Compounds useful as factor XIA inhibitors

Abstract

The present invention provides compounds useful for the treatment or prevention of diseases or conditions involving (a) thromboembolic disorders, (b) inflammatory disorders, or (c) plasma kallikrein activity. [Solution] A compound of formula (I), or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts or solvates is provided. TIFF2026062690000101.tif47128

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application is based on U.S. Provisional Patent Application No. 63 / 054,826, filed on July 22, 2020. The rights of the number are asserted, and the entirety thereof is incorporated herein by reference.

[0002] (Field of invention) The present invention relates to factor XIa inhibitors, their tautomers, stereoisomers, isotope substitutions, and Pharmacopoecially acceptable salts and solvates, pharmaceutical compositions containing the compound, and thromboembols Treatment of sexual disorders, inflammatory disorders, and diseases or conditions involving plasma kallikrein activity and / or This relates to the use of the compound in prevention. [Background technology]

[0003] Thromboembolic diseases are treated with warfarin (COUMADIN®), heparin, and hypochlorite. Anticoagulants such as lumens heparin (LMWH) and synthetic pentasaccharides, as well as aspirin and clopidogrel Despite the availability of antiplatelet agents such as Grel (PLAVIX®), It is a major cause of death in developed countries. The oral anticoagulant warfarin is a coagulation factor VII drug. It inhibits the posttranslational maturation of IX, X, and prothrombin, and causes both venous and arterial thrombosis. It has been proven to be effective. However, its usage is limited by its narrow therapeutic index and treatment. Slow onset of therapeutic effect, numerous food and drug interactions, and the need for monitoring and dose adjustment. It is limited by necessity. Therefore, for the prevention and treatment of widespread thromboembolic disorders The discovery and development of safe and effective oral anticoagulants is becoming increasingly important. .

[0004] Factor XIa is a plasma serine protease involved in regulating blood coagulation. While blood clotting is a necessary and important part of regulating homeostasis in living organisms, abnormal blood clotting can also have harmful effects. It can have an impact. For example, thrombosis is the formation or presence of a blood clot in a blood vessel or a cavity of the heart. Such blood clots can remain in the blood vessels, blocking circulation and potentially triggering a heart attack or stroke. Thromboembolic disorders are the leading cause of death and disability in industrialized societies.

[0005] Blood clotting is a process of controlling blood flow that is essential for the survival of mammals. Furthermore, the subsequent dissolution of the blood clot after wound healing begins after vascular injury and proceeds in four stages. It can be divided into two stages. The first stage, vascular stenosis or vasoconstriction, is blood loss in the injured area. This can lead to a decrease in platelet loss. In the next stage, platelet activation by thrombin, The platelets adhere to the site of damage to the blood vessel wall and form platelet aggregates. In the third stage, the coagulation complex The formation results in the massive production of thrombin, which is made possible by the cleavage of two small peptides. Soluble fibrinogen is converted to fibrin. In the fourth stage, after wound healing, the thrombus is internal It is dissolved by the action of plasmin, an important enzyme in the causative fibrinolytic system.

[0006] Two alternative pathways (endogenous and exogenous) can lead to fibrin clot formation. These pathways are initiated by different mechanisms, but in the later stages, they are common to the coagulation cascade. It converges to give the final pathway of coagulation. In this final pathway of coagulation, coagulation factor X is activated. It is converted. Activated factor X is converted from inactive precursor prothrombin circulating in the blood. It is involved in the formation of thrombin. Thrombus formation at the base of woundless vascular wall abnormalities is endogenous. It is a consequence of the pathway. Fibrin clot formation as a response to tissue damage or injury is exogenous. This is the result of the pathway. Both pathways contain a relatively large number of proteins known as coagulation factors. The endogenous pathway involves coagulation factors V, VIII, IX, X, XI, and XII, as well as pre- Kallikrein, high molecular weight kininogen, calcium ions, and phospholipids from platelets are essential. To be essential.

[0007] Factor XIa, a plasma serine protease involved in regulating blood coagulation, is tissue factor ( TF) binds to factor VII (FVII) to generate factor VIIa (FVIIa). The procedure is initiated in vivo. The resulting TF is as follows: FVIIa composite The body activates factor IX (FIX) and factor X (FX), and factor Xa (FXa) This leads to production. The generated FXa is produced by this pathway when tissue factor pathway inhibitors (TFPIs) are used. Before it is blocked, it catalyzes the conversion of a small amount of prothrombin to thrombin. Then, The coagulation process involves the catalytic release of factor V, factor VIII, and factor XI by catalytic amounts of thrombin. It is further propagated through feedback activation. (Gailani, D. et al.) ,Arterioscler.Thromb.Vasc.Biol.,27:2507- 2513 (2007). The resulting thrombin burst is fibrinogen It is converted into fibrin, which polymerizes to form the structural framework of the blood clot, and is an important component of coagulation. Activates platelets, which are a component of cells (Hoffman, M., Blood Reviews) ,17:S1-S5(2003)). Therefore, the XIa factor is the propagation of this amplification loop. It plays a crucial role in dissemination and is therefore an attractive target for antithrombotic therapy.

[0008] In addition to tissue factor-mediated stimuli, the coagulation system is particularly involved in the surface structure of foreign cells (e.g., bacteria). Furthermore, on negatively charged surfaces including artificial surfaces such as artificial blood vessels, stents, and extracorporeal circulation. It can be activated. On the surface, factor XII (FXII) is activated first, leading to factor XIIa. It becomes a factor, and subsequently, factor XI attached to the cell surface is activated to become factor XIa. This leads to further activation of the coagulation cascade as described above. In addition, factor XIIa The child also activates bound plasma prokallikrein into plasma kallikrein (PK), and this This leads to further factor XII activation in the enhancement loop, and the overall coagulation cascade This leads to an amplification of the onset of pharmacokinetics. Furthermore, PK is an important factor that leads to increased endothelial permeability. It is a nin-releasing protease. Further substrates described are prorenin and prouroxidil. These are ases, and their activation regulates the renin-angiotensin system and fibrinolysis. It can affect the process. Therefore, PK activation affects the coagulation process and the inflammatory process. This is an important link between the two. [Overview of the Initiative]

[0009] Therefore, as a human pharmaceutical product for the treatment and / or prevention of thromboembolic disorders Factor XIa inhibitor compounds with suitable pharmacokinetic and pharmacodynamic properties are still lacking. It is needed.

[0010] The present invention relates to a compound of formula (I),

[0011] [ka] 7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl) -3-(5-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)-1H- Imidazole-2-yl)-2,3,8,8a-tetrahydroindridine-5(1H) Compounds also known as -one, as well as their tautomers, stereoisomers, isotope substitutions, and This relates to pharmaceutically acceptable salts or solvates.

[0012] The present invention further comprises a compound of formula (II),

[0013] [ka] 4-(2-(7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl )phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindridine-3 Also known as -yl)-1H-imidazole-5-yl)-3-fluoropicolinic acid. Compounds, as well as their tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts. Or relating to solvates.

[0014] The present invention further relates to a compound of formula (III),

[0015] [ka] 4-(2-(7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl )phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindridine-3 -yl)-1H-imidazole-5-yl)-3-fluoro-2-(hydroxymethyl) A compound also known as pyridine 1-oxide, and its tautomers, stereoisomers, and the same This relates to toposubstituted compounds and pharmaceutically acceptable salts or solvates.

[0016] The present invention further relates to a compound of formula (IV),

[0017] [ka] 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3, A compound also known as 5,8,8a-hexahydroindridine-3-carboxylic acid, This relates to its stereoisomers, isotope substitutions, and salts.

[0018] The present invention further relates to a compound of formula (V),

[0019] [ka] In the formula, A 1 C 1~4 Alkyl compounds, as well as their stereoisomers and isotopic substitutions. Regarding the body and salt.

[0020] The present invention further relates to a compound of formula (VI),

[0021] [ka] In the formula, A 2 C 1~4 It is alkyl, A 3 -O-SO2-CF3, -O-SO A compound selected from 2-CF2CF2H or -O-SO2-CF2CF2CF3, This also relates to stereoisomers, isotopic substitutions, and salts thereof.

[0022] The present invention further relates to a compound of formula (I), a compound of formula (II), a compound of formula (III), and a compound of formula ( This relates to a preparation process for the compound of formula (IV), the compound of formula (V), or the compound of formula (VI). The present invention further comprises the chemical formula (I) prepared according to any of the processes described herein. Compound, compound of formula (II), compound of formula (III), compound of formula (IV), compound of formula (V) This relates to compounds of formula (VI).

[0023] Examples of the present invention include a pharmaceutically acceptable carrier as described herein and a compound of formula (I). This is a pharmaceutical composition comprising a substance, a compound of formula (II), or a compound of formula (III). Examples of the present invention include compounds of formula (I), compounds of formula (II), or formula ( A pharmaceutical product prepared by mixing the compound in (III) with a pharmaceutically acceptable carrier. The present invention is a composition. Examples of the present invention include compounds of formula (I) and formula (II) as described herein. Mixing the compound of formula (III) with a pharmaceutically acceptable carrier. This includes the process of manufacturing pharmaceutical compositions.

[0024] Examples of the present invention include thromboembolic disorders, inflammatory disorders, or plasma disorders, as described herein. A method for the treatment and / or prevention of a disease or condition in which kallikrein activity is involved. Then, a therapeutically effective amount of either the above compound or pharmaceutical composition is administered to the target that requires it. It is a method that includes giving in.

[0025] Examples of the present invention include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and arterial cerebrovascular disorders. Treatment and / or prevention of thromboembolic disorders, including thromboembolic disorders and venous cerebrovascular thromboembolic disorders. A method for prevention, which involves providing a therapeutically effective amount of the above compound or pharmaceutical combination to a target that requires it. This method involves administering one of the products. An example of thromboembolic disorder is anxiety. Angina pectoris, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, Transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis Deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism Medical implants in which blood is exposed to artificial surfaces that promote thrombosis, renal embolism, pulmonary embolism, and thrombosis This includes, but is not limited to, thrombosis resulting from rants, devices, or procedures.

[0026] In one embodiment, the present invention relates to a compound of formula (I) for use as a pharmaceutical, formula (I The present invention relates to compound I) or compound (III). In another embodiment, the present invention relates to a thrombus Treatment of embolic disorders, inflammatory disorders, or diseases or conditions involving plasma kallikrein activity. Compounds of formula (I), compounds of formula (II), or compounds of formula (II) for use in the prevention of / or infection Regarding compound I).

[0027] In another embodiment, the present invention relates to arterial cardiovascular thromboembolic disorders and venous cardiovascular thromboembolic disorders. Treatment of thromboembolic disorders such as arterial and cerebrovascular thromboembolic disorders and venous and cerebrovascular thromboembolic disorders. Compounds of formula (I), compound (II), or compound (III) for use in the prevention of / or infection. The present invention relates to compounds of ) another embodiment, unstable angina, acute coronary syndrome, atrial Fibrillation, initial myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, A Therotropic arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombotic vein Inflammation, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and From medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis Used for the treatment and / or prevention of thromboembolic disorders selected from the group consisting of resulting thrombosis. This relates to compounds of formula (I), formula (II), or formula (III) for the purpose of [details omitted]. In another embodiment, the present invention relates to hereditary angioedema (HAE) and diabetic macular edema (DME). A formula selected from the group consisting of ) for use in the treatment and / or prevention of thromboembolic disorders This relates to the compound of formula (I) or the compound of formula (II).

[0028] In another embodiment, the present invention relates to the treatment and / or treatment of the disorders, diseases or conditions described herein. Compounds of formula (I), compounds of formula (II), or compounds of formula (III) for use in prevention The present invention relates to compositions containing a compound. In another embodiment, the present invention relates to thromboembolic disorders, inflammatory disorders or used in the treatment and / or prevention of diseases or conditions in which plasma kallikrein activity is involved. It contains a compound of formula (I), a compound of formula (II), or a compound of formula (III) for use. Regarding compositions.

[0029] In another embodiment, the present invention relates to arterial cardiovascular thromboembolic disorders and venous cardiovascular thromboembolic disorders. Treatment of thromboembolic disorders such as arterial and cerebrovascular thromboembolic disorders and venous and cerebrovascular thromboembolic disorders. Compounds of formula (I), compound (II), or compound (III) for use in the prevention of / or infection. The present invention relates to a composition comprising the compound of ). In another embodiment, the present invention relates to unstable angina, acute coronary artery Syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack , stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis Thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, lung Embolism and medical implants and devices in which blood is exposed to an artificial surface that promotes thrombosis. Treatment and / or prognosis of thromboembolic disorders selected from the group consisting of thrombosis resulting from or from the procedure. Compounds of formula (I), compounds of formula (II), or compounds of formula (III) for use in prevention. The present invention relates to a composition containing a substance. In another embodiment, the present invention relates to hereditary angioedema (HAE) or This is for use in the treatment and / or prevention of thromboembolic disorders such as diabetic macular edema (DME). The present invention relates to compositions comprising a compound of formula (I) or a compound of formula (II).

[0030] Another example of the present invention is to treat and / or prevent the disorders, diseases, or conditions described herein. The use of any of the compounds described herein in the preparation of pharmaceuticals. Another example is a disease involving thromboembolic disorders, inflammatory disorders, or plasma kallikrein activity. The compounds described herein in the preparation of pharmaceuticals for treating and / or preventing a condition It is the use of one of the things.

[0031] Another example of the present invention is (a) arterial cardiovascular thromboembolic disorder, (b) venous cardiovascular thromboembolic disorder. (c) arterial cerebrovascular thromboembolic disorders, and (d) venous cerebrovascular thromboembolic disorders. In the preparation of pharmaceuticals for the treatment and / or prevention of thromboembolic disorders selected from, The use of any of the compounds described herein. Another example of the present invention is (a) unstable angina (b) acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction (f) sudden ischemic death, (g) transient ischemic attack, (h) stroke, (i) atherosclerotic vein (j) Peripheral occlusive arterial disease, (k) Venous thrombosis, (l) Deep vein thrombosis, (m ) thrombophlebitis, (n) arterial embolism, (o) coronary artery thrombosis, (p) cerebral artery thrombosis, (q (r) cerebral embolism, (r) renal embolism, (s) pulmonary thrombosis, or (t) blood on an artificial surface that promotes thrombosis. To treat and / or to treat thrombosis resulting from medical implants, devices, or procedures to which the fluid is exposed. This refers to the use of any of the compounds described herein in the preparation of a pharmaceutical product for prevention. Another example of the present invention is (a) hereditary angioedema (HAE) or (b) diabetic macular edema. The compounds described herein in the preparation of pharmaceuticals for the treatment and / or prevention of DME It is the use of one of the things.

[0032] Another example of the present invention is thromboembolic diseases, inflammatory diseases, or plasma kallikrei as described herein. In a method for treating a disease or condition involving phenoactivity, the target population requires the treatment of the disease. This involves the use of any of the compounds described herein.

[0033] Another example of the present invention is (a) arterial cardiovascular thromboembolic disorder, (b) venous cardiovascular thromboembolic disorder. (c) arterial cerebrovascular thromboembolic disorder, or (d) venous cerebrovascular thromboembolic disorder, and / or in a method of prevention, the compounds described herein in the subject requiring such a method. Either use. Another example of the present invention is (a) unstable angina, (b) acute coronary syndrome, (c) atrial fibrillation, (d) first myocardial infarction, (e) recurrent myocardial infarction, (f) sudden ischemic death, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis, (j) peripheral occlusion Arterial disease, (k) venous thrombosis, (l) deep vein thrombosis, (m) thrombophlebitis, (n) arterial disease (o) cerebral embolism, (p) coronary artery thrombosis, (q) cerebral embolism, (r) renal embolism (s) pulmonary thrombosis, or (t) medical injections in which blood is exposed to an artificial surface that promotes thrombosis. In methods for treating and / or preventing thrombosis arising from plants, devices, or procedures, The invention involves the use of any of the compounds described herein in an application requiring such use. Another example is (a) hereditary angioedema (HAE) or (b) diabetic macular edema (DME). Methods of treatment and / or prevention described herein for subjects requiring such treatment and / or prevention It involves the use of one of the compounds.

[0034] In another example, the present invention treats and / or prevents the disorders, diseases, or conditions described herein. The compounds described herein for use in the object requiring such use in the method thereof. In another example, the present invention relates to thromboembolic, inflammatory disorders as described herein. For the treatment and / or prevention of harm or diseases or conditions involving plasma kallikrein activity. Regarding the use of the compounds described herein in the law, in the case where such use is required do.

[0035] In another example, the present invention relates to arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and arteries. Treatment and / Or, in a method of prevention, for use in subjects requiring it, as described herein. The present invention relates to the compound described. In another example, the present invention relates to unstable angina, acute coronary syndrome, atrial fibrillation, First myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis Arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arteriosclerosis Pulmonary embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis This occurs from medical implants, devices, or procedures in which blood is exposed to the artificial surface that promotes blood flow. For use in subjects requiring the treatment and / or prevention of thrombosis The present invention relates to the compounds described herein. In another example, the present invention relates to hereditary angioedema (H In methods for treating and / or preventing AE) or diabetic macular edema (DME), This specification relates to the compounds described herein for use in the target area.

