。
MS m/z(ESI)：589[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.89(s，1H)，9.19(s，1H)，8.86(s，1H)，8.35(s，2H)，7.69(d，J＝8.0Hz，1H)，7.56-7.34(m，3H)，6.83(s，1H)，5.16-5.09(m，1H)，4.02(s，2H)，3.69(s，3H)，2.33-2.31(m，1H)，2.08(s，3H)，2.07-1.86(m，2H)，1.75-1.55(m，1H)，1.50-1.05(m，4H)，0.96(d，J＝6.8Hz，3H)，0.92-0.81(m，2H)，0.70-0.68(m，2H).
实施例5：((5R，9S，Z)-1 5-乙酰基-9-(4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-氧代-3，6-二氢吡啶-1(2H)-基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(5)的制备
Figure PCTCN2018094428-appb-000057
第一步：5-氯-2-(4-(三甲基甲硅烷基)-1H-1，2，3-三唑-1-基)苯甲醛(T5-2)的制备
在500mL的单口烧瓶中依次加入乙腈(200mL)和T5-1(2.00g，12.86mmol)，在冰浴下搅拌20分钟。然后依次加入亚硝酸异戊酯(3.01g，25.71mmol)和TMSN 3(2.96g，25.71mmol)，继续搅拌20分钟。移去冰浴，升温至30℃反应2小时，TLC监测至原料反应完全。然后依次加入氧化亚铜(1.84g，12.86mmol)和乙炔基三甲基甲硅烷(12.62g，128.55mmol)，在30℃下继续反应4小时，TLC监测至反应完全。过滤，浓缩后得到粗产品，然后将其通过柱层析纯化得到标题化合物(T5-2)(1.45g，40％)。
第二步：5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯甲醛(T5-3)的制备
在250ml的单口烧瓶中依次加入乙腈(72.5mL)和T5-2(1.45g，5.18mmol)，在室温下搅拌使其溶解，然后加入硅胶(7.25g)，搅拌10分钟，再加入NCS(2.42g，18.14mmol)，升温至80℃反应4小时，TLC监测至原料反应完全。将反应液过滤，浓缩后得到粗产品，然后将其通过柱层析纯化得到标题化合物(T5-3)(0.80g，64％)。
第三步：1-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)丙-2-烯-1-醇(T5-4)的制备
在-50℃下向化合物T5-3(800mg，3.3mmol)的THF(30mL)溶液中滴加乙烯基溴化镁(1.0M在THF中，8.3mL，8.3mmol)。在低温下搅拌2小时后，滴加饱和氯化铵溶液淬灭反应。将反应液通过加入乙酸乙酯稀释，分层，将水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤并浓缩滤液得到粗品，将其未经纯化直接用于下一步。
第四步：1-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)丙-2-烯-1-酮(T5-5)的制备
在冰水浴下，向T5-4的二氯甲烷(40mL)溶液中依次加入NaHCO 3(1.40g，16.7mmol)和DMP(2.83g，6.66mmol)，随后升至室温并搅拌。1小时后，滴加饱和Na 2SO 3溶液淬灭反应。将反应液通过加入二氯甲烷稀释，分层，将水相用二氯甲烷萃取，合并有机相。将有机相用Na 2SO 4干燥，过滤并浓缩滤液得到粗品，将其经硅胶柱层析纯化得到标题化合物(T5-5)(0.28g，两步收率32％)。
第五步：((5R，9S，Z)-1 5-乙酰基-9-(N-(3-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-3-氧代丙基)-2-(二乙氧基磷酰基)乙酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(T5-6)的制备
在冰水浴下，向(2-氯-2-氧代乙基)磷酸二乙酯(294mg，1.5mmol)的二氯甲烷(15mL)溶液中滴加数滴DMF，然后滴加草酰氯(0.15mL，1.8mmol)，在0℃下搅拌30分钟，升至室温搅拌1小时后静置待用。向Int-B(100mg，0.22mmol)的二氯甲烷(4mL)悬浮液中滴加DIPEA(0.13mL，0.72mmol)和T5-5(65mg，0.24mmol)。将反应液在室温下搅拌1小时后，滴加上述待用溶液(0.1M，4.0mL)。在室 温下继续搅拌30分钟后，滴加饱和碳酸氢钠溶液淬灭反应。将反应液通过加入二氯甲烷稀释，将水相用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤并浓缩滤液得粗品，将未经纯化直接用于下一步。
第六步：((5R，9S，Z)-1 5-乙酰基-9-(4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-氧代-3，6-二氢吡啶-1(2H)-基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(5)的制备
在冰水浴下，向T5-6粗品的MeOH(5mL)溶液滴加甲醇钠的MeOH溶液(5M，0.2mL)。在0℃下搅拌30分钟后，滴加1N盐酸溶液淬灭反应，直接浓缩反应液。将所得粗产品经硅胶柱层析纯化得到标题化合物5(40mg，两步收率26％)。
MS m/z(ESI)：707[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.88(s，1H)，9.36(s，1H)，8.86(s，1H)，7.81-7.66(m，3H)，7.53-7.40(m，2H)，7.36(s，1H)，6.89(s，1H)，5.70(s，1H)，5.52-5.49(m，1H)，3.69(s，3H)，2.37-2.20(m，3H)，2.14(s，3H)，2.02-2.00(m，1H)，1.90-1.60(m，3H)，1.46-1.44(m，1H)，1.25(s，2H)，1.11-1.09(m，1H)，0.93(s，3H).
