WO2018133793A1 - Inhibiteur du facteur xia de coagulation sanguine et ses utilisations - Google Patents

Inhibiteur du facteur xia de coagulation sanguine et ses utilisations Download PDF

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WO2018133793A1
WO2018133793A1 PCT/CN2018/072988 CN2018072988W WO2018133793A1 WO 2018133793 A1 WO2018133793 A1 WO 2018133793A1 CN 2018072988 W CN2018072988 W CN 2018072988W WO 2018133793 A1 WO2018133793 A1 WO 2018133793A1
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group
alkyl
atoms
independently
mmol
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PCT/CN2018/072988
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English (en)
Chinese (zh)
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左应林
王建成
林继华
张英勋
曹生田
吴方园
杨雯
许娟
王晓军
张英俊
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广东东阳光药业有限公司
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Priority to CN201880004854.3A priority Critical patent/CN110062757B/zh
Publication of WO2018133793A1 publication Critical patent/WO2018133793A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention belongs to the field of medicine, relates to a blood coagulation factor XIa inhibitor and uses thereof, and particularly to a macrocyclic compound having a blood coagulation factor XIa and/or a plasma kallikrein and a pharmaceutical composition thereof; wherein the macrocyclic compound And pharmaceutical compositions thereof for use in the treatment or prevention of thromboembolic disorders.
  • Procoagulant hemostasis
  • anticoagulation antithrombotic
  • Procoagulant and anticoagulation are two opposing mechanisms in the human blood system that contradict each other and maintain relative balance. This precise and harmonious process maintains the integrity of the circulatory system.
  • blood coagulation and anticoagulant function are out of balance, and coagulation occurs, which may cause thrombosis or embolism, which may lead to thromboembolism such as myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, etc. disease.
  • thromboembolic disease is the most serious disease in cardiovascular disease and the first killer of human health.
  • antithrombotic drugs have been researched and developed for the characteristics and causes of thrombosis, including inhibition of thrombosis (anticoagulation, for example, warfarin, heparin, low molecular weight heparin, etc.) And drugs that inhibit platelet aggregation (eg, aspirin, clopidogrel, etc.) and thrombolytic drugs.
  • the former mainly inhibits the formation and enlargement of thrombus, and the latter mainly dissolves the formed thrombus, thereby eliminating the harm caused by thrombotic diseases to humans.
  • the use of clinically applied anticoagulant drugs is still limited by various risks (eg, bleeding), and it is increasingly important to discover and develop safe and effective oral anticoagulant drugs for the prevention and treatment of extensive thromboembolic disorders. .
  • Factor XIa coagulation factor XIa
  • Factor XIa is a plasma serine protease involved in the regulation of blood coagulation, which is initiated by the in vivo binding of tissue factor (TF) to factor VII (FVII) to produce factor VIIa (FVIIa).
  • the TF:FVIIa complex produced therein activates Factor IX (FIX) and Factor X (FX), thereby causing the production of Factor Xa (FXa).
  • TFPI tissue factor pathway inhibitor
  • the resulting FXa catalyzes the conversion of prothrombin to a small amount of thrombin, and the catalytic amount of thrombin feedbacks the activation factors V, VIII and XI, thereby further expanding the coagulation process.
  • TFPI tissue factor pathway inhibitor
  • the thrombin burst caused by this process converts fibrinogen to fibrin, which polymerizes to form a structural framework for blood clots and activates platelets that are key cellular components of coagulation (Hoffman, M., Blood Reviews, 2003, 17: S1-S5). Therefore, Factor XIa plays a key role in expanding the amplification loop of the coagulation process, and thus it can serve as an attractive target for anti-thrombotic therapy.
  • Plasma prekallikrein is a chymase of trypsin-like serine protease which is present in plasma at a concentration of 35 ⁇ g/mL to 50 ⁇ g/mL.
  • the gene structure of plasma kallikrein is similar to that of factor XI; in general, the amino acid sequence of plasma kallikrein (PK) has 58% homology with factor XI.
  • Plasma kallikrein is thought to play a role in many inflammatory conditions.
  • the major inhibitor of plasma kallikrein is a serpin C1 esterase inhibitor.
  • HAE hereditary angioedema
  • DX-88 vascular permeability
  • a plasma kallikrein inhibitor For the treatment of hereditary angioedema and the prevention of blood loss in on-pumpcardiothoracic surgery, Expert Opin. Biol. Ther. 8, pp. 1187-99).
  • Kallikrein kinin system is a complex endogenous multi-enzyme system involved in the regulation of cardiovascular, renal, nervous system and other physiological functions, and heart disease, kidney disease, inflammatory response, cancer There is a close relationship between the occurrence of diseases. In recent years, research on the cardiovascular system has progressed rapidly. Many clinical studies and basic experiments have confirmed that the occurrence of diabetes, hypertension, heart failure, myocardial infarction and left ventricular hypertrophy is associated with decreased activity of KKS.
  • FXI factor XI
  • HK high molecular weight kininogen
  • PK prokallikrein
  • the present invention provides a macrocyclic compound suitable for a serine protease, particularly a selective inhibitor of factor XIa and/or plasma kallikrein, an analog thereof, and a pharmaceutical composition comprising the macrocyclic compound, the compound Or a thromboembolic disease in which the pharmaceutical composition is effective for the treatment and prevention.
  • the present invention provides a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride of a compound of formula (I) or a compound of formula (I), a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • Ring A is a C 7-12 carbocyclic group, a C 8-12 aryl group, a heterocyclic group consisting of 7 to 12 atoms or a heteroaryl group of 7 to 12 atoms;
  • Ring B is a C 5-12 carbocyclic group, a C 6-12 aryl group, a heterocyclic group consisting of 5 to 12 atoms or a heteroaryl group of 5 to 12 atoms;
  • Ring C is a C 3-12 carbocyclic group, a C 6-12 aryl group, a heterocyclic group consisting of 3 to 12 atoms or a heteroaryl group of 5 to 12 atoms;
  • Each R 3 is independently a C 1-6 alkyl group, a C 3-12 carbocyclic group, a C 6-12 aryl group, a heterocyclic group consisting of 3 to 12 atoms, or a heteroaryl group of 5 to 12 atoms; Wherein each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a ;
  • Each R 4 is independently H, hydrazine, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkyl, halo C 1 -6 alkoxy, -(CR 7a R 7b ) r -OR 8 , -(CR 7a R 7b ) r -NR 5a R 5b , -(CR 7a R 7b ) r -CN, or halogenated C 1-6 Or an alkyl group; or any two of the R 4 and the atom to which they are attached form a C 3-8 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group of 3 to 8 atoms, or 5 to 6 atoms.
  • any two R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;
  • R 9 , R 1a , R 2a and R 3a are independently independently substituted by 1, 2, 3, 4 or 5 R 10 ;
  • R 5 , R 9 and the atoms attached thereto form a heterocyclic group consisting of 3-8 atoms;
  • Each of R 6 and R 8 is independently hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy substituted C 1-6 Alkyl, amino-substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkyl, C 6- a 10 aryl group, a C 3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms;
  • R 7 , R 7a and R 7b is independently hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or halo C 1-6 alkyl;
  • Each m, n and t are independently 0, 1, 2, 3 or 4;
  • p 1, 2, 3 or 4;
  • Each r is independently 0, 1, 2, 3 or 4.
  • Ring C is a heterocyclic group consisting of 5-7 atoms or a heteroaryl group consisting of 5-6 atoms.
  • Ring C is of the following substructure:
  • each of Z, Z 1 and Z 2 is independently CH 2 or NH;
  • each of Z, Z 1 and Z 2 is independently CH or N;
  • Z 4 is CH 2 or NH
  • Each Z 3 and Z 5 are independently CH 2 , NH, S or O;
  • q 0, 1, or 2.
  • ring C is
  • the compound of formula (I) of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (II) or a compound of formula (II). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • each Z and Z 1 are independently CH 2 or NH; or When it is a double bond, each Z and Z 1 are independently CH or N;
  • Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , X, Y, n, m, p and t all have the meanings as described in the present invention.
  • each R 3 is independently C 1-4 alkyl, C 3-8 carbocyclyl, C 6-10 aryl, heterocyclyl consisting of 3-8 atoms, or 5-10 atoms. a heteroaryl group;
  • each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a .
  • each R 3 is independently methyl, ethyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, pyridyl, pyrimidinyl, fluorenyl, Carbazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolinyl or quinazolinyl ;
  • each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a .
  • the compound of formula (I) of the present invention is a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (III) or a compound of formula (III). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • Z when or When it is a single bond, Z is CH 2 or NH; or When it is a double bond, Z is CH or N;
  • f 0, 1, 2, 3, 4 or 5;
  • g 0, 1, 2, 3, 4, 5, 6, 7, or 8;
  • Ring A, Ring B, R 1 , R 2 , R 3a , R 4 , R 5 , R 9 , n, m and t all have the meanings as described in the present invention.
  • Ring A is a C 7-12 bicyclic carbocyclyl, a C 8-12 bicyclic aryl, a bicyclic heterocyclyl consisting of 7-12 atoms, or a bicyclic heteroaryl consisting of 7-12 atoms.
  • Ring A is of the following substructure:
  • each of T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 and T 8 are independently -CH- or -N-;
  • Each k and j are independently 0, 1, 2, 3 or 4.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring B is C 5-8 carbocyclyl, C 6-10 aryl, heterocyclyl consisting of 5-8 atoms, or heteroaryl consisting of 5-10 atoms;
  • Each R 2 is independently optionally substituted by 1, 2, 3 or 4 R 2a ;
  • R 2a , R 5a , R 5b , R 5c , R 5d , R 6 , R 7 , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • Ring B is of the following substructure:
  • Each of Q 2 , Q 3 , Q 4 , Q 5 , Q 7 and Q 8 is independently CH or N;
  • s 0, 1, 2 or 3;
  • R 2a , R 5a , R 5b , R 5c , R 5d , R 6 , R 7 , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • Ring B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • each R 2 is independently optionally substituted by 1, 2, 3 or 4 R 2a ; R 2a has the meanings as described herein.
  • Each R 4 is independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1,2-difluoro Ethyl, trifluoromethoxy, difluoromethoxy, -OMe, -OEt, -O(t-Bu), -CH 2 OH, -CH 2 CH 2 OH, -CN, -CH 2 CN, - CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OMe, -CH 2 CH 2 OMe, -NHMe or -N(Me) 2 ; alternatively, any two R 4 and the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;
  • any two R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;
  • R 9 , R 1a , R 2a and R 3a are independently independently substituted by 1, 2, 3, 4 or 5 R 10 ;
  • R 5a , R 5b , R 5c , R 6 , R 7a , R 7b , R 8 , R 10 and r all have the meanings as described in the present invention.
  • Each R 4 is independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, vinyl, propenyl, allyl, deuterated methyl, three Fluoromethyl, difluoromethyl, 1,2-difluoroethyl, -OMe, -OEt, -CH 2 OH, -CH 2 CH 2 OH, -CN, -CH 2 CN, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OMe, -CH 2 CH 2 OMe, -NHMe or -N(Me) 2 ; alternatively, any two R 4 and the atoms to which they are attached form a cyclopropyl group, a ring Butyl, epoxyalkyl or azetidinyl;
  • any two R 9 together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, pyrrole
  • R 9 , R 1a , R 2a and R 3a are independently independently substituted by 1, 2, 3, 4 or 5 R 10 ;
  • R 10 has the meanings as described in the present invention.