[0036] The present invention further relates to compounds, compositions (e.g., pharmaceutical compositions), therapeutic methods, etc., as described herein. Regarding preparation methods or use. [Modes for carrying out the invention]

[0037] The present invention relates to a compound of formula (I),

[0038] [ka] Also, their tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solutions. The present invention relates to a mediator. The present invention further relates to a compound of formula (II),

[0039] [ka] Also, their tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solutions. The present invention relates to a mediator. The present invention further relates to a compound of formula (III),

[0040] [ka] Also, their tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solutions. Regarding mediators.

[0041] The compounds of formula (I), formula (II), and formula (III) of the present invention are thrombotic Treatment of embolic disorders, inflammatory disorders and diseases or conditions involving plasma kallikrein activity and / or It is useful for prevention.

[0042] In a particular embodiment, the present invention relates to a compound of formula (IA),

[0043] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Compounds also known as lysine-5(1H)-one, and their tautomers and stereoisomers. This relates to isotope substitutions and pharmaceutically acceptable salts or solvates.

[0044] In certain embodiments, the present invention relates to a compound of formula (IB),

[0045] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl-4-d)-2,3,8,8a-tetrahydro A compound also known as loindolidine-5(1H)-one, and its tautomers, This relates to isomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates.

[0046] In certain embodiments, the present invention relates to a compound of formula (IC),

[0047] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyri (Zin-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Compounds also known as indolidine-5(1H)-one, and their tautomers, stereochemistry This relates to isomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates.

[0048] In a particular embodiment, the present invention relates to a compound of formula (ID),

[0049] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl A compound also known as lysine-5(1H)-one-8a-d, and its tautomers, This relates to stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates.

[0050] In certain embodiments, the present invention relates to a compound of formula (IE),

[0051] [ka] (3S * ,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazole- 1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine -4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroin Compounds also known as dridine-5(1H)-one-8a-d, and their tautomers This relates to stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates.

[0052] In certain embodiments, the present invention relates to a compound of formula (IF),

[0053] [ka] (3S,8aR * )-7-(3-chloro-2-fluoro-6-(1H-tetrazole- 1-Iyl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl-d2)py Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro The compound also known as loindinidine-5(1H)-one-8a-d, and its tautomas This relates to isomers, stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates.

[0054] In certain embodiments, the present invention relates to a compound of formula (IG),

[0055] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl The compound also known as lysine-5(1H)-one-1,1,8,8,8a-d5, and to the tautomers, stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates thereof Regarding.

[0056] In a particular embodiment, the present invention relates to a compound of formula (IH),

[0057] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl-d2)pyri (Jin-4-yl)-1H-imidazole-2-yl-4-d)-2,3,8,8a-teto The compound also known as lahydroindoridine-5(1H)-one, and its tautomerism This relates to isomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates.

[0058] In a particular embodiment, the present invention relates to a compound of formula (IJ),

[0059] [ka] (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl-d)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2) Pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroxy Compounds also known as doroindolidine-5(1H)-one, and their tautomers, This relates to stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates.

[0060] In certain embodiments, the present invention relates to a compound of formula (IK),

[0061] [ka] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Compounds also known as lysine-5(1H)-one-8,8,8a-d3, and their interactions Regarding mutants, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates. .

[0062] In a particular embodiment, the present invention relates to a compound of formula (IL),

[0063] [ka] (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl) Phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl )-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindolidine- Compounds also known as 5(1H)-ones, as well as their tautomers, stereoisomers, and isotopes. This relates to substituted compounds and pharmaceutically acceptable salts or solvates.

[0064] In a particular embodiment, the present invention relates to a compound of formula (II-A),

[0065] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl)-3-fluoropicolin Compounds also known as acids, as well as their tautomers, stereoisomers, isotope substitutions, and pharmaceuticals. This relates to scientifically acceptable salts or solvates.

[0066] In a particular embodiment, the present invention relates to a compound of formula (II-B),

[0067] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl-4-d)-3-fluoro Compounds also known as picolinic acid, as well as their tautomers, stereoisomers, and isotopic substitutions. , and relating to pharmaceutically acceptable salts or solvates.

[0068] In certain embodiments, the present invention relates to a compound of formula (II-D),

[0069] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl-8a-d)-1H-imidazole-5-yl)-3-fluor A compound also known as ropicorine, as well as its tautomers, stereoisomers, and isotopic substitutions. This relates to bodies and pharmaceutically acceptable salts or solvates.

[0070] In certain embodiments, the present invention relates to a compound of formula (II-E),

[0071] [ka] 4-(2-((3S,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetra hydroindolizin-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydro -8a-d)-1H-imidazol-5-yl)-3-fluoro picolinic acid, also known as the compound, and its tautomers, stereoisomers, isotope substitutions forms, and pharmaceutically acceptable salts or solvates thereof.

[0072] In certain embodiments, the present invention is a compound of formula (II-F), wherein

[0073]

Chemical formula

[0074] In certain embodiments, the present invention is a compound of formula (II-G), wherein

[0075]

Chemical formula

[0076] In certain embodiments, the present invention is a compound of formula (II-J),

[0077]

Chemical formula

[0078] In certain embodiments, the present invention is a compound of formula (II-K),

[0079]

Chemical formula

[0080] In certain embodiments, the present invention is a compound of formula (II-L),

[0081] [Chem.] 4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- -1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroind olizin-3-yl)-1H-imidazol-5-yl)-3-fluoropicolinic acid, and its tautomers, stereoisomers, isotope substituents, and pharmaceutically acceptable salts or solvates thereof.

[0082] In certain embodiments, the present invention relates to a compound of formula (III-A),

[0083] [Chem.] (4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-te trazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr oindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoro-2- (hydroxymethyl)pyridine 1-oxide, and its tautomers, stereoisomers, isotope substituents, and pharmaceutically acceptable salts or solvates thereof.

[0084] In certain embodiments, the present invention relates to a compound of formula (III-B),

[0085] [Chem.] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tet razol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl-4-d)-3-fluoro The compound also known as -2-(hydroxymethyl)pyridine 1-oxide, and its This relates to stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates.

[0086] In certain embodiments, the present invention relates to a compound of formula (III-C),

[0087] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl)-3-fluoro-2-( Compounds also known as hydroxymethyl-d2)pyridine 1-oxide, and their interactions Regarding mutants, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates. .

[0088] In certain embodiments, the present invention relates to a compound of formula (III-D),

[0089] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl-8a-d)-1H-imidazole-5-yl)-3-fluor The compound also known as 2-(hydroxymethyl)pyridine 1-oxide, and Regarding tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates of [the substance] Do.

[0090] In certain embodiments, the present invention is a compound of formula (III-E),

[0091]

Chemical formula

[0092] In certain embodiments, the present invention is a compound of formula (III-F),

[0093]

Chemical formula

[0094] In certain embodiments, the present invention is a compound of formula (III-G),

[0095] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindridinysine-3-yl-1,1,8,8,8a-d5)-1H-imidazole-5- Also known as yl-3-fluoro-2-(hydroxymethyl)pyridine 1-oxide Compounds, as well as their tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable compounds This relates to salts or solvates.

[0096] In certain embodiments, the present invention relates to a compound of formula (III-H),

[0097] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl-4-d)-3-fluoro A compound also known as -2-(hydroxymethyl-d2)pyridine 1-oxide, and to the tautomers, stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solvates thereof Regarding.

[0098] In certain embodiments, the present invention relates to a compound of formula (III-J),

[0099] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razol-1-yl-d)phenyl)-5-oxo-1,2,3,5,8,8a-hexa Hydroindolidine-3-yl)-1H-imidazole-5-yl)-3-fluoro-2 -(hydroxymethyl-d2)pyridine 1-oxide, also known as the compound, and Regarding tautomers, stereoisomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates of [the substance] do.

[0100] In certain embodiments, the present invention relates to a compound of formula (III-K),

[0101] [ka] 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl-8,8,8a-d3)-1H-imidazole-5-yl)- A compound also known as 3-fluoro-2-(hydroxymethyl)pyridine 1-oxide. , as well as their tautomers, stereoisomers, isotope substitutions, and pharmaceutically acceptable salts or solutions. Regarding mediators.

[0102] In certain embodiments, the present invention relates to a compound of formula (III-L),

[0103] [ka] 4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol -1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindo Lysine-3-yl)-1H-imidazole-5-yl)-3-fluoro-2-(hydrox Compounds also known as methyl(Pyridine)1-oxide, and their tautomers, stereochemistry This relates to isomers, isotopic substitutions, and pharmaceutically acceptable salts or solvates.

[0104] The present invention further relates to a compound of formula (IV),

[0105] [ka] 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3, A compound also known as 5,8,8a-hexahydroindridine-3-carboxylic acid, The present invention relates to the stereoisomers, isotope substitutions, and salts thereof. The present invention further relates to the compound of formula (V),

[0106] [ka] The present invention also relates to the stereoisomers, isotope substitutions, and salts thereof. It is a compound,

[0107] [ka] In the formula, A 2 C 1~4 It is alkyl, A 3 -O-SO2-CF3, -O-SO A compound selected from 2-CF2CF2H or -O-SO2-CF2CF2CF3, This also relates to stereoisomers, isotopic substitutions, and salts thereof.

[0108] Compound (IV), compound (V), and compound (VI) are compounds of formula (I). It is useful as an intermediate in the synthesis of compounds of formula (II) and / or formula (III). That is the case.

[0109] In certain embodiments, the present invention further relates to a compound of formula (IV-A),

[0110] [ka] (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 Also known as 2,3,5,8,8a-hexahydroindridine-3-carboxylic acid This relates to compounds, as well as their stereoisomers, isotopic substitutions, and salts.

[0111] In a particular embodiment of the present invention, A 1 is C 2~4 It is alkyl. A specific embodiment of the present invention In state, A 1 This is selected from the group consisting of methyl, ethyl, isopropyl, and t-butyl. In a particular embodiment of the present invention, A 1 is a group consisting of methyl, ethyl, and t-butyl A is selected. In a particular embodiment of the present invention, A 1 It is selected from methyl or ethyl. In a particular embodiment of the present invention, A 1 is methyl or t-butyl. Specific embodiment of the present invention In terms of form, A 1 is methyl. In a particular embodiment of the present invention, A 1 is ethyl or t-b It is chill. In a particular embodiment of the present invention, A 1 It is ethyl.

[0112] In certain embodiments, the present invention relates to a compound of formula (VS),

[0113] [ka] Also known as methyl 5,7-dioxooctahydroindidine-3-carboxylate This relates to compounds that can be used, as well as their stereoisomers, isotopic substitutions, and salts. In certain embodiments... The present invention further relates to a compound of formula (VA),

[0114] [ka] Methyl(3S)-5,7-dioxooctahydroindolidine-3-carboxylate This invention relates to a compound also known as, as well as its stereoisomers, isotopic substitutions, and salts.

[0115] In a particular embodiment of the present invention, A 2 These are methyl, ethyl, isopropyl, and t-butyl Selected from the group consisting of A 2 methyl, ethyl and Selected from the group consisting of t-butyl. In a particular embodiment of the present invention, A 2 is methyl or Selected from ethyl. In a particular embodiment of the present invention, A 2 is methyl or t-butyl In a particular embodiment of the present invention, A 2 It is methyl.

[0116] In a particular embodiment of the present invention, A 3 -O-SO2-CF3 or -O-SO2-CF Selected from 2CF2H. In a particular embodiment of the present invention, A 3 is -O-SO2-CF Selected from 3, or -O-SO2-CF2CF2CF3. In a particular embodiment of the present invention is, A 3 is -O-SO2-CF3. In a particular embodiment of the present invention, A 3 teeth,- In a particular embodiment of the present invention, A 3 is, -O- It is SO2-CF2CF2CF3.

[0117] The present invention relates to a compound of formula (VI-S),

[0118] [ka] Methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2, Also known as 3,5,8,8a-hexahydroindridine-3-carboxylate This relates to compounds, as well as their stereoisomers, isotope substitutions, and salts. In certain embodiments, Therefore, the present invention relates to a compound of formula (VI-A),

[0119] [ka] Methyl(3S,8aR)-5-oxo-7-(((trifluoromethyl)sulfonyl) Oxy)-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate This relates to a compound also known as t, as well as its stereoisomers, isotopic substitutions, and salts.

[0120] In certain embodiments of the present invention, a compound of formula (IV), a compound of formula (V), and / or formula ( The compound in VI) exists in excess of the corresponding 8S-enantiomer.

[0121] In certain embodiments, the present invention relates to a method for the treatment and / or prevention of thromboembolic disorders. A law that provides a therapeutically effective amount of the present invention to patients who require such treatment and / or prevention. At least one compound, or its stereoisomer, isotope substitution, or pharmaceutically acceptable The present invention relates to a method that includes administering a salt or solvate of the salt.

[0122] As used herein, the term "thromboembolic disorder" refers to arterial cardiovascular thromboembolic disorders. Disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the atrial or peripheral circulation. Including disorders. The term “thromboembolic disorder” as used herein also refers to unstable angina. , or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, sudden ischemic death, Hyperischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, Deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism , renal embolism, pulmonary embolism, and medical implants in which blood is exposed to artificial surfaces that promote thrombosis This includes certain disorders selected from thrombosis resulting from a thrombosis device or procedure, but these include Not limited to. Medical implants or devices include prosthetic valves. artificial valves, indwelling catheters, stents, hemoglobin generators, shunts, vascular devices Examples include cesports, ventricular assist devices and artificial hearts or atria, and vascular grafts. These are not the only options. Treatments include cardiopulmonary bypass and percutaneous coronary intervention. Examples include, but are not limited to, hemodialysis. In certain embodiments, "thrombotic The term "embolic disorders" includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism. In certain embodiments, "thromboembolic disorders" include hereditary angioedema (HAE) and One example is diabetic macular edema (DME).

[0123] In certain embodiments, the present invention relates to a method for the treatment and / or prevention of inflammatory disorders. If such treatment and / or prevention is required, the therapeutically effective amount of the compound of the present invention At least one of the substances, or its stereoisomers, isotopic substitutions, or pharmaceutically acceptable salts. The present invention relates to a method that includes administering a solvate or other solvate. An example of an inflammatory disorder is sepsis. Examples include, but are not limited to, acute respiratory distress syndrome and systemic inflammatory response syndrome. stomach.

[0124] In certain embodiments, the present invention treats diseases or conditions involving plasma kallikrein activity. and / or preventive methods, for patients in need of such treatment and / or prevention, A therapeutically effective amount of the compound of the present invention or its stereoisomer, isotope substitution, or pharmaceutically acceptable The present invention relates to a method comprising administering at least one of the salts or solvates of plasma. Diseases or conditions involving lyquelin activity include visual impairment, diabetic retinopathy, and diabetic jaundice. Spotted edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, related Adenitis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, This includes, but is not limited to, cardiopulmonary bypass surgery.

[0125] In certain embodiments, the present invention provides a method for the primary prevention of thromboembolic disorders. In certain embodiments, the present invention relates to a method for the primary prevention of thromboembolic disorders, wherein the thrombus Embolistic disorders include unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic death, and transient ischemic disease. Ischemic stroke, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep cerebral ischemic attack Vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, Renal embolism, pulmonary embolism, and medical implants in which blood is exposed to artificial surfaces that promote thrombosis. The present invention provides a method for thrombosis selected from, a device, or a procedure. Another embodiment Therefore, the present invention is a method for the primary prevention of thromboembolic disorders, wherein thromboembolic disorders are acute Coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical implants and devices. Provides a method to be selected from.

[0126] In certain embodiments, the present invention provides a method for the secondary prevention of thromboembolic disorders. In certain embodiments, the present invention is a method for secondary prevention of thromboembolic disorders, wherein the thrombus Embolistic disorders include unstable angina, acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, and transient ischemic attack (TIA). Seizures, strokes, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein blood Embolism, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism , pulmonary embolism, and medical implants, deba, where blood is exposed to an artificial surface that promotes thrombosis. The present invention provides a method for thrombosis resulting from a chair or procedure. In another embodiment, this The invention relates to a method for secondary prevention of thromboembolic disorders, which are thromboembolic disorders, including acute coronary syndrome. The present invention provides a method selected from stroke, atrial fibrillation, and venous thrombosis.