实施例6：((5R，9S，Z)-1 5-乙酰基-9-(4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-氧代嘧啶-1(6H)-基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(6)的制备
Figure PCTCN2018094428-appb-000058
第一步：4-氯-2-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯胺(T6-2)的制备
将化合物2-溴-4-氯苯胺(5.0g，20mmol)、联硼酸频那醇酯(61.0g，240mmol)和乙酸钾(7.0g，70mmol)溶于1，4-二氧六环(80mL)和水(20mL)的混合溶液中。在氮气保护下，加入Pd(PPh 3) 2Cl 2(1.7g，2mmol)，在75℃下搅拌3小时，然后将反应液用硅藻土过滤，乙酸乙酯萃取，合并有机相。将有机相用饱和食盐水溶液洗，无水硫酸钠干燥，过滤后浓缩滤液。将粗产品经硅胶柱层析纯化得标题化合物(T6-2)(5.0g，83％)。
第二步：4-氯-2-(6-甲氧基嘧啶-4-基)苯胺(T6-3)的制备
将化合物T6-2(2.0g，7.0mmol)、4-氯-6-甲氧基嘧啶(1.4g，9.0mmol)和乙酸钾(2.0g，2.0mmol)溶于1，4-二氧六环(40mL)和水(10mL)的混合溶液中，在氮气氛下加入Pd(dppf)Cl 2(0.6g，0.7mmol)，在65℃下搅拌3小时，然后通过硅藻土过滤反应液，用乙酸乙酯萃取，合并有机相。将有机相用饱和食盐水溶液洗涤，无水硫酸钠干燥，过滤后浓缩滤液。将粗产品经硅胶柱层析纯化得目标化合物(T6-3)(5.0g，83％)。
第三步：4-(5-氯-2-(4-(三甲基甲硅烷基)-1H-1，2，3-三唑-1-基)苯基)-6-甲氧基嘧啶(T6-4)的制备
将化合物T6-3(0.5g，2.0mmol)在乙腈(10mL)中溶解，冷却至0℃，加入亚硝酸异戊酯(0.4g，3.0mmol)和TMSN 3(0.4g，3.0mmol)，在0℃搅拌5分钟，升至室温并搅拌2小时。加入Cu 2O(0.03g，0.2mmol)和乙炔基三甲基甲硅烷(0.6g，0.6mmol)，继续在室温下搅拌3小时后，将反应液用氯化铵饱和水溶液淬灭，将水相用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，过滤后浓缩，将粗产品未经进一步纯化直接用于下一步。
第四步：4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-甲氧基嘧啶(T6-5)的制备
将化合物T6-4(0.65g，2mmol)、NCS(0.85g，6mmol)和硅胶(2.6g)在乙腈(14mL)中溶解，在80℃下搅拌1.5小时。LC-MS监测反应完毕后加水淬灭反应液，过滤，将水相用乙酸乙酯萃取，将有机 相用无水硫酸钠干燥，过滤后浓缩滤液。将粗品经硅胶柱层析纯化得标题化合物(T6-5)(0.36g，两步收率62％)。
第五步：6-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)嘧啶-4(3H)-酮(T6-6)的制备
向化合物T6-5(470mg，1.46mmol)的乙酸(4mL)溶液滴加48％的氢溴酸水溶液(2mL)。升温至80℃，搅拌2.5小时后直接将反应液旋转蒸发至干燥，然后加入乙酸乙酯和饱和碳酸氢钠溶液稀释，分层，将水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤后浓缩滤液，得到粗产物(T6-6)(450mg，100％)，将其未经纯化直接用于下一步。
第六步：((5R，9S，Z)-1 5-乙酰基-9-(4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-氧代嘧啶-1(6H)-基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(6)的制备
向化合物T6-6(60mg，0.19mmol)和HATU(289mg，0.76mmol)的MeCN(5mL)溶液中滴加DBU(174mg，1.14mmol)。在室温下搅拌30分钟后，加入化合物Int-B(95mg，0.21mmol)，然后滴加DMF(1mL)使反应体系澄清。将反应液升温至65℃搅拌10小时后直接浓缩得粗品，将粗品经硅胶柱层析纯化得到标题化合物(6)(37mg，28％)。
MS m/z(ESI)：706[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.88(s，1H)，9.34(s，1H)，8.77(s，1H)，8.62(s，1H)，7.93(s，1H)，7.83(dd，J＝8.4Hz，2.4Hz，1H)，7.76(d，J＝8.4，1H)，7.51-7.34(m，3H)，6.95(s，1H)，6.50(d，J＝6.8Hz，1H)，5.77-5.74(m，1H)，3.69(s，3H)，2.34-2.32(m，2H)，2.13(s，3H)，1.84(br，1H)，1.47(br，1H)，1.38-1.19(m，2H)，1.04-0.83(m，4H).
实施例7：((5R，9S，Z)-1 5-乙酰基-5-甲基-4-氧代-9-((1r，4S)-4-((((Z)-4-氧代戊-2-烯-2-基)氨基)甲基)环己烷-1-甲酰氨基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(7)的制备
Figure PCTCN2018094428-appb-000059
向TM3(26mg，0.044mmol)的MeOH(2mL)溶液中依次加入DIPEA(23mg，0.18mmol)和戊烷-2，4-二酮(18mg，0.088mmol)，将反应液在室温下搅拌。LC-MS监测反应完全后直接浓缩至干，浓缩后的粗品经制备HPLC纯化得到标题化合物(7mg，25％)。
MS m/z(ESI)：637[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ10.87(s，1H)，9.87(s，1H)，9.12(s，1H)，8.37(d，J＝6.8Hz，1H)，7.43(s，2H)，7.36(s，1H)，6.74(s，1H)，4.92(s，1H)，4.91-4.89(m，1H)3.68(s，3H)，3.12-3.09(m，2H)，2.28-2.26(m，1H)，2.22-1.94(m，4H)，1.89(s，3H)，1.85(s，3H)，1.80-1.66(m，4H)，1.48-1.16(m，9H)，1.01-0.98(m，2H)，0.94(d，J＝7.2Hz，3H).
实施例8：((5R，9S，Z)-9-(4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-氧代-3，6-二氢吡啶-1(2H)-基)-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(9)的制备
Figure PCTCN2018094428-appb-000060
除在实施例8中第五步用T1-3代替实施例5中第五步的Int-B外，采用与实施例5第一步至第六步所描述的类似方法合成化合物9。
MS m/z(ESI)：705[M+H] +.