  • Each of R 6 and R 8 is independently hydrogen, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy substituted C 1-4 Alkyl, amino substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, halo C 1-4 alkyl, C 6- a 10 aryl group, a C 3-6 cycloalkyl group, a heterocyclic group of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms;
  • R 7 , R 7a and R 7b is independently hydrogen, C 1-4 alkyl, deuterated C 1-4 alkyl or halo C 1-4 alkyl;
  • R 6 and R 8 is independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, deuterated methyl, vinyl, propynyl, hydroxymethyl, hydroxyethyl, methoxymethyl , methoxyethyl, ethoxymethyl, tert-butoxymethyl, tert-butoxyethyl, ethoxyethyl, isopropoxyethyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, phenyl, cyclopropyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridine , pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, furyl, thiazolyl, oxazolyl
  • R 7 , R 7a and R 7b is independently hydrogen, methyl, ethyl, propyl, butyl, deuterated methyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl or 2,2-difluoroethyl;
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the invention.
  • the pharmaceutical compositions of the present invention further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
  • the invention relates to the use of a compound or pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a thromboembolic disorder.
  • the use of the invention wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.
  • the use of the invention wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral Occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and due to medical implants, instruments, or The blood in the procedure is exposed to the artificial surface to promote thrombosis caused by thrombosis.
  • the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral Occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary
  • the invention relates to the use of a compound or pharmaceutical composition for the manufacture of a medicament for the treatment of disseminated intravascular coagulation (DIC) disease.
  • DIC disseminated intravascular coagulation
  • the invention relates to the use of a compound or pharmaceutical composition for the preparation of a medicament, wherein the medicament is for inhibiting the activity of Factor XIa and/or plasma kallikrein.
  • the compounds or pharmaceutical compositions of the invention are used to prevent, treat or ameliorate thromboembolic disorders.
  • the compound or pharmaceutical composition of the present invention is for use in preventing, treating or ameliorating a thromboembolic disease, wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolism Sexual disease, and thromboembolic disease in the ventricular or peripheral circulation.
  • a thromboembolic disease is an arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolism Sexual disease, and thromboembolic disease in the ventricular or peripheral circulation.
  • the compounds or pharmaceutical compositions of the invention are used to prevent, treat or ameliorate a thromboembolic disease, wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardium Infarction, 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 thrombosis caused by exposure of blood in a medical implant, device, or procedure to an artificial surface to promote thrombosis.
  • the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardium Infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thro
  • the compounds or pharmaceutical compositions of the invention are useful for inhibiting the activity of Factor XIa and/or plasma kallikrein.
  • the invention also relates to a method of preventing, treating or ameliorating a thromboembolic disease using a compound or pharmaceutical composition of the invention.
  • the method of the present invention wherein the thromboembolic disease is an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.
  • the method of the present invention wherein the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, Peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and medical implants, instruments Or blood in the procedure is exposed to an artificial surface to promote thrombosis caused by thrombosis.
  • the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, Peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronar
  • the invention also relates to a method of inhibiting the activity of Factor XIa and/or plasma kallikrein using a compound or pharmaceutical composition of the invention.
  • &quot refers to one or more components, i.e., more than one component may be considered for use or use in embodiments of the embodiments.
  • subject refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates eg, humans, males or females
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to a person (including adults and children) or other animal. In some embodiments, “patient” refers to a human.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomer refers to two isomers of a compound that are not superimposable but are mirror images of each other.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • substituents such as the compounds of the above formula, or specific examples, subclasses, and inclusions of the present invention.
  • a class of compounds may be used interchangeably.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group.
  • substituents When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • substituents mean one or more substituents, and the number of specific substituents is determined by the number of positions at which the substituent group can be substituted.
  • the present invention is described in the "C 4 alkylene group optionally substituted independently with one or more identical or different R 9 substituted" indicates that the group may be an alkylene or substituted with one or more R 9, particularly Said alkylene group may be independently and optionally substituted by 1, 2, 3, 4, 5, 6, 7 or 8 R 9 ; when said alkylene group is more than one R 9 When substituted, the R 9 may be the same or different.
  • each alkylamino group, arylamino group, alkoxy group, aryloxy group, hydroxyl group, mercapto group, alkyl group, haloalkyl group, carbocyclic group, heterocyclic group, aryl group, heteroaryl group, alkyl group in the substituent Sulfonyl, aminosulfonyl, hydroxyalkyl, aminoalkyl, alkylacyl, aminoacyl and alkylthio have the meanings as described herein and may be further monosubstituted or identical by the substituents described herein Or different multiple substitutions.
  • each R 9 , R 1a , R 2a and R 3a are independently hydrogen, deuterium, nitro or C 1-6 alkyl
  • R 9 may be hydrogen, deuterium, nitro or C 1-6 alkyl
  • R 1a may also be hydrogen, deuterium, nitro or C 1-6 alkyl
  • R 2a and R 3a may also be hydrogen, deuterium, nitro or C 1-6 alkane. base.
  • C 1 - 6-alkyl refers particularly disclosed independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 and C 6 alkyl group.
  • C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl), C 4 alkyl (ie butyl, including n-butyl) Base, isobutyl, sec-butyl and tert-butyl).
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the definition of the Markush group for the variable is "alkyl” or "aryl”
  • the “alkyl” or “aryl” respectively represent the attached An alkylene group or an arylene group.
  • the ring A in the structure of the formula (I) of the present invention may be a heteroaryl group, and the heteroaryl group herein represents an arylene group having two linking sites attached to the rest of the molecule, more specifically, for example
  • ring A is a quinolyl group, and the quinolyl group here represents a quinolinyl group.
  • C 1-6 alkoxy C 1-6 alkyl C 1-6 alkyl represents a C 1-6 alkylene group, including but not limited to, methylene, ethylene and the like.
  • alkyl or "alkyl group” as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be any Optionally, it is substituted with one or more substituents described herein. Unless otherwise specified, an alkyl group contains from 1 to 20 carbon atoms. In some embodiments, the alkyl group contains from 1 to 12 carbon atoms; in other embodiments, the alkyl group contains from 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 - 4 carbon atoms; in other embodiments, the alkyl group contains 1-3 carbon atoms.
  • C 1 - 6 alkyl denotes an alkyl group containing 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CHCH
  • alkenyl denotes a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp 2 double bond, wherein the alkenyl group may be optionally one or Substituted by a plurality of substituents described herein, which include the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in other embodiments, the alkenyl group contains 2-6 carbon atoms; in still other embodiments, the alkenyl group comprises 2 - 4 carbon atoms.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical containing from 2 to 12 carbon atoms, wherein at least one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally one or more Substituted by the substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms; in still other embodiments, the alkynyl group comprises 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • alkylene means a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, an alkylene group contains from 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The group contains 1-3 carbon atoms; in other embodiments, the alkylene group contains 1-2 carbon atoms.
  • Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 -), n-butylene (-CH 2 ) CH 2 CH 2 CH 2 -) and so on.
  • alkenylene means a divalent hydrocarbyl group derived by removing two hydrogen atoms from an alkenyl group. Unless otherwise specified, an alkenylene group contains from 1 to 12 carbon atoms. In some embodiments, the alkenylene group contains 1-6 carbon atoms; in other embodiments, the alkenylene group contains 1-4 carbon atoms; in still other embodiments, the alkenylene group The group contains 1-3 carbon atoms. Examples of such include propenylene, butenylene, and the like.
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • the alkoxy group contains from 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains from 1 to 4 carbon atoms; in still other embodiments, the alkoxy group The group contains 1-3 carbon atoms.
  • the alkoxy group can be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), and the like.
  • alkoxyalkyl denotes an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy have the meanings as described herein.
  • the alkoxyalkyl group can be optionally substituted with one or more substituents described herein.
  • the alkoxyalkyl group is a C 1-4 alkoxy C 1-4 alkyl group; in other embodiments, the alkoxyalkyl group is a C 1-2 alkoxy group C 1-3 Alkyl; In still other embodiments, the alkoxyalkyl group is a C1-3 alkoxy C1-3 alkyl group.
  • Such examples include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, tert-butoxymethyl, tert-butoxyethyl, and the like.
  • the alkoxyacyl, alkanoyl, or aminoacyl group may be optionally substituted with one or more substituents described herein.
  • alkyl sulfonyl denotes an alkyl group, an alkoxy group, an alkylamino group or an amino group (-NH 2) group bonded through a sulfonyl group (-SO 2 -) is attached to the remainder of the molecule wherein the alkyl, alkoxy, alkylamino group has the meaning as described herein.
  • the alkylsulfonyl, alkoxysulfonyl, alkylaminosulfonyl, aminosulfonyl group may be optionally substituted with one or more substituents described herein. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl (-SO 2 CH 3 ), ethylsulfonyl (-SO 2 CH 2 CH 3 ), and the like.
  • haloalkyl denotes an alkyl, alkenyl or alkoxy group substituted by one or more halogen atoms, examples of which include, but are not limited to, Trifluoromethyl, difluoromethyl 2,2-difluoroethyl, trifluoromethoxy, and the like.
  • haloalkyl or “deuterated alkoxy” denotes an alkyl or alkoxy group substituted by one or more deuterium atoms, examples of which include, but are not limited to, deuterated methyl (- CD 3 ), deuterated methoxy (-OCD 3 ), and the like.
  • carbocyclic or “carbocyclyl” refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms.
  • the carbocycle comprises from 3 to 10 ring carbon atoms; in other embodiments, the carbocycle comprises from 3 to 8 ring carbon atoms; in still other embodiments, the carbocycle comprises from 3 to 6 rings.
  • carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl , cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Wherein the carbocyclic group may be optionally substituted by one or more substituents described herein.
  • cycloalkyl refers to a monovalent or polyvalent, non-aromatic, saturated monocyclic, bicyclic or tricyclic system containing from 3 to 12 ring carbon atoms.
  • the cycloalkyl group contains 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms; in still other embodiments, the cycloalkyl group comprises 3- 6 ring carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group can be optionally substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein to refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring atoms, wherein at least one ring atom is selected. From nitrogen, sulfur and oxygen atoms, and any one of the heterocyclic ring systems is non-aromatic.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • the heterocyclic group is a heterocyclic group consisting of 5 to 12 atoms; in other embodiments, the heterocyclic group is a heterocyclic group of 5 to 8 atoms; in still other embodiments, The heterocyclic group is a heterocyclic group consisting of 5 to 7 atoms; and in some embodiments, the heterocyclic group is a heterocyclic group of 5 to 6 atoms.
  • the heterocyclic group may also be a bicyclic heterocyclic group; in some embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 7 to 12 atoms; in other embodiments, the heterocyclic group is composed of 7 to 10 atoms. Bicyclic heterocyclic groups; In still other embodiments, the heterocyclic group is a bicyclic heterocyclic group consisting of 8-10 atoms.
  • heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, dihydrothienyl, 1,3-dioxo Pentyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,2-dihydropyridyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, 1 , 6-dihydropyrimidinyl, 1,2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,3-oxazinyl, piperazinyl, oxazolidinyl, dioxoalkyl, Dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxetanyl,
  • sulfur atom in the heterocyclic group being oxidized examples include, but are not limited to, a sulfolane group, a 1,1-dioxothiomorpholinyl group, and a 1,1-dioxo-1,2-thiomorpholinyl group.
  • a heterocyclic group is a heterocyclic group consisting of 5-6 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 5 or 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen and sulfur. And oxygen atoms.
  • the heterocyclic group of 5-6 atoms include, but are not limited to, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuran.
  • Base tetrahydrothiophenyl, oxazolidinyl, piperidinyl, 1,2-dihydropyridyl, morpholinyl, thiomorpholinyl, hexahydropyrimidinyl, 1,6-dihydropyrimidinyl, 1 , 2-dihydropyrimidinyl, 1,2-dihydropyrazinyl, 1,3-oxazinyl, piperazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3, 4-tetrahydropyridyl, 1,2,3,4-tetrahydropyrimidinyl, 2,5-dihydro-1H-pyrrolyl and the like.
  • the heterocyclic group consisting of 5-6 atoms may be optionally substituted by one or more substituents described in the present invention.
  • unsaturated as used in the present invention means that the group contains one or more unsaturations.
  • heteroatom refers to O, S, N, P, and Si, including any form of oxidation states of N, S, and P; forms of primary, secondary, tertiary, and quaternary ammonium salts; or nitrogen atoms in heterocycles. a form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR).
