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WO2019218899A1 - 含聚乙二醇醚的四氢异喹啉酰胺化合物及其药物用途 - Google Patents

含聚乙二醇醚的四氢异喹啉酰胺化合物及其药物用途 Download PDF

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Publication number
WO2019218899A1
WO2019218899A1 PCT/CN2019/085873 CN2019085873W WO2019218899A1 WO 2019218899 A1 WO2019218899 A1 WO 2019218899A1 CN 2019085873 W CN2019085873 W CN 2019085873W WO 2019218899 A1 WO2019218899 A1 WO 2019218899A1
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Prior art keywords
compound
group
reaction
alkyl
pharmaceutically acceptable
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PCT/CN2019/085873
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English (en)
French (fr)
Inventor
朱加望
宋智泉
宋立强
吴勇勇
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 WO2019218899A1 publication Critical patent/WO2019218899A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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 poly(ethylene glycol ether)-containing tetrahydroisoquinolinamide compound or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or the compound Stereoisomers, tautomers or mixtures thereof, methods of preparing such compounds and use in the prevention or treatment of conditions associated with excessive activity of factor XIa, such as thromboembolic disorders.
  • Thromboembolic diseases have high morbidity, mortality or disability. Myocardial infarction, cerebral infarction and pulmonary infarction caused by thromboembolism are the leading causes of death.
  • Antithrombotic drugs mainly include anticoagulation, antiplatelet and thrombolytic drugs.
  • Traditional anticoagulant drugs such as warfarin, heparin), and rivaroxaban, clopidogrel, and dabigatran etexilate have good effects on reducing thrombus formation, but they cannot avoid potential bleeding complications. Danger. Therefore, there is an urgent need for clinical anti-thrombotic drugs for improving bleeding side effects.
  • the coagulation cascade is a process in which a series of coagulation factors are sequentially activated to form fibrin. This cascade reaction is divided into an endogenous pathway and an exogenous pathway.
  • Factor XIa is an endogenous pathway that plays a role in the amplification of cascade reactions. Inhibitor drugs targeting the XIa factor target can block the endogenous pathway and inhibit the amplification of the coagulation cascade, thereby having a better antithrombotic effect.
  • prodrugs of the compounds of the invention have improved oral drug absorption and plasma exposure and are useful in oral pharmaceutical formulations.
  • the invention also provides the compound, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer, tautomer of the compound
  • the present application relates to the following aspects:
  • the application provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or Stereoisomers, tautomers or mixtures thereof,
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and 3-10 membered heterocyclic, wherein said C 1-6 alkyl, C 2-6 The alkenyl group, the C 3-6 cycloalkyl group and the 3-10 membered heterocyclic group are optionally one or more selected from the group consisting of halogen, C 1-6 alkyl, -OH and -O-(C 1-6 alkyl) Substituted by a substituent;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl, -OH, -O-(C 1-6 alkyl), 3-6 membered heterocyclic, phenyl And a 5-6 membered heteroaryl group wherein the C 1-6 alkyl group, -O-(C 1-6 alkyl), 3-6 membered heterocyclic group, phenyl group and 5-6 membered heteroaryl group Optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH and -O-(C 1-6 alkyl);
  • Y is selected from the group consisting of C 2-4 alkenylene and 5-6 membered heteroarylene;
  • Ring A is selected from the following structures:
  • n is selected from an integer of 2-9.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, a method for preparing a tautomer or a mixture thereof, which comprises the following
  • R L1 and R L2 each independently represent a halogen or a C 1-3 alkyl sulfonate group optionally substituted by a halogen (eg, a triflate group);
  • PG 1 , PG 2 , PG 3 and PG 4 are protecting groups;
  • Z represents a leaving group
  • the leaving group is selected from the group consisting of H, halogen, C 1-3 alkyl sulfonate group optionally substituted by halogen, boronic acid group, boronic acid ester group, substituted silicon group or substituted metal group group;
  • Step 1 Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 2 Compound IM-1 undergoes a coupling reaction to form compound IM-2;
  • Step 3 Compound IM-2 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-3;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 4 Compound IM-3 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride to form compound IM- 4;
  • a reducing agent such as sodium borohydride or sodium cyanoborohydride
  • Step 5 Compound IM-4 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I).
  • R L1 , R L2 , R Lx , PG 1 , PG 2 , PG 3 , PG 4 and Z are as defined in the first method;
  • Step 1 Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 2 Compound IM-1 undergoes a coupling reaction to form compound IM-2;
  • Step 3 Compound IM-2 is subjected to chiral resolution to obtain compound IM-5;
  • Step 4 Compound IM-5 undergoes deprotection reaction and continues to carry out acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-6;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 5 Compound IM-6 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -7;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 6 Compound IM-7 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1.
  • R L1 , R L2 , R Lx , PG 3 , PG 4 and Z are as defined in the first method;
  • Step 1 Compound S-2 undergoes a coupling reaction to form compound IM-8;
  • Step 2 Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;
  • Step 3 Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 4 Compound IM-10 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I).
  • R L1 , R L2 , R Lx , PG 3 , PG 4 and Z are as defined in method one;
  • Step 1 Compound S-2 undergoes a coupling reaction to form compound IM-8;
  • Step 2 Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;
  • Step 3 Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 4 Compound IM-10 is subjected to chiral resolution to obtain compound IM-11;
  • Step 5 Compound IM-11 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1.
  • R L1 , R L2 , R Lx , PG 2 , PG 3 and PG 4 are as defined in method one;
  • Step 1 Compound S-5 and S-6 were subjected to a Buckwald coupling reaction to give compound IM-12.
  • S-5 and piperazine are subjected to a Buckwald coupling reaction and then subjected to a protective reaction to produce compound IM-12;
  • Step 2 Compound IM-12 is subjected to acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-13;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 3 Compound IM-13 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -14;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 4 Compound IM-14 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-15;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 5 Compound IM-15 is subjected to chiral resolution to obtain compound IM-16;
  • Step 6 Compound IM-16 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (VI).
  • method two, method three or method four, R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Y, W, Q and n are as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Y and n are as defined above.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or Stereoisomers, tautomers or mixtures thereof of the compounds preferably further comprise pharmaceutically acceptable excipients.
  • Another aspect of the invention provides a pharmaceutical formulation comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, Or a stereoisomer, a tautomer or a mixture thereof of the compound as an active ingredient, preferably, the preparation is in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound , tautomers or mixtures thereof, or a pharmaceutical composition of the invention, or the use of an agent of the invention in the manufacture of a medicament for the prevention or treatment of a condition associated with excessive activity of factor XIa (eg thromboembolism) sexual illness).
  • thromboembolic disorders include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders of the heart chamber.
  • the present invention significantly increases the water solubility of the compound by introducing a polyethylene glycol ether substituent on the tetrahydroisoquinoline structure, and at the same time, the compound of the present invention exhibits a good inhibitory activity against the XIa enzyme. Furthermore, the ester derivatives of the compounds of the invention provide an effective prodrug form which can be used in oral administration.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkyl is defined as a straight or branched saturated aliphatic hydrocarbon group.
  • an alkyl group has from 1 to 12 carbon atoms (denoted as “C 1-12 alkyl”), preferably from 1 to 6 carbon atoms (denoted as “C 1-6 alkyl”), It preferably has 1 to 4 carbon atoms (denoted as “C 1-4 alkyl group”, and still more preferably has 1 to 3 carbon atoms (denoted as "C 1-3 alkyl group”).
  • 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 or n-hexyl).
  • 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).
  • C 1-3 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 3 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl).
  • alkyl is optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl”) (for example, -CF 3 ) , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 , etc.).
  • suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl”) (for example, -CF 3 ) , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 , etc.).
  • alkenyl refers to a hydrocarbon group containing at least one carbon-carbon double bond.
  • an alkenyl group has 2 to 12 carbon atoms (denoted as "C 2-12 alkenyl”), preferably 2 to 6 carbon atoms (denoted as "C 2-6 alkenyl”).
  • the alkenyl group may be a linear or branched alkenyl group.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • the alkenyl group may be an unsubstituted alkenyl group or substituted by one or more substituents which may be the same or different, such as a halogen, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cyano group, a hydroxyl group or the like.
  • C 2-6 alkenyl refers to a hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon double bond (ie, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl) , n-pentenyl, n-hexenyl, etc.).
  • C2-4 alkenyl refers to a hydrocarbon radical of 2 to 4 carbon atoms containing at least one carbon-carbon double bond (ie, vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl) Wait).
  • alkylene means a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group.
  • the alkylene group contains 1-10 carbon atoms (denoted as “C 1-10 alkylene”), and in other embodiments, the alkylene group contains 1-6 carbons Atom (denoted as "C 1-6 alkylene”), in other embodiments, the alkylene group contains from 1 to 4 carbon atoms (denoted as "C 1-4 alkylene”).
  • Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH3)CH2-), and the like, wherein the alkylene group can be independently It is unsubstituted or substituted by one or more of the substituents described herein.
  • alkenylene means a divalent group obtained by removing one hydrogen atom from the alkenyl group defined by the present invention.
  • C 2-4 alkenylene refers to a divalent group obtained by removing one hydrogen atom from a C 2-4 alkenyl group (i.e., a vinylidene group, a propenylene group, a n-n-butenyl group, a sub-3-methyl group). But-2-enyl group, etc.).
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic ring (such as a C 3-10 cycloalkyl group, a C 3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).
  • cycloheptyl, cyclooctyl, cyclodecyl or polycyclic (including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2 .1] an octyl or bicyclo [5.2.0] fluorenyl, decahydronaphthyl, etc.) hydrocarbon ring optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • the cycloalkyl group has 3 to 15 carbon atoms, preferably 3 to 6 carbon atoms.
  • C 3-6 cycloalkyl refers to the saturation or unsaturation of 3 to 6 ring-forming carbon atoms.
  • Non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which are optionally suitably prepared by one or more (such as 1 to 3) Substituted by a substituent such as a methyl substituted cyclopropyl group.
  • heterocyclyl includes any of those having a carbon atom and at least one heteroatom (eg, O, S, N, P) or a heteroatom moiety (eg, SO 2 , CO, CONH, COO, PO, PO 2 ) in the ring.
  • a substituted non-aromatic ring group is selected.
  • the heterocyclic group has from 3 to 18 ring atoms, preferably from 3 to 10 ring atoms, more preferably from 3 to 6 ring atoms.
  • the heterocyclic group may be a saturated, partially saturated, non-aromatic monocyclic or fused ring group.
  • heterocyclic group examples include a cyclohexylimino group, an imidazolidinyl group, an imidazolinyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, a pyridyl group, a pyrrolidinyl group, a thienyl group, and a 4,5-dihydro-1H- group.
  • 3-10 membered heterocyclic group examples include oxiranyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, 2-pyrroline, 3-pyrrole Polinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, Thiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperid Azinyl, dioxoalkyl, dithiaalkyl, thiamethane, homo
  • 3-6 membered heterocyclic group examples include oxiranyl group, azetidinyl group, oxetanyl group, thioheterobutyl group, pyrrolidinyl group, 2-pyrroline group, 3-pyrrole group.
  • (sub)heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, preferably having 5, 6, 8, 9, 10, 11 , 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in each case, may be benzofused.
  • the (sub)heteroaryl group may be selected from (i)thienyl, (i)furanyl, (i)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.
  • 5-6 membered heteroaryl examples include pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolyl, Oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazinyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl.
  • protecting group refers to a chemical group having the following characteristics: i) reactable with a corresponding functional group to form a protected group; ii) stabilize the reaction conditions to which the protected group will be subjected; and iii) The protected group is removed to release the functional group.
  • anion means a negatively charged organic or inorganic ion, and specific examples thereof include fluoride ion, chloride ion, bromide ion, iodide ion, sulfate ion, phosphate ion, nitrate ion, carbonate ion, acetate ion, lactate ion, tartaric acid ion, Benzoic acid ion, citrate ion, trifluoroacetic acid ion, methanesulfonate ion, ethanesulfonic acid ion, methyl sulfate ion, benzenesulfonate ion, p-toluenesulfonic acid ion, isethionate ion, adipic acid ion, Ethane-1,2-disulfonic acid ion, 1,5-naphthalene disulfonic acid ion, naphthalene-2-
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • a solid line is used to delineate a bond design that is bonded to an asymmetric carbon atom, including all possible stereoisomers at that carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize the bond to an asymmetric carbon atom indicates 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 may 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.
  • the compounds 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, metabolites, prodrugs or stable isotope derivatives, in which they 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 administration.
  • a “compound of the invention” it is also intended to encompass the various derivative forms described above for the compound.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by a selected group, provided that the specified atom is not exceeded in the current situation. Normal valence and the substitution forms a stable compound. The number of alternative groups selected is permissible when such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, one or more hydrogens on the carbon may be replaced individually and/or together by an optional substituent that is independently selected. 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 may each be replaced by an independently selected optional substituent.
  • each substituent may be the same or different than 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 stable isotopic derivatives (isotopically labeled compounds) of the compounds of the invention, which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but differ in atomic mass or mass number in nature.
  • the atomic substitution of the dominant atomic mass or mass number is not limited to one or more atoms.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., hydrazine (D, 2 H), hydrazine (T, 3 H)); isotopes of carbon (e.g., 11 C, 13 C) And 14 C); isotope of chlorine (eg 36 Cl); isotope of fluorine (eg 18 F); isotope of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O, 17 O and 18 O); phosphorus isotopes (eg 32 P); and sulfur isotopes (eg 35 S).
  • isotopes of hydrogen e.g., hydrazine (D, 2 H), hydrazine (T, 3 H)
  • isotopes of carbon e.g., 11 C, 13 C) And 14 C
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted by an isotope, and the isotopically substituted crystallization solvent includes D 2 O, acetone-d 6 or DMSO-d 6 .
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Examples include salts formed from alkali metals, alkaline earth metals, ammonium, alkylammonium, and the like, and salts formed with inorganic or organic acids. These salts may, for example, be sodium, potassium, calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleic acid.
  • Salt tartrate, citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, B Sulfonate, 2-hydroxyethanesulfonate, besylate, p-toluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, tris Methylaminomethane salt, salt formed with cysteine, salt formed with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinic acid Salts, oxalates, picrates, thiocyanates, undecanoates, salts with acrylic polymers, salts with carboxyvinyl polymers, and the like.
  • esters of the compounds of the invention include those resulting from the esterification of an acid group of a compound of the invention with an alcohol.
  • 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.
  • 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, delipidization, 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) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association).
  • 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 Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the application provides a compound represented by the following formula (I), or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or the compound Stereoisomers, tautomers or mixtures thereof,
  • R 1 is selected from H, C 1-6 alkyl (e.g., C 1-3 alkyl), C 2-6 alkenyl (e.g., C 2-3 alkenyl), C 3-6 cycloalkyl, and 3-10.