1H NMR(400MHz，CD 3OD)δ8.45(s，1H)，7.69-7.60(m，2H)，7.60-7.55(m，1H)，7.39(s，1H)，7.38-7.33(m，1H)，7.30(d，J＝8.4Hz，1H)，6.93(s，1H)，5.79(s，1H)，5.66-5.56(m，1H)，5.12(s，1H)，5.04(s，1H)，3.73(s，3H)，3.55-3.36(m，2H)，2.50-2.37(m，1H)，2.33-2.17(m，2H)，1.92(s，3H)，1.83-1.68(m，2H)，1.51-1.39(m，1H)，1.34-1.27(m，2H)，1.20-1.12(m，1H)，1.08(d，J＝6.8Hz，3H)
实施例9：((5R，9S，Z)-9-(4-(氨甲基)-3-环丙基苯甲酰氨基)-5-甲基-4-氧代-1 5-(丙-1-烯-2-基)-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM41)的制备
Figure PCTCN2018094428-appb-000061
除在实施例9中第五步用T1-3代替实施例4中第五步的Int-B外，采用与实施例4第一步至第六步所描述的类似方法合成化合物TM41。
MS m/z(ESI)：587[M+H] +.
1H NMR(400MHz，CD 3OD)δ7.72(dd，J＝8.0，1.6Hz，1H)，7.58(s，1H)，7.46-7.38(m，2H)，7.36-7.30(m， 1H)，7.27(d，J＝8.0Hz，1H)，6.88(s，1H)，5.25(dd，J＝10.0，5.6Hz，1H)，5.11(s，1H)，4.98(s，1H)，4.25(s，2H)，3.74(s，3H)，2.58-2.48(m，1H)，2.08-1.99(m，1H)，1.92(s，3H)，1.97-1.87(m，1H)，1.85-1.74(m，1H)，1.64-1.54(m，1H)，1.44-1.34(m，1H)，1.32-1.23(m，1H)，1.19-1.09(m，1H)，1.09-1.01(m，5H)，0.83-0.75(m，2H).
实施例10：((5R，9S，Z)-9-(4-(5-氯-2-(4-氯-1H-1，2，3-三唑-1-基)苯基)-6-氧代-3，6-二氢吡啶-1(2H)-基)-1 5-(1，2-二羟基丙-2-基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(73)的制备
Figure PCTCN2018094428-appb-000062
将化合物9(100mg，0.14mmol)溶于丙酮/水(2/1，6mL)，加入AD-mix-α(200mg)，室温下搅拌1.5小时。LC-MS监测反应完毕后，加入饱和亚硫酸钠水溶液淬灭反应，将水相用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，过滤后浓缩滤液。将粗品经硅胶柱层析纯化得标题化合物(50mg，45％)。
MS m/z(ESI)：739[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.78(s，1H)，8.86(s，1H)，7.84-7.65(m，4H)，7.47-7.33(m，1H)，7.31(s，2H)，6.67(s，1H)，5.66(s，2H)，5.41(s，1H)，4.88-4.69(m，1H)，3.68(s，3H)，3.61-3.49(m，2H)，3.30-3.22(m，1H)，3.15-3.04(m，1H)，2.37-2.09(m，3H)，1.87-1.74(m，1H)，1.67-1.47(m，4H)，1.39(s，1H)，1.23(s，2H)，1.01-0.94(m，1H)，0.92-0.76(m，3H).
实施例11：((5R，9S，Z)-9-(4-(氨甲基)-3-环丙基苯甲酰氨基)-1 5-(1，2-二羟基丙-2-基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM75)的制备
Figure PCTCN2018094428-appb-000063
除在实施例11中用TM41代替实施例10中的化合物9，采用与实施例10所描述的类似方法合成标题化合物TM75。
MS m/z(ESI)：621[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.78(s，1H)，9.08(s，1H)，8.74(d，J＝8.0Hz，1H)，7.78-7.57(m，2H)，7.54-7.41(m，2H)，7.42-7.10(m，3H)，6.63(s，1H)，5.22-5.08(m，1H)，4.00(s，2H)，3.68(s，3H)，3.57-3.46(m，1H)，3.20-3.04(m，1H)，2.44-2.01(m，1H)，2.10-1.91(m，1H)，1.82(s，1H)，1.72-1.56(m，1H)，1.47(s，3H)，1.35-1.18(m，3H)，0.97-0.86(m，5H)，0.75-0.60(m，2H).
实施例12-((5R，9S，Z)-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-1 5-((二甲基氨基)甲基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM76)的制备
Figure PCTCN2018094428-appb-000064
第一步：((5R，9S，Z)-9-((1r，4S)-4-(((叔丁氧羰基)氨基)甲基)环己烷-1-甲酰氨基)-1 5-((二甲基氨基)甲基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯(T76-1)的制备
向Int-C(2.66g，5.30mmol)的DMF(30mL)溶液中依次加入DIPEA(2.67g，21.2mmol)、T3-1(2.2g，8.48mmol)和HATU(4.02g，10.6mmol)。室温搅拌反应4小时后，LC-MS监测反应完全。将反应液滴入150mL的水中直至固体析出完全，过滤得到标题化合物的粗产品，将粗产品经硅胶柱色谱法纯化得T76-1(1.52g，42％)。
第二步：((5R，9S，Z)-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-1 5-((二甲基氨基)甲基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-基)氨基甲酸甲酯盐酸盐(TM76)的制备
将T76-1(330mg，0.49mmol)溶解在20mL的甲醇中，然后向其中加入10mL的盐酸二氧六环溶液，室温搅拌3～4小时后，直接浓缩旋干溶剂，冻干后得到标题化合物(213mg，71％)。
MS m/z(ESI)：570[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.78(s，1H)，9.22(s，1H)，8.17(d，J＝7.6Hz，1H)，7.42-7.32(m，1H)，7.31-7.19(m，2H)，6.77(s，1H)，5.05-4.89(m，1H)，3.68(s，3H)，3.57(d，J＝14.4Hz，1H)，3.27(d，J＝14.0Hz，1H)，2.45(s，2H)，2.21-2.07(m，7H)，1.85-1.60(m，5H)，1.55-1.42(m，2H)，1.36-1.16(m，6H)， 0.92-0.78(m，5H)，0.77-0.60(m，1H).