[0127] In certain embodiments of the present invention, a compound of formula (I), a compound of formula (II), or a compound of formula (III) ) Compounds are used as one or more anticoagulants, antithrombin agents, antiplatelet agents, fibrinolytic agents, lipid-lowering agents. It can be administered in combination with laxatives, antihypertensives and / or anti-ischemic agents. A suitable example is... This includes warfarin, heparin, aprotinin, synthetic pentasaccharide, boroarginine derivative, and boropel Butide, heparin, hirudin, argatroban, thromboxane-A2 receptor antagonist Thromboxane-A2-synthetase inhibitors, PDE-III inhibitors, PDE V Inhibitors, ADP receptor antagonists, purinergic receptor P2Y1 antagonists, A purinergic receptor P2Y12 antagonist, tissue plasminogen activator, and These modified forms include anistreplasase, urokinase, streptokinase, and tenectepra. Lanoteplase, PAI-I inhibitors, alpha-2-antiplasmin inhibitors, Nisoylated plasminogen-streptokinase activator complex, HMG-CoA Original enzyme inhibitors, squalene synthase inhibitors, fibrates, bile acid scavengers, ACAT inhibitors Drugs, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, cholesterol Luester transfer protein inhibitors, α-adrenergic blockers, β-adrenergic blockers, Cal Rheum channel blockers, diuretics, renin inhibitors, angiotensin-converting enzyme inhibitors, Geotensin II receptor antagonist, ET receptor antagonist, Dual ET / A11 antagonist, neutral endopeptidase inhibitor, vasopeptidase inhibitor, Class I drugs, Class II drugs, Class III drugs, Class IV drugs, IAch inhibitors, IKur inhibitors Examples include, but are not limited to, harmful agents and cardiac glycosides.

[0128] When used herein, * The notation '' indicates the presence of a three-dimensional center.

[0129] If the compound according to the present invention has at least one chiral center, as a result they They can exist as enantiomers. If a compound has two or more chiral centers, they are di They may exist additionally as astereomers. All such isomers and mixtures thereof are part of the present invention. It is understood to be included within the scope of [the specified scope].

[0130] Those skilled in the art will know when naming the compound of the present invention, S * (or *S) and R * (or * R) The notation indicates that the compound is prepared / present in excess of the corresponding stereoisomer, but the exact stereochemistry is not accurate. Recognize that this indicates that it has not been determined. The notation S and R indicates that the compound corresponds to S Alternatively, it may be prepared / present in excess of the R stereoisomer and have the exact stereoconfiguration described. This indicates that.

[0131] Preferably, if the compound exists as an enantiomer, the enantiomer is approximately An enantiomer excess of 80% or more, more preferably about 90% or more. With an excess rate, more preferably with an enantiomer excess rate of about 95% or more, even more preferably With an enantiomer excess of approximately 98% or more, most preferably approximately 99% or more. - It exists in excess. Similarly, if the compound exists as a diastereomer, diastere Leomer has a diastereomer excess of over 80%, and comfortably over 90%. Diastereomer excess rate, even more preferably a diastereomer excess rate of approximately 95% or more And more preferably, with a diastereomer excess of about 98% or more, most preferably about 9 They are present at an excess rate of 9% or more of diastereomers.

[0132] In certain embodiments, the present invention relates to one of the R- or S-enantiomers (" * This is shown as " Compounds of formula (I) and compounds of formula (II) with an enantiomer excess of any of the stereocenters. , or relating to compounds of formula (III). In certain embodiments of the present invention, compounds of formula (I) The compound of formula (II), or the compound of formula (III), is either an R or an S-enantiomer. (" *The enantiomer excess rate of any of the stereocenters indicated by '' is approximately 55% and approximately 60%. Approximately 65%, 70%, 75%, 80%, 85%, 90%, 91%, and 92% It is present in approximately 93%, 94%, 95%, 96%, 97%, 98%, or 99% of cases. Preferably, the compound of formula (I), the compound of formula (II), or the compound of formula (III) One of the R- or S-enantiomers (" * The enantifest of any of the solid centers indicated by " The omer excess rate is approximately 80% or more, preferably approximately 90% or more, more preferably approximately 93% or more. More preferably about 95% or more, more preferably about 97% or more, more preferably about 98% or more More preferably, they are present in a concentration of approximately 99% or more.

[0133] In certain embodiments, the present invention relates to one diastereomer or stereoisomer of possible diastereomers. A compound of formula (I) with an excess of stereomers or stereoisomers, a compound of formula (II), or a compound of formula (II This relates to the compound of formula (I), formula (II). In a particular embodiment of the present invention, the compound of formula (I), formula (II) The compound or the compound of formula (III) is one of the possible diastereomers or stereoisomers. The excess percentage of astereomers or stereoisomers is approximately 55%, 60%, 65%, 70%, and 75%, approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately It is present in 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99%. Preferably, formula (I) The compound of formula (II) or the compound of formula (III) is a possible diastereomer or The stereoisomer has a diastereomer or stereoisomer excess of approximately 80% or more, which is preferable. More preferably about 90% or more, more preferably about 93% or more, more preferably about 95% or more, and even better Ideally, it should be approximately 97% or more, more preferably approximately 98% or more, and more preferably approximately 99% or more. To exist.

[0134] In certain embodiments, the present invention relates to the 3-position of hexahydroindridine-5(1H)-one. The stereocenter of isocenters exists in excess of the corresponding S or R stereoisomers in the chemical formula (I) This relates to compounds of formula (II) or formula (III).

[0135] In certain embodiments, the present invention relates to the 8-position of hexahydroindridine-5(1H)-one. The stereocenter of isocenters exists in excess of the corresponding S or R stereoisomers in the chemical formula (I) This relates to compounds of formula (II) or formula (III).

[0136] In certain embodiments, the present invention relates to the 3-position of hexahydroindridine-5(1H)-one. The stereocenter of the corresponding S stereoisomer is present in an excess of stereoisomers, and hexahydroindol The stereocenter at position 8 of din-5(1H)-one is in a stereoisomer excess of the corresponding R stereoisomer. This relates to existing compounds of formula (I), formula (II), or formula (III).

[0137] Furthermore, with respect to the compounds of the present invention, some of the crystalline forms may exist as polymorphs, and these may be... It is intended to include in the present invention as something like this. In addition, a part of the compound of the present invention It may form a solvate (i.e., hydrate) with water, or a solvate with common organic solvents. The invention may form substances, and such solvates are also intended to be included within the scope of the present invention. .

[0138] As used herein, unless otherwise stated, the term “isotope substitution” means This refers to molecules that differ only in their isotopic composition. More specifically, molecules that are identical in composition. A topologically substituted compound contains at least one atom that is an isotope (i.e., its parent atom and It differs from the parent molecule in that it has a different number of neutrons.

[0139] For example, while not limited to water isotopes, "light water" (HOH or H2O), pro "Semi-heavy water" (HDO or 1 H 2 HO), 1 minute "Heavy water" (D2O or 2 H2O), hydrogen atom tritium ( 3 H) "Superheavy water" or tritium water (T2O or 3 H2O), two heavy-oxygen water isotopes (H2 18 O and H2 17 O ) and isotopic substitutions in which hydrogen atoms and oxygen atoms can each be independently replaced by isotopes, For example, double-labeled water isotope D2 18 O is one example. In certain embodiments, isotope substitutions They may be "isotopic isomers." As isotopic isomers, structural isomers are based solely on isotopic position. Both whole bodies and stereoisomers are examples. For instance, CH3CHDCH3 and CH3CH2C H2D is a structural isotope isomer pair of n-propane, while (R)-CH3CHDO H and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3C H=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0140] Within the scope of the present invention, in particular compounds of formula (I), compounds of formula (II), or compounds of formula (III) When referring to a compound, any one or more elements are either naturally occurring or The element in question is either synthetically produced, naturally occurring, or in an isotopically enriched form. This shall include all isotopes and isotopic mixtures of the same species. For example, reference to hydrogen is within its scope. inside 1 H, 2 H(D), and 3 It contains H(T). Similarly, references to carbon and oxygen are also included. Within that range 12 C, 13 C and 14 C and 16 O and 18 Contains O. Such isotopes This may be a radioactive isotope or a non-radioactive isotope. The radiation of formula (I) A sex-labeled compound or a compound of formula (II) is 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Selected from the group Br It may contain one or more radioactive isotopes. Preferably, the radioactive isotopes are 3 H, 11 C, and Beauty 18 It is selected from group F.

[0141] In a particular embodiment of the present invention, a compound of formula (I), a compound of formula (II), or ( III) The compound has one or more carbon atoms bonded to the ring or chain carbon atoms, preferably 1 to 8. Preferably 1 to 6, more preferably 1 to 5, more preferably 1 to 3, and even more preferably It contains 1 to 2 deuterium atoms. In certain embodiments of the present invention, the compound of formula (I), The compound of formula (II) or the compound of formula (III) has one or more carbon atoms bonded to a ring or chain carbon atom. It contains multiple, preferably 1 to 3, more preferably 1 to 2, deuterium atoms.

[0142] A person skilled in the art can further explain that the compound of formula (I), the compound of formula (II), and the compound of formula (III) are Tautomers (i.e., structural isomers that can be easily interconverted), more specifically, the isomers of a compound It is recognized that this can exist as a tautomer of the midazolyl moiety. Those skilled in the art will further recognize formula (I) The compound of formula (II) and the compound of formula (III) are tautomers, or It is recognized that these tautomers can exist as any mixture of their respective forms.

[0143] This invention relates to all of its isomers (stereoisomers, enantiomers, diastereomers, and tartrates). This includes, but is not limited to, isomers, isotope substitutions, atropisomers, etc. It is further intended to include the compounds listed in the details.

[0144] Under the standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is listed first, followed by the end of the specified side chain. Adjacent functional groups follow each other towards the point of agreement. Therefore, for example, "phenyl C1-C6 aldehyde The substituents "Kylaminocarbonyl C1-C6 alkyl" are the bases of the following formulas.

[0145] [ka] It refers to.

[0146] The abbreviations used in this specification, particularly in the schemes and examples, are listed in Table A below. That's right.

[0147] [Table 1-1]

[0148] [Table 1-2]

[0149] As used herein, unless otherwise specified, the term “isolated form” means a compound that has been subjected to other chemical processes. It exists in a form separated from any solid mixture with a compound, solvent system, or biological environment. This shall mean that, in one embodiment of the present invention, the compound of formula (I) is isolated It exists in a form. In one embodiment of the present invention, the compound of formula (II) exists in an isolated form. It exists. In one embodiment of the present invention, the compound of formula (III) exists in an isolated form. .

[0150] As used herein, unless otherwise specified, the term “substantially pure form” means isolated The mole percent of impurities in the compound is less than about 5 mole percent, preferably about 2 mole percent. Less than 0.5 mole percent, more preferably less than about 0.5 mole percent, most preferably about 0. This means less than 1 mole percent. In one embodiment of the present invention Therefore, the compound of formula (I) exists in a substantially pure form. One embodiment of the present invention In this, the compound of formula (II) exists in a substantially pure form. One of the present inventions In the embodiment, the compound of formula (III) exists in a substantially pure form.

[0151] When used herein, unless otherwise specified, compounds of formula (I) and chemical compounds of formula (II) When used to describe a compound or compound of formula (III), the "corresponding salt form" is used. The term "substantially does not contain" refers to the isolated compound of formula (I), isolated compound of formula (II). The mole percent of the compound, or the corresponding salt form in an isolated compound of formula (II), is approximately Less than 5 mole percent, preferably less than about 2 mole percent, more preferably about 0.5 mole percent This means less than 0.1 mole percent, most preferably less than about 0.1 mole percent. In one embodiment of the present invention, the compound of formula (I) is expressed in the corresponding salt form. It exists in a form that is not qualitatively present. In one embodiment of the present invention, the compound of formula (II) It exists in a form that substantially does not contain the corresponding salt form. In one embodiment of the present invention Therefore, the compound of formula (III) exists in a form that substantially does not contain the corresponding salt form.

[0152] Where used herein, unless otherwise specified, terms such as "to treat" and "treatment" are used. , subjects or patients, preferably mammals, more preferably, for the purpose of combating a disease, condition, or disorder. This includes the management and care of humans, and the prevention of the onset of symptoms or complications. It alleviates complications, slows the progression of disease or disability, or eliminates disease, condition, or disability. This includes administering the compound of the present invention to eliminate. The term “to treat” or “to cure” is further defined as: (a) inhibiting the disease state, i.e., stopping its onset, and / or ( b) Including reducing the disease state, i.e., causing regression of the disease state.

[0153] As used herein, “prevention” means a therapeutically effective amount of at least one of the compounds of the present invention. The substance or its stereoisomers, isotope substitutions, pharmaceutically acceptable salts, or solvates may be administered to the patient. By administering it, the risk of disease status is reduced and / or minimized, and / Alternatively, it is a protective measure for the disease state to reduce the risk of recurrence of the disease state. Factors known to increase the risk of developing clinical disease conditions compared to the general population Based on the child, it may be selected for preventive therapy. For preventive therapy, the clinical disease state This may or may not be indicated. “Preventive” measures include (a) primary prevention and (b) It can be divided into secondary prevention. Primary prevention is for patients who do not yet show a clinical disease state. It is defined as a measure to reduce or minimize the risk of disease in individuals, and is a secondary prevention measure. This minimizes or reduces the risk of recurrence or a second occurrence of the same or similar clinical disease condition. It is defined as a matter.

[0154] As used herein, “prevention” means reducing the probability of developing a clinically diseased condition. This includes preventive measures for asymptomatic disease conditions in mammals, particularly humans, with the aim of [achieving this goal]. Patients are known to have an increased risk of developing clinical disease states compared to the general population. Preventive therapies are selected based on the factors present.

[0155] As used herein, “risk reduction” refers to a treatment that reduces the incidence of a clinical disease condition. It encompasses the law. Therefore, primary and secondary preventive therapies are examples of risk reduction.

[0156] Those skilled in the art will know that if the present invention relates to a preventive method, the target of the person who needs it ( For example, a subject requiring prevention must have at least one of the following conditions that should be prevented: Any subject or patient (preferably a mammal, more preferably) that has experienced or shown any of the following symptoms It is important to recognize that this may include (or human). Furthermore, patients who require this method may also be added. And, although they do not show any symptoms of any disorder, disease, or medical condition that should be prevented, , a physician, clinician or other healthcare professional who considers that there is a risk of developing a disease or medical condition The patient may be a mammal (preferably a human). For example, This is not limited to, but the following are relevant to the subject: family history, predisposition, co-occurring (overlapping) diseases or co-occurring (overlapping) diseases. ) As a result of the subject's medical history, including the condition, genetic testing, etc., the subject may be diagnosed with a disability, disease, or condition. It can be considered that there is a risk of developing the condition (and therefore a need for prevention or preventive treatment).

[0157] The term "subject" as used herein refers to an animal or other object that is the subject of treatment, observation, or experimentation. "Mashi" refers to mammals, most preferably humans. Preferably, the subject is one to be treated and / or They have experienced and / or exhibited at least one symptom of a disease or disorder that should be prevented.

[0158] As used herein, the term “composition” means a product containing a specific component in a specific amount, and Furthermore, any product resulting directly or indirectly from a specific combination of amounts of a particular component It shall be included.

[0159] As used herein, the term “therapeutic effective dose” refers to the dose used by researchers, veterinarians, physicians, or other clinical researchers. This includes the relief of symptoms of diseases or disorders being treated as required by a physician, including histological and motor systems. This refers to the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical reaction within a substance or a human being. It tastes good.

[0160] The compounds of the present invention are preferably administered to mammals alone in therapeutically effective doses. However, The compounds of the present invention can also be used in combination with further therapeutic agents as defined below to provide therapeutic effects. It can be administered to mammals in potency doses. When administered in combination, the combination of compounds is: A synergistic combination is preferable, but it is not necessarily required. Synergistic effects are... For example, the effect of a compound when administered in combination (in this case, inhibition of the desired target) is, This can occur when the combined effect of the compounds is greater than the additive effect when administered as a single agent. The synergistic effect is most clearly demonstrated at concentrations below the optimal level of the compound. Compared to that, it has lower cytotoxicity, increased anticoagulant effect, or a combination of several other It may relate to beneficial effects.

[0161] "Administered in combination" or "combination therapy" refers to the compounds of the present invention and one or more of them. This means that additional therapeutic agents are administered to the treated mammal simultaneously or consecutively. When administered in combination, each component may be administered simultaneously or in any order at different time points. They can be administered sequentially. Therefore, each component can be administered separately, but to achieve the desired therapeutic effect... It can be administered with sufficient time proximity to provide the necessary information.

[0162] Even when one or more additional pharmacologically active agents are administered in combination with the compound of the present invention, Good. Additional active agents include prodrugs that are converted to a pharmaceutically active form after administration. This is intended to mean a pharmacokinetically active drug that is active in the body, and this is the chemical expression of formula (I). Unlike the compound or compound of formula (II), and whether such a form is commercially available, If otherwise, if chemically possible, the free acid, free base and pharmaceutical of the additional active agent This also includes generally acceptable salts. Generally, but not limited to, antihypertensives, additional diuretics, and lipids. Any suitable anti-atherosclerotic agents, antidiabetic agents and / or anti-obesity agents, including quality-modifying compounds. Suitable additional activators include single-dose formulations (fixed-dose drug combinations) of compounds of formula (I) or It may be used in any combination with the compound of formula (II), or in parallel administration of the activator or The drug is administered to the patient in one or more separate formulations that allow for sequential administration (co-administration of separate activators). It may also be used.