  • a heterocyclic group for example, a 5-6 membered heterocyclic group
  • the C 1-6 alkyl group e.g., C 1-3 alkyl group
  • C 2-6 alkenyl group e.g., C 2-3 alkenyl group
  • C 3-6 cycloalkyl and 3-10 membered heterocyclyl for example, 5-6 members of a heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl (for example, C 1-3 alkyl), -OH, -O-(C 1-6 alkyl), a 3-6 membered heterocyclic group (for example, a 5-6 membered heterocyclic group having 1 or 2 hetero atoms selected from N, O, and S), a phenyl group, and a 5-6 membered heteroaryl group (for example, 5-6) a heteroaryl group having 1 or 2 hetero atoms selected from N, O, S), wherein the C 1-6 alkyl group (for example, C 1-3 alkyl group), -O-(C 1-6 Alkyl), -O-(C 1-6 alkyl), 3-6 membered heterocyclic group (for example, a heterocyclic group of 5-6 members containing one or two hetero atoms selected from N, O, and S) a phenyl group and a 5-6 membered heteroary
  • Y is selected from a C 2-4 alkenylene group and a 5-6 membered heteroarylene group (for example, a 5-6 membered heteroarylene group having 1 or 2 hetero atoms selected from N, O, S);
  • Ring A is selected from the following structures:
  • R 1 is selected from the group consisting of H, C 1-3 alkyl (eg methyl, ethyl, n-propyl, isopropyl) and halo C 1-3 alkyl (eg fluoro C 1 -3 alkyl groups such as fluoromethyl and fluoroethyl).
  • R 1 is selected from the group consisting of H, CH 3 , CF 3 and CH 2 CF 3 .
  • R 2 and R 4 are each independently selected from the group consisting of: H, halogen, unsubstituted or tetrazolyl substituted with one halogen atom (for example F, Cl, Br or I).
  • R 2 and R 4 are each independently selected from:
  • R 2 is selected from the group consisting of: H,
  • R 4 is selected from the group consisting of H, F and Cl.
  • R 3 is selected from the group consisting of H and halogen.
  • R 3 is selected from the group consisting of H, F and Cl.
  • R 3 is a halogen such as F or Cl.
  • Y is selected from the group consisting of vinylidene, propenylene, oxazolyl, oxazolyl, thiazolyl, isoisothiazolyl, imidazolyl, pyrazolyl.
  • Y is selected from the group consisting of vinylidene and isoxazolyl.
  • Y is selected from the following structures:
  • ring A is
  • n is selected from an integer from 2 to 4, such as 2, 3 or 4.
  • the structure of the compounds of the invention is as follows,
  • R 1 , R 2 , R 3 , R 4 , R 5 , ring A, n, And Y are as defined in formula (I).
  • the structure of the compounds of the invention is as follows,
  • R 1 , R 2 , R 3 , R 4 , R 5 , And Y are as defined in formula (I).
  • the structure of the compounds of the invention is as follows,
  • R 6 is selected from the group consisting of H, -CH 3 and -CH 2 CH 3 ;
  • R 7 is selected from the group consisting of -CH 3 , -CH 2 CH 3 and -CH(CH 3 ) 2 ;
  • R 1 , R 2 , R 3 , R 4 , And Y are as defined in formula (I).
  • R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;
  • R 2 is selected from the following structures:
  • R 3 and R 4 are each independently selected from the group consisting of H, F and Cl;
  • Y is selected from the following structures:
  • R 6 is selected from the group consisting of H, -CH 3 and -CH 2 CH 3 ;
  • R 7 is selected from the group consisting of -CH 3 , -CH 2 CH 3 and -CH(CH 3 ) 2 ;
  • the structure of the compounds of the invention is as follows,
  • R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;
  • R 2 is selected from the following structures:
  • R 3 and R 4 are each independently selected from the group consisting of H, F and Cl;
  • Y is selected from the following structures:
  • the structure of the compounds of the invention is as follows,
  • R 1 , R 2 , R 3 , R 4 , R 5 , Y and ring A are as defined in formula (I).
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the structure of the compounds of the invention is as follows:
  • the structure of the compounds of the invention is as follows:
  • a compound wherein R 5 is H is an active ingredient; a compound wherein R 5 is not H is a prodrug, and can be metabolized to a corresponding active ingredient (ie, a compound having R 5 is H) in a living body to exert pharmacological effects. effect.
  • 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 understand that 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.
  • Another aspect of the present application provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, a method for preparing a tautomer or a mixture thereof, comprising the following
  • R L1 and R L2 each independently represent a halogen or a C 1-3 alkyl sulfonate group optionally substituted by a halogen (eg, a triflate group);
  • PG 1 , PG 2 , PG 3 and PG 4 are protecting groups;
  • Z represents a leaving group
  • the leaving group is selected from the group consisting of H, halogen, C 1-3 alkyl sulfonate group optionally substituted by halogen, boronic acid group, boronic acid ester group, substituted silicon group or substituted metal group group;
  • Step 1 Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 2 Compound IM-1 undergoes a coupling reaction to form compound IM-2;
  • Step 3 Compound IM-2 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-3;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 4 Compound IM-3 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -4;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 5 Compound IM-4 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I).
  • R L1 , R L2 , R Lx , PG 1 , PG 2 , PG 3 , PG 4 and Z are as defined in the first method;
  • Step 1 Compound S-1 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-1;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 2 Compound IM-1 undergoes a coupling reaction to form compound IM-2;
  • Step 3 Compound IM-2 is subjected to chiral resolution to obtain compound IM-5;
  • Step 4 Compound IM-5 undergoes deprotection reaction and continues to carry out acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-6;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 5 Compound IM-6 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -7;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 6 Compound IM-7 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1.
  • R L1 , R L2 , R Lx , PG 3 , PG 4 and Z are as defined in the first method;
  • Step 1 Compound S-2 undergoes a coupling reaction to form compound IM-8;
  • Step 2 Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;
  • Step 3 Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 4 Compound IM-10 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I).
  • R L1 , R L2 , R Lx , PG 3 , PG 4 and Z are as defined in method one;
  • Step 1 Compound S-2 undergoes a coupling reaction to form compound IM-8;
  • Step 2 Compounds IM-8, S-3 and S-4 are subjected to Ugi reaction in an alcohol solvent to form compound IM-9;
  • Step 3 Compound IM-9 undergoes a deprotection reaction, and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -10;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 4 Compound IM-10 is subjected to chiral resolution to obtain compound IM-11;
  • Step 5 Compound IM-11 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (I)-1.
  • R L1 , R L2 , R Lx , PG 2 , PG 3 and PG 4 are as defined in method one;
  • Step 1 Compound S-5 and S-6 were subjected to a Buckwald coupling reaction to give compound IM-12.
  • S-5 and piperazine are subjected to a Buckwald coupling reaction and then subjected to a protective reaction to produce compound IM-12;
  • Step 2 Compound IM-12 is subjected to acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-13;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 3 Compound IM-13 undergoes a deprotection reaction and continues to carry out a substitution reaction in the presence of a base or a reductive amination reaction in the presence of a reducing agent such as sodium borohydride and sodium cyanoborohydride to form a compound IM -14;
  • a reducing agent such as sodium borohydride and sodium cyanoborohydride
  • Step 4 Compound IM-14 undergoes deprotection reaction and continues to undergo acid amine condensation reaction in the presence of a condensing agent (such as HATU, EDCI, etc.) to form compound IM-15;
  • a condensing agent such as HATU, EDCI, etc.
  • Step 5 Compound IM-15 is subjected to chiral resolution to obtain compound IM-16;
  • Step 6 Compound IM-16 undergoes a deprotection reaction and continues to undergo a substitution reaction in the presence of a base to form a compound of formula (VI).
  • method two, method three or method four, R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Y, W, Q and n are as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Y and n are as defined above.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stabilizing thereof Isotope derivatives, or stereoisomers, tautomers or mixtures thereof, of the compounds, optionally further comprising one or more pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carriers which may be employed include, but are not limited to, sterile liquids such as water and oils, including those oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, Mineral oil, sesame oil, etc.
  • Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline, glucose or an aqueous glycerin solution as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • transdermal administration or by oral, buccal, or oral administration.
  • the pharmaceutical compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups, and the like.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating a condition associated with excessive activity of factor XIa.
  • Another object of the present invention is to provide a process for the preparation of a pharmaceutical composition of the present invention which comprises administering a compound of the present invention or a pharmaceutically acceptable salt, ester, polymorph, solvate thereof, or a pharmaceutically acceptable salt thereof A drug or stable isotope derivative, or a stereoisomer, tautomer or mixture thereof, in combination with one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a pharmaceutical preparation comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or Stereoisomers, tautomers or mixtures thereof of the compounds, or pharmaceutical compositions of the invention.
  • Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound Use of a tautomer or a mixture thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for preventing or treating a disorder associated with excessive activity of factor XIa.
  • Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound A tautomer or a mixture thereof, or a pharmaceutical composition of the invention for use in preventing or treating a disorder associated with excessive activity of factor XIa.
  • Another object of the present invention is to provide a method for preventing or treating a disorder associated with excessive activity of factor XIa, which comprises administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, An ester, polymorph, solvate, prodrug or stable isotope derivative, or a stereoisomer, tautomer or mixture thereof of the compound, or a pharmaceutical composition of the invention.
  • the condition associated with excessive activity of factor XIa includes, but is not limited to, a thromboembolic disorder, preferably an arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder , or a thromboembolic disorder in the heart chamber.
  • the thromboembolic disorder is selected from the group consisting of unstable angina pectoris, 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 (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) extracorporeal circulation, (e) hemodialysis, or (f) exposure of blood to artificial surfaces that are prone to thrombosis Thrombosis.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this will add up to about 0.007 mg/day to about 3500 mg/day, for example from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.
  • “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.).
  • Another aspect of the present application provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, polymorph, solvate, prodrug or stable isotope derivative thereof, or a stereoisomer of the compound, A tautomer or a mixture thereof, or the use of a pharmaceutical composition of the invention in the preparation of a formulation for modulating (e.g., reducing or inhibiting) the activity of factor XIa in an individual cell.
  • Another aspect of the present application provides a method of modulating (e.g., reducing or inhibiting) the activity of Factor XIa in an individual cell comprising administering to said cell an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or ester thereof , a polymorph, a solvate, a prodrug or a stable isotope derivative, or a stereoisomer, tautomer or mixture thereof, or a pharmaceutical composition of the invention, or a pharmaceutical composition of the invention Pharmaceutical preparations.
  • the formulation is administered to an individual to modulate (eg, reduce or inhibit) the activity of factor XIa in a cell of the subject; or the formulation is administered to an in vitro cell (eg, a cell line or from an individual) Cells) to modulate (eg, reduce or inhibit) the activity of factor XIa in a cell.
  • an in vitro cell eg, a cell line or from an individual
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl and 3-10 membered heterocyclic, wherein the alkyl, alkenyl, cycloalkyl and hetero
  • the cyclo group is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, -OH and -O-(C 1-6 alkyl);
  • R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;
  • R 1 is selected from the group consisting of H, CH 3 , CF 3 and CH 2 CF 3 ;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of: H, halogen, C 1-6 alkyl, -OH, -O-(C 1-6 alkyl), -O-(C 1-6 alkane a 3-6 membered heterocyclic group, a phenyl group, and a 5-6 membered heteroaryl group, wherein the alkyl group, heterocyclic group, phenyl group, and heteroaryl group are optionally selected from one or more selected from the group consisting of halogen, Substituent substitution of C 1-6 alkyl, -OH and -O-(C 1-6 alkyl);
  • R 2 is selected from the group consisting of H, unsubstituted or tetrazolyl substituted with one halogen atom;
  • R 2 is selected from the following structures: H,
  • R 3 and R 4 are each independently selected from H, a halogen atom
  • R 3 and R 4 are each independently selected from the group consisting of H, F and Cl;
  • Y is selected from the group consisting of C 2-4 alkenylene and 5-6 membered heteroarylene;
  • Y is selected from the group consisting of vinylidene, propenylene, isoxazolyl, oxazolyl, thiazolyl, isoisothiazolyl, imidazolyl, pyrazolyl;
  • Y is selected from the following structures:
  • Ring A is selected from the following structures:
  • ring A is
  • n is selected from an integer of 2-9;
  • n is an integer selected from 2-4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , ring A, Q, W and Y are as defined for formula (I) in Scheme 1.
  • R 1 , R 2 , R 3 , R 4 , R 5 , Q, W and Y are as defined for formula (I) in Scheme 1.
  • R 6 is selected from the group consisting of H, -CH 3 and -CH 2 CH 3 ;
  • R 7 is selected from the group consisting of -CH 3 , -CH 2 CH 3 and -CH(CH 3 ) 2 ;
  • R 1 , R 2 , R 3 , R 4 , Q, W and Y as defined in formula 1 for formula (I);
  • R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;
  • R 2 is selected from the following structures:
  • R 3 and R 4 are each independently selected from the group consisting of H, F and Cl;
  • Y is selected from the following structures:
  • R 6 is selected from the group consisting of H, -CH 3 and -CH 2 CH 3 ;
  • R 7 is selected from the group consisting of -CH 3 , -CH 2 CH 3 and -CH(CH 3 ) 2 .
  • R 1 , R 2 , R 3 , R 4 , Q, W and Y are as defined for formula (I) in Scheme 1;
  • R 1 is selected from the group consisting of H, C 1-3 alkyl and halo C 1-3 alkyl;
  • R 2 is selected from the following structures:
  • R 3 and R 4 are each independently selected from the group consisting of H, F and Cl;
  • Y is selected from the following structures:
  • R 1 , R 2 , R 3 , R 4 , R 5 and ring A are as defined for formula (I) in Scheme 1.
  • a pharmaceutical preparation wherein the preparation comprises the compound according to any one of the items 1 to 6, a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer thereof, or any crystal form thereof. Or a racemate, a metabolite form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the invention, which is in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • the thromboembolic disorder comprises an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, and a thromboembolic disorder of the heart chamber;
  • the thromboembolic disorder comprises unstable angina pectoris, 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) resulting from prosthetic valves or other implants, (b) indwelling catheter, (c) stent, (d) extracorporeal circulation, (e) hemodialysis, or (f) exposure of blood to artificial surfaces that are prone to thrombosis Thrombosis.
  • the 1 H NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1 H NMR was measured by JEOL Eclipse 400 NMR, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexamethyl dimethyl sulfoxide (DMSO-d6), and the internal standard was four.
  • Methylsilane (TMS) chemical shift is given in units of 10 -6 (ppm)
  • MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B;
  • a high performance liquid phase was prepared using Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250 x 20 mml column).
  • Thin-layer chromatography silica gel plate was prepared by thin-layer chromatography using an aluminum plate (20 ⁇ 20 cm) manufactured by Merck.
  • the specification used for the purification was GF 254 (0.4-0.5 nm) from Yantai.
  • reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • TLC thin layer chromatography
  • LCMS LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • the polarity is adjusted differently or adjusted by adding triethylamine or the like.
  • the microwave reaction was carried out using a Biotage Initiator + (400 W, RT ⁇ 300 ° C) microwave reactor.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as a carrier.
  • the system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.
  • reaction temperature is room temperature (20 ° C ⁇ 30 ° C)
  • the reagents used in the present invention were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebe Chemical.
  • Boc tert-butoxycarbonyl N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Step 5 Preparation of (R)-3-(3-chloro-2-fluorobenzene)-4,5-dihydroisoxazole-5-carboxylic acid (Int-A)
  • Step 5 Preparation of (E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acrylic acid (Int-B)
  • Second step Preparation of 2,2,2-trifluoro-1-(4-(isoquinolin-5-yl)piperazin-1-yl)ethanone (1-2)
  • Step 5 (E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-5-(4- (2,2,2-Trifluoroacetyl)piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino)benzoic acid tert-butyl ester (1-5)
  • Step 6 (E)-4-(2-(3-(3-Chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-5-(piperazine) Of -1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino)benzoic acid tert-butyl ester (1-6)
  • Step 7 (S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)-piperazin-1-yl)-2-( 3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino
  • Step 8 (S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecyl-13-yl)-piperazin-1-yl)-2-( 3-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamino
  • T-1 benzoic acid
  • Example 2 1-((ethoxycarbonyl)oxy)ethyl(S,E)-4-(5-(4-(2,5,8,11-tetraoxatridecane-13-) -(piperazin-1-yl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazolyl-1-yl)phenyl)acryloyl)-1,2,3 Of 4-(4-tetrahydroisoquinoline-1-carbonylamido)benzoate (T-2)
  • Example 3 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra
  • T-3 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra
  • T-3 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyr
  • Step 2 (S)-4-(1-((4-(tert-Butoxycarbonyl)phenyl)aminocarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl) Preparation of -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3-3)
  • Step 5 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra
  • tert-butyl hydroperyl isoquinoline-1-carbonylamido)benzoate (3-6)
  • Step 6 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra
  • T-3 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl)-1,2,3,6-tetrahydropyridine-4 -yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-1,2,3,4-tetra
  • Example 4 1-((ethoxycarbonyl)oxy)ethyl 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl) -1,2,3,6-tetrahydropyridin-4-yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5 Of carbonyl-)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoic acid (T-4)
  • Example 5 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1-(2-(2-(2-ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline
  • T-5a 1-(carbonylamido)benzoic acid
  • T-5b 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)
  • Second step 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-5- (1,2,3,6-tetrahydropyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid trifluoroacetate (5-3)
  • Second step 4-((S)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carbonyl)-5-( 1-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid (T-6)
  • T-22 was synthesized in a similar manner to the eighth step of Example 1 except that in the present embodiment, a racemic mixture 7-1 was used instead of 1-7 in Example 1.
  • Example 8 1-((ethoxycarbonyl)oxy)ethyl (E)-4-(5-(4-(2,5,8,11-tetraoxatridecane-13-yl)) -piperazin-1-yl)-2-(3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4 -Preparation of tetrahydroisoquinoline-1-carbonylamido)benzoate (T-23)
  • T-23 was synthesized in a similar manner to Example 2 except that T-22 was used instead of T-1 in Example 2 in this example.
  • Second step 4-((S)-5-piperazinyl-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5- Preparation of carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoic acid (8-2)
  • T-8 was synthesized in a similar manner to the seventh and eighth steps of Example 1 except that in the third step, 8-2 was used instead of 1-6 in the seventh step of Example 1.
  • Example 10 1-((ethoxycarbonyl)oxy)ethyl 4-((S)-5-(4-(2,5,8,11-tetraoxatridecane-13-yl) -piperazin-1-yl)-2-((R)-3-(3-chloro-2-fluorophenyl)-4,5-dihydroisoxazole-5-carboyl)-1,2, Preparation of 3,4-tetrahydroisoquinoline-1-carbonylamido)benzoate (T-9)
  • T-9 was synthesized in a similar manner to Example 2 except that T-8 was used instead of T-1 in Example 2 in this example.
  • T-10 was synthesized in a similar manner to Example 3 except that in the first step, Int-B was used instead of Int-A in the third step of Example 3.
  • Example 12 1-((ethoxycarbonyl)oxy)ethyl 4-((S)-5-(1-(2,5,8,11-tetraoxatridecane-13-yl) -1,2,3,6-tetrahydropyridin-4-yl)-2-((E)-3-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)benzene Of acryl)-1,2,3,4-tetrahydroisoquinoline-1-carbonylamido)benzoate (T-11)
  • T-11 was synthesized in a similar manner to Example 2 except that T-10 was used instead of T-1 in Example 2 in this example.
  • Enzyme human coagulation factor XIa; manufacturer: Haemtech;
  • Substrate Boc-Ile-Glu-Gly-Arg-AMC Acetate salt; Manufacturer: 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. Coagulation factor XIa and the test compound were added to the well plate, and the mixture was incubated for 10 minutes at room temperature. The reaction was initiated by the addition of a substrate (Boc-Ile-Glu-Gly-Arg-AMC Acetate salt). 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 signal value. Read once every 30 seconds and continuously read 20 cycles. The inhibition rate of enzyme activity at different concentrations of the compound was calculated during the linear reaction period. Fitting half or compound with GraphPad Prism 5 software SigmaPlot inhibiting concentration 50 value IC (A indicates IC 50 ⁇ 1nM, B represents 10nM> IC 50> 1nM, C represents 50nM> IC 50> 10nM).
  • the compound of the present invention has a significant inhibitory effect on coagulation factor XIa.
  • Test compounds were prepared according to the method of Table 2
  • mice Male rats were intragastrically administered (po) to the test substance in solution state.
  • the plasma concentrations of the test substances and metabolites in the rats were determined by LC-MS/MS.
  • the main pharmacokinetic parameters were calculated by WinNonlin 6.3 software.
  • test design grouping is shown in Table 3 below.

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Abstract

公开了含聚乙二醇醚的四氢异喹啉酰胺化合物及其制药用途；具体而言，涉及式(I)所示的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物及其制备方法，以及用于预防或治疗与XIa因子的过度活性相关的病症中的用途。

Description

含聚乙二醇醚的四氢异喹啉酰胺化合物及其药物用途 技术领域
本发明涉及含聚乙二醇醚的四氢异喹啉酰胺化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，这类化合物的制备方法和在与XIa因子过度活性相关的病症(例如血栓栓塞性病症)的预防或治疗中的用途。
背景技术
血栓栓塞性疾病有很高的发病率、致死率或致残率，由血栓栓塞引起的心肌梗死、脑梗死和肺梗死居各种死亡原因之首。防治血栓的药物主要包括抗凝血、抗血小板和溶栓药物。传统的抗凝药物(如华法林、肝素)，以及利伐沙班、氯吡格雷和达比加群酯等对减少血栓的形成具有很好的效果，但是都无法避免潜在的出血并发症危险。因此，临床上对改善出血副作用的抗栓药物有着急切的需求。
凝血级联反应是系列凝血因子相继被激活，最终形成纤维蛋白的过程。该级联反应分为内源性途径和外源性途径。XIa因子属于内源性途径，在级联反应放大过程中发挥作用。针对XIa因子靶点的抑制剂药物可以阻断内源性途径并抑制凝血级联反应的放大，从而具有较好的抗血栓形成的作用。近年来的抗栓实验研究结果表明，XIa因子是出血风险小的抗栓防治新靶点，其研究与药物开发越来越引起人们的重视(WO2013093484、WO2013056060、US20160368923等)。
发明概述
本发明的目的在于提供一种强效、安全和/或成药性能更好的(例如具有更好溶解度)的可作为XIa因子抑制剂的化合物，或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物。特别地，本发明化合物的前药有改善的口服药物吸收和血浆暴露量，可用于口服药物制剂。本发明还提供了所述化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物的制备方法和在预防或治疗与XIa因子过度活性相关的病症(例如血栓栓塞性病症)中的用途。
具体而言，本申请涉及以下几个方面：
在一个方面，本申请提供了下述式(I)所示的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互 变异构体或其混合物，
Figure PCTCN2019085873-appb-000001
其中，
R 1选自H、C 1-6烷基、C 2-6烯基、C 3-6环烷基和3-10元杂环基，其中所述C 1-6烷基、C 2-6烯基、C 3-6环烷基和3-10元杂环基任选地被一个或多个选自卤素、C 1-6烷基、-OH和-O-(C 1-6烷基)的取代基取代；
Figure PCTCN2019085873-appb-000002
选自以下结构：
Figure PCTCN2019085873-appb-000003
R 2、R 3和R 4各自独立地选自：H、卤素、C 1-6烷基、-OH、-O-(C 1-6烷基)、3-6元杂环基、苯基和5-6元杂芳基，其中所述C 1-6烷基、-O-(C 1-6烷基)、3-6元杂环基、苯基和5-6元杂芳基任选地被一个或多个选自卤素、C 1-6烷基、-OH和-O-(C 1-6烷基)的取代基取代；
Y选自C 2-4亚烯基和5-6元亚杂芳基；
环A选自以下结构：
Figure PCTCN2019085873-appb-000004
R 5选自H、C 1-6烷基和-C 1-4亚烷基-O-C(＝O)O-C 1-4烷基；
n选自2-9的整数。
本发明的另一方面提供了本发明化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其 混合物的制备方法，其中包括以下方式，
方法一：
Figure PCTCN2019085873-appb-000005
在方法一中，R L1和R L2各自独立地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)；R Lx表示＝O、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)；PG 1、PG 2、PG 3和PG 4为保护基；Z表示离去基，优选地，所述离去基选自H、卤素、任选地被卤素取代的C 1-3烷基磺酸酯基、硼酸基、硼酸酯基、取代的硅基或取代的金属基团；
步骤一：化合物S-1经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-1；
步骤二：化合物IM-1经过偶联反应生成化合物IM-2；
步骤三：化合物IM-2经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-3；
步骤四：化合物IM-3经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠或氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-4；
步骤五：化合物IM-4经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或省略步骤五中的取代反应过程。
方法二：
Figure PCTCN2019085873-appb-000006
在方法二中，R L1、R L2、R Lx、PG 1、PG 2、PG 3、PG 4和Z如在方法一中所定义；
步骤一：化合物S-1经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-1；
步骤二：化合物IM-1经过偶联反应生成化合物IM-2；
步骤三：化合物IM-2经过手性拆分得到化合物IM-5；