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl denotes monocyclic, bicyclic and tricyclic hydrocarbyl groups containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 8 to 12 ring atoms, or from 6 to 10 ring atoms, Wherein at least one ring is aromatic and one or more attachment points in the aromatic system are attached to the remainder of the molecule.
  • aryl can be used interchangeably with the terms “aromatic ring” or "aromatic ring”.
  • the aryl group includes an aromatic ring and an aromatic ring, or a ring system in which an aromatic ring is fused with a non-aromatic carbocyclic ring.
  • aryl group may include phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, bicyclo[4,2,0 ] ⁇ -1(6), 2,4-trienyl.
  • heteroaryl denotes a monocyclic, bicyclic, and tricyclic ring system having 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains one or more heteroatoms wherein one or more attachment points in the heteroaryl system are attached to the remainder of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaryl ring” or "heteroaromatic compound”.
  • the heteroaryl group includes a heteroaryl ring and an aromatic ring, a heteroaryl ring and a heteroaryl ring, or a ring system in which a heteroaryl ring is fused with a non-aromatic carbocyclic or heterocyclic ring.
  • a heteroaryl group of 5-10 atoms comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • the heteroaryl is a heteroaryl group of 7 to 12 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N;
  • the heteroaryl group may be a single ring system or a bicyclic system containing two rings.
  • the heteroaryl is a heteroaryl group of 7-10 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; 7-10 atoms
  • the heteroaryl group may be a single ring system or a bicyclic system containing two rings.
  • heteroaryl groups include, but are not limited to, furyl, imidazolyl (eg, 1H-imidazol-1-yl), isoxazolyl, oxazolyl, pyrrolyl, 1,3,4-oxo Azyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), thiazolyl, 2- Thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl, 1H-pyrazol-1-yl), pyrazinyl, 1,3,5-triazinyl, triazolyl, tetrazolyl Etc.; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzothi
  • i atoms typically describes the number of ring atoms in the molecule in which the number of ring atoms is i.
  • a piperidinyl group is a heterocyclic alkyl group composed of 6 atoms
  • a quinolyl group or a 5,6,7,8-tetrahydroquinolyl group is a heteroaryl group composed of 10 atoms.
  • bicyclic carbocyclyl denote carbocyclyl, aryl, heteroaryl and heterocyclyl consisting of two rings
  • the carbocyclic, aryl, heteroaryl and heterocyclic groups described have the meanings as described herein.
  • the bicyclic carbocyclic group and the bicyclic heterocyclic group include a fused ring, a spiro ring and a bridged ring composed of two rings.
  • the bicyclic aryl, bicyclic heteroaryl is a ring system in which an aromatic ring (aryl or heteroaryl) and a non-aromatic ring (carbocyclic or heterocyclic) are fused, wherein
  • the non-aromatic ring may be saturated or unsaturated, for example, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 5,6,7,8 -tetrahydroquinolinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxin[2,3- b] pyridyl, 2,3-dihydrobenzo[b][1,4]dioxin, 6,7-dihydro-5H-cyclopenta[3,2-b]pyridinyl, 2, 3-dihydrofuran [3,2-b]pyridine, etc.; in
  • the system is, for example, a naphthyl group, a quinolyl group, an oxazolyl group or the like.
  • bicyclic aryl or bicyclic heteroaryl groups can be found in the foregoing examples of aryl and heteroaryl definitions.
  • the alkyl acyloxy group can be optionally substituted with one or more substituents described herein.
  • alkylamino includes “N-alkylamino” and “N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups.
  • the alkyl group having a suitable meaning as described in the present invention may be a monoalkylamino group or a dialkylamino group, and examples thereof include, but are not limited to, N-methylamino group, N- Ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.
  • amino-substituted alkyl includes C 1-10 straight or branched alkyl groups substituted with one or more amino groups.
  • the aminoalkyl group is a C1-6 "lower aminoalkyl group” substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl groups.
  • hydroxy substituted alkyl includes C 1-10 straight or branched alkyl groups substituted with one or more hydroxy groups.
  • the hydroxyalkyl group is a C 1-6 "lower hydroxyalkyl group" substituted with one or more hydroxy groups, examples of which include, but are not limited to, hydroxymethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl, and the like.
  • cyano-substituted alkyl includes C1-10 straight or branched alkyl groups substituted by one or more cyano groups.
  • the hydroxyalkyl group is a C 1-6 "lower cyanoalkyl group” substituted with one or more cyano groups, examples of which include, but are not limited to, cyano Base, cyanoethyl and the like.
  • the ring system formed by the substituent (R e ) n1 bonded to the central ring by a bond represents that n1 substituents R e may be substituted at any substitutable position on the ring, wherein n1 is at most The sum of the number of sites on the ring that can be replaced.
  • n1 may It is 1, 2, 3, 4, 5, 6, or 7; wherein, when n1 is greater than 1, each of the R e may be the same or different.
  • the system in which the substituent (R 9 ) g is bonded to the macrocycle by a bond represents that the substituents R 9 may be substituted at any substitutable position on the alkylene group.
  • R 9 in formula d can be a butylene group in the ring Substituting at any position that can be substituted, including but not limited to the case shown by formula d1; wherein g, R 9 , A, B, R 1 , R 2 , R 5 , m and n in formula d, d1 have The meaning of the invention.
  • the attachment point can be attached to the remainder of the molecule at any attachable position on the ring.
  • ring A a in formula b is a quinoline ring (as shown in formula b1)
  • any position on the A 2 ring or B 2 ring that may be attached may serve as a point of attachment.
  • the remainder of the molecule attached to the linkage is interchangeable.
  • the A a ring in formula c is a quinoline ring represented by formula c1
  • the quinoline ring may be attached to the remainder of the molecule through the E 1 and E 2 ends, and the E 1 and E 2 ends are linked.
  • protecting group refers to a class of substituents which, when reacted with other functional groups, are generally used to block or protect the particular functionality of the functional group.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • hydroxy protecting group refers to a substituent used to block or protect a hydroxyl group
  • suitable protecting groups include acetyl and silyl groups.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • prodrug means that a compound can be converted to a compound of the invention in vivo. Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • Metal product refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such a product may be obtained by administering a compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention includes metabolites of a compound, including metabolites produced by intimate contact of a compound of the invention with a mammal for a period of time.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • Room temperature in the present invention means that the temperature is from 10 ° C to 40 ° C. In some embodiments, “room temperature” refers to a temperature of from 20 °C to 30 °C; in other embodiments, “room temperature” refers to 25 °C.
  • treating any disease or condition, in some embodiments thereof, refers to ameliorating a disease or condition (i.e., slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms). In other embodiments, “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both. In other embodiments, “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • thromboembolic disease refers to a disease caused by two pathological processes of thrombosis and thromboembolism, which is also called a thrombotic disease.
  • thrombosis refers to a pathological process in which blood forms a part of an embolus in the blood vessel or in the inner membrane of the heart under certain conditions, causing partial or complete occlusion of the blood vessel and a blood supply disorder at the corresponding site.
  • Thromboembolism is a pathological process in which blood clots fall off from the site of formation and partially or completely block blood vessels during blood flow, causing ischemia or ischemia, hypoxia, necrosis, congestion and edema.
  • thromboembolic diseases include, but are not limited to, arterial cardiovascular thromboembolic disease, venous cardiovascular thromboembolic disease, and thromboembolic disease in the chamber of the heart. More specific examples of such diseases include, but are not limited to, myocardial infarction, angina pectoris (including unstable colic), acute coronary syndrome, reocclusion, and angioplasty or restenosis after aortic coronary venous shunt , stroke, transient ischemic attack, peripheral arterial occlusive disease, arterial thrombosis, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, thrombophlebitis, venous thrombosis or deep vein thrombosis Form, and so on.
  • DIC diffuse intravascular coagulation
  • the "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods.
  • such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K.
  • the free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the pharmaceutically acceptable salt may be a pharmaceutically acceptable acid addition salt which may be formed by the action of a compound of the invention with an inorganic acid and/or an organic acid, for example, with a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or sulfuric acid.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or sulfuric acid.
  • Salt formed formed; and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, stearic acid a salt formed of acid, succinic acid, sulfosalicylic acid, lactic acid, benzoic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid or naphthalene disulfonic acid.
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, malonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, stearic acid a salt formed of acid, succinic acid, sulfosalicylic
  • the pharmaceutically acceptable salt can be a pharmaceutically acceptable base addition salt formed by the action of a compound of the invention with an inorganic base and/or an organic base.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. .
  • the compounds disclosed in the present invention may also exist in the form of their hydrates or in the form of their solvents (e.g., ethanol, DMSO, etc.), and may be used for crystallization.
  • the compounds disclosed herein may form solvates either intrinsically or by design with pharmaceutically acceptable solvents, including water; thus, the compounds of the invention include both solvated and unsolvated forms.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • Isotopically enriched compounds of the invention can be prepared by conventional techniques familiar to those skilled in the art or by the use of suitable isotopically labeled reagents in place of the previously used unlabeled reagents as described in the Examples and Preparations of the present invention.
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • the indole in the present invention is considered to be a substituent of the compound of the present invention.
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a given isotope.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, DMSO-d 6 solvate of those.
  • the inventors of the present application have extensively studied and synthesized a series of macrocyclic compounds, and first discovered the following through FXIa enzyme inhibition activity screening, plasma kallikrein inhibition activity screening, metabolic screening, anticoagulant activity experiments, and other experiments.
  • the compound represented by the formula (I) has strong anti-FXIa activity and/or plasma kallikrein inhibitory activity, excellent drug metabolism properties and physicochemical properties, and is particularly suitable as an anticoagulant drug for treating thromboembolic diseases.
  • the present invention provides a macrocyclic compound represented by the formula (I), wherein the ring A is a bicyclic system, preferably, the ring A is a heterocyclic ring-containing fused bicyclic ring (including a fused bicyclic hetero ring and a fused bicyclic heteroaryl) Ring);
  • the ring A is a bicyclic system, preferably, the ring A is a heterocyclic ring-containing fused bicyclic ring (including a fused bicyclic hetero ring and a fused bicyclic heteroaryl) Ring);
  • the compounds involved in the ring A ring have good pharmacological activity data, and can effectively treat thromboembolic diseases.
  • the present invention relates to a compound which is a stereoisomer, a geometric isomer, a tautomer, an oxynitride, a hydrate, or a compound of the formula (I). a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • ring A, ring B, ring C, X, Y, R 1 , R 2 , R 3 , R 4 , n, m, p and t all have the meanings as described in the present invention.
  • the -8 alkylene group and the C 4-8 alkenylene group are each independently optionally substituted by one or more of the same or different R 9 ; wherein R 5 and R 9 have the meanings as described in the present invention.
  • the compound of formula (I) of the present invention is a compound of formula (Ia) or a stereoisomer, geometric isomer, tautomer, oxynitride of a compound of formula (Ia). a hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , g, n, m, p and t all have the meanings as described in the present invention.
  • Ring C is carbocyclyl, aryl, heterocyclyl or heteroaryl.
  • Ring C is a C 3-12 carbocyclyl, a C 6-12 aryl, a heterocyclic group consisting of 3-12 atoms, or a heteroaryl group of 5-12 atoms.
  • Ring C is a C 5-6 carbocyclic group, a C 6 aryl group, a heterocyclic group consisting of 5-7 atoms, or a heteroaryl group consisting of 5-6 atoms.
  • Ring C is of the following substructure:
  • each of Z, Z 1 and Z 2 is independently CH 2 or NH;
  • each of Z, Z 1 and Z 2 is independently CH or N;
  • Z 4 is CH 2 or NH
  • Each Z 3 and Z 5 are independently CH 2 , NH, S or O;
  • q 0, 1, or 2.
  • the substructure for or More specifically, the formula (C1) is
  • each of the above substructures C1, C1-a, C1-b, C1-c, C1-d, C1-e, C1-f or C1-g passes through an N atom and structure Connected with Independently a single bond or a double bond; Z has the meanings described herein.