[0163] Further activators that may be used include, but are not limited to, the following: A Gdiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, Seronapril, Cilazapril, Delapril, Enalapril, Enalaprilat, Fosino Prill, imidapril, lysinopril, mobertipril, perindopril, quinapril, Ramipril, Spirapril, Temocapril, or Trandolapril; Angiotensin Angiotensin II receptor antagonists, also known as antiretroactive drugs (ARBs) (examples) For example, losartan (i.e., COZAAR®), valsartan, candesal Tan, olmesartan, telmesartan, eprosartan, irbesartan, and HYZ AAR (registered trademark) (combination of hydrochlorothiazide and losartan), etc. Any of these drugs used in combination with lolothiazide; diuretics, e.g., hydro Chlorothiazide (HCTZ); potassium-sparing diuretics, e.g., amiloride HCl, spi Lonolactone, epleranone, triamterene (each also has an HCTZ) (Discussion); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidone) Aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors (examples) For example, di and tripeptide urea derivatives (see U.S. Patent No. 5,116,835), ami No acids and derivatives (U.S. Patent Nos. 5,095,119 and 5,104,869), non-pe amino acid chains linked by butyl bonds (U.S. Patent No. 5,114,937), di and Tripeptide derivatives (U.S. Patent No. 5,106,835), peptidylaminodiol ( U.S. Patent Nos. 5,063,208 and 4,845,079) and peptidyl β-amine Noacylaminodiol carbamate (U.S. Patent No. 5,089,471): Also, the following U.S. Patent Nos. 5,071,837, 5,064,965, and 5,063,20 No. 7, No. 5,036,054, No. 5,036,053, No. 5,034,512 Various other peptide analogs disclosed in Patent No. 4,894,437, and low Molecular weight renin inhibitors (diol sulfonamide and sulfinyl (US 5,098 (Patent No. 924), N-morpholino derivative (U.S. Patent No. 5,055,466), N-heterocyclic Alcohol (U.S. Patent No. 4,885,292) and pyrrolimidazolone Including olones (U.S. Patent No. 5,075,451); also containing staton-containing peptides Pepstatin derivatives (U.S. Patent No. 4,980,283) and fluoro and chloro derivatives Body (U.S. Patent No. 5,066,643); Enalcrane; RO 42-5892 (CA S Registration number 126222-34-2, also known as Remikilen); A 65317( CAS Registry Number 119625-78-4); CP 80794 (CAS Registry Number 1196 25-78-4, also known as tellacyrene); ES 1005 (CAS Registry Number 1 15404-79-0); ES 8891 (CAS Registry Number 129445-88-1); SQ 34017 (CAS Registry Number 695226-77-8); Aliskiren (2(S) ,4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5 -amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3- Methoxypropoxy)-phenyl]-octaneamide hemi-fumalate); endothelin Physiological antagonists; vasodilators (e.g., nitroprusside); calcium channel blockers (For example, amlodipine, nifedipine, verapamil, diltiazem, felodipine, g Lopamil, nimodipine, nicardipine; potassium channel activators (e.g., Nicorandil, Pinacidil, Chromacam, Minoxidil, Aprilcarim, Loprazola Mu); sympathetic nerve blockers; β-adrenergic blockers (e.g., acebutolol, atenolol) Betaxolol, bisoprolol, carvedilol, metoprolol, metoprol tartrate Roll, Nadolol, Propranolol, Sotalol, Timolol; α-adrenergic blockade Discontinuation of medication (e.g., doxazosin, prazosin, or alpha-methyldopa); central alpha-adrenergic N-agonists; peripheral vasodilators (e.g., hydralazine); lipid-lowering agents (e.g., lactol In prodrug form, ZOCOR (registered trademark) and MEVACOR (registered trademark) are marketed. HMs such as simvastatin and lovastatin are sold and function as inhibitors after administration. G-CoA reductase inhibitors, and atorvastatin (especially LIPITOR (registered trademark) Calcium salts sold by ), rosuvastatin (especially CRESTOR (registered trademark) Calcium salts sold under the name of ), pravastatin (especially PRAVACHOL (registered (Sodium salts) and fluvastatin (especially LESCOL (Registered Trademark) sold under this trademark) Dihydroxy ring-opening acid HMG-CoA reductase (such as sodium salt) sold under the trademark Pharmacologically acceptable salts of inhibitors; cholesterol such as ezetimibe (ZETIA®). Lipid absorption inhibitors, and any other lipid-lowering agents such as the above-mentioned HMG-CoA reductase inhibitors, In particular, simvastatin (VYTORIN®) or atorvastatin calcium Combined ezetimibe; immediate-release or controlled-release forms of niacin, especially laropiprant. DP antagonists such as (TREDAPTIVE(registered trademark)) and / or HMG-Co Niacin combined with A reductase inhibitors; niacin in immediate-release or controlled-release forms. In particular, DP antagonists such as Lalopiprant (TREDAPTIVE®) and / or niacin combined with an HMG-CoA reductase inhibitor; niacin receptor ago Niacin receptor partial agonists, such as acipimox and acifuran, and niacin receptor partial agonists Biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nate) Glinides, sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide) Thiazolidinedione (also known as glybride, trazamide, tolbutamide, or glitazone) (e.g., pioglitazone, rosiglitazone), α-glucosidase inhibitors (e.g., α-glucosidase inhibitors) Carbose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitaglipid) (JANUVIA®), alogliptin, vildagliptin, saxagliptin (Tin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (for example) (Bromocriptine), JANUMET (registered trademark) (Sitagliptin with metformin) ) and other concomitant medications, and injectable antidiabetic drugs such as exenatide and pramulintide acetate, etc. Metabolic agents including insulin sensitivity enhancers and related compounds for the treatment of diabetes; or the above Other drugs that are beneficial for the prevention or treatment of disease (including, but not limited to, diazoxide) (None); where chemically possible, free acids, free bases and pharmaceutically acceptable substances of the above active agents It includes salt forms. It can be administered in combination with the compounds of the present invention, either as an alternative or as an addition. Examples of compounds used include anticoagulants, antithrombin agents, antiplatelet agents, fibrinolytic agents, and lipid-lowering agents. Examples include, but are not limited to, antihypertensive agents and antiischemic agents.

[0164] Anticoagulants (or coagulation inhibitors) that can be used in combination with the compound of the present invention include, Rufarin, heparin (unfractionated heparin or any commercially available low molecular weight heparin, e.g., eno) Xaparin and dalteparin (either one), aprotinin, factor Xa synthetic pentasaccharide inhibitors For example, fondaparinux and hydraparinux, direct factor Xa inhibitors, for example, riba Roxaban, Apixaban, Betrixaban, Edoxaban, Otamixaban, Direct action Thrombin inhibitors, such as hirudin, dabigatran, argatroban, and ximelagatran. , melagatorin, repiridine, decilidine and bivaliridine, and other VIla factors Inhibitors, Villa inhibitors, DCa inhibitors, Xa inhibitors, XIa inhibitors, fibrinogen N receptor antagonists (including absiximab, eptifibatide, and tyrofiban) Examples include TAFI inhibitors, as well as others known in the art. DCa factor inhibitors. Examples of inhibitors include synthetic active site blockade competitive inhibitors, oral inhibitors, and RNA aptamers. These are from the previously cited Howard et al. reference (Howard et al. rd,EL,Becker KC,Rusconi,CP,Becker RC.Fac tor IXa Inhibitors as Novel Anticoagulan ts.Arterioscler Thromb Vase Biol.2007;27 It is described in 722-727.)

[0165] The term antiplatelet agent (or platelet inhibitor), as used herein, for example, Drugs that inhibit platelet function by inhibiting platelet aggregation, adhesion, or granule secretion. To show. Such drugs are not limited to aspirin and ibuprofen. Naproxen, Sulindac, Indomethacin, Mefenamate, Droxicam, Diclofenac Various known nonsteroidal antimicrobial agents such as lofenac, sulfinpyrazone, and piroxicam This includes inflammatory drugs (NSAIDs), and their pharmaceutically acceptable salts or prodrugs. It can be given. Among NSAIDs, aspirin (acetylsalicylic acid or ASA), and pi Roxicam is preferred. Other suitable platelet inhibitors include IIb / IIIa antagonists. Stromboxa (e.g., tyrofiban, eptifibatide, and absiximab), ¹-A2- receptor antagonists (e.g., ifetroban), thromboxane-A2- Synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (for example) (, dipyridamole, cilostazol), and PDE V inhibitors (e.g., sildenafil) ), as well as their pharmaceutically acceptable salts or prodrugs.

[0166] As used herein, the term antiplatelet agent (or platelet inhibitor) also means AD P (adenosine diphosphate) receptor antagonist, preferably purinergic receptor P2Y It is intended to include antagonists 1 and P2Y12, with P2Y12 being even more preferred. Yes. Preferred P2Y12 receptor antagonists include ticlopidine, prasugrel, This includes clopidogrel, erinogrel, ticagrelor, and cangrerol, and these drugs Examples include scientifically acceptable salts or prodrugs. Clopidogrel is even more preferable. These are gentle medications. Ticlopidine and clopidogrel are also gentle on the gastrointestinal tract when used. Since it is known that it is a preferred compound, the compound of the present invention combines with aprotinin. They can also be administered together.

[0167] The term thrombin inhibitor (or antithrombin agent) is used herein, This exhibits serine protease thrombin inhibitory properties. By inhibiting thrombin, Rhombin-mediated platelet activation (i.e., platelet aggregation, and / or plasmin α-activator inhibitor-I and / or serotonin granule secretion), endothelial cell activation, inflammation Various thrombin-mediated processes, including reactions and / or fibrin formation, are disrupted. Many thrombin inhibitors are known to those skilled in the art, and these inhibitors can be combined with the compounds of the present invention. They are intended to be used in combination. Such inhibitors include boroarginine inducers. Body, boropeptides, heparin, hirudin, dabigatran and argatroban (these drugs) Examples include, but are not limited to, scientifically acceptable salts and prodrugs. Examples of boroarginine derivatives and boropeptides include N-acetyl and peptides of boronic acid. Derivatives, for example, lysine, ornithine, arginine, homoarginine and their corresponding Examples include C-terminal α-aminoboronic acid derivatives of isothiouronium analogs. When used, the term hirudin is a preferred form of hirudin referred to herein as hirulog. The present invention includes suitable derivatives or analogues, such as disulfatovirdin.

[0168] Protease-activated receptor (PAR) antagonist or PAR-1 antagonist The term "thrombin receptor antagonist," also known as a thrombotic, inflammatory, and inflammatory drug, is used to describe thrombotic, inflammatory, and inflammatory drugs. Theromatic and fibroproliferative disorders, as well as the pathological role of thrombin and its receptors. It is useful in treating other disorders. Thrombin receptor antagonist peptide is useful in treating thrombin It has been identified based on structure-activity testing involving amino acid substitutions on the receptor. Berna towicz et al,J Med.Chem.,vol.39,pp.4879- 4887 (1996) describes tetra- and pentapeptides as potent thrombin receptor receptors. It is disclosed as an antagonist, for example, N-trans-cinnamoyl-p-fluoro Phe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans -Cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg -Arg-NH2. The peptide thrombin receptor antagonist is also internationally published. Disclosed in publication 94 / 03479. Substituting tricyclic thrombin receptor antagonists are U.S. Patent No. 6,063,847, U.S. Patent No. 6,326,380, and International Publication No. 01 / 96 Disclosed in U.S. Patent No. 330 and U.S. Patent No. 7,037,920. Other thrombin receptors As an antagonist, it is U.S. patent numbers 7,304,078 and 7,235,567. , Patent No. 7,037,920, Patent No. 6,645,987, and European Patent No. 14950 Examples include those disclosed in Patent No. 18 and European Patent No. 1294714.

[0169] When used herein, thrombolytic (or fibrinolytic) agents (or thrombolytic agents or fibrinolytic agents) The term "viscolytic agent" refers to a drug that dissolves blood clots (thrombi). Therefore, tissue plasminogen activator (TPA, natural or recombinant) and its modified forms. Anistreplasse, urokinase, streptokinase, tenecteplase (TNK) ), lanoteplase (nPA), factor VIla inhibitors, PAI-I inhibitors (i.e., (Inactivator of tissue plasminogen activation inhibitors), alpha-2-antiplasm The inhibitor and the anisoylated plasminogen-streptokinase activator complex This includes pharmaceutically acceptable salts or prodrugs of anistreplasm and The terms used herein are, for example, those described in European Patent No. 0028489. This refers to an anisoylated plasminogen streptokinase activator complex. When used in the specification, the term urokinase refers to both double-chain and single-chain urokinases. This is intended to indicate a -ase, the latter of which is also called prourokinase in this specification. Examples of antiarrhythmic agents suitable for use in combination with the compound of the invention include the following: These include: Class I agents (propafenone, etc.); Class II agents (carvedilol and pro Pranolol, etc.; Class III drugs (sotalol, dofetilide, amiodarone, azimi) Lido and ibutilide, etc.; Class IV agents (e.g., dithiazem and verapamil); IAC h inhibitors and IKur inhibitors (for example, those disclosed in International Publication No. 01 / 40231) Compounds of substances, etc.

[0170] When given more broadly in the description, "to cause to react" and "reacted" Terms such as "(a) the actual written form of these chemical substances, and (b) the compound When naming a substance, it takes on any of the arbitrary forms of these chemical substances in the medium considered. In this document, the term refers to the chemical substance.

[0171] Those skilled in the art will know, unless otherwise specified, that the reaction steps are carried out under preferred conditions and in accordance with known methods. We recognize that we provide the desired product. Those skilled in the art will further recognize the methods presented herein. In the specification and claims, reagents or categories / types of reagents (e.g., bases, solvents, etc.) If ) is listed as more than one step in the process, each reagent is involved in its respective reaction. The processes are independently selected and may be identical or different from each other. They will be aware of this. For example, two steps of the method list organic or inorganic bases as reagents. In this case, the organic or inorganic base selected for the first step is the organic or inorganic base of the second step. It may be the same as or different from the present invention. Furthermore, those skilled in the art will be able to perform the reaction steps of the present invention in various ways. This can be carried out in a suitable solvent or solvent system, and such reaction steps can also be carried out in a suitable solvent or solvent system You will realize that this can also be done in mixtures.

[0172] Those skilled in the art will know that the reaction steps / processes of the present invention can be carried out in various solvents or solvent systems. This reaction can be performed in a suitable solvent or a mixture of solvent systems. They will realize that this is also possible.

[0173] To those skilled in the art, each step of the reaction or process described herein is well known to those skilled in the art. The reaction can be measured by any method, for example, chromatography (e.g., HPLC). It is important to recognize that the process can be carried out over a sufficient period of time until the response is completed. In this regard, "a completed step of a reaction or process" means each of the steps present at the start of the reaction. Compared to the amount of the reaction mixture, the amount of starting materials / reagents decreased significantly and the amount increased significantly. This means that it contains the desired product.

[0174] To provide a more accurate explanation, some of the quantitative expressions presented herein are expressed using the term "about". Not modified by. Regardless of whether the term "about" is explicitly used or not, this statement In this book, all quantities given refer to actual given values, and such places Ordinary skill in the art, including approximations of given values ​​by experimental and / or measurement conditions. It also means that it refers to an approximation of such a given value that can be reasonably inferred based on [the given data]. It will be understood.

[0175] To provide a more accurate description, in this specification, some quantitative expressions are derived from approximately X amount to approximately It is cited as the range of quantity Y. If a range is given, that range is... Not limited to upper and lower limits, but the entire range from approximately X to approximately Y, or any amount within that range. It is understood that "ku" includes the range.

[0176] Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided herein. Further details will be provided in the following description. Those skilled in the art will understand that the above list of examples is not provided in this specification. The present invention as described in the "Claims" that follows is intended to be limited in any respect. It will be recognized that this is not a limitation, nor should it be considered a limitation.

[0177] As used herein, unless otherwise specified, the term “leaving group” refers to a substitution or displacement reaction. This refers to charged or uncharged atoms or groups that detach during the response. A preferred example is... Examples include Br, Cl, I, mesylates, tosylates, etc., but are not limited to these. stomach.

[0178] In any of the processes for preparing the compound of the present invention, any of the relevant molecules In some cases, it may be necessary and / or desirable to protect the sensitive or reactive groups in such a location. This is Protective Groups in Organic Chemist ry, ed. JFWMcOmie, Plenum Press, 1973, and T .W.Greene & PGMWuts,Protective Groups in Organic Synthesis,John Wiley&Sons,19 This can be achieved by conventional protecting groups such as those described in 91. The protecting group is then conveniently At this stage, it can be removed using methods well known in the relevant art.

[0179] As used herein, unless otherwise specified, the term "nitrogen protecting group" refers to a nitrogen atom. It can bond and protect the nitrogen atom from participating in the reaction, and it can also be easily removed after the reaction. This refers to a group that can be removed. Suitable nitrogen protecting groups include, in the formula, where R is, for example, me These include t-butyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CH-CH2-, etc. A carbamate group of the formula -C(O)OR; where R' is, for example, methyl, phenyl, and t An amide group of the formula -C(O)-R', such as difluoromethyl; where R'' is, for example, a toryl phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-I Examples include 2,3,6-trimethyl-4-methoxybenzene, and others, with the formula -SO2-R” Examples of N-sulfonyl derivative groups include, but are not limited to, the N-sulfonyl derivative group. Other suitable nitrogen protecting groups TWGreene & PGMWuts, Protective Gro ups in Organic Synthesis,John Wiley&Sons This can be identified in documents such as 1991.