步骤四：化合物IM-5经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-6；
步骤五：化合物IM-6经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-7；
步骤六：化合物IM-7经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)-1化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或省略步骤六中的取代反应过程。
方法三：
Figure PCTCN2019085873-appb-000007
在方法三中，R L1、R L2、R Lx、PG 3、PG 4和Z如在方法一中所定义；
步骤一：化合物S-2经过偶联反应生成化合物IM-8；
步骤二：化合物IM-8，S-3和S-4在醇溶剂进行Ugi反应生成化合物IM-9；
步骤三：化合物IM-9经过脱保护反应，以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-10；
步骤四：化合物IM-10经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或省略步骤四中的取代反应过程。
方法四：
Figure PCTCN2019085873-appb-000008
在方法四中，R L1、R L2、R Lx、PG 3、PG 4和Z如在方法一中所定义；
步骤一：化合物S-2经过偶联反应生成化合物IM-8；
步骤二：化合物IM-8，S-3和S-4在醇溶剂进行Ugi反应生成化合物IM-9；
步骤三：化合物IM-9经过脱保护反应，以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-10；
步骤四：化合物IM-10经过手性拆分得到化合物IM-11；
步骤五：化合物IM-11经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)-1化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或省略步骤五中的取代反应过程。
方法五：
Figure PCTCN2019085873-appb-000009
在方法五中，R L1、R L2、R Lx、PG 2、PG 3和PG 4如在方法一中所定义；
步骤一：化合物S-5与S-6经过Buckwald偶联反应生成化合物IM-12。在一些实施例中，S-5与哌嗪先经过Buckwald偶联反应再经过保护反应生产化合物IM-12；
步骤二：化合物IM-12在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-13；
步骤三：化合物IM-13经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-14；
步骤四：化合物IM-14经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-15；
步骤五：化合物IM-15经过手性拆分得到化合物IM-16；
步骤六：化合物IM-16经过脱保护反应以及继续在碱的存在下进行取代反应生成式(VI)化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或省略步骤六中的取代反应过程。
在上述方法一、方法二、方法三或方法四中，R 1、R 2、R 3、R 4、R 5、环A、Y、W、Q和n如上文所定义。
在上述方法五中，R 1、R 2、R 3、R 4、R 5、环A、Y和n如上文所定义。
本发明的另一方面提供了一种药物组合物，其含有本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，优选进一步含有药学上可以接受的辅料。
本发明的另一方面提供了一种药物制剂，所述制剂包含本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物作为活性成分，优选地，所述制剂是固体制剂、半固体制剂、液体制剂或气态制剂的形式。
本发明的另一方面提供了本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，或者本发明的药物组合物，或者本发明的药剂在制备药物中的应用，所述药物用于预防或治疗与XIa因子过度活性相关的病症(例如血栓栓塞性病症)。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，和心脏腔室的血栓栓塞性病症。
发明效果
本发明通过在四氢异喹啉结构上引入聚乙二醇醚取代基，显著提高了化合物的水溶性，同时，本发明的化合物表现出了良好的对XIa酶的抑制活性。此外，本发明化合物的酯衍生物提供了一种有效的前药形式，可以用于口服药。
发明详述
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。
术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
术语“烷基”定义为直链或支链饱和脂肪族烃基。在一些实施方案中，烷基具有1至12个碳原子(表示为“C 1-12烷基”)，优选具有1至6个碳原子(表示为“C 1-6烷基”)，更优选具有1至4个碳原子(表示为“C 1-4烷基”)，还更优选具有1至3个碳原子(表示为“C 1-3烷基”)。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、正戊基或正己基)。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)。术语“C 1-3烷基”指1至3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)。在本发明中，“烷基”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-CF 3、-C 2F 5、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等)。
术语“烯基”是指含有至少一个碳-碳双键的烃基。在一些实施方案中，烯基具有2至12个碳原子(表示为“C 2-12烯基”)，优选具有2至6个碳原子(表示为“C 2-6烯基”)。烯基可以是直链或支链烯基。烯基的非限制性例子包括乙烯基，丙烯基，正丁烯基，3-甲基丁-2-烯基，正戊烯基，辛烯基和癸烯基。烯基可以是未取代的烯基，或被一个或多个相同或不同的取代基取代，例如卤素，烯基，炔基，芳基，环烷基，氰基，羟基等取代基。术语“C 2-6烯基”指2至6个碳原子、含有至少一个碳-碳双键的烃基(即乙烯基，丙烯基，正丁烯基，3-甲基丁-2-烯基，正戊烯基、正己烯基等)。术语“C 2-4烯基”指2至4个碳原子、含有至少一个碳-碳双键的烃基(即乙烯基、丙烯基、正丁烯基、3-甲基丁-2-烯基等)。
术语“亚烷基”表示从直链或支链的饱和烃基中去掉两个氢原子所得到的饱和的二价烃基。在部分实施例中，亚烷基基团含有1-10个碳原子(表示为“C 1-10亚烷基”)，在另外一些实施例中，亚烷基基团含有1-6个碳原子(表示为“C 1-6亚烷基”)，在另外一些实施例中，亚烷基基团含有1-4个碳原子(表示为“C 1-4亚烷基”)。这样的实例包括亚甲基(-CH 2-)，亚乙基(-CH 2CH 2-)，亚异丙基(-CH(CH3)CH2-)等等，其中所述亚烷基可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“亚烯基”是指从本发明定义的烯基上除去一个氢原子得到的二价基团。亚烯基的非限制性实例包括-CH＝CH-、-C(CH 3)＝CH-、和-CH＝CHCH 2-。术语“C 2-4亚烯基”指从C 2-4烯基上除去一个氢原子得到的二价基团(即亚乙烯基、亚丙烯基、亚正丁烯基、亚3-甲基丁-2-烯基等)。
术语“环烷基”指饱和或不饱和的非芳族单环(诸如C 3-10环烷基、C 3-6环烷基，例如环 丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基)或多环(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)烃环，其任选地被1或多个(诸如1至3个)适合的取代基取代。在部分实施例中，所述环烷基具有3至15个碳原子，优选具有3至6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或不饱和的非芳族单环或多环(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。
术语“杂环基”包括在环中具有碳原子和至少一个杂原子(例如O、S、N、P)或杂原子部分(例如SO 2、CO、CONH、COO、PO、PO 2)的任选取代的非芳族环基。在部分实施例中，所述杂环基的成环原子数为3至18个，优选成环原子数为3至10个，更优选成环原子数为3至6个。所述杂环基可以是饱和、部分饱和的非芳族单环或稠环基。杂环基的实例包括环己基亚氨基、咪唑烷基、咪唑啉基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷基、噻吩基、4，5-二氢-1H-咪唑基、1，2，3，6-四氢吡啶基、3-氧代哌嗪、4H-1，3-噁嗪基、5，6-二氢-4H-1，3-噁嗪基。
术语“3-10元杂环基”的实例包括环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂基，二氮杂基，硫氮杂基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基、嘧啶二酮基。
术语“3-6元杂环基”的实例包括环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基。
术语“(亚)杂芳基”指含有至少一个选自N、O和S的杂原子的单环、双环或三环芳族环系，其优选具有5、6、8、9、10、11、12、13或14个环原子，特别是含有1或2或3或4或5或6或9或10个碳原子，并且，另外在每一种情况下可为苯并稠合的。例如，(亚)杂芳基可选自(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。术语“5-6元杂芳基”的实例包括吡啶基，吡嗪基，呋喃基，噻吩基，嘧啶基，吡啶酮(包括N-取代的吡啶酮)，异噁唑基，异噻唑基，噁唑基，噁二唑基，噻唑基，吡唑基，呋咱基，吡咯基，三唑基，1,2,4-噻二唑基，吡嗪基，哒嗪基。
术语“保护基”是指具有如下特征的化学基团：i)可与相应官能团反应形成受保护的基团；ii)对受保护的基团将经受的反应条件稳定；和iii)可从受保护的基团脱除而释放官能团。
术语“阴离子”表示带负电荷的有机或无机离子，具体可以列举氟离子、氯离子、溴离子、碘离子、硫酸离子、磷酸离子、硝酸离子、碳酸离子、乙酸离子、乳酸离子、酒石酸离子、苯甲酸离子、柠檬酸离子、三氟乙酸离子、甲磺酸离子、乙磺酸离子、甲基硫酸离子、苯磺酸离子、对甲苯磺酸离子、羟乙磺酸离子、己二酸离子、乙烷-1,2-二磺酸离子、1,5-萘二磺酸离子、萘-2-磺酸离子、苹果酸离子、马来酸离子、丙二酸离子、富马酸离子、琥珀酸离子、1-羟基-2-萘甲酸离子、邻苯二甲酸离子、山梨酸离子、油酸离子和葡萄糖醛酸离子等，其中优选是氟离子、氯离子、溴离子、碘离子、三氟乙酸离子、硫酸离子、乳酸离子、酒石酸离子、苯甲酸离子、柠檬酸离子、甲磺酸离子、苯磺酸离子、对甲苯磺酸离子、己二酸离子、乙烷-1,2-二磺酸离子、1，5-萘二磺酸离子、萘-2-磺酸离子、苹果酸离子、马来酸离子、丙二酸离子、富马酸离子、琥珀酸离子、1-羟基-2-萘甲酸离子或葡萄糖醛酸离子。
本文中可使用实线
Figure PCTCN2019085873-appb-000010
实楔形
Figure PCTCN2019085873-appb-000011
虚楔形
Figure PCTCN2019085873-appb-000012
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表示，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表示，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可以为立体异构体(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、代谢物、前药或稳定的同位素衍生物，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。
术语“取代”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被所选择的基团代替，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。所选的替代基团数量是当这种组合形成稳定的化合物时才允许的。
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”，则各取代基可与另一(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键而未指定位置时，则这样的取代基可键连至该可取代的环中的任一适当的成环原子。
本发明还包括本发明化合物的稳定同位素衍生物(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(D， 2H)、氚(T， 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)。某些同位素标记的本发明的化合物可用于药物和/或底物组织分布研究(例如分析)中。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，所述被同位素取代的结晶溶剂包括，D 2O、丙酮-d 6或DMSO-d 6。
除此之外，这里未定义的基团遵照通常的定义。
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。实例包括碱金属、碱土金属、铵、烷基铵等形成的盐，与无机酸或有机酸形成的盐。这些盐可以列举钠盐、钾盐、钙盐、铵盐、铝盐、三乙基铵盐、醋酸盐、丙酸盐、酪酸盐、甲酸盐、三氟醋酸盐、马来酸盐、酒石酸盐、枸橼酸盐、硬脂酸盐、琥珀酸盐、乙基琥珀酸盐、乳糖酸盐、葡萄糖酸盐、葡庚糖酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、月桂基硫酸盐、苹果酸盐、天冬氨酸盐、谷氨酸盐、己二酸盐、三羟甲基氨基甲烷盐、与半胱氨酸形成的盐、与N-乙酰基半胱氨酸形成的盐、盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、氢碘酸盐、烟酸盐、草酸盐、苦味酸盐、硫氰酸 盐、十一烷酸盐、与丙烯酸聚合物形成的盐、与羧基乙烯基聚合物形成的盐等。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。
本发明的化合物的药学上可接受的酯包括本发明的化合物的酸基团与醇发生酯化反应生成的化合物。
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。
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、脱脂化、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)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。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Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和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。
化合物
在一个方面，本申请提供下述式(I)所示的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变 异构体或其混合物，
Figure PCTCN2019085873-appb-000013
其中，
R 1选自H、C 1-6烷基(例如C 1-3烷基)、C 2-6烯基(例如C 2-3烯基)、C 3-6环烷基和3-10元杂环基(例如5-6元杂环基)，其中所述C 1-6烷基(例如C 1-3烷基)、C 2-6烯基(例如C 2-3烯基)、C 3-6环烷基和3-10元杂环基(例如5-6元含1个或2个选自N、O、S的杂原子的杂环基)任选地被一个或多个选自卤素、C 1-6烷基(例如C 1-3烷基)、-OH和-O-(C 1-6烷基)(例如-O-(C 1-3烷基))的取代基取代；
Figure PCTCN2019085873-appb-000014
选自以下结构：
Figure PCTCN2019085873-appb-000015
R 2、R 3和R 4各自独立地任选自：H、卤素、C 1-6烷基(例如C 1-3烷基)、-OH、-O-(C 1-6烷基)、3-6元杂环基(例如5-6元含1个或2个选自N、O、S的杂原子的杂环基)、苯基和5-6元杂芳基(例如5-6元含1个或2个选自N、O、S的杂原子的杂芳基)，其中所述C 1-6烷基(例如C 1-3烷基)、-O-(C 1-6烷基)、-O-(C 1-6烷基)、3-6元杂环基(例如5-6元含1个或2个选自N、O、S的杂原子的杂环基)、苯基和5-6元杂芳基(例如5-6元含1个或2个选自N、O、S的杂原子的杂芳基)任选地被一个或多个选自卤素、C 1-6烷基(例如C 1-3烷基)、-OH和-O-(C 1-6烷基)(例如-O-(C 1-3烷基))的取代基取代；
Y选自C 2-4亚烯基和5-6元亚杂芳基(例如5-6元含1个或2个选自N、O、S的杂原子的亚杂芳基)；
环A选自以下结构：
Figure PCTCN2019085873-appb-000016
R 5选自H、C 1-6烷基(例如C 1-3烷基)和-C 1-4亚烷基-O-C(＝O)O-C 1-4烷基；n选自2-9的整数，例如2、3、4、5、6、7、8或9。在优选的实施方案中，R 1选自H、C 1-3烷基(例如甲基、乙基、正丙基、异丙基)和卤代C 1-3烷基(例如氟代C 1-3烷基，例如氟代甲基和氟代乙基)。
在更优选的实施方案中，R 1选自H、CH 3、CF 3和CH 2CF 3。
在优选的实施方案中，R 2和R 4各自独立地选自：H、卤素、未取代或被一个卤素原子(例如F、Cl、Br或I)取代的四唑基。
在更优选的实施方案中，R 2和R 4各自独立地选自：
F、Cl、H、
Figure PCTCN2019085873-appb-000017
优选地，R 2选自：H、
Figure PCTCN2019085873-appb-000018
优选地，R 4选自H、F和Cl。
在优选的实施方案中，R 3选自H和卤素。
在更优选的实施方案中，R 3选自H、F和Cl。
在优选的实施方案中，R 3为卤素，例如F或Cl。
在优选的实施方案中，Y选自亚乙烯基、亚丙烯基、亚异噁唑基、亚噁唑基、亚噻唑基、亚异噻唑基、亚咪唑基、亚吡唑基。
在优选的实施方案中，Y选自亚乙烯基和亚异噁唑基。
在更优选的实施方案中，Y选自以下结构：
Figure PCTCN2019085873-appb-000019
在优选的实施方案中，环A为
Figure PCTCN2019085873-appb-000020
在优选的实施方案中，R 5选自H、C 1-3烷基(例如甲基、乙基、正丙基、异丙基)和-C 1-3亚烷基-O-C(＝O)O-C 1-3烷基。
在优选的实施方案中，所述-C 1-3亚烷基-O-C(＝O)O-C 1-3烷基为
Figure PCTCN2019085873-appb-000021
其中，R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2。
在优选的实施方案中，n选自2-4的整数，例如2、3或4。
在部分实施方案中，本发明化合物的结构如下所示，
Figure PCTCN2019085873-appb-000022
其中，R 1、R 2、R 3、R 4、R 5、环A、n、
Figure PCTCN2019085873-appb-000023
和Y如式(I)所定义。
在部分实施方案中，本发明化合物的结构如下所示，
Figure PCTCN2019085873-appb-000024
其中，R 1、R 2、R 3、R 4、R 5、
Figure PCTCN2019085873-appb-000025
和Y如式(I)所定义。
在部分实施方案中，本发明化合物的结构如下所示，
Figure PCTCN2019085873-appb-000026
其中，R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2；R 1、R 2、R 3、R 4、
Figure PCTCN2019085873-appb-000027
和Y如式(I)所定义。
在部分实施方案中，上述式(III)中，
R 1选自H、C 1-3烷基和卤代C 1-3烷基；
R 2选自以下结构：
Figure PCTCN2019085873-appb-000028
R 3和R 4各自独立地任选自H、F和Cl；
Figure PCTCN2019085873-appb-000029
选自以下结构：
Figure PCTCN2019085873-appb-000030
Y选自以下结构：