  • ring C is Where ring C passes through the N atom and structure Connected.
  • the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (II) or a compound of formula (II).
  • Body nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each Z and Z 1 are independently CH 2 or NH; or When it is a double bond, each Z and Z 1 are independently CH or N;
  • Ring A, Ring B, X, Y, R 1 , R 2 , R 3 , R 4 , n, m, p and t all have the meanings as described herein.
  • the compound of formula (I) according to the invention may be a compound of formula (IIa), or a stereoisomer, geometric isomer, tautomer of a compound of formula (IIa) a construct, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • each Z and Z 1 are independently CH 2 or NH; or When it is a double bond, each Z and Z 1 are independently CH or N; ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , g, n, m, p and t All have the meanings described in the present invention.
  • each R 3 is independently halo, C 1-6 alkyl, C 3-12 carbocyclyl, C 6-12 aryl, heterocyclyl consisting of 3-12 atoms, or 5-12 A heteroaryl group consisting of atoms; wherein each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 identical or different R 3a ; wherein R 3a has the meanings as described herein.
  • each R 3 is independently C 1-4 alkyl, C 3-8 carbocyclyl, C 6-10 aryl, heterocyclyl consisting of 3-8 atoms, or 5-10 atoms. a heteroaryl group; wherein each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a ; R 3a has the meanings as described herein.
  • each R 3 is independently
  • each of E 1 , E 2 and E 3 is independently CH or N;
  • Each of E 4 and E 5 is independently CH 2 , O, S or NH;
  • Each e is independently 0, 1, 2 or 3;
  • each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a ; R 3a has the meanings as described herein.
  • each R 3 is independently methyl, ethyl, F, Cl, Br, phenyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolinyl, triazolyl, pyridyl, pyrimidinyl , mercapto, carbazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl Or quinazolinyl;
  • each R 3 is independently optionally substituted by 1, 2, 3, 4 or 5 R 3a ; R 3a has the meanings as described herein.
  • the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (IIIa) or a compound of formula (IIIa).
  • Body nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each Z and Z 1 when or When it is a single bond, each Z and Z 1 are independently CH 2 or NH; or When it is a double bond, each Z and Z 1 are independently CH or N; ring A, ring B, R 1 , R 2 , R 4 , R 5 , R 9 , R 3a , E 1 , E 2 , E 3 , n, m, f, g, and t all have the meanings described herein.
  • the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (IIIb) or a compound of formula (IIIb).
  • Body nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each Z and Z 1 when or When it is a single bond, each Z and Z 1 are independently CH 2 or NH; or When it is a double bond, each Z and Z 1 are independently CH or N; ring A, ring B, R 1 , R 2 , R 4 , R 5 , R 9 , R 3a , E 1 , E 2 , E 3 , n, m, f, g, and t all have the meanings described herein.
  • the compound of formula (I) according to the invention may be a stereoisomer, a geometric isomer, a tautomer of a compound of formula (III) or a compound of formula (III).
  • Body nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each Z and Z 2 are independently CH 2 or NH; or When it is a double bond, each Z and Z 2 is independently CH or N; ring A, ring B, R 1 , R 2 , R 4 , R 5 , R 9 , R 3a , n, m, f, g and t All have the meanings described in the present invention.
  • the compound of formula (I) according to the invention may be a compound of formula (IIIc), or a stereoisomer, geometric isomer, tautomer of a compound of formula (IIIc) a construct, an oxynitride, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • each Z and Z 2 are independently CH 2 or NH; or When it is a double bond, each Z and Z 2 is independently CH or N; ring A, ring B, R 1 , R 2 , R 4 , R 5 , R 9 , R 3a , n, m, f, g and t All have the meanings described in the present invention.
  • the substructure for among them, Through N atoms and structures Connected.
  • the substructure for among them, Through N atoms and structures Connected.
  • Ring A is a C 7-12 carbocyclyl, a C 8-12 aryl, a heterocyclic group consisting of 7-12 atoms, or a heteroaryl group of 7-12 atoms.
  • Ring A is a C 7-12 bicyclic carbocyclyl, a C 8-12 bicyclic aryl, a bicyclic heterocyclyl consisting of 7-12 atoms, or a bicyclic heteroaryl consisting of 7-12 atoms.
  • Ring A is of the following substructure:
  • each of T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 and T 8 are independently -CH- or -N-;
  • Each k and j are independently 0, 1, 2, 3 or 4.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring B is carbocyclyl, aryl, heterocyclyl or heteroaryl.
  • Ring B is a C 5-8 carbocyclic group, a C 6-10 aryl group, a heterocyclic group consisting of 5-8 atoms, or a heteroaryl group consisting of 5-10 atoms.
  • Ring B is of the following substructure:
  • Each of Q 2 , Q 3 , Q 4 , Q 5 , Q 7 and Q 8 is independently CH or N;
  • s 0, 1, 2 or 3.
  • Ring B is
  • each R 1 is independently optionally substituted by 1, 2, 3 or 4 identical or different R 1a ;
  • R 1a , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • each R 1 is independently optionally substituted by 1, 2, 3 or 4 identical or different R 1a ;
  • R 1a , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • Each R 2 is independently optionally substituted by 1, 2, 3 or 4 identical or different R 2a ;
  • R 2a , R 5a , R 5b , R 5c , R 5d , R 6 , R 7 , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • Each R 2 is independently optionally substituted by 1, 2, 3 or 4 identical or different R 2a ;
  • R 2a , R 5a , R 5b , R 5c , R 5d , R 6 , R 7 , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • each R 2 is independently optionally substituted by 1, 2, 3 or 4 identical or different R 2a ; R 2a has the meanings as described herein.
  • each R 4 is independently H, deuterium, halogen, hydroxy, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, deuterated C 1-6 alkane Base, deuterated C 1-6 alkoxy, halo C 1-6 alkoxy, -(CR 7a R 7b ) r -OR 8 , -(CR 7a R 7b ) r -NR 5a R 5b , -( CR 7a R 7b ) r CN, or halogenated C 1-6 alkyl;
  • R 5a , R 5b , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • any two R 4 and the atoms to which they are attached form a C 3-8 cycloalkyl group, a C 6-10 aryl group, a heterocyclic group consisting of 3-8 atoms, or 5-6 atoms.
  • each R 4 is independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydrazine C 1-4 alkyl, deuterated C 1-4 alkoxy, halo C 1-4 alkoxy, -(CR 7a R 7b ) r -OR 8 , -(CR 7a R 7b ) r -NR 5a R 5b , -(CR 7a R 7b ) r CN, or halogenated C 1-4 alkyl;
  • R 5a , R 5b , R 7a , R 7b , R 8 and r all have the meanings as described in the present invention.
  • any two R 4 and the atoms to which they are attached form a C 3-6 cycloalkyl group, a C 6 aryl group, a heterocyclic group consisting of 3-6 atoms, or 5-6 atoms. a heteroaryl group; the C 3-6 cycloalkyl group, a C 6 aryl group, a heterocyclic group composed of 3 to 6 atoms, and a heteroaryl group composed of 5 to 6 atoms, optionally independently one or more Substituted by R 10 ; said R 10 has the meanings as described in the present invention.
  • each R 4 is independently H, hydrazine, F, Cl, Br, I, hydroxy, amino, methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, 1,2-difluoroethyl, trifluoromethoxy, difluoromethoxy, -OMe, -OEt, -O(t-Bu), -CH 2 OH, -CH 2 CH 2 OH, -CN, -CH 2 CN, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 OMe, -CH 2 CH 2 OMe, -NHMe or -N(Me) 2 .
  • any two R 4 and the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, oxetanyl, tetrahydrofuranyl, pyrrolidine , piperidinyl, piperazinyl, morpholinyl or azetidinyl; said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, oxetanyl, tetrahydrofuran
  • the base, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and azetidinyl are optionally independently substituted by one or more R 10 ; said R 10 has the meanings as described herein.
  • any two R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;
  • each R 9 , R 1a , R 2a and R 3a are independently independently substituted by 1, 2, 3, 4 or 5 identical or different R 10 ;
  • R 5a , R 5b , R 5c , R 6 , R 7a , R 7b , R 8 , R 10 and r all have the meanings as described in the present invention.
  • any two R 9 together with the atoms to which they are attached form a C 3-6 cycloalkyl group or a heterocyclic group consisting of 3 to 6 atoms;
  • each R 9 , R 1a , R 2a and R 3a are independently independently substituted by 1, 2, 3, 4 or 5 identical or different R 10 ;
  • R 5a , R 5b , R 5c , R 6 , R 7a , R 7b , R 8 , R 10 and r all have the meanings as described in the present invention.
  • any two R 9 together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkylene oxide, epoxybutyl, azetidinyl, tetrahydrofuranyl, pyrrole
  • each R 9 , R 1a , R 2a and R 3a is independently optionally substituted by 1, 2, 3, 4 or 5 identical or different R 10 ; said R 10 has the meanings as described herein.
  • R 5 , R 9 and the atoms attached thereto form a heterocyclic group consisting of 3-8 atoms.
  • R 5 , R 9 and the atoms attached thereto form a heterocyclic group of 3 to 6 atoms.
  • each R 6 and R 8 are independently hydrogen, deuterium, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy Substituted C 1-6 alkyl, amino substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 An alkyl group, a C 6-10 aryl group, a C 3-10 cycloalkyl group, a heterocyclic group of 3 to 10 atoms or a heteroaryl group of 5 to 10 atoms.
  • each R 6 and R 8 are independently hydrogen, deuterium, C 1-4 alkyl, deuterated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxy Substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, halo C 1-4 An alkyl group, a C 6-10 aryl group, a C 3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms or a heteroaryl group of 5 to 6 atoms.
  • each R 6 and R 8 are independently hydrogen, deuterium, methyl, ethyl, propyl, butyl, deuterated methyl, vinyl, propynyl, hydroxymethyl, hydroxyethyl , methoxymethyl, methoxyethyl, ethoxymethyl, tert-butoxymethyl, tert-butoxyethyl, ethoxyethyl, isopropoxyethyl, trifluoromethyl , difluoromethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, phenyl, cyclopropyl, cyclohexyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidine Base, piperazinyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazolyl, pyrazinyl, furyl, thiazolyl,
  • each R 7 , R 7a , and R 7b are, independently, hydrogen, C 1-6 alkyl, deuterated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or Halogenated C 1-6 alkyl.
  • each R 7 , R 7a , and R 7b is independently hydrogen, C 1-4 alkyl, deuterated C 1-4 alkyl, or halo C 1-4 alkyl.
  • each R 7 , R 7a and R 7b are independently hydrogen, methyl, ethyl, propyl, butyl, deuterated methyl, trifluoromethyl, difluoromethyl, 1, 2-difluoroethyl or 2,2-difluoroethyl.
  • each m, n, and t are independently 0, 1, 2, 3, or 4.
  • p is 1, 2, 3 or 4.
  • each r is independently 0, 1, 2, 3 or 4.
  • f is 0, 1, 2, 3, 4 or 5;
  • g is 0, 1, 2, 3, 4, 5, 6, 7, or 8.
  • the present invention relates to a compound which is one of the following structures:
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the invention.
  • the pharmaceutical compositions of the present invention further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
  • the invention relates to the use of a compound or pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a thromboembolic disorder.
  • the compounds or pharmaceutical compositions of the invention are used to prevent, treat or ameliorate thromboembolic disorders.
  • the invention also relates to a method of using a compound or pharmaceutical composition of the invention to prevent, treat or ameliorate a thromboembolic disorder.
  • the thromboembolic disease of the invention is an arterial cardiovascular thromboembolic disease, a venous cardiovascular thromboembolic disease, and a thromboembolic disease in the ventricular or peripheral circulation.
  • the thromboembolic disease is angina pectoris, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis , deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and exposure to blood from artificial surfaces in medical implants, instruments, or procedures Thereby promoting thrombosis caused by thrombosis.