实施例13：(5R，9S，Z)-1 5-乙酰基-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸盐酸盐(TM47)的制备
Figure PCTCN2018094428-appb-000065
第一步：(S)-3-氨基-4-(5-(1-((叔丁氧羰基)氨基)丁-3-烯-1-基)噻吩-3-基)苯甲酸甲酯(47-1)的合成
向反应瓶中依次加入化合物A-5(1.03g，3.1mmol)、SM-4(1.04g，3.7mmol)、DMSO(30mL)、七水合磷酸钾(3.17g，9.3mmol)和Pd(dppf)Cl 2 .CH 2Cl 2(344mg，0.4mmol)，氮气置换5次，并升温至80℃搅拌反应2小时，LC-MS监测反应完毕。将反应液冷却至室温后加水，用EA萃取，无水硫酸钠干燥，浓缩后经柱层析纯化得目标产物47-1(黄色油状物，0.936g，75％)。
MS m/z(ESI)：347[M+H-56] +.
第二步：4-(5-((S)-1-((叔丁氧羰基)氨基)丁-3-烯-1-基)噻吩-3-基)-3-((R)-2-甲基丁-3-烯酰氨基)苯甲酸甲酯(47-2)的合成
在氮气保护下，将中间体SM-2(388mg，3.9mmol)溶于DCM(10mL)中，加入数滴DMF，冰浴下缓慢滴入草酰氯(655mg，5.1mmol)，继续在冰浴条件下搅拌30分钟，然后升温至室温搅拌1小时，待用。
另外准备一个三颈瓶，氮气保护下向其中加入化合物47-1(1.04g，2.6mmol)、DCM(10mL)和吡啶(408mg，5.1mmol)，然后将上面制备好的酰氯缓慢滴入该反应体系中，滴加完毕后，室温反应1小时。LC-MS监测反应完毕，向反应液中加入3N盐酸，用DCM萃取，无水硫酸钠干燥，浓缩后经柱层析纯化得目标产物47-2(近无色油状物，479mg，38％)。
MS m/z(ESI)：429[M+H-56] +.
第三步：((1 2Z，5R，6E)-9-((叔丁氧羰基)氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-6-烯-2 4-甲酸甲酯(47-3)的合成
将化合物47-2(426mg，0.88mmol)溶于DCM(700mL)中，加入Grubbs II催化剂(163mg，0.26mmol)，氮气置换5次，在氮气保护下升温至50℃回流反应18小时。TLC监测反应完毕，将反应液浓缩后经柱层析纯化得目标产物47-3(浅褐色固体，92mg，23％)。
MS m/z(ESI)：401[M+H-56] +.
第四步：((5R，9S，Z)-9-((叔丁氧羰基)氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸甲酯(47-4)的合成
将化合物47-3(91mg，0.2mmol)溶于EA(10mL)，加入二氧化铂(10mg，0.04mmol)，用氢气置换5次，氢气氛围下于室温下反应2小时。TLC监测反应完毕，将反应液过滤，将滤液浓缩后经柱层析纯化目标产物47-4(白色固体，56mg，61％)。
MS m/z(ESI)：403[M+H-56] +.
第五步：((5R，9S，Z)-1 5-溴-9-((叔丁氧羰基)氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸甲酯(47-5)的合成
将化合物47-4(1.0g，2.18mmol)溶于DMF/CH 3CN(5mL)，冰浴下缓慢滴入NBS(583mg，3.28mmol)，室温反应1小时。TLC监测反应完毕，将反应液加入水中，析出固体，过滤，收集固体得47-5(760mg，65％)
MS m/z(ESI)：481[M+H-56] +.
第六步：((5R，9S，Z)-1 5-乙酰基-9-((叔丁氧羰基)氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸甲酯(47-6)的合成
向反应瓶中依次加入化合物47-5(180mg，0.34mmol)、三丁基(1-乙氧基乙烯基)锡(242g，0.68mmol)、二氧六环(5mL)和Pd(PPh 3) 2Cl 2(24mg，0.034mmol)，氮气置换5次，并升温至90℃搅拌反应2小时。LC-MS监测反应完毕，将反应液冷却至室温后加入1mL 3N盐酸，加水，用EA萃取，无水硫酸钠干燥，浓缩后经柱层析纯化得目标产物47-6(黄色油状物，130mg，76％)。
MS m/z(ESI)：445[M+H-56] +.
第七步：((5R，9S，Z)-1 5-乙酰基-9-氨基-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸甲酯(47-7)的合成
将化合物47-6(130mg，0.26mmol)溶于MeOH(5mL)，缓慢滴入4M盐酸/二氧六环溶液(2mL)，室温反应2小时。TLC监测反应完毕，将反应液浓缩得目标产物47-7(白色固体，114mg，99％)
MS m/z(ESI)：401[M+H] +.
第八步：((5R，9S，Z)-1 5-乙酰基-9-((1r，4S)-4-(((叔丁氧羰基)氨基)甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸甲酯(47-8)的合成
将化合物47-7(114mg，0.26mmol)和(1r，4r)-4-(((叔丁氧基羰基)氨基)甲基)环己烷-1-羧酸(67mg，0.26mmol)溶于DMF(3mL)，然后加入DIPEA(67mg，0.52mmol)和HATU(108mg，0.286mmol)，室温反应1小时。LC-MS监测反应完毕，向反应物中加水，过滤，将固体干燥得目标产物47-8(101mg，61％)。
MS m/z(ESI)：540[M+H-100] +.
第九步：(5R，9S，Z)-1 5-乙酰基-9-((1r，4S)-4-(氨甲基)环己烷-1-甲酰氨基)-5-甲基-4-氧代-3-氮杂-1(4，2)-噻吩杂-2(1，2)-苯杂环壬芳-2 4-甲酸盐酸盐(TM47)的合成
将化合物47-8(101mg，0.158mmol)溶于THF(3mL)中，加入NaOH(12.6mg，0..316mmol)，并加入数滴水，室温反应2小时。LC-MS监测反应完毕，再向反应体系中缓慢加入4M盐酸/二氧六环溶液(3mL)，室温反应3小时，LC-MS监测反应完毕。将反应液浓缩，经制备HPLC纯化得目标化合物(28mg，34％)。
MS m/z(ESI)：526[M+H] +.