[0180] As used herein, unless otherwise specified, the term "oxygen protecting group" refers to a group attached to an oxygen atom. By combining them, it is possible to prevent such oxygen atoms from participating in the reaction, and after the reaction... This refers to a group that can be easily removed. Suitable oxygen protecting groups include acetyl, Benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, TH Examples include P, but are not limited to these. Other suitable oxygen protecting groups include TWGr. eene & PGMWuts,Protective Groups in O Texts such as "Graphic Synthesis," John Wiley & Sons, 1991. It can be identified by the book.

[0181] If a mixture of stereoisomers is produced by the process of preparing the compound according to the present invention, These isomers can be separated using conventional techniques such as preparative chromatography. The compound may be prepared as a racemic mixture, or the individual enantiomers may be enantioselectively combined. It can also be prepared by either compounding or decomposition. The compound is, for example, (-)-di- p-Toluoyl-D-tartaric acid and / or (+)-di-p-Toluoyl-L-tartaric acid After forming diastereomer pairs by forming salts with an optically active acid, fractional crystallization is performed. It is broken down into its enantiomer components by standard methods such as chemical reactions and the regeneration of free bases. The compound can also form a diastereomer ester or amide, Decomposition can also be achieved by performing chromatographic separation and removing the chiral auxiliary groups. Alternatively, the compound may be separated using a chiral HPLC column.

[0182] Furthermore, the enantiomer excess (%ee) was measured using chiral HPLC compared with a standard substance. This can be determined. The enantiomer excess rate may be calculated as follows: [(R moles - S moles) / (R moles + S moles)] × 100% In the formula, R moles and S moles are the mole fractions of R and S in the mixture, and R moles + S moles = The result is 1. Alternatively, from the specific rotation of the desired enantiomer and the prepared mixture, the following can be obtained: You may also calculate the excess enantiomer rate of sea urchin: ee=([α-obs] / [α-max])×100.

[0183] The scope of the present invention includes prodrugs of the compounds of the present invention. Generally speaking, such Prodrugs are functional derivatives of compounds that can be easily converted into the required compounds in vivo. Therefore, in the therapeutic method of the present invention, the term "administration" refers to the chemical combination specifically disclosed. Using a substance, or even if not specifically disclosed, in vivo after administration to a patient, a specific This includes the treatment of various disorders described using compounds that are converted into other compounds. A typical procedure for selecting and preparing suitable prodrug derivatives is, for example, "Desig n of Prodrugs”, ed. H. Bundgaard, Elsevier, 1 It is described in 985.

[0184] With regard to pharmaceutical use, the salts of the compounds of this invention refer to non-toxic, "pharmaceutically acceptable salts." However, other salts may be compounds according to the present invention or pharmaceutically acceptable salts thereof. It may be useful in preparation. Suitable pharmaceutically acceptable salts of the compound include acid addition salts. For example, acid addition salts can be used to add solutions of compounds with hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, etc. Pharmacologically acceptable substances such as citric acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. It can be formed by mixing with an acidic solution. Furthermore, if the compound of the present invention has an acidic portion In addition, suitable pharmaceutically acceptable salts include, for example, alkali metal salts, for example , sodium salts or potassium salts, alkaline earth metal salts, for example, calcium salts or magnesium salts Salts formed with nesium salts and suitable organic ligands, such as quaternary ammonium salts. These can be listed. Therefore, the following are representative pharmaceutically acceptable salts. : Acetates, benzenesulfonic acid, benzoates, bicarbonates, bisulfates, tartrates, boric acid Salt, bromide, calcium edetate, cansylate, carbonate, chloride, clavulanate, Ethanol, dihydrochloride, edetate, edisylate, estolate, esyl acid Salt (esylate), fumarate, gluceptate, gluconate, glutamate, glyco Glycollylarsanilate, hexylresorcinol, hydravamin Hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate (isothi (onate), lactate, lactobionate, laurate, malate, maleate, man Delates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucinates, napsil Salts, nitrates, N-methylglucamine ammonium salts, oleates, pamoates (embossed (Phosphate), palmitate, pantothenate, phosphate / diphosphate, polygalacturon Salts, salicylates, stearates, sulfates, basic acetates, succinates, tannic acids Examples include salts, tartrates, theoclates, tosylates, triethiozides, and valersates. However, these are not the only ones.

[0185] Typical acids that can be used in the preparation of pharmaceutically acceptable salts include the following: However, it is not limited to these. Acetic acid, 2,2-dichloroacetic acid, acylated amino acids, azi Fibic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoate Camphor acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphor sulfonic acid, (+ )-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, Cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, Tansulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, Gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamine Acids, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L- Lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malo Mandelic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, na Phthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid Oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutinate Minic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, Sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and Decylenic acid.

[0186] The following are some typical bases that can be used to prepare pharmaceutically acceptable salts. However, it is not limited to these. Ammonia, L-arginine, benetamine, benzati N, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2 -(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl - Glucamine, hydravamin, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2- Hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, trometa Mine and zinc hydroxide.

[0187] synthesis The present invention relates to the compound of formula (I), the compound of formula (II), the compound of formula (III), and the compound of formula (IV). The compounds of formula (V) and formula (VI) are as described in the following synthesis examples. It can be prepared as follows. The preparation of the starting materials used in the following synthesis examples is well done by those skilled in the art. It is within the scope of the technology.

[0188] Pharmaceutical composition The present invention relates to a compound of formula (I) and / or a compound of formula (II) and / or a compound of formula (III). The pharmaceutical composition further comprises a compound and a pharmaceutically acceptable carrier. A pharmaceutical composition containing one or more compounds of the present invention described herein is one or more The above compound is prepared by thoroughly mixing it with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can be in various forms depending on the desired route of administration (e.g., oral, parenteral). It can have such properties. Therefore, oral liquids such as suspensions, elixirs, and solutions. For compound formulations, suitable carriers and additives include water, glycol, oil, alcohol, and flavorings. Examples include preservatives, stabilizers, colorants, etc., and oral solid formulations such as powders, capsules, and tablets. In the case of formulations, suitable carriers and additives include starch, sugars, diluents, granulators, and lubricants. These include binders and disintegrants. Oral solid dosage forms are coated with substances such as sugar. They may be coated with enteric-coated material to modify the primary absorption site. For oral administration, the carrier is usually composed of sterile water, with other components added for increased solubility or preservation. Minutes may be added. Suspensions or solutions for injection may also be prepared with an aqueous carrier along with appropriate additives. It may be used in the manufacturing process.

[0189] To prepare the pharmaceutical composition of the present invention, one or more compounds of the present invention are used as active ingredients. In accordance with conventional pharmaceutical formulation technology, the pharmaceutical carrier is thoroughly mixed with the pharmaceutical carrier, but this carrier Depending on the preferred preparation method for parenteral administration, such as oral or intramuscular administration, various forms are available. It can be taken. When preparing the composition in oral form, any ordinary pharmaceutical medium can be used. This is possible. Therefore, for example, oral liquid formulations such as suspensions, elixirs, and solutions In this case, suitable carriers and additives include water, glycol, oil, alcohol, fragrance, and preservatives. Examples include formulations, colorants, etc. Powders, capsules, caplets, gel caps, and tablets. In the case of oral solid dosage forms such as the above, suitable carriers and additives include starch, sugars, diluents, Examples include granulators, lubricants, binders, and disintegrants. Because administration is easy, tablets and capsules are available. Psells are the most advantageous form of oral medication, but in this case, a solid drug carrier is used. This is clear. If desired, tablets can be coated with sugar or enteric coating using standard techniques. It may be used. In the case of parenteral administration, the carrier usually contains sterile water, but for example, solubility Other ingredients may be included for purposes such as aiding or preservation. Prepare the suspension for injection. This may be done, in which case a suitable liquid carrier, suspending agent, etc., may be used. The product is packaged in units of medication, such as tablets, capsules, powders, injections, or teaspoons. This will contain the amount of active ingredient necessary to deliver the effective dose described herein. The composition is, per unit dose, for example, tablets, capsules, powders, injections, suppositories, etc. Each spoonful contains approximately 0.01 mg to approximately 1000 mg, or any amount or range within that range. Including the range, approximately 0.05 mg / day to approximately 1000 mg / day, or any amount or range within that range. Approximately 0.1 mg / day to approximately 500 mg / day, or any amount or range within that range, preferred The dosage is approximately 1 mg / day to approximately 300 mg / day, or any amount or range within that range. It may be permitted.

[0190] However, the dosage may be changed depending on the patient's needs, the severity of the condition being treated, and the compound used. This may be done. Daily or intermittent administration may be used.

[0191] Preferably, these compositions are intended for oral, parenteral, intranasal, sublingual, or rectal administration. Tablets, pills, capsules, powders, granules for administration by inhalation or air infusion. sterile parenteral solutions or suspensions, metered-dose aerosols or liquid sprays, drops, amplifiers It is a single-dose medication form such as a suppository, automatic infusion device, or other. Oral, parenteral, intranasal, sublingual, or It is intended for rectal administration, or administration by inhalation or blown-in. Alternatively, this composition is administered once a week. It may be provided in a form suitable for single or monthly administration. For example, a depot formulation for intramuscular injection. Insoluble salts of active compounds such as decanoates can also be formulated to provide the necessary benefits, such as tablets. Regarding the preparation of the solid composition, the main active ingredient is a pharmaceutical carrier, for example, corn dextrose. Pungum, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate Conventional tableting ingredients such as um, dicalcium phosphate, or gum, and other pharmaceutical diluents, for example When mixed with water, it contains a homogeneous mixture of the compound of the present invention or a pharmaceutically acceptable salt thereof. A solid pre-formulation composition is formed. When these pre-formulation compositions are called homogeneous, the composition is It can be easily subdivided into equally effective dosage forms such as tablets, pills, and capsules. This means that the active ingredients are uniformly dispersed throughout the composition. The composition is then approximately 0.01 mg to approximately 1,000 mg (or any amount or range within that range). The active ingredient of the present invention is further divided into the above-described unit dosage forms. Novel composition Tablets or pills of substances are coated to provide a dosage form that offers the advantage of long-lasting action. They may be compounded or otherwise formulated. For example, tablets or pills may be It may contain an inner shell-administered component and an outer shell-administered component, the latter being in a form that encapsulates the former. The two components work to resist disintegration in the stomach, and their core components remain intact in the duodenum. Separation by an enteric-coated layer that allows passage to the interior or delays release. This can be done. Various substances can be used for such enteric-coated layers or coatings. These substances are often found together with substances such as shellac, cetyl alcohol, and cellulose acetate. It contains polymer acids.

[0192] A liquid form into which the novel composition of the present invention can be incorporated for oral or infusion administration. For example, an aqueous liquid, a suitably flavored syrup, an aqueous or oily suspension, and cottonseed oil. Emulsified with edible oils such as sesame oil, coconut oil, or peanut oil, and Examples include elixirs and similar pharmaceutical excipients. Suitable dispersants or suspensions for aqueous suspensions. The refining agents include synthetic and natural rubbers, such as tragacanth, acacia, alginates, and dextrin. Stran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-p Examples include loridone or gelatin.

[0193] The method for treating and / or preventing thromboembolic disorders described in the present invention is also defined herein. This is carried out using a pharmaceutical composition comprising one of the compounds and a pharmaceutically acceptable carrier. It is possible. The pharmaceutical composition contains approximately 0.01 mg to approximately 1000 mg of the compound, or the Any amount or range of the compound, preferably about 0.05 mg to about 300 mg, or Any amount or range within that, more preferably about 0.1 mg to about 100 mg of the compound, This includes any amount or range within that, more preferably about 0.1 mg to about 50 mg of the compound. Or it may contain any amount or range thereof, in any form suitable for the selected mode of administration. It can be composed of a binder, suspending agent, lubricant, flavoring agent, sweetener, and preservative. Examples include, but are not limited to, dyes and coatings, as well as any other inert medical treatment required. Contains drug excipients. Suitable compositions for oral administration include solid dosage forms, such as pills and tablets. Caplets, capsules (each including immediate-release, time-release, and sustained-release formulations), granules Granules and powders, as well as liquid dosage forms, such as liquids, syrups, elixirs, and ema. Examples include lujons and suspensions. Useful forms for parenteral administration include sterile solutions. Examples include emulsions and suspensions.

[0194] Advantageously, the compound of the present invention can be administered in a once-daily dose, or throughout the day. The drug dose may be divided and administered in two, three, or four doses per day. Furthermore, the present invention The compound is administered intranasally via topical use of a suitable nasal vehicle, as is well known to those skilled in the art. It can be administered in a transdermal manner or via a transdermal skin patch. For administration, the dosage should, of course, be continuous throughout the entire administration regimen, not intermittently. It will continue.

[0195] For example, when administering orally in the form of tablets or capsules, the active drug component is ethanol. Combined with oral, non-toxic, pharmaceutically acceptable, and well-inactive carriers such as glycerol and water. It can also be combined with a suitable binder, lubricant, disintegrant, and if desired or necessary. Colorants may also be incorporated into the mixture. Suitable binders include starch and gelatin. Natural sugars such as tin, glucose or β-lactose, corn sweetener, acacia, traga Natural and synthetic gums such as Kant, or sodium oleate, sodium stearate, Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Examples include, but are not limited to, starch and methylcellulose. Examples include, but are not limited to, agar, bentonite, and xanthan gum.

[0196] The liquid is synthetic and natural rubber, such as tragacanth, acacia, and methylcellulose. It may contain any suitably flavored suspending or dispersing agent. For parenteral administration, Sterile suspensions and solutions are preferred. If intravenous administration is desired, a suitable preservative is generally included. Use an isotonic preparation.

[0197] To prepare the pharmaceutical composition of the present invention, a compound of formula (I) and / or as the active ingredient Compound (II) and / or compound (III) are formulated according to conventional pharmaceutical formulation techniques. It is closely mixed with the drug carrier, which comes in a wide variety of forms depending on the desired form of the preparation for administration. It can take any form (e.g., orally or parenterally). A pharmaceutically acceptable preferred carrier is This is well known in the art. Some descriptions of these pharmaceutically acceptable carriers This is The Handbook of, published by the American Pharmaceutical Association and the British Pharmaceutical Association. This can be found under Pharmaceutical Excipients. The method for formulating the product is described in L published by Marcel Dekker, Inc. Pharmaceutical Dosage Forms:T (edited by Ieberman et al.) ablets,Second Edition,Revised and Expand ed, Volumes 1-3; Pharmaceutical Doss, edited by Avis et al. age Forms:Parental Medications,Volumes 1-2; and Pharmaceutical Dosage edited by Lieberman et al. Forms: Disperse Systems, Volumes 1-2, etc. It is mentioned in this publication, but is also mentioned in many other publications such as [publication name].

[0198] The compounds of the present invention, in any of the aforementioned compositions, cause thromboembolic disorders, inflammatory disorders, or blood disorders. When treatment or prevention is needed for a disease or condition involving serous kallikrein activity, In any case, it may be administered according to the dosage regimens established in the art.

[0199] The daily dose of the product is approximately 0.01 mg to 1,000 mg per adult human per day. Or it may vary widely over any amount or range within this. For oral administration: Preferably, 0.01, 0.05, 0.01 for symptomatic adjustment of the dosage for patients to be treated. 1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 10 In the form of tablets containing 0, 150, 200, 250, and 500 milligrams of the active ingredient, The composition is provided. An effective amount of the drug is usually about 0.005 mg / kg to about 10 mg / kg It can be supplied at a dosage level of g body weight / day, or any amount or range within that. The range is approximately 0.01 to approximately 5.0 mg / kg body weight / day, or any amount within that range. This is a range, more preferably about 0.1 to about 1.0 mg / kg body weight / day, or any amount within that range. Alternatively, within a range, more preferably about 0.1 to about 0.5 mg / kg body weight / day, or any within that range. This refers to the amount or range of the compound. The compound is administered in a regimen (medication plan) of 1 to 4 times per day. It may be given.

[0200] The optimal dose to be administered can be easily determined by those skilled in the art, and can be used The specific compound, administration method, formulation strength, and disease progression all change. In addition, Patient age, weight, diet, and number of doses, as well as other factors relevant to the specific patient receiving treatment. Depending on the contributing factors, dosage adjustments may be necessary.

[0201] Those skilled in the art can use suitable, known, and generally accepted cell and / or animal models. In vitro and in vitro studies determine whether the test compound treats or prevents a given disease. Recognize that ability is a predictive tool.

[0202] A person skilled in the art would know how to first target healthy patients and / or patients with a given disability. Human clinical trials, including in-human studies, dose range and efficacy studies, are conducted for clinical and medical purposes. It will become even more apparent that this can be carried out in the field according to well-known methods.

[0203] The following examples are provided to aid in understanding the present invention and are not included herein. The purpose is to limit the invention described in the "claims" in any sense. It was not done, nor should it be interpreted in that way.