  • the invention relates to the use of a compound or pharmaceutical composition for the manufacture of a medicament for the treatment of disseminated intravascular coagulation (DIC) disease.
  • DIC disseminated intravascular coagulation
  • the invention relates to the use of a compound or pharmaceutical composition for the preparation of a medicament for inhibiting the activity of factor XIa and/or plasma kallikrein.
  • the compounds or pharmaceutical compositions of the invention are used to inhibit the activity of Factor XIa and/or plasma kallikrein.
  • the invention also relates to a method of inhibiting the activity of Factor XIa and/or plasma kallikrein using a compound or pharmaceutical composition of the invention.
  • the present invention encompasses the use of the compounds and their pharmaceutically acceptable salts for the manufacture of pharmaceutical products for the treatment of thromboembolic disorders in patients, including those described herein.
  • the invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle.
  • the invention also encompasses a method of treating or ameliorating, or susceptibility to, a thromboembolic disease in a patient comprising treating a patient with a therapeutically effective amount of a compound of the invention.
  • the thromboembolic diseases of the present invention include myocardial infarction, angina pectoris, re-occlusion and angioplasty or restenosis after aortic coronary venous shunt, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism Or deep vein thrombosis.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically relevant to the other components of the formulation and to the mammal being treated.
  • Salts of the compounds of the invention also include the intermediates used in the preparation or purification of the compounds of the invention or the isolated enantiomers of the compounds of the invention, but are not necessarily pharmaceutically acceptable salts.
  • the desired salt can be prepared by any suitable method provided in the literature, for example, using a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like.
  • organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranoic acid such as glucitol Acids and galacturonic acids; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, Ethane sulfonic acid, and so on.
  • organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid
  • pyranoic acid such as glucitol Acids and galacturonic acids
  • the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), alkali metal hydroxide or alkaline earth. Metal hydroxide, and so on.
  • Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine Etc., and inorganic salts are obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the pharmaceutical composition of the present invention comprises the formula (I) or formula (Ia) or formula (II) or formula (IIa) or formula (III) or formula (IIIa) or formula (IIIb) or formula A compound represented by (IIIc), a compound listed in the present invention, or a compound of Examples 1-11, and a pharmaceutically acceptable carrier, adjuvant, or excipient.
  • the amount of the compound in the composition of the present invention is effective for treating or alleviating a thromboembolic disease in a patient, or effectively inhibiting the activity of factor XIa and/or plasma kallikrein.
  • the pharmaceutical composition of the present invention comprises any one of the compounds of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof; In some embodiments, the pharmaceutical compositions of the present invention comprise any combination of any of the compounds described herein.
  • the pharmaceutical compositions of the present invention further comprise additional therapeutic agents.
  • the other therapeutic agent is selected from the group consisting of an antiarrhythmic agent, an antihypertensive agent, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, Potassium channel blockers, cholesterol/lipid lowering agents, or combinations thereof.
  • the present invention provides a pharmaceutical composition wherein the other therapeutic agent is an antihypertensive agent selected from the group consisting of an ACE inhibitor, an AT-1 receptor antagonist, a beta adrenergic receptor antagonist, ETA receptor antagonist, dual ETA/AT-1 receptor antagonist, renin inhibitor (alliskerin) and vasopressin inhibitor), antiarrhythmic agent (selected from IKur inhibition)
  • Anticoagulant which is selected from the group consisting of thrombin inhibitors, antithrombin-III activators, heparin cofactor II activators, other factor XIa inhibitors, other kallikrein inhibitors, plasmin Pro-activator inhibitor (PAI-1) antagonist, thrombin-activated fibrinolysis inhibitor (TAFI) inhibitor, factor VIIa inhibitor, factor IXa inhibitor and factor Xa inhibitor) or anti-platelet agent GPIIb/IIIa blocker, GP Ib/IX blocker, protease activated receptor 1 (PAR-1) antagonist, protease
  • the other therapeutic agents included in the pharmaceutical compositions of the invention are antiplatelet agents or a combination thereof.
  • the anti-platelet agent includes, but is not limited to, clopidogrel and/or aspirin or a combination thereof.
  • the pharmaceutical composition of the present invention comprises other therapeutic agents: warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, bupro Fen, naproxen, sulindac, indomethacin, mefima, dipyridamol, dioxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, Tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, hirudin sulfate, tissue plasminogen activator, modified tissue plasminogen activator Agent, anipase, urokinase, and streptokinase or a combination thereof.
  • other therapeutic agents warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argat
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, ester salts, or any other agent which can be administered, directly or indirectly, depending on the needs of the patient.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form.
  • a pharmaceutically acceptable carrier including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbus Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa
  • the compounds of the present invention can be administered in the form of oral preparations, such as tablets, capsules (each of which includes a sustained release or timed release formulation), pills, powders, granules, elixirs, elixirs, suspensions, syrups. , and emulsifiers. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly. All dosage forms used are well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the mode of administration chosen and standard pharmaceutical practice.
  • the dosage regimen of the compounds of the invention will vary with various factors known, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health, medical condition and weight of the recipient; The nature and extent of the symptoms; the type of treatment being treated; the frequency of treatment; the route of administration, the kidney and liver function of the patient, and the desired effect.
  • a physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, counteract or prevent the development of a thromboembolic disease.
  • the daily oral dose of each active ingredient used ranges from about 0.001 to 1000 mg/kg body weight, preferably between about 0.01 and 100 mg/kg body weight. . Moreover, most preferably, it is between about 1.0 and 20 mg/kg body weight per day.
  • the most preferred dosage range during a conventional rate of infusion is from about 1 to about 10 mg/kg body weight per minute.
  • the compounds of the invention may be administered once daily, or may be administered in two, three or four times daily.
  • the compounds of the invention may be administered in intranasal form via topical use of a suitable intranasal vehicle or by transdermal routes using transdermal patches.
  • a suitable intranasal vehicle or by transdermal routes using transdermal patches.
  • the dosage administered throughout the administration is continuous rather than intermittent.
  • the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (herein referred to as a pharmaceutical carrier), depending on the form of administration and conventional pharmaceutical practice, in the form of an oral tablet.
  • a suitable pharmaceutical diluent excipient, or carrier
  • a pharmaceutical carrier depending on the form of administration and conventional pharmaceutical practice, in the form of an oral tablet.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combine, such as ethanol, glycerin, water, etc. Moreover, suitable binders, lubricants, decomposition agents, and colorants can also be added to the mixture as needed or necessary.
  • an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.
  • any oral, non-toxic, pharmaceutically acceptable inert carrier Combine such as ethanol, glycerin,
  • Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia), tragacanth, or sodium alginate, carboxymethyl fibers. , polyethylene glycol, wax and so on.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Decomposers include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed by different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
  • the compounds of the invention are also coupled to a soluble polymer that acts as a targeted pharmaceutical carrier.
  • soluble polymer include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylate-phenol, polyhydroxyethylaspartamide phenol, or polyethylene oxide substituted with palmitoyl residues-poly Amino acid.
  • the compounds of the invention can be coupled to a class of biodegradable polymers for accomplishable controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.
  • biodegradable polymers for accomplishable controlled drug release for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.
  • Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1 mg to about 100 mg of the active ingredient.
  • the weight of the active ingredient will generally comprise from about 0.5% to about 95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient as well as powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • Compressed tablets can be made using similar diluents. Tablets and capsules can be made as a product of sustained release to provide a continuous release of the drug over a period of time.
  • Compressed tablets may be sugar coated or coated with a film to mask any unpleasant taste and to isolate the tablet from the air, or an enteric coating for selective decomposition in the gastrointestinal tract.
  • Liquid dosage forms for oral administration may contain coloring and flavoring to enhance patient acceptance.
  • water, a suitable oil, saline, hydrated dextrose (glucose), and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions.
  • the solution for parenteral administration preferably contains a water-soluble salt of the active ingredient, a suitable stabilizer, and possibly a buffer material.
  • the antioxidant is a suitable stabilizer such as sodium hydrogen sulfite, sodium sulfite, or vitamin C, either alone or in combination, or citric acid and a salt thereof, and sodium EDTA.
  • parenteral solutions also contain preservatives such as benzalkonium, methyl- or propyl-p-hydroxybenzoate, and chlorobutanol.
  • a daily dose may be from about 0.1 to 100 mg of a compound of the invention and from about 1 to 7.5 mg of a second anticoagulant combination.
  • the compound of the invention will generally be from about 5 to 10 mg per dosage unit, and the amount of the second anti-aggregating agent will be from about 1 to 5 mg per dosage unit.
  • anticoagulant reagents include, but are not limited to, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran (dabigatran), bemiparin, enoxaparin sodium, tinzaparin sodium, danaparoid sodium, pentosan sodium, nadroparin calcium, aspartame sodium, palparin sodium and the like.
  • the compounds of the invention may be used alone or in combination with other therapeutic agents, either sequentially or sequentially.
  • the other therapeutic agent is selected from the group consisting of a factor Xa inhibitor (eg, apixaban, rivaroxaban, betrixaban, edoxaban), an anticoagulant, an antiplatelet agent, thrombin inhibition Agents (eg, dabigatran), thrombolytic agents, and fibrinolytic agents.
  • the other therapeutic agent is at least one agent selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen ( Ibuprofen), naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone ), piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran ), desulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase.
  • the additional therapeutic agent is at least one anti-platelet agent.
  • the antiplatelet agent is clopidogrel and/or aspirin or
  • the compounds of the invention are administered in combination with an anti-platelet agent.
  • a typical daily dose may be from about 0.01 to 300 mg of the compound of the invention per kg of body weight of the patient and from about 50 to 150 mg of the anti-platelet agent, preferably about 0.1 to 4 mg of a compound of the invention and about 1 to 3 mg of an anti-platelet agent.
  • the usual daily dose may be from about 0.1 to 100 mg of the compound of the present invention per kg of the patient's body weight, and in the presence of a thrombolytic agent, generally when administered alone with the thrombolytic agent.
  • the dosage of the thrombolytic agent can be reduced by about 50-80%.
  • each of the typical daily dosages and typical dosage forms may be decreased relative to the usual dose when administered alone.
  • one active ingredient can be an enteric coating.
  • an enteric coating By coating an active ingredient with an enteric coating, it is possible to not only minimize contact between the combined active ingredients, but it is also possible to control the release of one of these ingredients in the gastrointestinal tract so that one of these components It is not released in the stomach but released in the small intestine.
  • One of the active ingredients may also be coated with a material which affects its sustained release in the gastrointestinal tract and which may also be used to reduce physical contact between the combined active ingredients.
  • the sustained release component may also be additionally coated with an enteric coating. This ingredient is only released in the intestines.
  • Still another method involves the formulation of a combination product in which one component is coated with a continuous and/or enteric release polymer and the other component is also a polymer such as a low viscosity grade hydroxyl group.
  • HPMC Propylmethylcellulose
  • Polymer coating creates an additional barrier to reaction with other components.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof can be effectively used for preventing, treating or ameliorating a thromboembolic disease in a patient;
  • the thromboembolic disorder includes an arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolism Symptoms, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
  • thromboembolic disorders include, but are not limited to, unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis Hardening, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and medical implants, The blood in the device or procedure is exposed to an artificial surface to promote thrombosis caused by thrombosis.
  • the compounds or pharmaceutical compositions provided herein can also be used to treat, prevent or treat inflammatory diseases; including, but not limited to, sepsis, acute respiratory distress syndrome, or systemic inflammatory response syndrome.
  • the compound or pharmaceutical composition provided by the present invention can be used for preventing, treating or ameliorating a disease associated with plasma kallikrein; wherein the disease associated with plasma kallikrein includes, but is not limited to, visual acuity Damage, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, kidney disease, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer Adult respiratory distress syndrome, disseminated intravascular coagulation and cardiopulmonary bypass.