1H NMR(400MHz，DMSO-d 6)δ9.35(s，1H)，8.51(s，1H)，8.08(s，3H)，7.90(d，J＝6.4Hz，1H)，7.81-7.64(m，2H)，6.78(s，1H)，4.88(s，1H)，3.40(s，3H)，2.63(s，2H)，2.19-2.00(m，4H)，1.87-1.70(m，4H)，1.54(s，1H)，1.37-1.16(m，6H)，1.05-0.91(m，5H).
其他化合物均可参考上述实施例的制备方法合成。
药理学测试
试验例1：抑制因子XIa活性的检测
酶：人因子XIa，购自Haemtech公司。
底物：Boc-Ile-Glu-Gly-Arg-AMC乙酸盐，购自Bachem。
检测方法：
将待测化合物以不同浓度溶解于检测缓冲液(50mM HEPES，145mM NaCl，5mM KCl，0.1％BSA，pH 7.4)中。在384孔板中加入因子XIa和待测化合物，混匀后在室温下孵育10分钟。加入底物(Boc-Ile-Glu-Gly-Arg-AMC乙酸盐)启动反应。将384孔板放入酶标仪中，在酶动力学模式下，选择激发光波长为380nm，发射光波长为460nm来读取荧光值。每30秒读取1次，连续读取20个循环。在线性反应期内计算各试验组的酶活性抑制率。利用作图软件Prism 5制作受试化合物浓度-抑制率信号曲线，按照四参数模型拟合曲线，计算IC 50值。
表1：化合物对因子XIa的抑制作用
化合物 IC 50(nM)
实施例1 0.59±0.10
实施例2 0.90±0.04
实施例3 0.60±0.03
实施例4 0.44±0.04
实施例5 1.07±0.10
实施例6 0.82±0.07
实施例8 3.63±0.56
实施例9 0.51±0.05
实施例10 0.57±0.03
实施例11 1.98±0.15
实施例12 1.49±0.15
由表1的试验数据可见，本发明的化合物对因子XIa的IC 50为nM级。特别是表1中所列的化合物对XIa因子具有较强的抑制作用：化合物的IC 50小于4.0nM，优选化合物的IC 50小于1.0nM，最优选化合物的IC 50小于0.5nM。
试验例2：抑制因子VIIa活性的检测
酶：人因子VIIa；购自Haematologic Technologies公司。
底物：Boc-VPR-AMC；购自R&D。
组织因子：组织因子F3，购自Sino Biological。
检测方法：将待测化合物溶解于检测缓冲液(50mM Hepes，150mM NaCl，5mM CaCl 2，pH 7.4)中。将因子VIIa和组织因子等摩尔浓度混匀，在37℃孵育15分钟后，加入待测化合物，在室温下孵育10分钟，最后加入底物(Boc-VPR-AMC)启动反应。将板放入酶标仪中，在酶动力学模式下，选择激发光波长为380nm，发射光波长为460nm来读取荧光值。每30秒读取1次，连续读取20个循环。在线性反应期内计算各试验组的酶活性抑制率。根据不同浓度下抑制率来判断IC 50的范围。
表2：化合物对因子VIIa的抑制作用
化合物 IC 50(μM)
实施例1 16.02
实施例2 8.23
实施例3 14.93
实施例4 ＞20
实施例6 ＞20
由表2的试验数据可知，本发明的化合物对因子VIIa的IC 50为μM级。对比表1的试验数据可见本发明的化合物对因子XIa的抑制作用强于对VIIa的抑制作用，因此本发明的化合物具有选择性抑制因子XIa的作用。
试验例3：抑制因子Xa活性的检测
酶：人因子Xa，购自R&D。
底物：Mca-RPKPVE-Nval-WRK(Dnp)-NH2，购自R&D。
检测方法：
首先将待测化合物溶解于检测缓冲液(50mM Tris，150mM NaCl，10mM CaCl 2，0.05％Brij35，pH 7.5)中。在384孔板中加入因子Xa和待测化合物，混匀后室温孵育10分钟。加入底物(Mca-RPKPVE-Nval-WRK(Dnp)-NH2)启动反应。将板放入酶标仪中，在酶动力学模式下，选择激发光波长为320nm，发射光波长为405nm来读取荧光值。每30秒读取1次，连续读取20个循环。在线性反应期内计算各试验组的酶活性抑制率。根据不同浓度下抑制率来判断IC 50的范围。
表3：化合物对因子Xa的抑制作用
化合物 IC 50(μM)
实施例1 ＞20
实施例2 ＞20
实施例3 ＞20
实施例4 ＞20
实施例6 ＞20
由表3试验数据可知，本发明的化合物对因子Xa的IC 50为μM级，例如所有实施例化合物的IC 50均＞20μM。对比表1的实验数据可见本发明的化合物对因子XIa的抑制作用强于对Xa的抑制作用，因此本发明的化合物具有选择性抑制因子XIa的作用。
试验例4：化合物在体外对凝血APTT(activated partial thromboplastin time，活化部分凝血活 酶时间)和PT(prothrombin time，凝血酶原时间)的影响
APTT试剂购自希森美康。
PT试剂购自希森美康。
检测方法：
将犬和人的血液用柠檬酸钠抗凝后，离心收集上层血浆，并等量分成多份，向其中分别加入不同待测化合物，使待测化合物终浓度为10μM，混匀后在37℃下孵育3分钟，然后把样品放入希森美康全自动凝血分析仪CA1500中进行APTT和PT的检测。空白组血浆(不加化合物)作为对照，计算所有测试组与空白血浆的APTT和PT的比值。向抗凝血剂中加入APTT试剂后，启动内源性凝血途径，使XI激活XIa，若化合物能抑制XIa，会使APTT延长(与空白组血浆APTT的比值大于1)；而PT试剂激活外源性凝血途径，与XIa不相关，加入XIa抑制剂不会延长PT(与空白组血浆PT比值约为1)。
表4：与空白组血浆相比，犬血液中化合物对APTT和PT的影响(n＝3)
化合物 APTT(测试组/空白组) PT(测试组/空白组)
实施例1 3.65 0.99
实施例2 4.69 1.01
实施例3 4.04 1.00
实施例4 3.71 0.99
实施例6 3.47 0.99
表5：与空白组血浆相比，人血液中化合物对APTT和PT的影响(n＝3)
化合物 APTT(测试组/空白组) PT(测试组/空白组)
实施例1 2.82 1.01
实施例2 3.15 1.03
实施例3 2.98 1.01
实施例4 2.88 1.00
实施例6 2.99 1.03
实施例9 2.15 1.02
实施例10 2.38 1.01
实施例12 2.89 1.00
由表4、5可见，本发明的化合物在犬和人的血液中使APTT延长，说明本发明的化合物抑制了犬和人的内源性凝血途径。
此外，本发明的化合物加入犬和人的血液中后，PT无显著变化(测试组与空白组的PT比值约为1)，说明本发明的化合物不会抑制外源性凝血途径。
本发明的化合物在小鼠、大鼠、猴血浆中对APTT和PT具有类似的效果。
试验例5：体外安全性试验
采用Predictor TM hERG荧光偏振测定法，检测待测化合物对hERG钾离子通道的作用，测试浓度为1和10μM。试验结果如表6中所示：
表6：hERG试验结果
化合物 IC 50(μM)
实施例1 ＞10
实施例2 ＞10
实施例3 ＞10
实施例4 ＞10
实施例5 ＞10
实施例6 ＞10
实施例9 ＞10
实施例10 ＞10
实施例11 ＞10
实施例12 ＞10
由表6的结果可见，本发明的化合物对于hERG的IC 50均大于10μM。因此，本发明的化合物对hERG无抑制作用，无导致心脏QT间期延长的安全性隐患。