Figure PCTCN2019085873-appb-000031
R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2；
在部分实施方案中，本发明化合物的结构如下所示，
Figure PCTCN2019085873-appb-000032
其中，R 1、R 2、R 3、R 4、
Figure PCTCN2019085873-appb-000033
和Y如式(I)所定义；
在部分实施方案中，上述式(V)中，
R 1选自H、C 1-3烷基和卤代C 1-3烷基；
R 2选自以下结构：
Figure PCTCN2019085873-appb-000034
R 3和R 4各自独立地任选自H、F和Cl；
Figure PCTCN2019085873-appb-000035
选自以下结构：
Figure PCTCN2019085873-appb-000036
Y选自以下结构：
Figure PCTCN2019085873-appb-000037
在部分实施方案中，本发明化合物的结构如下所示，
Figure PCTCN2019085873-appb-000038
其中，R 1、R 2、R 3、R 4、R 5、Y和环A如式(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。在部分实施方案中，本发明化合物的结构如下所示：
Figure PCTCN2019085873-appb-000039
Figure PCTCN2019085873-appb-000040
Figure PCTCN2019085873-appb-000041
Figure PCTCN2019085873-appb-000042
在部分实施方案中，本发明化合物的结构如下所示：
Figure PCTCN2019085873-appb-000043
Figure PCTCN2019085873-appb-000044
Figure PCTCN2019085873-appb-000045
Figure PCTCN2019085873-appb-000046
在本发明的化合物中，R 5为H的化合物为活性成分；R 5不为H的化合物为前药，在生物体内可代谢成相应的活性成分(即R 5为H的化合物)从而发挥药理作用。
制备方法
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。
本申请的另一方面提供了本发明化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物的制备方法，包括以下方式，
方法一：
Figure PCTCN2019085873-appb-000047
在方法一中，R L1和R L2各自独立地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)；R Lx表示＝O、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)；PG 1、PG 2、PG 3和PG 4为保护基；Z表示离去基，优选地，所述离去基选自H、卤素、任选地被卤素取代的C 1-3烷基磺酸酯基、硼酸基、硼酸酯基、取代的硅基或取代的金属基团；
步骤一：化合物S-1经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-1；
步骤二：化合物IM-1经过偶联反应生成化合物IM-2；
步骤三：化合物IM-2经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-3；
步骤四：化合物IM-3经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-4；
步骤五：化合物IM-4经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或者省略步骤五中的取代反应过程。
方法二：
Figure PCTCN2019085873-appb-000048
在方法二中，R L1、R L2、R Lx、PG 1、PG 2、PG 3、PG 4和Z如在方法一中所定义；
步骤一：化合物S-1经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-1；
步骤二：化合物IM-1经过偶联反应生成化合物IM-2；
步骤三：化合物IM-2经过手性拆分得到化合物IM-5；
步骤四：化合物IM-5经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-6；
步骤五：化合物IM-6经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-7；
步骤六：化合物IM-7经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)-1化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或者省略步骤六中的取代反应过程。
方法三：
Figure PCTCN2019085873-appb-000049
在方法三中，R L1、R L2、R Lx、PG 3、PG 4和Z如在方法一中所定义；
步骤一：化合物S-2经过偶联反应生成化合物IM-8；
步骤二：化合物IM-8，S-3和S-4在醇溶剂进行Ugi反应生成化合物IM-9；
步骤三：化合物IM-9经过脱保护反应，以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-10；
步骤四：化合物IM-10经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或者省略步骤四中的取代反应过程。
方法四：
Figure PCTCN2019085873-appb-000050
在方法四中，R L1、R L2、R Lx、PG 3、PG 4和Z如在方法一中所定义；
步骤一：化合物S-2经过偶联反应生成化合物IM-8；
步骤二：化合物IM-8，S-3和S-4在醇溶剂进行Ugi反应生成化合物IM-9；
步骤三：化合物IM-9经过脱保护反应，以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-10；
步骤四：化合物IM-10经过手性拆分得到化合物IM-11；
步骤五：化合物IM-11经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)-1化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或者省略步骤五中的取代反应过程。
方法五：
Figure PCTCN2019085873-appb-000051
在方法五中，R L1、R L2、R Lx、PG 2、PG 3和PG 4如在方法一中所定义；
步骤一：化合物S-5与S-6经过Buckwald偶联反应生成化合物IM-12。在一些实施例中，S-5与哌嗪先经过Buckwald偶联反应再经过保护反应生产化合物IM-12；
步骤二：化合物IM-12在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-13；
步骤三：化合物IM-13经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-14；
步骤四：化合物IM-14经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-15；
步骤五：化合物IM-15经过手性拆分得到化合物IM-16；
步骤六：化合物IM-16经过脱保护反应以及继续在碱的存在下进行取代反应生成式(VI)化合物。
本领域技术人员会明白，可根据需要调整上述过程的顺序，或者省略步骤六中的取代反应过程。
在上述方法一、方法二、方法三或方法四中，R 1、R 2、R 3、R 4、R 5、环A、Y、W、Q和n如上文所定义。
在上述方法五中，R 1、R 2、R 3、R 4、R 5、环A、Y和n如上文所定义。
药物组合物和药物制剂
本发明的另一目的在于提供一种药物组合物，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、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，，任选地还包括一种或多种药学上可接受的载体。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中，可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水、葡萄糖或甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或者通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂等。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。
根据本发明的一个实施方案，所述药物组合物还可包含一种或多种其它治疗剂，例如用于预防或治疗与XIa因子的过度活性相关的病症的其它治疗剂。
本发明的另一目的在于提供一种制备本发明的药物组合物的方法，所述方法包括将本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，与一种或多种药学上可接受的载体组合。
本发明的另一目的在于提供一种药物制剂，其包含本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立 体异构体、互变异构体或其混合物，，或者本发明的药物组合物。
治疗方法和用途
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，或者本发明的药物组合物在制备用于预防或治疗与XIa因子的过度活性相关的病症的药物中的用途。
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，或者本发明的药物组合物，其用于预防或治疗与XIa因子的过度活性相关的病症。
本发明的另一目的在于提供预防或治疗与XIa因子的过度活性相关的病症的方法，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、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，，或者本发明的药物组合物。
根据本发明的一个实施方案，所述与XIa因子的过度活性相关的病症包括但不限于血栓栓塞性病症，所述血栓栓塞性病症优选动脉心血管血栓栓塞性病症，静脉心血管血栓栓塞性病症，或心脏腔室的血栓栓塞性病症。
更优选地，所述血栓栓塞性病症选自不稳定型心绞痛，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，和由于(a)人工瓣膜或其它植入物所得，(b)留置导管，(c)支架，(d)体外循环，(e)血液透析，或(f)血液暴露于易血栓形成的人造表面而引起的血栓形成。
术语语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计 为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
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)。
本申请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、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，或者，本发明的药物组合物在制备制剂中的用途，所述制剂用于调节(例如降低或抑制)个体细胞中的XIa因子的活性。
本申请的另一方面提供一种调节(例如降低或抑制)个体细胞中的XIa因子的活性的方法，包括对所述细胞给予有效量的本发明的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，或者本发明的药物组合物，或者本发明的药物制剂。
在一些实施方案中，所述制剂被施用至个体体内，以调节(例如降低或抑制)个体体内细胞中XIa因子的活性；或者，所述制剂被施用至体外细胞(例如细胞系或者来自个体的细胞)，以调节(例如降低或抑制)细胞中XIa因子的活性。
本申请还涉及以下技术方案：
方案1.下述式(I)所示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、同位素标记的化合物，特别是前药化合物，
Figure PCTCN2019085873-appb-000052
上述式(I)中，
R 1选自H、C 1-6烷基、C 2-6烯基、C 3-6环烷基和3-10元杂环基，其中所述烷基、烯基、环烷基和杂环基任选地被一个或多个选自卤素、C 1-6烷基、-OH和-O-(C 1-6烷基)的取代基取代；
优选R 1选自H、C 1-3烷基和卤代C 1-3烷基；
更优选R 1选自H、CH 3、CF 3和CH 2CF 3；
Figure PCTCN2019085873-appb-000053
选自以下结构：
Figure PCTCN2019085873-appb-000054
R 2、R 3和R 4各自独立地任选自：H、卤素、C 1-6烷基、-OH、-O-(C 1-6烷基)、-O-(C 1-6烷基)、3-6元杂环基、苯基和5-6元杂芳基，其中所述烷基、杂环基、苯基和杂芳基任选地被一个或多个选自卤素、C 1-6烷基、-OH和-O-(C 1-6烷基)的取代基取代；
优选R 2选自以下结构：H、未取代或被一个卤素原子取代的四唑基；
更优选R 2选自以下结构：H、
Figure PCTCN2019085873-appb-000055
优选R 3和R 4各自独立地任选自H、卤素原子；
更优选R 3和R 4各自独立地任选自H、F和Cl；Y选自C 2-4亚烯基和5-6元亚杂芳基；
优选Y选自亚乙烯基、亚丙烯基、亚异噁唑基、亚噁唑基、亚噻唑基、亚异噻唑基、亚咪唑基、亚吡唑基；
更优选Y选自以下结构：
Figure PCTCN2019085873-appb-000056
环A选自以下结构：
Figure PCTCN2019085873-appb-000057
优选环A为
Figure PCTCN2019085873-appb-000058
R 5选自H、C 1-6烷基和-C 1-4亚烷基-O-C(＝O)O-C 1-4烷基；
优选R 5选自H和-C 1-3亚烷基-O-C(＝O)O-C 1-3烷基；
n选自2-9的整数；
优选n选自2-4的整数。
方案2.根据方案1所述的化合物，其结构如下所示，
Figure PCTCN2019085873-appb-000059
其中，R 1、R 2、R 3、R 4、R 5、环A、Q、W和Y如方案1中对于式(I)所定义。
方案3.根据方案1所述的化合物，其结构如下所示：
Figure PCTCN2019085873-appb-000060
其中，R 1、R 2、R 3、R 4、R 5、Q、W和Y如方案1中对于式(I)所定义。
方案4.根据方案1所述的化合物，其结构如下所示：
Figure PCTCN2019085873-appb-000061
其中，R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2；R 1、R 2、R 3、R 4、Q、W和Y如方案1中对于式(I)所定义；
优选地，上述式(III)中，
R 1选自H、C 1-3烷基和卤代C 1-3烷基；
R 2选自以下结构：
H、
Figure PCTCN2019085873-appb-000062
R 3和R 4各自独立地任选自H、F和Cl；
Figure PCTCN2019085873-appb-000063
选自以下结构：
Figure PCTCN2019085873-appb-000064
Y选自以下结构：
Figure PCTCN2019085873-appb-000065
R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2。
方案5.根据方案1所述的化合物，其结构如下所示：
Figure PCTCN2019085873-appb-000066
其中，R 1、R 2、R 3、R 4、Q、W和Y如方案1中对于式(I)所定义；
优选地，上述式(V)中，
R 1选自H、C 1-3烷基和卤代C 1-3烷基；
R 2选自以下结构：
H、
Figure PCTCN2019085873-appb-000067
R 3和R 4各自独立地任选自H、F和Cl；
Figure PCTCN2019085873-appb-000068
选自以下结构：
Figure PCTCN2019085873-appb-000069
Y选自以下结构：
Figure PCTCN2019085873-appb-000070
方案6.根据方案1所述的化合物，其结构如下所示，
Figure PCTCN2019085873-appb-000071
其中，R 1、R 2、R 3、R 4、R 5和环A如方案1中对于式(I)所定义。
方案7.一种药物组合物，其含有方案1－6中任一项所述的化合物、其药学可接受的盐、酯、溶剂化物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，以及一种或多种药学上可以接受的载体。
方案8.一种药物制剂，其中该制剂包含：方案1－6中任一项所述的化合物、其药学可接受的盐、酯、溶剂化物、水合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物作为活性成分，或者本发明的药物组合物，该制剂是固体制剂、半固体制剂、液体制剂或气态制剂的形式。
方案9.方案1－6中任一项的化合物、其药学可接受的盐、酯、溶剂化物、水合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者方案8所述的药物组合物，或者方案11所述的药物制剂在制备用于治疗与XI因子的抑制相关疾病的药物中的应用。
方案10.根据方案9所述的应用，其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，和心脏腔室的血栓栓塞性病症；
更优选地，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，和由于(a)人工瓣膜或其它植入物所得，(b)留置导管，(c)支架，(d)体外循环，(e)血液透析，或(f)血液暴露于易血栓形成的人造表面而引起的血栓形成。
具体实施方式
制备实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
以下的实施例中记载的化合物的结构通过核磁共振( 1HNMR)或质谱(MS)来确定。
1HNMR位移(δ)以百万分之一(ppm)的单位给出。 1HNMR的测定是用JEOL Eclipse 400核磁仪，测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)、六氘代二甲基亚砜(DMSO-d6)，内标为四甲基硅烷(TMS)，化学位移是以10 -6(ppm)作为单位给出,
实施例中使用的核磁共振(NMR)图谱中的缩写示于以下:
s：单峰、d：二重峰、t：三重峰、q：四重峰、dd：双二重峰、qd：四二重峰、ddd：双双二重峰、ddt：双双三重峰、dddd：双双双二重峰、m：多重峰、br：宽峰(broad)、J：偶合常数、Hz：赫兹。
MS的测定用Agilent(ESI)质谱仪，生产商:Agilent，型号:Agilent 6120B；
制备高效液相使用岛津LC-8A制备液相色谱仪(YMC，ODS,250×20mml色谱柱)。
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm),薄层层析分离纯化采用的规格是烟台产GF 254(0.4～0.5nm)。
反应的监测采用薄层色谱法(TLC)或LCMS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，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。
微波反应使用BiotageInitiator+(400W,RT～300℃)微波反应器。
柱层析一般使用青岛海洋200～300目硅胶为载体。洗脱剂的体系包括:二氯甲烷和甲醇体系，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进行调节。
实施例中无特殊说明，反应的温度为室温(20℃～30℃)
本发明所使用的试剂购自Acros Organics,Aldrich Chemical Company,特伯化学等公司。
在常规的合成法以及实施例、和中间体合成例中，各缩写的意思如以下所示：
aq.：水溶液                           HPLC：高效液相色谱
AcOH：醋酸                            LC-MS：液相色谱-质谱联用
BINAP：1,1'-联萘-2,2'-双二苯膦        MnO 2：二氧化锰
DMF：N，N-二甲基甲酰胺                NaCl：氯化钠
DMP：戴斯马丁氧化剂                   NaI：碘化钠
DABCO：三乙烯二胺                     NaOH：氢氧化钠
DIEA：二异丙基乙基胺                  NaO tBu：叔丁醇钠