[0204] The following examples list the synthetic products isolated as residues. (The term "residue" is used.) This does not limit the physical state in which the product is isolated, for example, solids, oils, Those skilled in the art will understand that it may include foamy substances, gum, syrup, etc.

[0205] Synthesis Examples Example 1: Intermediate compound of formula (IV-A) (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-Hexahydroindolidine-3-carboxylic acid

[0206] [ka]

[0207] Step 1: 1-(tert-butyl)2-methyl(2S)-5-methoxypyrrolidine-1 Synthesis of 2-dicarboxylate 1-(tert-butyl)2-methyl(S)-5-oxopyrrolidine-1,2-dical Dissolution of voxylate (2.1g, 8.63 mmol, 1.0 equivalent) in THF (40mL) In the solution, add lithium triethylborohydride (13 mL, 13 mmol, 1.5 equivalents, THF) The medium (1M) solution was added dropwise at -78°C under N2 conditions. The reaction mixture was stirred at -78°C for 40 minutes, and then Then, Na2CO3 (aqueous solution, 10 mL) was added at -78°C, and the mixture was heated to 0°C. Hydrogen oxide (1 mL, 30%) was added, and the resulting mixture was stirred at room temperature for 30 minutes. F is removed from the mixture under vacuum, and the resulting residue is extracted with diethyl ether, and the brine The oil was washed, dried, and concentrated under vacuum to obtain a colorless oil. The colorless oil was then mixed with methanol (40 mL). Dissolve in ( ) and add p-toluenesulfonic acid (149 mg, 0.86 mmol, 0.1 equivalents) It was added to the mixture. The resulting solution was stirred overnight at room temperature. The reactants were quenched with water, and the solution was obtained. The mixture was extracted with diethyl ether. The combined organic layer was washed with brine and Na Dry with 2SO4 and concentrate to obtain 1-(tert-butyl)2-methyl(2S)-5-methyl Toxypyrrolidine-1,2-dicarboxylate was obtained as a colorless oil.

[0208] Step 2: 1-(tert-butyl)2-methyl(2S)-5-allylpyrrolidine-1, Synthesis of 2-dicarboxylate 1-(tert-butyl)2-methyl(2S)-5-methoxypyrrolidine-1,2-di Carboxylate (10g, 38.6 mmol, 1.0 equivalent) solution in Et2O (200 (mL) contains allyltrimethylsilane (27mL, 169.7 mmol, 4.4 equivalents) and Boron trifluoride etherate (6.57g, 46.3 mmol, 1.2 equivalents) at -40°C The mixture was added under an N2 atmosphere. The resulting mixture was stirred at -40°C for 30 minutes and then heated to room temperature. Then, the mixture was stirred for 40 minutes. The reaction product was quenched with Na2CO3 (aqueous solution) and obtained The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na2SO4. The solution was dried and concentrated. The resulting residue was subjected to silica gel chromatography (0-20% EtOA). purified by c / petroleum ether, 1-(tert-butyl)2-methyl(2S)- 5-Allylpyrrolidine-1,2-dicarboxylate was obtained as a yellow oil. LC / MS: C 14 H 23 Calculated mass for NO4: 269.16, measured value: 270.20 [M +H] + .

[0209] Step 3: 1-(tert-butyl)2-methyl(2S)-5-(2-oxoethyl) Synthesis of loridine-1,2-dicarboxylate 1-(tert-butyl)2-methyl(2S)-5-allylpyrrolidine-1,2-dika Luboxylate (7.3g, 27.1mmol, 1.0 equivalent) THF / H2O (120 OsO4 (347 mg, 1.36 mmol, 0.05 equivalents) was added to a solution in (mL). The resulting mixture was stirred in the dark at room temperature for 5 minutes, and then sodium periodate (14.5%) was added. (g, 67.8 mmol, 2.5 equivalents) was added. The mixture was stirred at room temperature for 4 hours. The substance was quenched with water, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were then bran. Washed with water and dried with Na2SO4. Solid matter was filtered off. The filtrate was concentrated under vacuum. The obtained residue was then purified by silica gel chromatography (0-40% EA / PE). Prepared as 1-(tert-butyl)2-methyl(2S)-5-(2-oxoethyl)pyro Lysine-1,2-dicarboxylate was obtained as a yellow oil. LC / MS:C 13 H 21 N Calculated mass for O5: 271.14, measured mass: 272.15 [M+H] + ,twenty one 6.05 [M-C4H9] + .

[0210] Step 4: Racemic 1-(tert-butyl)2-methyl(2R)-5-(4-ethoxy- Synthesis of 2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxylate Ethyl acetate (0.936 mL, 9.583 mmol, 4 equivalents) tetrahydrofuran ( (10 mL) Solution: 1 M lithium bis(trimethylsilyl)amide (9.583 mL) 9.583 mmol (4 equivalents) was added under an N2 atmosphere at -78°C. At the same temperature for 30 After stirring for minutes, add 1-(tert-butyl) in tetrahydrofuran (10 mL) to the mixture. )2-methyl(2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate Add (650 mg, 2.396 mmol, 1 equivalent) and incubate the mixture at -78°C for 30 minutes. The mixture was stirred. The reaction was quenched with saturated ammonium chloride aqueous solution, followed by ethyl acetate (3 Extraction was performed using (20 mL ×). The organic layer was dried over magnesium sulfate, filtered, and removed under vacuum. The solution was concentrated using silica gel chromatography (0-45% ethyl acetate / silver). Purified with oil ether, rac-1-(tert-butyl)2-methyl(2R)- 5-(4-ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dical The oxylate was obtained as yellow oil (747 mg, yield 86.751%). LC / MS:C 17 H 29 Calculated mass for NO7: 359, measured value: 382[M+Na]+.

[0211] Step 5: 1-(tert-butyl)2-methyl(2S)-5-(4-ethoxy-2,4 Synthesis of dioxobutyl)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-methyl(2S)-5- in acetonitrile (30 mL) (4-Ethoxy-2-hydroxy-4-oxobutyl)pyrrolidine-1,2-dicarboxy A solution of silate (3.3 g, 9.2 mmol, 1.0 equivalent) is mixed with 2-iodoxybenzoic acid. (IBX) (10.3 g, 36.8 mmol, 4.0 equivalents) was added. The resulting mixture The mixture was stirred overnight at 50°C. The solvent was removed, and the mixture was separated between RINKAN and brine. The layers were separated, dried, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography. Refined by Fi (0-80% phenyl / petroleum ether), 1-(tert-butyl 2-methyl(2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine 1,2-dicarboxylate was obtained as a yellow oil. LC / MS:C 17 H 27 Against NO7 Calculated mass: 357.18, measured mass: 380.15 [M+Na] + .

[0212] Step 6: Methyl(3S)-5,7-dioxooctahydroindolidine-3-carboxy Silate synthesis 1-(tert-butyl)2-methyl(2S)-5-(4-ethoxy-2,4-dioxy) (Sobutyl)pyrrolidine-1,2-dicarboxylate (900 mg, 2.5 mmol, 1 In a solution of 0.0 equivalents) in DCM (2.5 ml), add HCl (1,4-dioxane, 4 M, 2 0.5 ml was added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. A yellow oil was obtained. The yellow oil was dissolved in toluene (5 mL), and sodium bicarbonate (2.1 g) was added. 25.2 mmol (10.0 equivalents) was added. The resulting mixture was stirred overnight at 110°C. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine. The solution was purified, dried with Na2SO4, and concentrated. The resulting residue was then subjected to silica gel chromatography. Refined with (0-50% ethyl acetate / petroleum ether), methyl(3S)-5,7 -Dioxooctahydroindolinidine-3-carboxylate was obtained as a yellow solid. C / MS:C 10 H 13 Calculated mass for NO4: 211.08, measured value: 212 .10[M+H] + .

[0213] Step 7: Methyl(3S)-5-oxo-7-(((trifluoromethyl)sulfonyl) Oxy)-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate Synthesis of Methyl(3S)-5,7-dioxooctahydroindidine-3-carboxylate In a solution of (370 mg, 1.75 mmol, 1.0 equivalent) of dichloromethane (5 mL), Triethylamine (355 mg, 3.5 mmol, 2.0 equivalents) and N,N-bis(tri Fluoromethylsulfonylaniline (751 mg, 2.1 mmol, 1.2 equivalents) is added. It was added. The resulting solution was stirred at room temperature overnight. Then the mixture was concentrated, and the residue was silicified. Purified by Kagel chromatography (0-80% EA / PE), then methyl(3S)- 5-Oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5, 8,8a-Hexahydroindridine-3-carboxylate was obtained as a yellow solid. C / MS:C 11 H 12 Calculated mass for F3NO6S: 343.03, measured value: 344.05 [M+H] + .

[0214] Step 8: Methyl(3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-Oxo-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate Synthesis of te Methyl(3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy) -1,2,3,5,8,8a-Hexahydroindidine-3-carboxylate (35 (0 mg, 1.02 mmol, 1.0 equivalent), (6-amino-3-chloro-2-fluorophosphate) Enylboronic acid (232 mg, 1.2 mmol, 1.2 equivalents) and potassium carbonate (28 1,4-dioxane / H2O (5 mL, 10 / ) (2 g, 2.04 mmol, 2.0 equivalents) 1) To the solution, [1,1'-bis(diphenylphosphino)ferrocene]dichloropara dium(II) (37 mg, 0.05 mmol, 0.1 eq) was added. The resulting mixture was stirred at 80 °C for 2 h under N2. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solids were filtered off, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0 - 100% EtOAc / petroleum ether) to give methyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a -hexahydroindolizine-3-carboxylate as a yellow solid. LC / MS : C 16 H 16 Calculated mass for C H + ClFN2O3: 338.08, found: 339

[0215] Step 9: Synthesis of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid To a solution of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (2 10 mg, 0.62 mmol, 1.0 eq) in THF / H2O / MeOH (5 mL, 3 / 1 / 1), lithium hydroxide (124 mg, 3.10 mmol, 5.0 eq) was added. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was adjusted to pH 4 with HCl, then extracted with ethyl acetate, washed with brine, dried, and concentrated under vacuum to give ( 3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2 ,3,5,8,8a-Hexahydroindridine-3-carboxylic acid was obtained as a yellow solid. LC / MS:C 15 H 14 Calculated mass for ClFN2O3: 324.07, measured Fixed value: 325.05[M+H] + .

[0216] Example 2: Two intermediate compounds of formula (VA) Methyl(3S)-5,7-dioxooctahydroindidine-3-carboxylate

[0217] [ka]

[0218] Step 1: Synthesis of methyl(2S)-5-allylpyrrolidine-2-carboxylate 1-(tert-butyl)2-methyl(2S)-5-allylpyrrolidine-1,2-dika Ruboxylate (10g, 37.128 nmol, 1.0 equivalent) in HCl solution (90ml) Dissolved in L, 10 equivalents (4M in 1,4-dioxane). The resulting mixture was stirred. The mixture was maintained at room temperature for 2 hours. The solvent was removed under reduced pressure, and methyl(2S)-5-allylpyrrhetinol was extracted. Zin-2-carboxylate was obtained and used in the next step without further purification.

[0219] Step 2: Methyl(2S)-1-acryloyl-5-allylpyrrolidine-2-carboxy Rate synthesis At -78℃, methyl(2S)-5-allylpyrrolidine-2-carboxylate (6g, A solution of 35.457 mmol (1.0 equivalent) in THF (200 mL) is mixed with TEA (23 ml). (L, 177.283 mmol, 5.0 equivalents) was added, followed by acryloyl chloride (3.2 (g, 35.457 mmol, 1.0 equivalent) was added. The resulting mixture was heated in a room while stirring. The mixture was maintained at a temperature for 40 minutes. The reactants were quenched with an aqueous NH4Cl solution, and the resulting layer was separated. The aqueous phase was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (ۯ / PE). Then, methyl(2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylate To was obtained as yellow oil.

[0220] Step 3: Methyl(3S)-5-oxo-1,2,3,5,8,8a-hexahydroin Synthesis of dridine-3-carboxylate Under N2 conditions, methyl(2S)-1-acryloyl-5-allylpyrrolidine-2-carbone Dissolve silate (7.2g, 32.248 mmol, 1.0 equivalent) in DCM (100mL). Add Grubbs second-generation catalyst (2.7g, 3.225 mmol, 0.1 equivalent) to the solution. The mixture was heated at 45°C for 10 hours. The solvent was removed under reduced pressure, and the remaining The residue was purified by silica gel column chromatography (EA / PE) and methyl(3) S)-5-oxo-1,2,3,5,8,8a-hexahydroindridine-3-carb The xylate was obtained as a brown oil.

[0221] Step 4: (3S)-methyl7-hydroxy-5-oxo-octahydroindolidine- Synthesis of 3-carboxylates Under N2 conditions, CuCl (0.102 g, 1.025 mmol, 0.2 equivalents) in THF (1 Add BINAP (0.638g, 1.025 mmol, 0.2 equivalents) to a 00 mL solution. It was added. The resulting mixture was maintained at room temperature for 15 minutes while stirring. t-BuONa(0 (0.098 g, 1.025 mmol, 0.2 equivalents) was added to the mixture. The mixture was stirred for 30 minutes. Later, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3, Add 2-dioxaborolane (1.561 g, 6.147 mmol, 1.2 equivalents) to the mixture. Add, followed by (3S)-methyl 5-oxo-1,2,3,5,8,8a-hexahydro Indoridine-3-carboxylate (1g, 5.123 mmol, 1.0 equivalent) was added. Next, MeOH (0.328g, 10.245 mmol, 2.0 equivalents) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours, then cooled to 0°C. Then, H2O2 Add (6 mL, 51.226 mmol, 10 equivalents), and stir the resulting mixture for a further 1 hour. Mixed. Remove the solvent under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM / Purified by MeOH, (3S)-methyl7-hydroxy-5-oxo-octahy Droindridine-3-carboxylate was obtained as a brown oil.

[0222] Step 5: (3S)-methyl 5,7-dioxo-octahydroindolidine-3-carb xylate synthesis (3S)-methyl7-hydroxy-5-oxo-octahydroindridine-3-cal A solution of voxylate (1g) in DCM (100mL) contains pyridinium chlorochromate ( 2 g (9.38 mmol, 2.0 equivalents) was added. The resulting mixture was stirred at room temperature for 16 hours. Mixed. Remove the solvent under reduced pressure, and the residue was chromatographed using silica gel column chromatography (EA / P). Purified by E), (3S)-methyl5,7-dioxo-octahydroindrine -3-carboxylate was obtained as a yellow oil.

[0223] Example 3: Three intermediate compounds of formula (VI-A) Methyl(3S,8aR)-5-oxo-7-(((trifluoromethyl)sulfonyl) Oxy)-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate to

[0224] [ka]

[0225] Step 1: 7-benzyl-1-methyl(S)-2-((tert-butoxycarbonyl) Synthesis of mino-5-oxoheptanediate In a 10L three-necked round-bottom flask that has been purged and maintained in an inert atmosphere of nitrogen, the THF is used. 1M LDA (1132.2 mL, 1.00 equivalent), solvent THF (3400.00 mL) Add the following, and then stir at -78°C: benzyl acetate (170.00g, 1131 A solution of 0.998 mmol (1.00 equivalent) in THF (850.0 mL) was added dropwise. The prepared solution was stirred at -78°C for 30 minutes. Then, while stirring at -78°C, 1 -tert-butyl2-methyl(2S)-5-oxopyrrolidine-1,2-dicarboxy THF (850) of rate (275.37g, 1131.998 mmol, 1.00 equivalent) The solution in 0.0 mL was added dropwise. The resulting solution was maintained at room temperature overnight with stirring, and then, The solution was quenched by adding 5000 mL of NH4Cl. The resulting solution was then mixed with ethyl acetate (3 Extraction was performed using (4000 mL). The resulting mixture was washed with brine (1 × 1000 mL). The resulting mixture was dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was then vinegared. Purified by silica gel column elution with ethyl acid / petroleum ether (1:9), 7-B 1-methyl(2S)-2-[(tert-butoxycarbonyl)amino]-5-O Xosoheptanediate was obtained as a yellow oil.

[0226] Step 2: Methyl(S,Z)-5-(2-(benzyloxy)-2-oxoethylidene) Synthesis of pyrrolidine-2-carboxylate 7-benzyl 1-Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-5-oxohe Butanediate (290.00g, 1.00 equivalent) and TFA (469.50g, 6. (00 equivalents) was added. The resulting solution was stirred at room temperature for 2 hours, and then concentrated under vacuum. Most of the TFA was removed. The pH of the solution was adjusted to 8 with Na2CO3. The resulting solution The organic phase was extracted using DCM (3 x 500 mL). The combined organic phase was then treated with brine (1 x 500 mL). The mixture was washed. The mixture was dried with anhydrous sodium sulfate and concentrated under vacuum, then methyl (2S) was added. ,5Z)-5-[2-(benzyloxy)-2-oxoethylidene]pyrrolidine-2-ca Luboxylate was obtained as a semi-solid.