另外，在大鼠、小鼠、犬和猴上实施了动静脉分流血栓模型试验。试验结果表明，给药各实施例的化合物后，血栓形成被有效抑制。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (14)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：
    Figure PCTCN2018094428-appb-100001
    其中：
    Figure PCTCN2018094428-appb-100002
    表示单键或双键；
    R 1选自H、卤素、羟基、C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基，其中所述C 1-6烷基、-O-(C 1-6烷基)和C 3-6环烷基各自独立地任选地被一个或多个选自卤素、-OH、氰基、C 1-3烷基、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2和-O-(C 1-3烷基)的取代基取代；
    R 2和R 3各自独立地选自H、卤素、-OH和氧代基(＝O)；
    Figure PCTCN2018094428-appb-100003
    不存在或者选自任选地被R 7、R 8和R 9中的一个或多个取代的饱和或不饱和的C 3-10亚环烃基、饱和或不饱和的3-10元亚杂环基、C 6-14亚芳基、5-14元亚杂芳基、饱和或不饱和的C 5-14亚桥环烃基、饱和或不饱和的C 5-14亚螺环烃基、饱和或不饱和的5-14元亚氮杂桥环基和饱和或不饱和的5-14元亚氮杂螺环基；
    B选自H、卤素以及任选地被R 10、R 11和R 12中的一个或多个取代的-C(＝NH)NH 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-4亚烷基)-NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)、-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)、饱和或不饱和的C 3-10环烃基、饱和或不饱和的3-10元杂环基、C 6-14芳基、5-14元杂芳基、饱和或不饱和的C 5-14桥环烃基、饱和或不饱和的C 5-14螺环烃基、饱和或不饱和的5-14元氮杂桥环基和饱和或不饱和的5-14元氮杂螺环基；
    L 1为-C(＝O)NR 4-或基团
    Figure PCTCN2018094428-appb-100004
    R 4选自H、C 1-5烷基和C 2-5烯基，其中所述C 1-5烷基和C 2-5烯基各自独立地任选地被一个或多个选自卤素、-OH、氰基、C 1-5烷基、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-O-(C 1-3烷基)和卤代C 1-6烷基的取代基取代；
    基团
    Figure PCTCN2018094428-appb-100005
    表示任选地另外含有独立地选自N、O、C＝O、S、S＝O和S(＝O) 2的1、2或3个环成员的3-10元含氮杂环，其任选地被R 7和/或R 8取代，并且其通过所述含氮杂环中的氮原子以及任一其余环原子经单键或双键与分子的其余部分连接，所述3-10元含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接；
    Y选自C、CH、CH 2、N、NH和O；
    优选地，Y选自CH、CH 2、N、NH和O；
    R 5选自-C(＝O)(C 1-3烷基)、-C(＝O)(C 3-6环烷基)、-CH(OH)-C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-CH 2NH 2、-CH 2NH(C 1-3烷基)、-CH 2N(C 1-3烷基) 2、-C 2-5烯基和-C 2-5炔基，所述烷基、亚烷基、环烷基、烯基和炔基任选地被一个或多个选自卤素、羟基、-C 1-6亚烷基-OH、-O-(C 1-3烷基)、-C 1-6亚烷基-O-(C 1-3烷基)、氨基、-C 1-6亚烷基-NH 2、-C 1-6亚烷基-NH-(C 1-6烷基)和-C 1-6亚烷基-N(C 1-3烷基) 2的取代基取代；
    R 5’选自H、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、-OH、-(C 1-4亚烷基)-OH、-O-(C 1-4烷基)、 -(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(卤代C 1-4烷基)、-NH 2、-NH-(C 1-6烷基)和-N(C 1-6烷基) 2；
    R 6和R 6’各自独立地选自H、卤素、氰基、-OH、C 1-4烷基、-COOH、-C(＝O)O(C 1-4烷基)、-(C 1-6亚烷基)-COOH、-(C 1-6亚烷基)-COO(C 1-6烷基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-O-(C 1-4烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-NHC(＝O)(C 1-4烷基)、-NHC(＝O)O(C 1-4烷基)、-NHC(＝O)O(C 3-6环烷基)、-NHC(＝O)O(C 1-4亚烷基)-OH、-NHC(＝O)O(C 1-4亚烷基)-O-(C 1-4烷基)、-NHC(＝O)O(C 1-4亚烷基)-COOH、-(C 1-4亚烷基)NHC(＝O)O(C 1-4烷基)、-NHC(＝O)N(C 1-4烷基) 2和-NHSO 2(C 1-4烷基)，所述烷基或亚烷基任选地被一个或多个选自卤素、氰基、-NH 2和-OH的取代基取代；
    或者R 6和R 6’连同其所连接的碳原子共同形成任选被卤素和/或-NH 2取代的饱和或不饱和的C 5-6环烃基、饱和或不饱和的5-6元杂环基、C 6-14芳基或5-14元杂芳基；
    R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、卤素、氰基、氧代基、-OH、-(C 1-4亚烷基)-OH、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-6亚烷基)-NH 2、-CONH 2、-COOH、C 1-6烷基、卤代C 1-6烷基、-O-(C 1-4烷基)、-(C 1-3亚烷基)-O-(C 1-3烷基)、-O-(卤代C 1-4烷基)、饱和或不饱和的C 3-6环烃基、饱和或不饱和的3-10元杂环基、C 6-14芳基、5-14元杂芳基、-C(＝NH)NH 2、-C(＝O)(C 1-4烷基)、-C(＝O)O(C 1-4烷基)、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)和-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)；并且
    W为CH或N。
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中L 1选自-C(＝O)NH-、-C(＝O)N(CH 3)-、