THF：四氢呋喃                         NaBH 3CN：氰基硼氢化钠
MeOH：甲醇                            NaBH 4：硼氢化钠
MeCN：乙腈                            HATU：O-(7-氮杂苯并三唑-1-基)-
Boc：叔丁氧基羰基                     N,N,N’,N’-四甲基脲六氟磷酸盐
NCS：N-氯代丁二酰亚胺                 DCM:二氯甲烷
TFA：三氟醋酸                         EA：乙酸乙酯
TFAA：三氟乙酸酐
NH 2OH .HCl：羟胺盐酸盐
HCl：氯化氢
EtOH：乙醇
nBuLi：正丁基锂
I 2：碘
E 3N：三乙胺
EDCI：1-(3-二甲基氨基丙基)-3-乙基
碳二亚胺
Dioxane：1,4-二氧六环
Pd(OAc) 2：醋酸钯
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
HC(OMe) 3：原甲酸三甲酯
K 2CO 3：碳酸钾
TMSN 3:叠氮基三甲基硅烷
TLC：薄层色谱
实施例A：(R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-甲酸(Int-A)的制备
Figure PCTCN2019085873-appb-000072
第一步：3-氯-2-氟苯甲醛肟(A-2)的制备
将化合物3-氯-2-氟苯甲醛(50.0g,0.32mol)和盐酸羟胺(22.2g,0.32mol)溶于THF(400mL)，加入Et 3N(32.3g,0.32mol)后搅拌过夜，反应液用水淬灭，乙酸乙酯萃取，有机相用饱和NaCl水溶液洗两次，无水硫酸镁干燥，过滤，浓缩后的粗产品经硅胶柱纯化得标题化合物(29.1g,53％)。MS m/z(ESI):174[M+H] +
第二步：3-氯-2-氟-N-羟基苯甲亚胺氯(A-3)的制备
将化合物3-氯-2-氟苯甲醛肟(28.0g,0.16mol)溶于DMF(200mL)，加入NCS(25.4g,0.19mol),室温搅拌3小时后加水淬灭，乙酸乙酯萃取，有机相洗涤，干燥，过滤，浓缩得标题化合物(37.6g)，无需纯化，直接用于下一步反应。MS m/z(ESI):208[M+H] +
第三步：3-(3-氯-2-氟苯)-4,5-二氢异噁唑-5-甲酸叔丁酯(A-4)的制备
将化合物3-氯-2-氟-N-羟基苯甲亚胺氯(37.6g,粗品)和丙烯酸叔丁酯(46g,0.36mol)溶于二氯甲烷(300mL)，加入Et 3N(27.3g,0.27mol)，反应液室温搅拌过夜，LC-MS监测反应完毕，反应液加水淬灭，除去二氯甲烷，水相用乙酸乙酯萃取，有机相用无水硫酸镁干燥，过滤，浓缩得粗品，粗品过硅胶柱纯化得标题化合物(36.7g,两步收率：76％)。MS m/z(ESI):300[M+H] +
第四步：(R)-3-(3-氯-2-氟苯)-4,5-二氢异噁唑-5-甲酸叔丁酯(A-5)的制备
将3-(3-氯-2-氟苯)-4,5-二氢异噁唑-5-甲酸叔丁酯(18g)，经手性HPLC拆分分离纯化(仪器型号：Shimadzu LC-20AD，色谱柱：IG(IG00CD-UF004)(0.46cm I.D.×15cm L)；色谱柱温：35℃；流速：1.0mL/min；检测波长：UV 254nm；流动相A：100％MeOH；保留时间：4.868min.)，即得到标题化合物(7.2g,40％)。MS m/z(ESI):300[M+H] +
第五步：(R)-3-(3-氯-2-氟苯)-4,5-二氢异噁唑-5-甲酸(Int-A)的制备
将化合物(R)-3-(3-氯-2-氟苯)-4,5-二氢异噁唑-5-甲酸叔丁酯(5.0g,16.68mmol)溶于 二氯甲烷(10mL)，加入三氟乙酸(10mL)，室温搅拌过夜，LC-MS监测反应完毕，除去溶剂，剩余物加入乙醚(50mL)，过滤，滤饼干燥得标题化合物(4.0g,100％)。MS m/z(ESI):244[M+H] +
实施例B：(E)-3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酸(Int-B)的制备
Figure PCTCN2019085873-appb-000073
第一步：N-(4-氯-3-氟苯基)-2,2,2-三氟乙酰胺(B-2)的制备
向3L三口瓶中加入4-氯-3氟苯胺(450g,3.1mol)和四氢呋喃(1L)，充分搅拌下缓慢加入三氟乙酸酐(715g,3.4mol)。室温反应3小时，浓缩反应液，得黄色油状液体用石油醚打浆，过滤，得标题化合物B-2(600g,80％)。MS m/z(ESI):242[M+H] +
第二步：N-(4-氯-3-氟-2-碘苯基)-2,2,2-三氟乙酰胺(B-3)的制备
向3L三口瓶中加入B-2(100g,0.41mol)和四氢呋喃(1L)，氮气保护下冷却到-78℃，慢慢加入正丁基锂溶液(2.5M，500mL)，滴加完成后在该温度下搅拌1小时。加完后再慢慢加入单质碘(300g,1.18mol)的THF溶液(600mL),滴加完成后在该温度下搅拌1小时。LC-MS监测反应完毕，将反应液倾倒入1N盐酸(1.4L)溶液中，充分搅拌后加入饱和硫代硫酸钠溶液，直到溶液由褐色变为淡黄色。用乙酸乙酯(5L)分三次萃取后，合并有机相，用无水硫酸钠干燥、过滤，浓缩滤液，将粗产品经硅胶柱层析纯化得化合物B-3(110g,72％)。MS m/z(ESI):368[M+H] +
第三步：(E)-3-(3-氯-2-氟-6-(2,2,2-三氟乙酰胺基)苯基)丙烯酸叔丁酯(B-4)的制备
向2L单口瓶中加入化合物B-3(100g,272mmol)、丙烯酸叔丁酯(105g,816mmol)、醋酸钯(4.3g,19.1mmol)、无水三乙烯二胺(180g,816mmol)和DMF(500mL)，氮气保护下加热至回流反应过夜。LC-MS监测反应完毕，冷却到室温后，用稀盐酸调pH到3左右。用乙酸乙酯(3L)分三次萃取后合并有机相，用无水硫酸钠干燥、过滤，浓缩滤液，将粗产品经硅胶柱层析纯化得标题化合物B-4(82g,81％)。MS m/z(ESI):368[M+H] +
第四步：(E)-3-(3-氯-2-氟-6-(2,2,2-三氟乙酰胺基)苯基)丙烯酸(B-5)的制备：
将化合物B-4(97g,263.8mmol)溶于无水乙醇(1L)中，再加入NaOH(32.3g,791.4mmol)的水溶液(100mL)，有大量棕黄色固体析出。加热至85℃反应16小时, LC-MS监测反应完毕。浓缩除去部分溶剂，残余物过滤，滤饼用丙酮洗涤，得到标题化合物B-5(62g,98％)。MS m/z(ESI):216[M+H] +
第五步：(E)-3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酸(Int-B)的制备
将化合物B-5(60g,253mmol)溶于冰乙酸(1.8L)，再加入原甲酸三甲酯(410g,3790mmol)，黄色浑浊液逐渐变澄清。室温反应4小时后，加入TMSN 3(148g,1260mmol)，加热至80℃反应18小时。LC-MS监测反应完毕,反应液浓缩至干，残余物加入3L水溶解。再用EA/THF(1/1)萃取，有机层再用饱和氯化钠洗涤，干燥，浓缩至干。所得黄色固体再用乙酸乙酯(0.1L)打浆，过滤，滤饼用乙酸乙酯洗涤，得到得到标题化合物Int-B(32g,47％)。MS m/z(ESI):269[M+H] +
1H NMR(400MHz,DMSO-)δ12.80(br,1H),9.87(s,1H),8.03–7.88(m,1H),7.67(dd,J＝8.8,1.6Hz,1H),6.97(d,J＝16.0Hz,1H),6.31(dd,J＝16.4,1.6Hz,1H).
实施例1：(S,E)-4-(5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-1)的制备
Figure PCTCN2019085873-appb-000074
第一步：5-(哌嗪-1-基)异喹啉(1-1)的制备
将化合物5-溴异喹啉(25g,120mmol)和哌嗪(31g,360mmol)溶于甲苯(600mL)中，加入三(二亚苄基丙酮)二钯(1.10g,1.20mmol)、BINAP(2.2g,3.60mmol)和叔丁醇钠(17.3g,180mmol)，98℃反应4小时。LC-MS监测反应完毕，将反应液冷至室温，加入适量 水。减压蒸馏除去大部分甲苯，二氯甲烷/甲醇(10/1)萃取，合并有机层，无水硫酸钠干燥，过滤浓缩，所得粗品经硅胶柱层析纯化得标题化合物1-1(20g,78％)。MS m/z(ESI):214[M+H] +
第二步：2,2,2-三氟-1-(4-(异喹啉-5-基)哌嗪-1-基)乙酮(1-2)的制备
将化合物1-1(20g,93.8mmol)溶于DCM(200mL)，加入三乙胺(38g,375mmol)和三氟乙酸酐(39g,188mmol)，20℃反应4小时。LC-MS监测反应完毕，将反应液减压蒸馏旋干，所得粗品经硅胶柱层析纯化得标题化合物1-2(27g,93％)。MS m/z(ESI):310[M+H] +
第三步：2,2,2-三氟-1-(4-(1,2,3,4-四氢异喹啉-5-基)哌嗪-1-基)乙酮(1-3)的制备
将化合物1-2(27g,87.3mmol)溶于MeOH/CH 3COOH(1:1,270mL)中，分批次加入氰基硼氢化钠(16.5g,261.9mmol)，室温反应4小时。LC-MS监测反应完毕，将反应液倒于水(1.35L)中稀释，缓慢加入碳酸钠，调节pH＝8，二氯甲烷/甲醇(10/1)萃取，合并有机相，无水硫酸钠干燥，过滤浓缩，所得粗品直接用作下一步。MS m/z(ESI):314[M+H] +
第四步：1-(4-(3,4-二氢异喹啉-5-基)哌嗪-1-基)-2,2,2-三氟乙酮(1-4)的制备
将化合物1-3(32.6g,104mmol)溶于二氯甲烷(870mL)，加入二氧化锰(137g，1560mmol)，40℃反应12小时。LC-MS监测反应完毕，反应液经硅藻土过滤，除去二氧化锰，滤液浓缩，所得粗品经硅胶柱层析纯化得标题化合物1-4(10.2g,两步收率：31％)。MS m/z(ESI):312[M+H] +
第五步：(E)-4-(2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-5-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸叔丁酯(1-5)的制备
将化合物1-4(10.2g,32.6mmol)、Int-B(4.4g,16.3mmol)和4-异腈基苯甲酸叔丁酯(9.3g,45.7mmol)溶于乙醇(320mL)，氮气保护下，90℃回流12小时。LC-MS监测反应完毕，冷却至室温，减压浓缩，所得粗品经硅胶柱层析纯化得标题化合物1-5(4.1g,16％)。MS m/z(ESI):783[M+H] +
第六步：(E)-4-(2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-5-(哌嗪-1-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸叔丁酯(1-6)的制备
将化合物1-5(4.1g,5.24mmol)溶于MeOH(240mL)中，加入NaBH 4(2.0g,52.4mmol)，20℃反应30分钟。LC-MS监测反应完毕，减压浓缩，所得粗品直接用作下一步。MS m/z(ESI):687[M+H] +
第七步：(S,E)-4-(5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸叔丁酯(1-7)的制备
将化合物1-6(5.01g,7.28mmol)和1-[2-[2-(2-溴乙氧基)乙氧基]乙氧基]-2-甲氧基-乙烷(3.95g,14.6mmol)溶于乙腈(70mL)，加入碘化钠(218mg,1.46mmol)和碳酸钾(4.02g,29.1mmol)，75℃反应2小时。LC-MS监测反应完毕，减压浓缩，所得粗品经硅胶柱层析纯化得外消旋标题化合物(1-7,2.80g,两步收率：43％)。将外消旋化合物经手性HPLC分离(仪器型号：Shimadzu LC-20AD，色谱柱：IC(IC00CD-TB016)(0.46cm I.D.×15cm L)；色谱柱温：35℃；流速：2.0mL/min；检测波长：UV 254nm；流动相：MeOH/TEA＝100/0.1(V/V)；保留时间：11.046min.)，即可得到手性纯标题化合物1-7(0.85g,30％)。MS m/z(ESI):877[M+H] +
第八步：(S,E)-4-(5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-1)的制备
向化合物1-7(833mg,0.95mmol)的DCM(15mL)溶液中，加入TFA(5mL)，然后室温搅拌。LC-MS监测反应完毕，直接旋干，所得粗品经制备HPLC纯化得标题化合物T-1(390mg,50％)。MS m/z(ESI):821[M+H] +
1H NMR(400MHz,DMSO)12.71(br,1H),10.74(s,1H),9.87(s,1H),8.00–7.92(m,1H),7.90–7.83(m,2H),7.71–7.59(m,3H),7.33(d,J＝7.6Hz,1H),7.25–7.16(m,1H),7.09(d,J＝16.0Hz,1H),7.02–6.89(m,2H),5.73(s,1H),4.14–4.04(m,1H),3.63–3.45(m,12H),3.44–3.40(m,3H),3.22(s,3H),3.10–2.95(m,2H),2.93–2.84(m,2H),2.83–2.73(m,2H),2.71–2.52(m,6H).
实施例2：1-((乙氧碳酰基)氧基)乙基(S,E)-4-(5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸酯(T-2)的制备
Figure PCTCN2019085873-appb-000075
室温下，向T-1(143mg,0.17mmol)的MeCN(4mL)溶液中，加入K 2CO 3(240mg,1.70mmol)、1-氯乙基乙基碳酸酯(133mg,0.85mmol)和NaI(26mg,0.17mmol)，然后70℃搅拌。LC-MS监测反应完毕，加MeCN稀释，垫硅藻土抽滤，DCM洗涤，浓缩，所得粗品经制备HPLC纯化得到标题化合物T-2(70mg,41％)。MS m/z(ESI):937[M+H] +
1H NMR(400MHz,DMSO)δ10.85(s,1H),9.87(s,1H),8.01–7.93(m,1H),7.93–7.85(m,2H),7.76–7.69(m,2H),7.67(dd,J＝8.8,1.2Hz,1H),7.32(d,J＝7.6Hz,1H),7.28–7.17(m,1H),7.09(d,J＝15.6Hz,1H),7.02–6.89(m,2H),6.89–6.79(m,1H),5.73(s,1H),4.20–4.03(m,3H),3.58(s,2H),3.56–3.48(m,10H),3.48–3.46(m,1H),3.44–3.40(m,2H),3.22(s,3H),3.10–2.95(m,2H),2.96–2.86(m,3H),2.86–2.76(m,2H),2.76–2.53(m,5H),1.56(d,J＝5.2Hz,3H),1.20(t,J＝8.0Hz,3H).
实施例3：4-((S)-5-(1-(2,5,8,11-四氧杂十三烷-13-基)-1,2,3,6-四氢吡啶-4-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-3)的制备
Figure PCTCN2019085873-appb-000076
第一步：4-(1-((4-(叔丁氧基羰基)苯基)氨基甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(3-2)的制备
将化合物4-(5-溴-1,2,3,4-四氢异喹啉-1-甲酰胺)苯甲酸叔丁酯盐酸盐Int-C(20.0g,43.0 mmol)(参见专利CN107540659A)，叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯3-1(14.6g,47.3mmol)，碳酸钠(29.0g，215mmol)溶于1,4-二氧六环/水(5/1)的混合溶剂(180mL)中，N 2置换三次后，在N 2氛围下加入Pd(dppf)Cl 2(3.1g，4.3mmol)，之后置于120℃的油浴中反应过夜。LC-MS监测反应完毕，将反应降至室温后加水淬灭反应，乙酸乙酯萃取，浓缩，柱层析分离得到标题化合物3-2(20.7g,90％)。MS m/z(ESI):534[M+H] +
第二步：(S)-4-(1-((4-(叔丁氧基羰基)苯基)氨基碳酰基)-1,2,3,4-四氢异喹啉-5-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(3-3)的制备
将化合物叔丁基4-(1-((4-(叔丁氧基羰基)苯基)氨基甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(32.6g)经手性HPLC分离(色谱柱：IF Column；流动相：Hexane/EtOH/HAc＝80/20/0.1(V/V/V)；流速：1.0ml/min；检测波长：214nm；保留时间：11.97min)，即得到标题化合物3-3(11.7g,36％)。MS m/z(ESI):534[M+H] +
第三步：((S)-1-((4-(叔丁氧羰基)苯基)氨基碳酰基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-5-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(3-4)的制备
将化合物叔丁基(S)-4-(1-((4-(叔丁氧基羰基)苯基)氨基甲酰基)-1,2,3,4-四氢异喹啉-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(3-3，10g,19mmol)，(R)-3-(3-氯-2-氟苯)-4,5-二氢异噁唑-5-甲酸Int-A(4.6g,19mmol)溶于DMF(25mL)，加入DIPEA(7.4g,57mmol)和HATU(8.7g,23mmol)，加毕，室温搅拌反应过夜。LC-MS监测反应完毕，加入水中，搅拌10分钟，过滤，滤饼干燥后过硅胶柱纯化得标题化合物3-4(12.6g,85％)。MS m/z(ESI):779[M+H] +
第四步：((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸盐酸盐(3-5)的制备
将化合物((S)-1-((4-(叔丁氧羰基)苯基)氨基甲酰)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-羰基)-1,2,3,4-四氢异喹啉-5-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯3-4(700mg,0.92mmol)溶于四氢呋喃(18mL)，冰浴冷却至0℃，滴加盐酸-1,4二氧六环溶液(4M,12mL)，滴毕，室温搅拌。LC-MS监测反应完毕，加入乙醚(50mL)，冷却至0℃搅拌30分钟后过滤，滤饼干燥得标题化合物3-5(540mg,88％)。MS m/z(ESI):659[M+H] +
第五步：4-((S)-5-(1-(2,5,8,11-四氧杂十三烷-13-基)-1,2,3,6-四氢吡啶-4-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸叔丁酯(3-6)的制备
室温下，向化合物3-5(540mg,0.82mmol)的MeCN(20mL)溶液中，加入1-[2-[2-(2-溴乙氧基)乙氧基]乙氧基]-2-甲氧基-乙烷(444mg,1.64mmol)、K 2CO 3(566mg,4.10mmol)和NaI(49mg,0.33mmol)，然后75℃搅拌。LC-MS监测反应完毕，加水淬灭反 应，乙酸乙酯萃取，合并有机相，干燥，抽滤，浓缩，所得粗品经柱层析纯化得标题化合物3-6(450mg,65％)。MS m/z(ESI):761[M+H] +
第六步：4-((S)-5-(1-(2,5,8,11-四氧杂十三烷-13-基)-1,2,3,6-四氢吡啶-4-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-3)的制备
室温下，向化合物3-6(110.00mg,0.13mmol)的DCM(15mL)溶液中，加入TFA(5mL)，然后室温搅拌。LC-MS监测反应完毕，直接旋干，所得粗品经冻干得标题化合物T-3(102mg,100％)。MS m/z(ESI):793[M+H] +
1H NMR(400MHz,DMSO)δ10.88(s,1H),9.80(s,1H),7.92–7.85(m,2H),7.80–7.66(m,4H),7.63–7.57(m,1H),7.36–7.27(m,2H),7.19–7.13(m,1H),5.81(s,1H),5.76(dd,J＝11.6,7.6Hz,1H),5.62(s,1H),4.31–4.20(m,2H),4.06–3.94(m,2H),3.91–3.76(m,4H),3.76–3.57(m,7H),3.57–3.46(m,6H),3.47–3.37(m,4H),3.20(s,3H),),3.22–3.10(m,1H),3.08–2.97(m,2H).