  • the disease associated with plasma kallikrein includes, but is not limited to, visual acuity Damage, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, kidney disease, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer Adult respiratory distress syndrome, disseminated intravascular coagulation and cardiopulmonary bypass.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined in (I) or Formula (Ia) or Formula (II) or Formula (IIa) or Formula (III) or formula (IIIa) or formula (IIIb) or formula (IIIc).
  • the following reaction schemes and Examples 1-11 are used to further illustrate the contents of the present invention.
  • the reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated.
  • the general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dried.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh
  • Nuclear magnetic resonance spectroscopy data was determined by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer with CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as solvent (reported in ppm) TMS (0 ppm) or chloroform (7.25 ppm) was used as a reference standard.
  • MS mass spectrometry
  • the purity of the compound is characterized by: Agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP, 50/80 mm, DAC) at 210 nm /254nm with UV detection.
  • Grubbs 2nd generation catalyst Grubb second generation catalyst, benzylidene-1,3-bis(2,4,6-trimethylphenyl)-2-(imidazoline carbene) (tricyclohexylphosphine) ruthenium dichloride
  • Dess-Martin oxidant (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodo-3(1H)-one
  • PEG8000 polyethylene glycol 8000
  • Compound 1c can be prepared by the method described in Synthesis Scheme 1.
  • HATU 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DBU monocarb-7-ene
  • Compound 2f can be prepared by the method described in Synthesis Scheme 2.
  • Compound 2a is first subjected to a Michael addition reaction with compound 2c in a solvent such as tetrahydrofuran or the like, and then subjected to a compound 2d under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine).
  • a compound 2d under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine).
  • Acetylation gives compound 2e.
  • Compound 2e is subjected to ring closure under basic conditions (e.g., sodium methoxide or sodium hydride) to give compound 2f.
  • basic conditions e.g., sodium methoxide or sodium hydride
  • the intermediate compound 2e can also be produced by the following method: Compound 2a is first added in the presence of trimethylchlorosilane (TMSCl) and sodium iodide (NaI) in a solvent (for example, acetonitrile and water). The reaction gives compound 2b; compound 2b and compound 2c undergo a substitution reaction under basic conditions (for example, under the action of triethylamine), and then under basic conditions (for example, in pyridine or 4-dimethylaminopyridine) The compound 2d is acetylated to give the compound 2e.
  • TMSCl trimethylchlorosilane
  • NaI sodium iodide
  • Compound 3h can be prepared by the method described in Synthetic Scheme 3.
  • Compound 3a is reacted with a vinyl Grignard reagent (such as vinylmagnesium bromide) to obtain compound 3b; compound 3b is subjected to an oxidation reaction (such as reaction with Jones (Jone's) reagent or Dess-Martin oxidant, etc.) to obtain compound 3c.
  • Compound 3c is first subjected to a Michael addition reaction with compound 3e in a solvent such as tetrahydrofuran or the like, and then acetylated by compound 3f under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine).
  • Compound 3g is obtained; compound 3g is subjected to ring closure under basic conditions (e.g., under sodium methoxide, sodium hydride, etc.) to afford compound 3h.
  • the intermediate compound 3g can also be produced by the following method: the compound 3c is first subjected to an addition reaction in the presence of TMSCl and NaI in a solvent (for example, acetonitrile and water) to obtain a compound 3d; the compound 3d is further reacted with the compound 3e.
  • the substitution reaction occurs under basic conditions (for example, under the action of triethylamine), and then acetylated by 3f under basic conditions (for example, under the action of pyridine or 4-dimethylaminopyridine) to obtain a compound 3g. .
  • the intermediate compound 4m can be produced by the method described in Synthesis Scheme 4.
  • the aldehyde 4a and (S)-2-methylpropyl-2-sulfinamide are condensed in a solvent such as dichloromethane in the presence of anhydrous copper sulfate to give compound 4b.
  • Compound 4b is reacted with allyl magnesium bromide under the action of indium trichloride catalyzed to obtain compound 4c; compound 4c is subjected to acidic conditions (for example, under the action of HCl), and (S)-2-A is removed.
  • Base propyl-2-sulfinyl group gives compound 4d; compound 4d is amino protected to give compound 4e; compound 4e and compound 4f are in a catalyst (such as Pd(dppf)Cl 2 -CH 2 Cl 2 ) and a base (such as cesium carbonate)
  • a catalyst such as Pd(dppf)Cl 2 -CH 2 Cl 2
  • a base such as cesium carbonate
  • the Suzuki coupling reaction is carried out in a solvent such as dioxane and water to obtain a compound 4g; the compound 4g is subjected to a reduction reaction (for example, a nitro group is reduced in a zinc powder-ammonium chloride system) to obtain a compound 4h.
  • Compound 4h is substituted with compound 4i under basic conditions (such as pyridine) to obtain compound 4j; compound 4j is subjected to ring-closing metathesis reaction under the action of a catalyst (such as Grubbs 2 generation catalyst) to obtain macrocyclic compound 4k; compound 4k Hydrogenation by catalysis (e.g., Pd/C catalysis) affords compound 41; compound 41 is deprotected (e.g., the Boc protecting group is removed under acidic conditions such as trifluoroacetic acid) to afford compound 4m.
  • a catalyst such as Grubbs 2 generation catalyst
  • the intermediate compound 5i can be produced by the method described in Synthesis Scheme 5.
  • Compound 4e and compound 5b are subjected to Suzuki coupling reaction in a solvent such as dioxane and water in the presence of a catalyst such as Pd(dppf)Cl 2 -CH 2 Cl 2 ) and a base such as cesium carbonate.
  • a catalyst such as Pd(dppf)Cl 2 -CH 2 Cl 2
  • a base such as cesium carbonate.
  • Compound 5c; compound 5c is reacted by reduction (such as reduction of nitro group to amino group in zinc powder-ammonium chloride system) to obtain compound 5d;
  • compound 5d and compound 4i are substituted under basic conditions (such as pyridine) to obtain compound 5f.
  • Compound 5f is subjected to a ring-closing metathesis reaction in the presence of a catalyst (such as Grubbs 2nd generation catalyst) to obtain a macrocyclic compound 5g; compound 5g is catalyzed (e.g., Pd/C catalyzed) hydrogenation reduction to obtain compound 5h; compound 5h is deprotected (for example, Removal of the Boc protecting group under acidic conditions such as trifluoroacetic acid affords compound 5i.
  • a catalyst such as Grubbs 2nd generation catalyst
  • the intermediate compound 6j can be produced by the method described in Synthesis Scheme 6.
  • Compound 4e and compound 6b are subjected to Suzuki coupling reaction in a solvent such as dioxane and water in the presence of a catalyst such as Pd(dppf)Cl 2 -CH 2 Cl 2 ) and a base such as cesium carbonate.
  • a catalyst such as Pd(dppf)Cl 2 -CH 2 Cl 2
  • a base such as cesium carbonate.
  • the intermediate compound 7i can be produced by the method described in Synthesis Scheme 7.
  • Compound 4e and compound 7b are in the presence of a palladium (II) catalyst (such as Pd(OAC) 2 ), a phosphorus ligand (such as n-butylbis(1-adamantyl)phosphine), and a base (such as potassium carbonate).
  • a palladium (II) catalyst such as Pd(OAC) 2
  • a phosphorus ligand such as n-butylbis(1-adamantyl)phosphine
  • a base such as potassium carbonate
  • a coupling reaction occurs in a solvent (such as N, N-dimethylformamide) to obtain a compound 7c; a compound 7c is reduced (for example, a nitro group is reduced to an amino group in a zinc powder-ammonium chloride system) to obtain a compound 7d; Compound 7d and compound 4i are subjected to a substitution reaction in a solvent (such as dichloromethane) under basic conditions (such as pyridine) to obtain compound 7f; and compound 7f is subjected to a ring-closing metathesis reaction under the action of a catalyst (such as Grubbs 2 generation catalyst).
  • a solvent such as N, N-dimethylformamide
  • a compound 7c is reduced (for example, a nitro group is reduced to an amino group in a zinc powder-ammonium chloride system) to obtain a compound 7d
  • Compound 7d and compound 4i are subjected to a substitution reaction in a solvent (such as dichloromethane) under basic conditions (such
  • the ring compound 7g; the compound 7g is hydrogenated by catalytic (e.g., Pd/C catalysis) reduction to give the compound 7h, and then deprotected (for example, the Boc protecting group is removed under acidic conditions such as trifluoroacetic acid) to obtain the compound 7i.
  • catalytic e.g., Pd/C catalysis
  • deprotected for example, the Boc protecting group is removed under acidic conditions such as trifluoroacetic acid
  • Phosphorus oxybromide (8.9 g, 31 mmol) and sodium carbonate (4.3 g, 31 mmol) were added to a solution of 1B (2.1 g, 10 mmol) in anhydrous acetonitrile (45 mL). Stir at 92 ° C for 2 hours. Then it was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in EtOAc (EtOAc)EtOAc.
  • Step 6 (S)-N-((S)-1-(4-bromoquinolin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide ( 1F)
  • Step 8 (S)-(1-(4-Bromoquinolin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (1H)
  • Step 9 (S)-(1-(4-(4-Amino-2-nitrophenyl)quinolin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (1I)
  • Step 10 (S)-(1-(4-(4-(methoxy)amino)-2-nitrophenyl)quinolin-2-yl)but-3-en-1-yl)carbamic acid Tert-butyl ester (1J)
  • Step 11 (S)-(1-(4-(4-(methoxy)amino)-2-aminophenyl)quinolin-2-yl)but-3-en-1-yl)carbamic acid Butyl ester (1K)
  • Zinc powder (4.26 g, 65.20 mmol) and ammonium chloride (3.49 g, 65.20 mmol) were added to a solution containing 1 J (3.21 g, 6.52 mmol) in methanol (65 mL) and the mixture was stirred at room temperature for 2.5 hours. .
  • the reaction was stopped, filtered, and the filter cake was washed with methanol (10 mL ⁇ 3), and the filtrate was concentrated to give residue.
  • the residue was dissolved in dichloromethane (100mL), washed with water (30mL ⁇ 2) and brine (30mL) The aqueous solution was dried with EtOAc (EtOAc m.
  • Step 12 (S)-(1-(4-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)quinoline-2 -yl)but-3-en-1-yl)carbamic acid Butyl ester (1L)
  • Step 13 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 2.7 .0 17, 22 ] icosane -1(23),2(3),4,6,11(12),15,17(22),18,20-nonenylene-5-yl)methyl carbamate (1M)
  • P-toluenesulfonic acid monohydrate (0.84 g, 4.28 mmol) was placed in a two-necked flask at room temperature, heated to 80 ° C, and dried under reduced pressure for about 1 hour.
  • a solution of 1 L (2.12 g, 3.89 mmol) in dry methylene chloride (100 mL) was then taken and then cooled to room temperature and stirred for 45 min.
  • a solution of Grubbs 2 Generation Catalyst (1.05 g, 1.22 mmol) in dry dichloromethane (20 mL) was then slowly taken and then warmed to reflux and stirred overnight. The reaction was quenched and cooled to room temperature.
  • Step 14 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 2.7 .0 17, 22 ] icosane -1(23),2(3),4,6,15,17(22),18,20-octadec-5-yl)carbamate (1N)
  • Step 15 N - ((10R, 14S) -14- amino-10-methyl-9-oxo-8,16-diaza- tetracyclo [13.7.1.0 2.7 .0 17,22] tricosane -1(23),2(3),4,6,15,17(22),18,20-octadec-5-yl)carbamate (1O)
  • Trifluoroacetic acid (4.6 g, 3.0 mL, 40.00 mmol) was added to 1N (0.67 g, 1.28 mmol) in dry dichloromethane (30 mL) The reaction was quenched, EtOAc (EtOAc m. The combined organic layers were dried with EtOAc EtOAcjjjjjjjjj
  • Step 16 1-(6-Bromo-3-chloro-2-fluorophenyl)-3-iodopropan-1-one (1P)
  • Trimethylchlorosilane (0.78 g, 0.62 mL, 7.13 mmol) was added to a system containing sodium iodide (1.10 g, 7.3 mmol) and acetonitrile (5 mL) at room temperature, stirred for 10 min, then water was added (0.50g), after stirring for 5 minutes, adding 1-(6-bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one (prepared by the synthesis method of intermediate 2 of patent WO 2014022766) (1.25 g, 4.74 mmol), stirring was continued for 2 hours. The reaction was stopped, water (5 mL) was added and the mixture was extracted with ethyl acetate (20mL ⁇ 3). The organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated to crystals crystals crystals crystals Liquid (1.35 g, 72.7%).