[0227] Step 3: 1-(tert-butyl)2-methyl(2S,5R)-5-(2-(benzyl Synthesis of oxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate. In a 5000 mL autoclave, methyl(2S,5Z)-5-[2-(benzyl oxyphosphate) [C)-2-oxoethylidene]pyrrolidine-2-carboxylate (175.00g, 6 35.661mmol, 1.00eq), MeOH (3500.00mL), (Boc) 2O (138.73g, 635.661 mmol, 1.00 equivalent), and PtO2 (43 (0.30 g, 190.698 mmol, 0.30 equivalents) was added. The resulting mixture was then subjected to a hydrogen atmosphere. The reaction was carried out under atmospheric pressure (15 atm). The resulting solution was stirred at 35°C for 12 hours. Precipitation The substance is filtered off, and the filtrate is concentrated to obtain 1-(tert-butyl)2-methyl(2S,5R)-5 -(2-(benzyloxy)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate We obtained a sample and used it directly in the next step.

[0228] Step 4: Methyl(2S,5R)-5-(2-(benzyloxy)-2-oxoethyl) Synthesis of pyrrolidine-2-carboxylate hydrochloride Purged under an inert nitrogen atmosphere and maintained, 1,4-diodeoxycholic acid was added to a 5000 mL round-bottom flask. Xan (220.00 g, 4,000 mmol, 5.00 equivalents) contains 1-tert-butyl 2-methyl(2S,5R)-5-[2-(benzyloxy)-2-oxoethyl]pylori Zin-1,2-dicarboxylate (244.00 g, 1.00 equivalent), DCM (244 0.00 mL of HCl (gas) was added. The resulting solution was stirred at room temperature for 3 hours. The product is concentrated to obtain methyl(2S,5R)-5-[2-(benzyloxy)-2-oxoye [Cyl]pyrrolidine-2-carboxylate hydrochloride was obtained as a yellow oil.

[0229] Step 5: Methyl(2S,5R)-5-(2-(benzyloxy)-2-oxoethyl) -1-(3-methoxy-3-oxopropanoyl)pyrroridine-2-carboxylate synthesis A 5000 mL three-necked round-bottom flask, purged and maintained under an inert nitrogen atmosphere, was then filled with methyl Lu(2S,5R)-5-[2-(benzyloxy)-2-oxoethyl]pyrrolidine-2 -Carboxylate (197.00g, 710.371 mmol, 1.00 equivalent), DM F (1970.00 mL) and 1-methyl-3-potassium propanediol (221.8 9g (1420.741 mmol, 2.00 equivalents) was added. Following this, pyridine ( 140.48 g (1775.927 mmol, 2.50 equivalents) was added at 0°C. To the resulting mixture, add T3P (452.05 g, 1420.742 mmol, 2.00 equivalent). A quantity of (20) was added at 0°C. The resulting solution was stirred at 25°C for 12 hours. Then, water (20 The reaction mixture is quenched by adding ethyl acetate (3 × 2000 mL). Extracted using ). The combined organic phase was washed with brine (1 × 2000 mL). The mixture was then treated with The residue was dried with anhydrous magnesium sulfate and concentrated. The resulting residue was then processed under the following conditions: F Purified by lash-Prep-HPLC (IntelFlash-1): Column , C 18 Silica gel; mobile phase, ACN-H2O = 45 to ACN-H2O = within 20 minutes Increased to 60, methyl(2S,5R)-5-[2-(benzyloxy)-2-oxoethyl ]-1-(3-methoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate It was obtained as yellow oil.

[0230] Process 6: 2-((2R,5S)-1-(3-methoxy-3-oxopropanoyl)-5 Synthesis of (methoxycarbonyl)pyrrolidine-2-yl)acetic acid In a 3000 mL round-bottom flask, add methyl(2S,5R)-5-[2-(benzyloxy )-2-oxoethyl]-1-(3-methoxy-3-oxopropanoyl)pyrrolidine- 2-carboxylate (151.00 g), IPA (1510.00 mL), and Pd / C (15.10g) was added. The resulting suspension was stirred at room temperature under 2 atmospheres of H2 for 2 hours. The precipitate is filtered off, and the filtrate is concentrated to obtain [(2R,5S)-1-(3-methoxy-3-oxo [Propanoyl)-5-(methoxycarbonyl)pyrrolidine-2-yl]acetic acid is used as a yellow oil. I obtained it.

[0231] Step 7: Dimethyl(3S,8aR)-5,7-Dioxooctahydroindidine-3 Synthesis of ,6-dicarboxylate Purged under an inert nitrogen atmosphere and maintained in a 5000 mL three-neck round-bottom flask, [(2 R,5S)-1-(3-methoxy-3-oxopropanoyl)-5-(methoxycarbonyl) [Pyrrolidine-2-yl]acetic acid (104.00g, 362.031mmol, 1.00 (Equivalent), THF (3120.00 mL) and CDI (88.05 g, 543.047 ml) (1.50 equivalents of ol) was added. The resulting mixture was stirred at room temperature for 0.5 hours. Then, Add DBU (82.67 g, 543.047 mmol, 1.50 equivalents) to the resulting mixture. The mixture was stirred at room temperature for 2 hours, and then the addition of water / ice (2000 mL) was performed. Quenched. The pH of the solution was adjusted to pH 3 using HCl (2 mol / L). The solution was extracted with DCM / MeOH = 3:1 (3 × 1500 mL) and anhydrous sodium sulfate. It is dried and concentrated, and 3,6-dimethyl(3S,8aR)-5,7-dioxohexa Hydroindridine-3,6-dicarboxylate was obtained as a pale yellow oil.

[0232] Step 8: Methyl(3S,8aR)-5,7-dioxooctahydroindridine-3- Synthesis of carboxylates In a 3000 mL round-bottom flask, add 3,6-dimethyl(3S,8aR)-5,7-dioxo -Hexahydroindolidine-3,6-dicarboxylate (94.00g, 1.00g) Add (amount) and AcOH (940.00 mL). The resulting solution was incubated at 110°C for 30 minutes. The mixture was stirred. The resulting solution was extracted with DCM / MeOH = 2:1 (3 × 2000 mL) and then... Dry with sodium hydroxide sulfate and concentrate to methyl(3S,8aR)-5,7-dioxo Hexahydroindridine-3-carboxylate was obtained as a yellow oil.

[0233] Step 9: Methyl(3S,8aR)-5-oxo-7-(((trifluoromethyl)sulfite Honyl)oxy)-1,2,3,5,8,8a-Hexahydroindolidine-3-carb xylate synthesis Purged under an inert nitrogen atmosphere, a 3000 mL round-bottom flask was filled with methyl (3) S,8aR)-5,7-Dioxo-hexahydroindidine-3-carboxylate ( 55.00g, 1.00 eq), DCM (1100.00mL), DIEA (67.38 g (2.00 equivalents) and PhNTf2 (111.73 g, 1.20 equivalents) were added. The prepared solution was stirred at room temperature for 4 hours. The resulting mixture was then converted to NaHCO3 (2 × 2000 mL). The mixture was washed. The resulting mixture was concentrated under vacuum, and the residue was treated with PE / EA=1 / 4. Purified by Ricagel, methyl(3S,8aR)-5-oxo-7-(trifluoromethyl) Tansulfonyloxy)-1,2,3,5,8,8a-Hexahydro-1H-Indride n-3-carboxylate was obtained as a white solid.

[0234] Example 4: Intermediate 4 (6-amino-3-chloro-2-fluorophenyl)boronic acid

[0235] [ka]

[0236] Step 1: N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetate Synthesis of toamide 4-Chloro-3-fluorobenzeneamine (20g, 137.398 mmol, 1.0 E of 0 equivalents) and Na2CO3 (24.7g, 233.577 mmol, 1.70 equivalents) In a mixture in t2O (400 mL), TFAA (34.6 g, 164.878 mmol, 1 (0.20 equivalents) was added dropwise while stirring at -10°C. The resulting mixture was warmed overnight to room temperature. Next, it was diluted with hexane (400 mL) and filtered. The filtrate was then saturated with sodium bicarbonate. Wash with solution (2 x 200 mL) and brine (2 x 200 mL), then dry with Na2SO4. The filtrate was filtered. The filtrate was concentrated to obtain N-(4-chloro-3-fluorophenyl)-2,2,2 - Trifluoroacetamide was obtained as a white solid.

[0237] Step 2: Synthesis of 6-amino-3-chloro-2-fluorophenylboronic acid Under an inert atmosphere of nitrogen, N-(4-chloro-3-fluorophenyl)-2,2,2- Trifluoroacetamide (30g, 124.188 mmol, 1.00 equivalent) THF (500 mL) Mixture contains n-BuLi (99 mL, 248.375 mmol, 2.0 0 equivalents (2.5 M in hexane) were added dropwise while stirring at -78°C. The resulting mixture was then prepared. The mixture was stirred at 78°C for 15 minutes, and then heated to -50°C. The resulting clear brown solution was then heated to -78°C. Cool to °C, then add B(O-iPr)3(51.3g, 273.213 mmol, 2. 20 equivalents were added dropwise. The mixture was stirred at -78°C for 10 minutes, and then warmed to room temperature. The resulting orange suspension was stirred at room temperature for 4 hours, then cooled in an ice bath, and dissolved in 1M HCl(3 Quenched with 00 mL. The resulting mixture was stirred overnight at room temperature, then toluene (3 Extraction was performed using 00 mL x 3, dried with Na2SO4, and filtered. The filtrate was concentrated, and the residue was removed. Recrystallized (siRNA / PE:1 / 10), 6-amino-3-chloro-2-fluorophosphate Phenylboronic acid was obtained as a white solid.

[0238] Example 5: Compound of formula (IA) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one

[0239] [ka]

[0240] Step 1: 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluor Synthesis of lopyridine (3-Fluoropyridine-2-yl)methanol (15.0g, 118.002mO) In a solution of 1.0 equivalent (1 / 1) in DMF (200 mL), add imidazole (16.1 g, 236 Add 0.496 mmol (2.0 equivalents), followed by tert-butylchlorodimethylsilamine. (21.3g, 141.320 mmol, 1.2 equivalents) was added. The mixture was left at room temperature. Stirred overnight. The reaction mixture was quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3×400 mL) and then washed with water (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 - 30% PE / EA) to give 2 - ((((tert - butyl dimethylsilyl)oxy)methyl) - 3 - fluoropyridine as a yellow oil. LC / MS: C 12 H 20 Mass calculated for FNOSi: 241.13, measured: 24 2.10 [M + H] + .

[0241] Step 2: Synthesis of 2 - ((((tert - butyldimethylsilyl)oxy)methyl) - 3 - fluoro - 4 - iodopyridine To a solution of 2 - ((((tert - butyldimethylsilyl)oxy)methyl) - 3 - fluoropyridine (24.0 g, 99.430 mmol, 1.0 eq) in THF (400 mL) , LDA (59.7 mL, 119.4 mmol, 1.2 eq) was added at - 78 °C. The mixture was stirred at - 78 °C for 0.5 h. Then, to the resulting mixture, a solution of iodine (30.3 g , 119.381 mmol, 1.2 eq) in THF (60 mL) was added at - 78 °C . The mixture was stirred at - 78 °C for 3 h. The reaction mixture was quenched with NH4Cl solution (200 mL) and extracted with ethyl acetate (3×400 mL). The combined extracts were washed with water, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0 - 30% EA / PE) to give 2 - ((((tert - butyldimethylsilyl)oxy)methyl) - 3 - fluoro - 4 - iodopyridine as a white solid. L​​​​​​ C / MS:C 12 H 19 Mass calculated for FINOSi: 367.03, measured value: 368.20[M+H] + .

[0242] Step 3: 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1- Synthesis of ethoxyvinyl-3-fluoropyridine 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4- Iodopyridine (20.0 g, 54.455 mmol, 1.0 equivalent) and bis(trife) Nylphosphine) Palladium(II) Chloride (3.8g, 5.414mmol, 0.1 In a solution of equivalent volume of 1,4-dioxane (200 mL), add tributyl (1-ethoxyvinyl Stanan (29.5g, 81.683 mmol, 1.5 equivalents) was added. Mixture 9 The mixture was stirred at 0°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water (200 mL), and then... Then, it was extracted with ethyl acetate (3 x 300 mL). The organic layers were combined with anhydrous sodium sulfate. The mixture was dried, filtered, and concentrated. The resulting residue was subjected to Al2O3 chromatography (0-5). Purified with 0% ethyl acetate / petroleum ether, then 2-(((tert-butyldimethyl Silyl(oxy)methyl)-4-(1-ethoxyvinyl)-3-fluoropyridine is yellow Obtained as oil. LC / MS:C 16 H 26 Calculated mass for FNO2Si: 311 0.17, measured value 312.15 [M+H] + .

[0243] Step 4: 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy) Synthesis of thyl-3-fluoropyridine-4-yl)ethane-1-one 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxy Vinyl-3-fluoropyridine (15g, 48.159 mmol, 1.0 equivalent) TH In a mixture of F (120 mL) and H2O (30 mL), add NBS (8.6 g, 48.31 g) mmol (1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 2 hours. Then, the resulting Dilute the mixture with ethyl acetate (700 mL), wash with brine (3 × 200 mL), and rinse with N Dry with a2SO4 and concentrate to 2-bromo-1-(2-(((tert-butyldimethyl (Tylsilyl)oxy)methyl)-3-fluoropyridine-4-yl)ethane-1-one It was obtained as an off-white solid. LC / MS:C 14 H 21 Calculation for BrFNO2Si Mass measured: 361.05, Measured value: 362.00 [M+H] + .

[0244] Step 5: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- Fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino-3-k (Lolo-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydro Synthesis of indoridine-3-carboxylate (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-Hexahydroindolidine-3-carboxylic acid (9.3g, 28 (0.64 mmol, 1.0 equivalent) and Cs2CO3 (5.6 g, 17.18 mmol, 0. The mixture in 6 equivalents of DMF (90 mL) was stirred at 40°C for 30 minutes. Then, 2-bromfed Mo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluor Lopyridine-4-yl)ethane-1-one (14.5g, 40.09 mmol, 1.4 units) The mixture was stirred at room temperature for 4 hours after adding (amount) HCl (900 ml). Dilute with (L), wash with water (3 x 150 mL) and brine (2 x 150 mL), then Na2S The residue was dried with O4 and concentrated. The resulting residue was analyzed on a silica gel column (330g, MeOH / Applicable to DCM:1 / 20), 2-(2-(((tert-butyldimethylsilyl)o Xy(methyl)-3-fluoropyridine-4-yl)-2-oxoethyl(3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a-Hexahydroindridine-3-carboxylate was obtained as a pale yellow solid. C / MS:C 29 H 34 Calculated mass for ClF2N3O5Si: 605.19 Measured value: 606.15 [M+H] + .

[0245] Step 6: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-( 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoromethyl Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Synthesis of loindridine-5(1H)-one Under an inert atmosphere of nitrogen, 2-(2-(((tert-butyldimethylsilyl)oxy )methyl)-3-fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6 -amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8 α-Hexahydroindridine-3-carboxylate (15.0g, 24.75mmo) (1.0 equivalent) and NH4OAc (19.1 g, 247.47 mmol, 10.0 equivalent) The mixture of ) in AcOH (30 mL) and toluene (300 mL) was stirred at 110°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was analyzed using a silica gel column (330 g, Me Apply to OH / DCM:1 / 15) and (3S)-7-(6-amino-3-chloro-2- Fluorophenyl)-3-(5-(2-((tert-butyldimethylsilyloxy) (Tyl)-3-fluoropyridine-4-yl)-1H-imidazole-2-yl)-2,3 ,8,8a-tetrahydroindridine-5(1H)-one was obtained as a pale yellow solid. C / MS:C 29 H 34 Calculated mass for ClF2N5O2Si: 585.21 Measured value: 586.15 [M+H] + .

[0246] Step 7: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Synthesis of loindridine-5(1H)-one (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2 -((tert-butyldimethylsilyloxy)methyl)-3-fluoropyridine-4- Il)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindolide N-5(1H)-ON (8g, 13.648 mmol, 1.00 equivalent), TMSN3(1 5.724 g, 136.484 mmol, 10.00 equivalents) and trimethoxymethane (1 Mix 4.484g, 136.484 mmol, 10.00 equivalents of AcOH (60mL) The mixture was stirred overnight at 55°C. The resulting mixture was concentrated under reduced pressure. The residue was subjected to C18 reverse phase. Column (330g, ACN / H2O (0.05%NH4HCO3): 5%>>>35%> >>Applicable to 40%), (3S)-7-(3-chloro-2-fluoro-6-(1H-tetra Trazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl (Lu)pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-teto Lahydroindridine-5(1H)-one was obtained as a white solid. The white solid was then prepared by Prep- SFC (Column: Exsil Chiral-NR, 250mm) * 30mm, 8um; transfer Dynamic phase A: CO2, Mobile phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 1 00 mL / min; gradient: 50% B; 220 nm; RT1: 6.78, RT2: 8.45, Note Further purification was performed using (3S,8aR)-7-(3- Chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-3-(5- (3-fluoro-2-(hydroxymethyl)pyridine-4-yl)-1H-imidazole -2-yl)-2,3,8,8a-tetrahydroindoridine-5(1H)-one is white It was obtained as a solid.