实施例4：1-((乙氧碳酰基)氧基)乙基4-((S)-5-(1-(2,5,8,11-四氧杂十三烷-13-基)-1,2,3,6-四氢吡啶-4-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-4)的制备
Figure PCTCN2019085873-appb-000077
将化合物T-3(100mg,0.13mmol)溶于MeCN(4mL)，加入K 2CO 3(87mg,0.63mmol)、1-氯乙基乙基碳酸酯(96mg,0.63mmol)和NaI(9.6mg,0.06mmol)，然后70℃搅拌。LC-MS监测反应完毕，加MeCN稀释，垫硅藻土抽滤，DCM洗涤，浓缩，所得粗品经柱层析纯化得标题化合物T-4(100mg,84％)。MS m/z(ESI):909[M+H] +
1H NMR(400MHz,DMSO)δ10.96(s,1H),7.99–7.87(m,2H),7.85–7.63(m,4H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.24(t,J＝7.2Hz,1H),7.10(d,J＝7.6Hz,1H),6.84(q,J＝5.4Hz,1H),5.79(s,1H),5.74(dd,J＝11.2,7.6Hz,1H),5.55(s,1H),4.29–4.19(m,1H),4.14(q,J＝7.2Hz,2H),3.86(dd,J＝17.2,7.2Hz,1H),3.75–3.62(m,2H),3.62–3.45(m,10H),3.45–3.40(m,2H),3.34–3.30(m,4H),3.22(s,3H),3.18–3.06(m, 2H),3.18–3.06(m,2H),3.01–2.92(m,1H),2.72–2.57(m,3H),2.39–2.20(m,2H),1.56(d,J＝5.6Hz,3H),1.19(t,J＝7.2Hz,3H).
实施例5：4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1-(2-(2-(2-乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-5a)的制备和4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1-(2-(2-(2-乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸甲酯(T-5b)的制备
Figure PCTCN2019085873-appb-000078
第一步：2-(2-(2-甲氧基乙氧基)乙氧基)乙醛(5-2)的制备
将化合物2-(2-(2-甲氧基乙氧基)乙氧基)乙-1-醇(5-1，1.04g，6.35mmol)溶于DCM(20mL)中，将体系温度降至0℃，在向体系中加入碳酸氢钠(2.13g，25.4mmol)后再分批缓慢加入DMP(5.38g，12.7mmol)，之后将体系温度升至室温继续反应，LC-MS监测反应进程。反应结束后，向体系中加入饱和硫代硫酸钠溶液(20mL)淬灭反应，体系用DCM萃取(3×30mL)，合并的有机相经干燥浓缩后所得剩余物可直接用于之后的反应。MS m/z(ESI):163[M+H] +
第二步：4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰胺基)苯甲酸三氟乙酸盐(5-3)的制备
将化合物3-4(1.00g，1.52mmol)溶于DCM(10mL)中，0℃下，向体系中缓慢滴 加TFA(10mL)，之后升至室温反应1h，LC-MS监测反应进程。反应结束后，向反应体系中加入大量乙醚至无固体再析出，过滤，滤饼用乙醚洗涤(3×5mL)。滤饼干燥后即为标题化合物5-3(1.07g，收率：98％)。MS m/z(ESI):603[M+H] +
第三步：4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1-(2-(2-(2-乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-5a)的制备和4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1-(2-(2-(2-乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸甲酯(T-5b)的制备
将化合物5-3(228mg，0.38mmol)溶于pH＝4的MeOH(15mL)中，将体系温度降至0℃，之后向体系中滴加2-(2-(2-甲氧基乙氧基)乙氧基)乙醛(1-2，306mg，1.9mmol)，滴加完毕后将体系温度升至60℃，LC-MS监测反应进程。反应结束后，减压蒸去多余的溶剂，所得剩余物经HPLC分离即可得到标题化合物(T-5a,8mg，3％；T-5b,19mg，6％)
T-5a：
MS m/z(ESI):749[M+H] +
T-5b：
MS m/z(ESI):763[M+H] +
1H NMR(500MHz,DMSO)δ12.72(s,1H),10.84(s,1H),7.87(d,J＝7.7Hz,2H),7.75–7.65(m,4H),7.56–7.53(m,1H),7.34–7.23(m,2H),7.14–7.10(m,1H),6.55(s,1H),5.80(s,1H),5.76–5.70(m,1H),5.62(s,1H),4.27–4.19(m,1H),4.15–4.05(m,2H),3.90–3.82(m,1H),3.74–3.61(m,4H),3.55–3.49(m,1H),3.45–3.19(m,13H),3.16–3.07(m,1H),3.01–2.93(m,1H),2.43–2.21(m,2H),2.10–2.04(m,3H).
实施例6：4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-6)的制备
Figure PCTCN2019085873-appb-000079
第一步：4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-5-(1-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸叔丁酯(6-1)的制备
将化合物3-5(100mg，0.15mmol)溶于MeCN(15mL)中，将体系温度降至0℃，再向体系中加入碳酸钾(105mg，0.76mmol)和2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙-1-醇(78mg，0.3mmol)，之后将体系温度升至80℃反应，LC-MS监测反应进程。反应结束后，减压蒸去多余的溶剂，所得剩余物经HPLC分离即可得到标题化合物6-1(70mg,55％)。MS m/z(ESI):835[M+H] +
第二步：4-((S)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-羰基)-5-(1-(2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)乙基)-1,2,3,6-四氢吡啶-4-基)-1,2,3,4-四氢异喹啉-1-甲酰胺基)苯甲酸(T-6)的制备
将化合物6-1(70mg，0.08mmol)溶于DCM(3mL)中，将体系温度降至0℃，向其中缓慢滴加三氟乙酸(382mg，3.4mmol)，之后将体系温度升至室温继续反应，LC-MS监测反应进程。反应结束后，向体系中加入大量乙醚(8mL)至再无固体析出，抽滤，所得滤饼经HPLC纯化即可得到标题化合物T-6(10mg,15％)。MS m/z(ESI):779[M+H] +
1H NMR(400MHz,DMSO)δ10.82(s,1H),8.19(s,1H),7.87(d,J＝8.7Hz,1H),7.77–7.65(m,3H),7.52(d,J＝7.3Hz,1H),7.32(t,J＝8.1Hz,1H),7.23(t,J＝7.6Hz,1H),7.09(d,J＝6.9Hz,1H),5.79(s,1H),5.79–5.71(m,1H),5.55(s,1H),4.24–4.21(m,1H),3.88–3.82(m,1H),3.75–3.66(m,1H),3.58(t,J＝5.9Hz,2H),3.53–3.52(m,5H),3.44–3.42(m,16H),3.12(s,2H),2.69–2.67(m,2H),2.63–2.60(m,2H).
实施例7：(E)-4-(5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-22)的制备
Figure PCTCN2019085873-appb-000080
除在本实施例中用外消旋混合物7-1代替实施例1中的1-7，采用与实施例1中第八步类似的方法合成T-22。MS m/z(ESI):821[M+H] +
1H NMR(400MHz,DMSO)12.71(br,1H),10.74(s,1H),9.87(s,1H),8.00–7.92(m,1H),7.90–7.83(m,2H),7.71–7.59(m,3H),7.33(d,J＝7.6Hz,1H),7.25–7.16(m,1H),7.09(d,J＝16.0Hz,1H),7.02–6.89(m,2H),5.73(s,1H),4.14–4.04(m,1H),3.63–3.45(m,12H),3.44–3.40(m,3H),3.22(s,3H),3.10–2.95(m,2H),2.93–2.84(m,2H),2.83– 2.73(m,2H),2.71–2.52(m,6H).
实施例8：1-((乙氧碳酰基)氧基)乙基(E)-4-(5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸酯(T-23)的制备
Figure PCTCN2019085873-appb-000081
除在本实施例中用T-22代替实施例2中的T-1，采用与实施例2类似的方法合成T-23。
MS m/z(ESI):937[M+H] +
1H NMR(400MHz,DMSO)δ10.85(s,1H),9.87(s,1H),8.01–7.93(m,1H),7.93–7.85(m,2H),7.76–7.69(m,2H),7.67(dd,J＝8.8,1.2Hz,1H),7.32(d,J＝7.6Hz,1H),7.28–7.17(m,1H),7.09(d,J＝15.6Hz,1H),7.02–6.89(m,2H),6.89–6.79(m,1H),5.73(s,1H),4.20–4.03(m,3H),3.58(s,2H),3.56–3.48(m,10H),3.48–3.46(m,1H),3.44–3.40(m,2H),3.22(s,3H),3.10–2.95(m,2H),2.96–2.86(m,3H),2.86–2.76(m,2H),2.76–2.53(m,5H),1.56(d,J＝5.2Hz,3H),1.20(t,J＝8.0Hz,3H).
实施例9：4-((S)-5-(4-(2,5,8,11-四氧杂十三烷-13-基)哌嗪-1-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-8)的制备
Figure PCTCN2019085873-appb-000082
第一步：4-((S)-5-(4-(2,2,2-三氟乙酰基)哌嗪-1-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(8-1)的制备
将化合物1-4(100mg,0.32mmol)、Int-A(54.8mg,0.22mmol)和4-异腈基苯甲酸叔丁酯(84.9mg,0.42mmol)溶于乙醇(10mL)，氮气保护下，80℃回流24小时。LC-MS监测反应完毕，冷却至室温，减压浓缩，所得粗品经硅胶柱层析纯化分离非对映异构体得标题化合物1-5(4.1g,16％)。MS m/z(ESI):783[M+H] +
第二步：4-((S)-5-哌嗪基-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(8-2)的制备
将8-1(452mg,0.58mmol)溶于MeCN/MeOH(10/10mL)，加入碳酸钾(807mg,5.84mmol)，然后室温搅拌。LCMS显示原料基本消失，加水淬灭反应，MeOH/DCM萃取，合并有机相，干燥，抽滤，浓缩，得标题化合物8-2的粗品直接用作下一步。
第三、四步：4-((S)-5-(4-(2,5,8,11-四氧杂十三烷-13-基)哌嗪-1-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-8)的制备
除在第三步中用8-2代替实施例1中第七步的1-6，采用与实施例1中第七步和第八步的类似的方法合成得到T-8。MS m/z(ESI):796[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.75(s,1H),10.81(s,1H),7.86(dd,J＝8.8Hz,2H),7.77–7.70(m,2H),7.68(dd,J＝8.8Hz,2H),7.36–7.28(m,2H),7.22(t,J＝8.0Hz,1H),6.99(d,J＝7.6Hz,1H),5.74(dd,J＝11.2,7.2Hz,1H),5.72(s,1H),4.27–4.20(m,1H),3.86(dd,J＝16.0,7.2Hz,1H),3.68(dd,J＝16.4,11.6Hz,1H),3.62–3.48(m,12H),3.42(dd,J＝ 5.2,2.8Hz,2H),3.23(s,3H),3.13–3.00(m,2H),2.98–2.74(m,5H),2.67–2.52(m,6H).
实施例10：1-((乙氧碳酰基)氧基)乙基4-((S)-5-(4-(2,5,8,11-四氧杂十三烷-13-基)-哌嗪-1-基)-2-((R)-3-(3-氯-2-氟苯基)-4,5-二氢异噁唑-5-碳酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸酯(T-9)的制备
Figure PCTCN2019085873-appb-000083
除在本实施例中用T-8代替实施例2中的T-1，采用与实施例2类似的方法合成T-9。
MS m/z(ESI):912[M+H] +
1H NMR(400MHz,DMSO-d 6)δ10.92(s,1H),7.91(d,J＝8.4Hz,2H),7.78–7.65(m,4H),7.36–7.28(m,2H),7.22(t,J＝8.0Hz,1H),6.99(d,J＝8.0Hz,1H),6.83(q,J＝4.8Hz,1H),5.81–5.71(m,1H),5.71(s,1H),4.30–4.21(m,1H),4.14(q,J＝7.2Hz,2H),3.86(dd,J＝17.6,7.6Hz,1H),3.68(dd,J＝11.6,17.2Hz,1H),,3.65–3.47(m,13H),3.46–3.40(m,2H),3.23(s,2H),3.13–3.00(m,2H),2.93–2.76(m,4H),2.70–2.53(m,6H),1.56(d,J＝5.2Hz,3H),1.20(t,J＝7.2Hz,3H).