  • Step 17 N-((10R,14S)-14-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -8,16-diazatetracyclic [13.7.1.0 2.7 .0 17,22] tricosa-1 (23), 2 (3), 4,6,15,17 (22), 18,20- eight-5-yl) carbamic acid Methyl ester (1Q)
  • Step 18 N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-8,16-diaza- tetracyclo [13.7.1.0 2.7 .0 17,22] tricosa-1 (23), 2 (3), 4,6,15,17 (22), 18 Methyl 20-octadec-5-yl)carbamate (1R)
  • Step 19 N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-8,16-diazo Oxatetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22), 18,20- eight 5-ene Methyl carbamate
  • the organic layer was dried (MgSO4) (mjjjjjjj
  • Step 8 (S,E)-N-((4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)methylene)-2-methylpropane- 2-sulfinamide (2H)
  • Step 9 (S)-N-((S)-1-(4-bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)but-3-ene-1 -yl)-2-methylpropane-2-sulfinamide (2I)
  • Step 10 (S)-1-(4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)but-3-en-1-amine (2J)
  • Step 11 (S)-(1-(4-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)but-3-en-1-yl)carbamic acid Butyl ester (2K)
  • Step 12 (S)-(1-(4-(4-Amino-2-nitrophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)- Tert-butyl 3-en-1-yl)carbamate (2L)
  • Step 13 N-[4-[2-[(S)-1-(tert-Butoxycarbonylamino)but-3-enyl]-6,7-dihydro-5H-cyclopenta[b]pyridine 4-yl]-3-nitro-phenyl]amino Methyl formate (2M)
  • Step 14 N-[3-Amino-4-[2-[(S)-1-(tert-butoxycarbonylamino)but-3-enyl]-6,7-dihydro-5H-cyclopentane [b]pyridin-4-yl]phenyl]carbamate Methyl ester (2N)
  • Zinc powder (10.03 g, 153.3 mmol) and ammonium chloride (8.36 g, 156 mmol) were added to a solution of 2M (7.32 g, 15.2 mmol) in methanol (200 mL) at room temperature overnight.
  • the reaction was terminated, the reaction solution was suction filtered with celite, and the filter cake was washed with methanol (30mL ⁇ 3), the solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (500 mL)
  • the organic layer was dried over anhydrous sodium sulfate and filtered and evaporated to dryness crystals
  • Step 15 N-[4-[2-[(1S)-1-(tert-Butoxycarbonylamino)but-3-enyl]-6,7-dihydro-5H-cyclopenta[b]pyridine 4-yl]-3-[[(2S)-2-methylbutyl) Methyl 3-enoyl]amino]phenyl]carbamate (2O)
  • Step 16 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17, 21 ]tetracosane -1(22),2(3),4,6,11(12),15,17(21)-hepten-5-yl)carbamic acid methyl ester (2P)
  • p-toluenesulfonic acid monohydrate (0.297 g, 1.56 mmol) was weighed into a two-necked bottle, and the two vials were placed in an 80 ° C oil bath and dried under reduced pressure for 0.5 hour. The oil bath was heated to dryness, cooled to room temperature, and a solution of EtOAc (EtOAc) A solution of Grubbs 2 generation catalyst (0.369 g, 0.435 mmol) in dry dichloromethane (50 mL) was then added dropwise to the system and the mixture was stirred at 45 ° C overnight.
  • EtOAc EtOAc
  • Step 17 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17, 21 ]tetracosane -1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (2Q)
  • Step 18 N - ((10R, 14S) -14- amino-10-methyl-9-oxo-8,16-diaza- tetracyclo [13.6.1.0 2.7 .0 17,21] behenic -1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (2R)
  • Step 19 N-((10R,14S)-14-(3-(6-Bromo-3-chloro-4-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -8,16-diazatetracyclic [13.6.1.0 2.7 .0 17,21 ]Tetradane-1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (2S )
  • Step 20 N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-4-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17,21 ]tetracosane-1(22), 2(3), 4,6,15,17(21)-six Methyl ene-5-yl)carbamate (2T)
  • Step 21 N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-8,16-diazo Heterotetracycline [13.6.1.0 2,7 .0 17,21 ]tetracosane-1(22), 2(7),3,5,15,17(21)-hexa-5-yl)amino Methyl formate
  • Step 5 (S)-N-((4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)methylene)-2-methylpropane-2-sulfinamide (3E )
  • Step 6 (S)-N-((S)-1-(4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)but-3-en-1-yl)-2 -methylpropane-2-sulfinamide (3F)
  • Step 8 (S)-(1-(4-Bromo-5,6,7,8-tetrahydroquinolin-2-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (3H)
  • Step 9 (S)-(1-(4-(4-Amino-2-nitrophenyl)-5,6,7,8-tetrahydroquinolin-2-yl)but-3-ene-1 -yl)-tert-butyl carbamate (3I)
  • Step 10 (S)-(1-(4-(4-(methoxy)amino)-2-nitrophenyl)-5,6,7,8-tetrahydroquinolin-2-yl) Tert-butyl 3--3-en-1-ylcarbamate (3J)
  • Step 11 (S)-(1-(4-(4-(methoxy)amino)-2-aminophenyl)-5,6,7,8-tetrahydroquinolin-2-yl)- Tert-butyl 3-en-1-yl)carbamate (3K)
  • Zinc powder (4.51 g, 69.03 mmol) and ammonium chloride (3.71 g, 69.0 mmol) were added to a solution containing 3J (3.41 g, 6.87 mmol) in methanol (60 mL) at room temperature. hour.
  • the reaction was stopped, filtered, and the filter cake was washed with methanol (10 mL ⁇ 3), and the filtrate was concentrated.
  • the residue was dissolved in dichloromethane (100 mL), washed with water (30mL ⁇ 2) and brine (30mL)
  • the sodium was dried, filtered, and evaporated tolulululululululululululululululululululululululululululululululu
  • Step 12 (S)-(1-(4-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)-5,6 ,7,8-tetrahydroquinolin-2-yl)but-3-en-1-yl) Tert-butyl carbamate (3L)
  • Step 13 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 2.7 .0 17, 22 ] icosane -1(23),2(7),3,5,11(12),15,17(22)-hepten-5-yl)carbamic acid methyl ester (3M)
  • Pentyl p-toluenesulfonic acid monohydrate (0.45 g, 2.30 mmol) was placed in a two-necked flask at room temperature, heated to 80 ° C, and dried under reduced pressure for about 1 hour. After cooling to room temperature, a solution of 3 L (1.15 g, 2.10 mmol) in dry dichloromethane (100 mL) was then poured into the system and stirred for 30 min. A solution of Grubbs 2 Generation Catalyst (0.54 g, 0.63 mmol) in dry dichloromethane (20 mL) was then taken and evaporated. The reaction was quenched and cooled to room temperature.
  • Step 14 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-8,16-diazatetracyclo[13.7.1.0 2.7 .0 17, 22 ] icosane -1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (3N)
  • Step 15 N - ((10R, 14S) -14- amino-10-methyl-9-oxo-8,16-diaza- tetracyclo [13.7.1.0 2.7 .0 17,22] tricosane -1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (3O)
  • Trifluoroacetic acid (4.61 g, 3.0 mL, 40.02 mmol) was added to 3N (0.69 g, 1.33 mmol) in dry dichloromethane (30 mL) The reaction was quenched, EtOAc (EtOAc m. The combined organic layers were dried with EtOAc EtOAc EtOAcjjjjjjj
  • Step 16 N-((10R,14S)-14-(3-(6-Bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -8,16-diazatetracyclic [13.7.1.0 2.7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-5-yl) carbamate (3P )
  • Step 17 N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-8,16-diaza- tetracyclo [13.7.1.0 2.7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - six Methyl ene-5-yl)carbamate (3Q)
  • Step 18 N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-8,16-diazo Oxatetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-5-yl) amino Methyl formate
  • Hexylphosphine (8.30 g, 29.6 mmol), (dba) 3 Pd 2 (9.00 g, 9.83 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaboron Pentacyclo(36.0 mL, 212 mmol) and N,N-dimethylformamide (900 mL) were then stirred and stirred at 100 ° C overnight.
  • the mixture was cooled to room temperature, filtered, and evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 10 (S)-N-((S)-1-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)but-3- En-1-yl)-2-methylpropane-2-sulfinamide (4J)
  • Step 11 (S)-1-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)but-3-en-1-amine (4K )
  • Step 12 (S)-(1-(8-Bromo-3,4-dihydro-2H-pyrano[3,2-b]pyridin-6-yl)but-3-en-1-yl) Tert-butyl carbamate (4L)
  • Step 13 (S)-(1-(8-(4-Amino-2-nitrophenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-6-yl Tert-butyl 3-buten-1-yl)carbamate (4M)
  • Step 14 (S)-(1-(8-(4-(methoxy)amino)-2-nitrophenyl)-3,4-dihydro-2H-pyrano[3,2-b Pyridine-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (4N)
  • Step 15 (S)-(1-(8-(4-(methoxy)amino)-2-aminophenyl)-3,4-dihydro-2H-pyrano[3,2-b] Pyridin-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (4O)
  • Step 16 (S)-(1-(8-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)-3,4 -dihydro-2H-pyrano[3,2-b]pyridine-6- Tert-butyl 3-buten-1-yl)carbamate (4P)
  • Step 17 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-21-oxa-8,16-diazatetracyclo[13.7.1.0 2,7 .0 17,22 ]Twenty Trioxane-1(23), 2(3),5,6,11(12),15,17(22)-hepten-5-yl)carbamic acid methyl ester (4Q)
  • Step 18 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-21-oxa-8,16-diazatetracyclo[13.7.1.0 2,7 .0 17,22 ]Twenty Trioxane-1(23), 2(3),5,6,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (4R)
  • Step 19 N-((10R,14S)-14-Amino-10-methyl-9-oxo-21-oxa-8,16-diazatetracyclo[13.7.1.0 2,7 .0 17 ,22 ]tetracosane -1(23),2(3),5,6,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (4S)
  • Step 20 N-((10R,14S)-14-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -21-oxa-8,16-diazatetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (3), 5,6,15,17 (22) - Six-5-yl) carbamate (4T)
  • Step 21 N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- -21- oxo-oxa-8,16-diaza- tetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (3), 5,6,15 ,17(22)-hexaen-5-yl)carbamic acid methyl ester (4U)
  • Step 22 N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-21-oxa 8,16-diaza- tetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - six Methyl ene-5-yl)carbamate
  • Potassium hydroxide 38 g, 677.3 mmol was weighed into a flask, and water (260 mL), 2-bromopyridin-3-ol (100 g, 574.71 mmol), EDTA-2Na (4.36 g, 13.0 mmol) and formaldehyde were added thereto.
  • Aqueous solution (38%, 156 mL) was warmed to 90 ° C for 5 hours. The reaction was stopped, cooled to room temperature, neutralized with acetic acid, and extracted with ethyl acetate (100 mL ⁇ 2). The organic phase was washed with water (50 mL) and brine (50 mL) Yellow solid (101 g, 86.14%).
  • 5D (23.06 g, 152.7 mmol) was weighed into a flask, and dichloromethane (500 mL) and m-chloroperoxybenzoic acid (31 g, 152.7 mmol) were added thereto, and reacted at room temperature for 24 hours. The reaction was quenched and EtOAc (EtOAc)EtOAc.