    Figure PCTCN2018094428-appb-100006
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 5选自-CH(OH)C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-CH 2N(C 1-3烷基) 2、-C 2-5烯基、-C 2-5炔基和-C(＝O)(C 1-3烷基)；优选地，R 5选自-CH(OH)C 1-3烷基、-CH(OH)-C 1-3亚烷基-OH、-C(C 1-3烷基)(OH)-C 1-3烷基、-C(C 1-3烷基)(OH)-C 1-3亚烷基-OH、-C 2-5烯基、-C 2-5炔基和-C(＝O)(C 1-3烷基)；所述烷基、亚烷基、烯基和炔基任选地被一个或多个选自卤素、-NH 2、-OH、-CH 2OH、-OCH 3和-CH 2OCH 3的取代基取代；并且R 5’选自H、卤素、氰基、-OH、-O-(C 1-4烷基)和-NH 2；
    优选地，R 5选自-C(＝O)CH 3、-CH＝CH 2、-C(＝CH 2)CH 3、-CH(OH)CH 3、-CH(OH)CH 2OH、-C(CH 3)(OH)-CH 2OH、-CH 2N(CH 3) 2、-C≡CH、-C≡CHCH 2OCH 3和-C≡CHCH 2OH；更优选地，R 5选自-C(＝O)CH 3、-CH＝CH 2、-C(＝CH 2)CH 3、-CH(OH)CH 3、-CH(OH)CH 2OH、-C(CH 3)(OH)-CH 2OH、-C≡CH、-C≡CCH 2OCH 3和-C≡CCH 2OH；并且R 5’为H。
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 6和R 6’各自独立地选自H、-COOH、-C(＝O)O(C 1-4烷基)、-NHC(＝O)O(C 1-4烷基)和-NHC(＝O)O(C 1-4亚烷基)-OH，所述烷基任选地被一个或多个选自卤素、氰基、-NH 2和-OH的取代基取代；或者R 6和R 6’连同其所连接的碳原子共同形成被-NH 2取代的5-6元杂芳基；
    优选地，R 6和R 6’各自独立地选自H、-COOH、-NHC(＝O)OCH 3和-NHC(＝O)OCH 2CH 2OH；或者R 6和R 6’连同其所连接的碳原子共同形成
    Figure PCTCN2018094428-appb-100007
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中当
    Figure PCTCN2018094428-appb-100008
    不存在时，B不为H；或者
    Figure PCTCN2018094428-appb-100009
    选自任选地被R 7、R 8和R 9中的一个或多个取代的饱和或不饱和的C 5-6亚环烃基、饱和或不饱和的5-6元亚杂环基、C 6-10亚芳基、5-10元亚杂芳基、饱和或不饱和的C 5-14亚桥环烃基和 饱和或不饱和的5-14元亚氮杂螺环基；
    优选地，
    Figure PCTCN2018094428-appb-100010
    选自
    Figure PCTCN2018094428-appb-100011
    Figure PCTCN2018094428-appb-100012
    其任选地被R 7、R 8和R 9中的一个或多个取代。
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中B选自H、卤素以及任选地被R 10、R 11和R 12中的一个或多个取代的-C(＝NH)NH 2、-(C 1-6亚烷基)-NH 2、-(卤代C 1-4亚烷基)-NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)、-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)、饱和或不饱和的C 3-10环烃基、饱和或不饱和的5-6元杂环基、C 6-10芳基、5-10元杂芳基、饱和或不饱和的C 5-14桥环烃基和饱和或不饱和的5-14元氮杂螺环基；
    优选地，B选自H、F、Cl、Br、I、-CH 2NH 2、-C(＝NH)NH 2、-CH 2NHC(CH 3)＝CHC(＝O)CH 3、-CH 2NHC(＝O)O-CH(CH 3)-OC(＝O)CH 2CH 3、
    Figure PCTCN2018094428-appb-100013
    Figure PCTCN2018094428-appb-100014
    其任选地被R 10、R 11和R 12中的一个或多个取代。
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、卤素、-(C 1-4亚烷基)-OH、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、-(C 1-6亚烷基)-NH 2、C 1-6烷基、卤代C 1-6烷基、饱和或不饱和的C 3-6环烃基、饱和或不饱和的3-10元杂环基、C 6-10芳基、5-10元杂芳基、-C(＝NH)NH 2、-(C 1-4亚烷基)-NH-(C 2-6亚烯基)C(＝O)(C 1-4烷基)和-(C 1-4亚烷基)-NHC(＝O)O-(C 1-4亚烷基)-OC(＝O)-(C 1-4烷基)；
    优选地，R 7、R 8、R 9、R 10、R 11和R 12各自独立地选自H、F、Cl、Br、-NH 2、-CH 2OH、-CH 2NH 2、-CF 3、-CH 2NHC(CH 3)＝CHC(＝O)CH 3、-CH 2NHC(＝O)O-CH(CH 3)-OC(＝O)CH 2CH 3、
    Figure PCTCN2018094428-appb-100015
    Figure PCTCN2018094428-appb-100016
  8. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(II)、式(III)、式(IV)、式(V)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)或式(XII)的结构：
    Figure PCTCN2018094428-appb-100017
    Figure PCTCN2018094428-appb-100018
    Figure PCTCN2018094428-appb-100019
    其中
    B、R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 10、R 11、R 12和W如权利要求1-7中任一项所定义；
    R 13选自H、卤素、C 1-5烷基和卤代C 1-5烷基；并且
    Figure PCTCN2018094428-appb-100020
    选自：
    Figure PCTCN2018094428-appb-100021
  9. 权利要求1或8的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(II’)、式(IV’)、式(VI’)、式(IX’)或式(XII’)结构：