实施例11：(S,E)-4-(5-(1-(2,5,8,11-四氧杂十三烷-13-基)-1,2,3,6-四氢吡啶-4-基)-2-(3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸(T-10)的制备
Figure PCTCN2019085873-appb-000084
除在本实施例中第一步用Int-B代替实施例3中第三步的Int-A，采用与实施例3类似的方法合成T-10。
MS m/z(ESI):818[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.61(br,1H),10.81(s,1H),9.88(s,1H),7.97(t,J＝8.4Hz,1H),7.89(d,J＝8.8Hz,2H),7.77–7.60(m,3H),7.55(d,J＝7.6Hz,1H),7.23(t,J＝7.6Hz,1H),7.14–7.05(m,2H),6.95(d,J＝16.0Hz,1H),5.85(s,1H),5.54(s,1H),4.15–4.05(m,1H),3.71–3.45(m,13H),3.44–3.39(m,2H),3.22(s,3H),3.16–3.04(m,3H),2.95–2.86(m,1H),2.80–2.54(m,4H),2.31–2.18(m,2H).
实施例12：1-((乙氧碳酰基)氧基)乙基4-((S)-5-(1-(2,5,8,11-四氧杂十三烷-13-基)-1,2,3,6-四氢吡啶-4-基)-2-((E)-3-(3-氯-2-氟-6-(1H-四氮唑-1-基)苯基)丙烯酰基)-1,2,3,4-四氢异喹啉-1-碳酰氨基)苯甲酸酯(T-11)的制备
Figure PCTCN2019085873-appb-000085
除在本实施例中用T-10代替实施例2中的T-1，采用与实施例2类似的方法合成T-11。
MS m/z(ESI):934[M+H] +
1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),9.88(s,1H),7.97(t,J＝8.7Hz,1H),7.92(d,J＝8.8Hz,2H),7.74(d,J＝8.8Hz,2H),7.68(dd,J＝8.4,1.2Hz,1H),7.64–7.52(m,1H),7.31–7.22(m,1H),7.08–6.93(m,2H),6.84(q,J＝5.2Hz,1H),5.81(s,1H),5.58(s,1H),4.15(q,J＝7.2Hz,2H),4.12–4.04(m,1H),3.74–3.45(m,12H),3.41(dd,J＝5.2,3.2Hz,2H),3.34–3.29(m,4H),3.20(s,3H),3.17–3.03(m,2H),3.02–2.83(m,2H),2.83–2.54(m,3H),1.56(d,J＝5.2Hz,3H),1.20(t,J＝7.2Hz,3H).
实验例一、对凝血因子XIa酶的抑制作用
试剂：
酶：人凝血因子XIa；厂家：Haemtech公司；
底物：Boc-Ile-Glu-Gly-Arg-AMC Acetate salt；厂家：Bachem；
检测方法：
将待测化合物按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。在孔板中加入凝血因子XIa和待测化合物，混匀后室温孵育10分钟。加入底物(Boc-Ile-Glu-Gly-Arg-AMC Acetate salt)启动反应。在酶动力学模式下，选择激发光波长为380nm，发射光波长为460nm读取荧光信号值。每30秒读取1次，连续读取20个循环。在线性反应期内计算化合物不同浓度下酶活抑制率。用SigmaPlot或GraphPad Prism 5软件拟合化合物的半数抑制浓度IC 50值(A表示IC 50<1nM，B表示10nM>IC 50>1nM，C表示50nM>IC 50>10nM)。
表1.化合物对凝血因子XIa的抑制作用
化合物编号 IC 50
T-1 A
T-2 C
T-3 A
T-4 B
T-22 A
T-8 A
由表1可见，本发明的化合物对凝血因子XIa具有明显的抑制效果。
实验例二、大鼠PK试验
供试品配制：
测试化合物按下表2方法配制
表2.待测化合物供试品配制表
Figure PCTCN2019085873-appb-000086
试验方法：
雄性大鼠灌胃(po)给予溶液状态的受试物，采用LC-MS/MS测定大鼠体内受试物及代谢产物的血药浓度，利用WinNonlin 6.3软件计算主要药代动力学参数。
试验设计分组见下表3。
表3.试验设计分组表
Figure PCTCN2019085873-appb-000087
Figure PCTCN2019085873-appb-000088
试验结果：
化合物在大鼠血浆中的PK测试结果见下表4
表4.大鼠PK测试结果
Figure PCTCN2019085873-appb-000089
结果表明，本发明的化合物T-23作为T-22的前药，T-2作为T-1的前药，以及T-9作为T-8的前药，于溶液状态下口服给药，大鼠体内吸收均良好。
除本文中描述的那些外，根据前述描述，本发明的多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 (20)

  1. 下述式(I)所示的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，
    Figure PCTCN2019085873-appb-100001
    其中，
    R 1选自H、C 1-6烷基、C 2-6烯基、C 3-6环烷基和3-10元杂环基，其中所述C 1-6烷基、C 2-6烯基、C 3-6环烷基和3-10元杂环基任选地被一个或多个选自卤素、C 1-6烷基、-OH和-O-(C 1-6烷基)的取代基取代；
    Figure PCTCN2019085873-appb-100002
    选自以下结构：
    Figure PCTCN2019085873-appb-100003
    R 2、R 3和R 4各自独立地任选自：H、卤素、C 1-6烷基、-OH、-O-(C 1-6烷基)、3-6元杂环基、苯基和5-6元杂芳基，其中所述C 1-6烷基、-O-(C 1-6烷基)、-O-(C 1-6烷基)、3-6元杂环基、苯基和5-6元杂芳基任选地被一个或多个选自卤素、C 1-6烷基、-OH和-O-(C 1- 6烷基)的取代基取代；
    Y选自C 2-4亚烯基和5-6元亚杂芳基；
    环A选自以下结构：
    Figure PCTCN2019085873-appb-100004
    R 5选自H、C 1-6烷基和-C 1-4亚烷基-O-C(＝O)O-C 1-4烷基；
    n选自2-9的整数。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    R 1选自H、C 1-3烷基和卤代C 1-3烷基；
    优选地，R 1选自H、CH 3、CF 3和CH 2CF 3。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    R 2和R 4各自独立地选自：H、卤素、未取代或被一个卤素原子(例如F、Cl、Br或I)取代的四唑基；
    优选地，R 2和R 4各自独立地选自：
    F、Cl、
    Figure PCTCN2019085873-appb-100005
    优选地，R 2选自：
    Figure PCTCN2019085873-appb-100006
    优选地，R 4选自H、F和Cl。
  4. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    R 3选自H、卤素；
    优选地，R 3为卤素，例如F或Cl。
  5. 根据权利要求1-4任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    Y选自亚乙烯基、亚丙烯基、亚异噁唑基、亚噁唑基、亚噻唑基、亚异噻唑基、亚咪唑基、亚吡唑基；
    优选地，Y选自以下结构：
    Figure PCTCN2019085873-appb-100007
  6. 根据权利要求1-5任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    环A为
    Figure PCTCN2019085873-appb-100008
  7. 根据权利要求1-6任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    R 5选自H和-C 1-3亚烷基-O-C(＝O)O-C 1-3烷基。
  8. 根据权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，其中，
    n为2、3或4。
  9. 根据权利要求1-8任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物的结构如式(I)-1所示，
    Figure PCTCN2019085873-appb-100009
    其中，R 1、R 2、R 3、R 4、R 5、环A、n、
    Figure PCTCN2019085873-appb-100010
    和Y如权利要求1-8任一项所定义。
  10. 根据权利要求1-5、7任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物的结构如式(II)所示：
    Figure PCTCN2019085873-appb-100011
    其中，R 1、R 2、R 3、R 4、R 5、
    Figure PCTCN2019085873-appb-100012
    和Y如权利要求1-5、7任一项中所定义。
  11. 根据权利要求1-5任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物的结构如式(III)所示：
    Figure PCTCN2019085873-appb-100013
    其中，R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2；R 1、R 2、R 3、R 4、
    Figure PCTCN2019085873-appb-100014
    和Y如权利要求1-5任一项中所定义；
    优选地，式(III)所示的化合物中，
    R 1选自H、C 1-3烷基和卤代C 1-3烷基；
    R 2选自以下结构：
    Figure PCTCN2019085873-appb-100015
    R 3和R 4各自独立地任选自F和Cl；
    Figure PCTCN2019085873-appb-100016
    选自以下结构：
    Figure PCTCN2019085873-appb-100017
    Y选自以下结构：
    Figure PCTCN2019085873-appb-100018
    R 6选自H、-CH 3和-CH 2CH 3；R 7选自-CH 3、-CH 2CH 3和-CH(CH 3) 2。
  12. 根据权利要求1-5任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物的结构如下所示：
    Figure PCTCN2019085873-appb-100019
    其中，R 1、R 2、R 3、R 4、
    Figure PCTCN2019085873-appb-100020
    和Y如权利要求1-5任一项中所定义；
    优选地，式(V)所示的化合物中，
    R 1选自H、C 1-3烷基和卤代C 1-3烷基；
    R 2选自以下结构：
    Figure PCTCN2019085873-appb-100021
    R 3和R 4各自独立地任选自F和Cl；
    Figure PCTCN2019085873-appb-100022
    选自以下结构：
    Figure PCTCN2019085873-appb-100023
    Y选自以下结构：
  13. 根据权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物的结构如下所示：
    Figure PCTCN2019085873-appb-100025
    其中，R 1、R 2、R 3、R 4、R 5、Y和环A如权利要求1-7任一项所定义。
  14. 根据权利要求1-13任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物选自：
    Figure PCTCN2019085873-appb-100026
    Figure PCTCN2019085873-appb-100027
    Figure PCTCN2019085873-appb-100028
    Figure PCTCN2019085873-appb-100029
  15. 根据权利要求1-13任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，所述化合物选自：
    Figure PCTCN2019085873-appb-100030
    Figure PCTCN2019085873-appb-100031
    Figure PCTCN2019085873-appb-100032
    Figure PCTCN2019085873-appb-100033
  16. 制备权利要求1-15任一项的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物的方法，选自：
    方法一：
    Figure PCTCN2019085873-appb-100034
    在方法一中，R L1和R L2各自独立地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)；R Lx表示＝O、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)；PG 1、PG 2、PG 3和PG 4为保护基；Z表示离去基，优选地，所述离去基选自H、卤素、任选地被卤素取代的C 1-3烷基磺酸酯基、硼酸基、硼酸酯基、取代的硅基或取代的金属基团；
    步骤一：化合物S-1经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-1；
    步骤二：化合物IM-1经过偶联反应生成化合物IM-2；
    步骤三：化合物IM-2经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-3；
    步骤四：化合物IM-3经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-4；
    步骤五：化合物IM-4经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)化合物；
    其中，可根据需要调整上述过程的顺序；
    方法二：
    Figure PCTCN2019085873-appb-100035
    在方法二中，R L1、R L2、R Lx、PG 1、PG 2、PG 3、PG 4和Z如上述在方法一中所定义；
    步骤一：化合物S-1经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-1；
    步骤二：化合物IM-1经过偶联反应生成化合物IM-2；
    步骤三：化合物IM-2经过手性拆分得到化合物IM-5；
    步骤四：化合物IM-5经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-6；
    步骤五：化合物IM-6经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-7；
    步骤六：化合物IM-7经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)-1化合物；
    其中，可根据需要调整上述过程的顺序；
    方法三：
    Figure PCTCN2019085873-appb-100036
    在方法三中，R L1、R L2、R Lx、PG 3、PG 4和Z如上述在方法一中所定义；
    步骤一：化合物S-2经过偶联反应生成化合物IM-8；
    步骤二：化合物IM-8，S-3和S-4在醇溶剂进行Ugi反应生成化合物IM-9；
    步骤三：化合物IM-9经过脱保护反应，以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-10；
    步骤四：化合物IM-10经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)化合物；
    其中，可根据需要调整上述过程的顺序；
    方法四：
    Figure PCTCN2019085873-appb-100037
    在方法四中，R L1、R L2、R Lx、PG 3、PG 4和Z如上述在方法一中所定义；
    步骤一：化合物S-2经过偶联反应生成化合物IM-8；
    Figure PCTCN2019085873-appb-100038
    步骤二：化合物IM-8，S-3和S-4在醇溶剂进行Ugi反应生成化合物IM-9；
    步骤三：化合物IM-9经过脱保护反应，以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成化合物IM-10；
    步骤四：化合物IM-10经过手性拆分得到化合物IM-11；
    步骤五：化合物IM-11经过脱保护反应以及继续在碱的存在下进行取代反应生成式(I)-1化合物；
    方法五：
    在方法五中，R L1、R L2、R Lx、PG 2、PG 3和PG 4如在方法一中所定义；
    步骤一：化合物S-5与S-6经过Buckwald偶联反应生成化合物IM-12；优选地，S-5与哌嗪先经过Buckwald偶联反应再经过保护反应生产化合物IM-12；
    步骤二：化合物IM-12在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-13；
    步骤三：化合物IM-13经过脱保护反应以及继续在碱的存在下进行取代反应或在还原剂(如硼氢化钠和氰基硼氢化钠等)的存在下进行还原胺化反应生成式化合物IM-14；
    步骤四：化合物IM-14经过脱保护反应以及继续在缩合剂(如HATU、EDCI等)的存在下进行酸胺缩合反应生成化合物IM-15；
    步骤五：化合物IM-15经过手性拆分得到化合物IM-16；
    步骤六：化合物IM-16经过脱保护反应以及继续在碱的存在下进行取代反应生成式(VI)化合物；
    本领域技术人员会明白，可根据需要调整上述过程的顺序，以及省略步骤六中的取代反应过程；
    在上述方法一、方法二、方法三或方法四中，R 1、R 2、R 3、R 4、R 5、环A、Y、W、Q和n如权利要求1-13任一项所定义；
    在上述方法五中，R 1、R 2、R 3、R 4、R 5、环A、Y和n如权利要求1-13任一项所定义。
  17. 一种药物组合物，其含有权利要求1-15中任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，，任选地，还包括一种或多种药学上可以接受的载体。
  18. 一种药物制剂，其中该制剂包含：权利要求1-15中任一项所述的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，作为活性成分，或者权利要求17的药物组合物；优选地，所述制剂是固体制剂、半固体制剂、液体制剂或气态制剂的形式。
  19. 权利要求1-15中任一项的化合物或其药学上可接受的盐、酯、多晶型物、溶剂合物、前药或稳定的同位素衍生物，或者所述化合物的立体异构体、互变异构体或其混合物，或者权利要求17所述的药物组合物，或者权利要求18所述的药物制剂在制备用于治疗与XIa因子的过度活性相关的病症的药物中的应用。
  20. 根据权利要求19所述的应用，其中所述与XIa因子的过度活性相关的病症为血栓栓塞性病症，例如动脉心血管血栓栓塞性病症，静脉心血管血栓栓塞性病症，或心脏腔室的血栓栓塞性病症；
    优选地，所述血栓栓塞性病症选自：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，和由于(a)人工瓣膜或其它植入物所得，(b)留置导管，(c)支架，(d)体外循环，(e)血液透析，或(f)血液暴露于易血栓形成的人造表面而引起的血栓形成。
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