  • Step 9 (S,E)-N-((7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)methylene)-2-methylpropane-2 - sulfinamide (5I)
  • Step 10 (S)-N-((S)-1-(7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)but-3-ene-1- Base)-2-methylpropane-2-sulfinamide (5J)
  • Step 11 (S)-1-(7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)but-3-en-1-amine (5K)
  • Step 12 (S)-(1-(7-Bromo-2,3-dihydrofuro[3,2-b]pyridin-5-yl)but-3-en-1-yl)carbamic acid tert-butyl Ester (5L)
  • Step 13 (S)-(1-(7-(4-Amino-2-nitrophenyl)-2,3-dihydrofuro[3,2-b]pyridin-5-yl)butene-3 -en-1-yl)carbamic acid tert-butyl ester (5M)
  • Step 14 (S)-(1-(7-(4-(methoxy)amino)-2-nitrophenyl)-2,3-dihydrofuro[3,2-b]pyridine-5 -yl)but-3-en-1-yl)carbamic acid Butyl ester (5N)
  • Step 15 (S)-(1-(7-(4-(methoxy)amino)-2-aminophenyl)-2,3-dihydrofuro[3,2-b]pyridine-5- Tert-but-3-en-1-yl)carbamic acid Butyl ester (5O)
  • Zinc powder (15.36 g, 234.8 mmol) and ammonium chloride (12.58 g, 784.2 mmol) were added to a solution of 5N (11.4 g, 23.5 mmol) in methanol (300 mL) at room temperature for 12 hours at room temperature.
  • the reaction was terminated, the reaction solution was suction filtered with celite, and the filter cake was washed with methanol (50mL ⁇ 3), the solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (300 mL). Washed with saturated brine (300 mL), dried over anhydrous sodium sulfate.
  • Step 16 (S)-(1-(7-(4-(methoxy)amino)-2-((S)-2-methylbut-3-enoylamino)phenyl)-2,3 -dihydrofuro[3,2-b]pyridin-5-yl) Tert-butyl 3--3-en-1-ylcarbamate (5P)
  • Step 17 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17,21 ] twenty Dioxane-1(22),2(3),4,6,11(12),15,17(21)-hepten-5-yl)carbamic acid methyl ester (5Q)
  • Step 18 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17,21 ] twenty Dioxane-1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (5R)
  • Step 19 N-((10R,14S)-14-Amino-10-methyl-9-oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17,21 Tetane -1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (5S)
  • Step 20 N-((10R,14S)-14-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -20-oxa-8,16-diazatetracyclo [13.6.1.0 2.7 .0 17,21 ]Tetradane-1(22),2(3),4,6,15,17(21)-hexaen-5-yl)carbamic acid methyl ester (5T )
  • Step 21 N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-20-oxa-8,16-diazatetracyclo[13.6.1.0 2.7 .0 17,21 ]tetracosane-1 (22), 2 (3), 4, 6, 15, 17 (21)-hexaen-5-yl)carbamic acid methyl ester (5U)
  • Step 22 N-((10R,14S)-14-(4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-20-oxa -8,16-diazatetracyclo[13.6.1.0 2,7 .0 17,21 ]docosane-1(22),2(7),3,5,15,17(21)-six Methyl ene-5-yl)carbamate
  • Step 3 8-Iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridine-6-carbaldehyde (6C)
  • Step 4 (S,E)-N-((8-iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl)methylene)- 2-methylpropane-2-sulfinamide (6D)
  • Step 5 (S)-N-((S)-1-(8-iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl) 3--3-en-1-yl)-2-methylpropane-2-sulfinamide (6E)
  • Step 6 (S)-1-(8-iodo-2,3-dihydro-[1,4]dioxa[2,3-b]pyridin-6-yl)but-3-ene-1- Amine (6F)
  • Step 7 (S)-(1-(8-iodo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)but-3-ene-1 -yl)-tert-butyl carbamate (6G)
  • Step 8 (S)-(1-(8-(4-Amino-2-nitrophenyl)-2,3-dihydro-[1,4]dioxa[2,3-b]pyridine- 6-yl)but-3-en-1-yl)carbamic acid tert-butyl ester (6H)
  • Step 9 (S)-(1-(8-(4-(methoxy)amino)-2-nitrophenyl)-2,3-dihydro-[1,4]dioxin[2, 3-b]pyridin-6-yl)but-3-en-1-yl)carbamate Tert-butyl acid ester (6I)
  • Step 10 (S)-(1-(8-(4-(methoxy)amino)-2-aminophenyl)-2,3-dihydro-[1,4]dioxo[2,3 -b]pyridine-6-yl)but-3-en-1-yl)amino Tert-butyl formate (6J)
  • Step 11 (S)-(1-(8-(4-(methoxy)amino)-2-((R)-2-methylbut-3-enoylamino)phenyl)-2,3 -dihydro-[1,4]dioxa-[2,3-b]pyridine-6- Tert-butyl 3-buten-1-yl)carbamate (6K)
  • Step 12 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-18,21-dioxa-8,16-diazatetracyclo[ 13.7.1.0 2,7 .0 17,22] Tridecane-1(23), 2(7),3,5,11(12),15,17(22)-hepten-5-yl)carbamic acid methyl ester (6L)
  • Step 13 N-((10R,14S)-14-(tert-Butoxycarbonylamino)-10-methyl-9-oxo-18,21-dioxa-8,16-diazatetracyclo[ 13.7.1.0 2,7 .0 17,22] Tridecane-1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (6M)
  • Step 14 N-((10R,14S)-14-Amino-10-methyl-9-oxo-18,21-dioxa-8,16-diazatetracyclo[13.7.1.0 2,7 .0 17,22 ]tetracosane -1(23),2(7),3,5,15,17(22)-hexaen-5-yl)carbamic acid methyl ester (6N)
  • Step 15 N-((10R,14S)-14-(3-(6-Bromo-3-chloro-2-fluorophenyl)-3-oxopropylamino)-10-methyl-9-oxo -18,21-dioxa-8,16-diaza Tetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Six-5-yl) carbamic acid Methyl ester (6O)
  • Step 16 N-((10R,14S)-14-(N-(3-(6-bromo-3-chloro-2-fluorophenyl)-3-oxopropyl)-2-(diethoxy) Phosphoryl)acetamido)-10-methyl-9- Oxo-dioxa-8,16-diaza -18,21- tetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (7), 3, 5,15,17(22)-hexaen-5-yl)carbamic acid Methyl ester (6P)
  • Step 17 N-((10R,14S)-14-(4-(6-Bromo-3-chloro-4-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridine- 1-yl)-10-methyl-9-oxo-18,21-dioxo Heteroaryl 8,16-diaza tetracyclo [13.7.1.0 2,7 .0 17,22] tricosa-1 (23), 2 (7), 3,5,15,17 (22) - Methyl hexene-5-yl)carbamate
  • Step 3 (S)-2-Methyl-N-((S)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3- Butyr-3-en-1-yl)propane-2-sulfinamide (7C)
  • Step 4 (S)-N-((S)-1-(1H-indazol-3-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (7D )
  • Step 5 (4-(3-((S)-1-((S)-1,1-dimethylethylsulfonylamino)but-3-en-1-yl)-1H-carbazole Methyl -1-yl)-3-nitrophenyl)carbamate (7E)

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Abstract

L'invention concerne un composé macrocyclique ayant une activité inhibitrice du facteur XIA de coagulation sanguine et/ou de l'activité de la kallicréine plasmatique et une composition pharmaceutique de celui-ci. Selon l'invention, le composé macrocyclique et la composition pharmaceutique de celui-ci peuvent être utilisés pour traiter ou prévenir des maladies thromboemboliques.
PCT/CN2018/072988 2017-01-18 2018-01-17 Inhibiteur du facteur xia de coagulation sanguine et ses utilisations WO2018133793A1 (fr)

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WO2020210613A1 (fr) * 2019-04-11 2020-10-15 Bristol-Myers Squibb Company Nouvelles options synthétiques pour la fabrication de (6r,10s)-10-{4-[5-chloro-2-(4-chloro-1h-1,2,3-triazol-1-yl) phényl]-6-oxo-1(6h)-pyrimidinyl}1-(difluorométhyl)-6-méthyl-1,4,7,8,9,10-hexahydro-11,15- (metheno)pyrazolo [4,3-b] [1,7] diazacyclotétradecin-5 (6h)-one
WO2020211781A1 (fr) 2019-04-16 2020-10-22 南京明德新药研发有限公司 Dérivés macrocycliques agissant comme inhibiteur du facteur xia
WO2021013209A1 (fr) 2019-07-23 2021-01-28 南京明德新药研发有限公司 Dérivés macrocycliques en tant qu'inhibiteurs du facteur xia
CN113004286A (zh) * 2019-12-20 2021-06-22 成都康弘药业集团股份有限公司 作为血浆激肽释放酶抑制剂的三环类化合物及其用途
WO2021136390A1 (fr) * 2019-12-31 2021-07-08 上海京新生物医药有限公司 Inhibiteur du facteur xia de coagulation sanguine
CN114984820A (zh) * 2022-05-27 2022-09-02 吉林大学 一种采血管晃动式达到血液混合的摇匀台
CN115215867A (zh) * 2021-04-21 2022-10-21 上海美悦生物科技发展有限公司 FXIa抑制剂及其药物组合物、制备方法和用途

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EP4234555A3 (fr) * 2019-04-11 2024-01-03 Bristol-Myers Squibb Company Nouvelles options synthétiques pour la fabrication de (6r,10s)-10-{4-[5-chloro-2-(4-chloro-1h-1,2,3-triazol-1-yl) phényl]-6-oxo-1(6h)-pyrimidinyl}1-(difluorométhyl)-6-méthyl-1,4,7,8,9,10-hexahydro-11,15- (metheno)pyrazolo [4,3-b] [1,7] diazacyclotétradecin-5 (6h)-one
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JP7286001B2 (ja) 2019-07-23 2023-06-02 メッドシャイン ディスカバリー インコーポレイテッド 第ＸＩａ因子阻害剤としての大環状誘導体
WO2021013209A1 (fr) 2019-07-23 2021-01-28 南京明德新药研发有限公司 Dérivés macrocycliques en tant qu'inhibiteurs du facteur xia
CN114008047A (zh) * 2019-07-23 2022-02-01 南京明德新药研发有限公司 作为XIa因子抑制剂的大环衍生物
JP2022541927A (ja) * 2019-07-23 2022-09-28 メッドシャイン ディスカバリー インコーポレイテッド 第ＸＩａ因子阻害剤としての大環状誘導体
EP4006029A4 (fr) * 2019-07-23 2023-06-21 Medshine Discovery Inc. Dérivés macrocycliques en tant qu'inhibiteurs du facteur xia
CN114008047B (zh) * 2019-07-23 2023-03-21 南京明德新药研发有限公司 作为XIa因子抑制剂的大环衍生物
CN113004286A (zh) * 2019-12-20 2021-06-22 成都康弘药业集团股份有限公司 作为血浆激肽释放酶抑制剂的三环类化合物及其用途
CN113004286B (zh) * 2019-12-20 2022-08-12 成都康弘药业集团股份有限公司 作为血浆激肽释放酶抑制剂的三环类化合物及其用途
WO2021136390A1 (fr) * 2019-12-31 2021-07-08 上海京新生物医药有限公司 Inhibiteur du facteur xia de coagulation sanguine
CN115215867A (zh) * 2021-04-21 2022-10-21 上海美悦生物科技发展有限公司 FXIa抑制剂及其药物组合物、制备方法和用途
CN115215867B (zh) * 2021-04-21 2023-12-26 上海美悦生物科技发展有限公司 FXIa抑制剂及其药物组合物、制备方法和用途
CN114984820B (zh) * 2022-05-27 2023-09-29 吉林大学 一种采血管晃动式达到血液混合的摇匀台
CN114984820A (zh) * 2022-05-27 2022-09-02 吉林大学 一种采血管晃动式达到血液混合的摇匀台

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