    Figure PCTCN2018094428-appb-100022
    Figure PCTCN2018094428-appb-100023
    其中，B、R4、R 5、R 5’、R 6、R 10、R 11和R 12如权利要求1-8中任一项所定义；
    优选地，R 6选自-COOH和-NHC(＝O)OCH 3；并且B、R4、R 5、R 5’、R 10、R 11和R 12如权利要求1-8中任一项所定义。
  10. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
    Figure PCTCN2018094428-appb-100024
    Figure PCTCN2018094428-appb-100025
    Figure PCTCN2018094428-appb-100026
    Figure PCTCN2018094428-appb-100027
    Figure PCTCN2018094428-appb-100028
  11. 制备式(I)的化合物的方法，
    所述方法为方法一，其包括以下步骤：
    Figure PCTCN2018094428-appb-100029
    其中：
    X为卤素或任选地被卤素取代的C 1-3烷基磺酸酯基(例如三氟甲磺酸酯基)；并且R 5a和R 5a’与R 5和R 5’相同，或者R 5a和R 5a’为R 5和R 5’的前体基团；R 6a和R 6a’与R 6和R 6’相同，或者R 6a和R 6a’为R 6和R 6’的前体基团；
    其余各基团如权利要求1-10中任一项所定义；
    或者，所述方法为方法二，其包括以下步骤：
    Figure PCTCN2018094428-appb-100030
    其中：
    X、R 5a、R 5a’、R 6a和R 6a’如在方法一中所定义，并且其余各基团如权利要求1-10中任一项所定义。
  12. 药物组合物，其包含预防或治疗有效量的权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
  13. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者权利要求12的药物组合物在制备用作凝血因子XIa抑制剂的药物中的用途。
  14. 权利要求13的用途，其中所述药物用于预防或治疗血栓栓塞性病症，所述血栓栓塞性病症包括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、静脉脑血管血栓栓塞性病症和心脏腔室血栓栓塞性病症；所述血栓栓塞性病症优选包括不稳定型心绞痛、急性冠状动脉综合症、心房纤维性颤动、首次心肌梗塞、复发性心肌梗塞、缺血性猝死、短暂性脑缺血发作、中风、动脉粥样硬化、外周闭塞性动脉疾病、静脉血栓形成、深静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状动脉血栓形成、脑动脉血栓形成、脑栓塞、肾栓塞、肺栓塞，以及由于(a)人工瓣膜、留置导管、支架或其它植入物；(b)体外循环；(c)血液透析或(d)血液暴露于易引发血栓形成的人造表面而导致的血栓形成。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753555A (zh) * 2010-02-11 2012-10-24 百时美施贵宝公司 作为因子xia抑制剂的大环类
CN103702999A (zh) * 2011-08-05 2014-04-02 百时美施贵宝公司 作为因子xia抑制剂的环状p1连接体
CN103857681A (zh) * 2011-08-05 2014-06-11 百时美施贵宝公司 作为因子xia抑制剂的新的大环
CN104507924A (zh) * 2012-08-03 2015-04-08 百时美施贵宝公司 二氢吡啶酮p1作为凝血因子xia抑制剂
WO2015123090A1 (en) * 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Factor xia inhibitors
WO2015123093A1 (en) * 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Factor xia inhibitors
CN106132962A (zh) * 2014-01-31 2016-11-16 百时美施贵宝公司 作为凝血因子xia抑制剂的具有芳族p2’基团的大环化合物

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102753555A (zh) * 2010-02-11 2012-10-24 百时美施贵宝公司 作为因子xia抑制剂的大环类
CN102834397A (zh) * 2010-02-11 2012-12-19 百时美施贵宝公司 作为凝血因子xia抑制剂的大环化合物
CN103702999A (zh) * 2011-08-05 2014-04-02 百时美施贵宝公司 作为因子xia抑制剂的环状p1连接体
CN103857681A (zh) * 2011-08-05 2014-06-11 百时美施贵宝公司 作为因子xia抑制剂的新的大环
CN104507924A (zh) * 2012-08-03 2015-04-08 百时美施贵宝公司 二氢吡啶酮p1作为凝血因子xia抑制剂
CN106132962A (zh) * 2014-01-31 2016-11-16 百时美施贵宝公司 作为凝血因子xia抑制剂的具有芳族p2’基团的大环化合物
WO2015123090A1 (en) * 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Factor xia inhibitors
WO2015123093A1 (en) * 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Factor xia inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JAMES R. CORTE ET AL.: "Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 23 June 2017 (2017-06-23), XP085144474, ISSN: 0960-894X, DOI: doi:10.1016/j.bmcl.2017.06.058 *
JAMES R. CORTE ET AL.: "Structure-Based Design of Macrocyclic Factor Xla Inhibitors:Discovery of the Macrocyclic Amide Linker", JOURNAL OF MEDICINAL CHEMISTRY, 13 January 2017 (2017-01-13), ISSN: 0022-2623 *

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