[0247] 1 H NMR(400MHz,DMSO-d6)δ 12.25(s,1H),9.8 2(s,1H),8.32(d,J=5.0Hz,1H),7.95(t,J=8.7H z,1H),7.88(t,J=5.4Hz,1H),7.70(d,J=8.7Hz, 1H),7.55(d,J=3.9Hz,1H),5.68(d,J=2.6Hz,1H ),5.26(t,J=5.9Hz,1H),5.02(d,J=8.7Hz,1H), 4.61(dd,J=5.9,2.3Hz,2H),3.68-3.75(m,1H), 2.67-2.75(m,1H),2.52-2.54(m,1H),2.14-2.2 1(m,1H),2.05-2.11(m,1H),1.93-1.97(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -112.85,-130.14 LC / MS:C 24 H 19 Calculated mass for ClF2N8O2: 524.13 Measured value: 525.10 [M+H] + .

[0248] Example 6: Compound of formula (IB) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl-4-d)-2,3,8,8a-tetrahydro Loindrindidine-5(1H)-one

[0249] [ka]

[0250] Step 1: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-4-indo-1H-imidazole-2-yl)-2,3,8,8a Synthesis of tetrahydroindridine-5(1H)-one (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one (180 mg, 0.343 mmol, 1.0 equivalent) and NIS Mixture of (77 mg, 0.342 mmol, 1.0 equivalent) in DMF (8 mL) at room temperature for 2 hours. The mixture was stirred for a certain amount of time. The resulting mixture was diluted with HCl (80 mL) and water (4 × 20 mL). The solution was washed with brine (2 x 20 mL), dried with Na2SO4, and concentrated. The residue was then processed. Applied to a ricagel column (40g, MeOH / DCM: 1 / 15), (3S, 8aR) -7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl) -3-(5-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)-4-yl) (-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindolidine -5(1H)-one was obtained as a pale yellow solid. LC / MS:C 24 H 18 ClF2IN8 Calculated mass for O2: 650.03, measured mass: 650.95 [M+H] + .

[0251] Step 2: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-1H-imidazole-2-yl-4-d)-2,3,8,8a-te Synthesis of trahydroindolidine-5(1H)-one (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-4-iodo-1H-imidazole-2-yl)-2,3,8,8a-tetra Hydroindolidine-5(1H)-one (210 mg, 0.323 mmol, 1.0 equivalent) ) and Zn (211 mg, 3.226 mmol, 10.0 equivalents) CD3COOD (8m The mixture in L) and D2O (4 mL) was stirred at room temperature for 10 minutes. The resulting mixture was filtered. The filtrate was concentrated. The residue was analyzed using a C18 reversed-phase column (330g, ACN / H2O (0.05%)). Applied to NH4HCO3):5%>>>40%>>>40%), (3S,8aR)-7 -(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-3 -(5-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)-1H-imi Dazole-2-yl-4-d)-2,3,8,8a-tetrahydroindolidine-5(1 H)-one was obtained as a pale yellow solid.

[0252] 1 H NMR(400MHz,DMSO-d6)δ 12.30(br,1H),9. 84(s,1H),8.30-8.40(m,1H),7.97(t,J=7.9Hz, 1H),7.89(t,J=5.4Hz,1H),7.71(dd,J=8.7,1.5 Hz,1H),5.70(d,J=2.7Hz,1H),5.13-5.50(m,1H ),5.05(d,J=8.7Hz,1H),4.64(s,2H),3.65-3.8 3(m,1H),2.62-2.83(m,1H),2.53-2.60(m,1H), 2.05-2.30(m,2H),1.83-2.04(m,2H); 19 F NMR ( 376MHz,DMSO-d6)δ-112.51,-130.07;LC / MS:C2 4H 18 Calculated mass for ClDF2N8O2: 525.14, measured mass: 526. 15[M+H] + .

[0253] Example 7A: Compound of formula (IC) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyri (Zin-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Indoridine-5(1H)-one

[0254] [ka]

[0255] Step 1: Synthesis of (3-fluoropyridine-2-yl)methane-d2-ol E of methyl 3-fluoropicolinate (5g, 32.232 mmol, 1.00 equivalent) Mixture in tOH (80 mL): NaBD4 (4.0 g, 96.696 mmol, 3.0 The equivalent amount was divided and added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. Then, the reaction was carried out. The solution was quenched with saturated ammonium chloride solution (60 mL). EtOH solvent was added to ROTO It was removed by reduced-pressure evaporation using VAP. Then, the resulting mixture was dimethylated (3 × 1 Extract with (00 mL), dry with Na2SO4, concentrate, and (3-fluoropyridine-2) -yl)methane-d2-ol was obtained as a pale yellow solid.

[0256] Step 2: 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3- Synthesis of fluoropyridine (3-Fluoropyridine-2-yl)methane-d2-ol (3.2g, 24.781) mmol (1.0 equivalent) and TBSCl (5.6 g, 37.172 mmol, 1.5 equivalents) A mixture of ) in DMF (60 mL) contains Et3N (7.5 g, 74.344 mmol, 3. (0 equivalents) was added. The resulting mixture was then stirred at room temperature for 5 hours. The resulting mixture Dilute with ethyl acetate (600 mL), add water (3 x 150 mL), and brine (2 x 150 mL) Washed with L), dried with Na2SO4, and concentrated. The residue was collected on a silica gel column (80g). Applied to , siRNA / PE:1 / 3), 2-(((tert-butyldimethylsilyl )Oxy)methyl-d2)-3-fluoropyridine was obtained as a pale yellow solid. LC / MS :C 12 H 18 Calculated mass for D2FNOSi: 243.14, measured mass: 244 .10[M+H] + .

[0257] Step 3: 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3- Synthesis of fluoro-4-iodopyridine Under an inert atmosphere of nitrogen, 2-(((tert-butyldimethylsilyl)oxy)methyl Lu-d2)-3-fluoropyridine (4.8g, 19.721mmol, 1.00 equivalent) In a mixture of THF (120 mL), LDA (11.8 mL, 23.666 mmol, Add 1.2 equivalents (2M in THF) at -78°C, and leave the resulting mixture at -78°C for 30 minutes. The mixture was stirred. Then, I2(5.5g, 21.694 mmol, 1.1) was added to the resulting mixture. The solution in 25 mL of THF (equivalent volume) was added at -78°C. The mixture was incubated at -78°C for 2 hours. Stirring. Quench the resulting mixture with saturated ammonium chloride solution (200 mL) and E Extracted with tOAc (3 × 200 mL), dried with Na2SO4, and concentrated. The residue was then processed. Apply to a licagel column (80g, toluene / PE:1 / 4) and 2-(((tert -Butyldimethylsilyl)oxy)methyl-d2)-3-fluoro-4-iodopyridine It was obtained as a pale yellow solid.

[0258] Step 4: 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-4- Synthesis of (1-ethoxyvinyl)-3-fluoropyridine Under an inert atmosphere of nitrogen, 2-(((tert-butyldimethylsilyl)oxy)methyl Lu-d2)-3-fluoro-4-iodopyridine (2.7g, 7.311mmol, 1. (0 equivalents), tributyl(1-ethoxyvinyl) stanane (5.3g, 14.623 mmol) (1, 2.0 equivalents) and Pd(PPh3)4 (845 mg, 0.731 mmol, 0.1 equivalents) The mixture in 1,4-dioxane (50 mL) was stirred overnight at 100°C. The mixture was concentrated, and the residue was applied to a silica gel column (80g, .'' / PE:1 / 3). Then, 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-4-(1 Ethoxyvinyl)-3-fluoropyridine was obtained as a yellow solid. LC / MS:C 16 H 24 Calculated mass for D2FNO2Si: 313.18, measured mass: 314.10 [M+H] + .

[0259] Step 5: 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy) Synthesis of til-d2)-3-fluoropyridine-4-yl)ethane-1-one 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-4-(1-E Toxyvinyl-3-fluoropyridine (2.5g, 7.975mmol, 1.0 equivalent) In a mixture of THF (60 mL) and H2O (20 mL), add NBS (1.4 g, 7.975 An mmol (1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture Next, dilute with ethyl acetate (500 mL), wash with brine (3 x 100 mL), and then Na2 Dry with SO4 and concentrate to 2-bromo-1-(2-(((tert-butyldimethyl Silyl(oxy)methyl-d2)-3-fluoropyridine-4-yl)ethane-1-one It was obtained as a pale yellow oil.

[0260] Step 6: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2) -3-Fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino- 3-Chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexa Synthesis of hydroindolidine-3-carboxylate (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-Hexahydroindolidine-3-carboxylic acid (2.4g, 7. (391 mmol, 1.0 equivalent) and Cs2CO3 (1.4 g, 4.434 mmol, 0. The mixture in 60 mL of DMF (6 equivalents) was stirred at 40°C for 30 minutes. Then, 2-bromfed Mo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3- Fluoropyridine-4-yl)ethane-1-one (2.7g, 7.391mmol, 1. (0 equivalents) was added, and the mixture was stirred at room temperature for 4 hours. Then, the resulting mixture was mixed with EtOA Dilute with c (500 mL), then wash with water (3 x 100 mL) and brine (2 x 100 mL). The solution was dried with Na2SO4 and concentrated. The residue was analyzed using a silica gel column (80g, MeOH). Apply to / DCM:1 / 20) and 2-(2-(((tert-butyldimethylsilyl) Oxy)methyl-d2)-3-fluoropyridine-4-yl)-2-oxoethyl(3S )-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3 5,8,8a-Hexahydroindolidine-3-carboxylate was obtained as a yellow solid. . LC / MS:C 29 H 32 Calculated mass for ClD2F2N3O5Si: 60 7.20, Measured value: 608.15 [M+H] + .

[0261] Step 7: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-( 4-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-full Olopyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-teto Synthesis of lahydroindridine-5(1H)-one Under an inert atmosphere of nitrogen, 2-(2-(((tert-butyldimethylsilyl)oxy) Methyl-d2)-3-fluoropyridine-4-yl)-2-oxoethyl(3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a-Hexahydroindolidine-3-carboxylate (3.5g, 5.755mg) (1.0 equivalent) and NH4OAc (3.5g, 46.042 mmol, 8.0 equivalents) The mixture in AcOH (10 mL) and toluene (100 mL) was stirred at 110°C for 1 hour. The resulting mixture was concentrated. The residue was analyzed using a silica gel column (80g, MeOH / DCM). Apply to 1 / 15) and (3S)-7-(6-amino-3-chloro-2-fluorophenyl Nyl)-3-(4-(2-(((tert-butyldimethylsilyl)oxy)methyl-d 2)-3-fluoropyridine-4-yl)-1H-imidazole-2-yl)-2,3, 8,8a-tetrahydroindridine-5(1H)-one was obtained as a pale yellow solid. LC / MS:C 29 H 32 Calculated mass for ClD2F2N5O2Si: 587.23 Measured value: 588.15 [M+H] + .

[0262] Step 8: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d 2) Pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-teto Synthesis of lahydroindridine-5(1H)-one (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(2 -(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyrrheal (Zin-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Indoridine-5(1H)-ONE (2.8g, 4.761 mmol, 1.0 equivalent), TM SN3 (5.5g, 47.606 mmol, 10.0 equivalents) and trimethoxymethane (5 Mix 0.1g, 47.606 mmol, 10.0 equivalents) in 50mL of AcOH (55 The mixture was stirred overnight at °C. The resulting mixture was concentrated. The residue was C 18 Reverse-phase column (330g, Applicable to ACN / H2O (0.05% NH4HCO3): 5% >>> 35% >>> 40%) (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-i Phenyl-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyridine -4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroin Dridine-5(1H)-one was obtained as a white solid. The white solid was then processed using Prep-SFC (color M: Exsil Chiral-NR, 250mm * 30mm, 8um; Mobile phase A: CO 2. Mobile phase B: MeOH (0.5% 2M NH3-MeOH)-HPLC; flow rate: 10 0 mL / min; gradient: 45%B; 220 nm; RT1: 9.02; RT2: 11.5; injection Further purification was performed using (3S,8aR)-7-(3) (Volume: 4.8 ml; Number of operations: 13). -Chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-3-(4 -(3-fluoro-2-(hydroxymethyl-d2)pyridine-4-yl)-1H-imi Dazole-2-yl)-2,3,8,8a-tetrahydroindolidine-5(1H)-ol The substance was obtained as a white solid.

[0263] 1 H NMR(400MHz,DMSO-d6)δ 12.27(s,1H),9.8 5(s,1H),8.35(d,J=5.0Hz,1H),7.98(t,J=8.0H z,1H),7.90(t,J=5.4Hz,1H),7.72(dd,J=8.7,1 .5Hz,1H),7.58(d,J=1.6Hz,1H),5.71(d,J=2.8 Hz,1H),5.24(s,1H),5.05(d,J=8.7Hz,1H),3.6 5-3.84(m,1H),2.73(t,J=15.4Hz,1H),2.54-2. 62(m,1H),2.17-2.30(m,1H),2.06-2.16(m,1H) ,1.89-2.05(m,2H); 19 F NMR (376MHz, DMSO-d6) δ-112.85,-130.23;LC / MS:C 24 H 17 To ClD2F2N8O2 In contrast, the calculated mass was 526.14, while the measured mass was 527.05 [M+H]. + .

[0264] Example 7B: Compound of formula (IC) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyri (Zin-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Indoridine-5(1H)-one

[0265] [ka]

[0266] Step 1: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2) -3-Fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino- 3-Chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexa Hydroindolidine-3-carboxylate ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-Hexahydroindridine-3-carboxylic acid (260 mg, (0.80 mmol, 1.0 equivalent) and Cs2CO3 (156 mg, 0.48 mmol, 0 The mixture in 0.6 equivalents of DMF (12 mL) was stirred at 40°C for 30 minutes. Then, 2-B Romo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3 -Fluoropyridine-4-yl)ethane-1-one (437 mg, 1.20 mmol, 1 (0.5 equivalents) was added to the mixture. The reaction mixture was stirred at room temperature for 4 hours. Then, the resulting Dilute the mixture with EA (120 mL), add water (3 x 30 mL), and brine (2 x 20 mL). Washed, dried with Na2SO4, and concentrated. Residue was collected on a silica gel flash column. Purified by chromatography (0 → 10% MeOH / DCM), 2-(2-((( tert-butyldimethylsilyl(oxy)methyl-d2)-3-fluoropyridine-4 -yl)-2-oxoethyl(3S)-7-(6-amino-3-chloro-2-fluorophosphate (enyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolidine-3-ca The ruboxylate was obtained as a yellow solid. LC / MS:C 29 H 32 ClD2F2N3O5 Calculated mass for Si: 607.20, measured mass: 608.10 [M+H] + .

[0267] Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-( 4-(3-fluoro-2-(hydroxymethyl-d2)pyridine-4-yl)-1H-yl Midazole-2-yl)-2,3,8,8a-tetrahydroindolidine-5(1H)- on 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-f Luoropyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino-3-chloro) (-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydrophenyl Andridine-3-carboxylate (280 mg, 0.46 mmol, 1.0 equivalent) and NH4OAc (355 mg, 4.60 mmol, 10.0 eq.) in AcOH (3 mL) and Stir the mixture in toluene (30 mL) at 110°C for 1 hour, then cool to room temperature. The solution was concentrated under reduced pressure. The residue was analyzed by flash column chromatography using silica gel (0-9%). Purified by MeOH / DCM, (3S)-7-(6-amino-3-chloro-2- Fluorophenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyri (Zin-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Indoridine-5(1H)-one was obtained as a yellow solid. LC / MS:C 23 H 18 Cl Calculated mass for D2F2N5O2: 473.14, measured mass: 474.05 [M+ H] + .

[0268] Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d 2) Pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-teto Lahydroindoridine-5(1H)-one ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-( 3-Fluoro-2-(hydroxymethyl-d2)pyridine-4-yl)-1H-imidazo (-2-yl)-2,3,8,8a-tetrahydroindolidine-5(1H)-one 200mg, 0.422mmol, 1.00eq), TMSN3 (486mg, 4.22 mmol, 10.0 equivalents) and trimethoxymethane (448 mg, 4.22 mmol, 1 The mixture in 0.0 equivalent (10 mL) AcOH was stirred at 50°C for 4 hours, and then under reduced pressure. The solution was concentrated using [method]. The residue was analyzed by flash column chromatography using silica gel (0→10%M). Purified by eOH / DCM, (3S)-7-(3-chloro-2-fluoro-6-( 1H-tetrazole-1-yl)phenyl)-3-(4-(3-fluoro-2-(hydro Xymethyl-d2)pyridine-4-yl)-1H-imidazole-2-yl)-2,3, 8,8a-tetrahydroindridine-5(1H)-one was obtained as a pale yellow solid, and this Further purification by chiral HPLC yielded (3S,8aR)-7-(3-chloro-2-flu). Oro-6-(1H-tetrazole-1-yl)phenyl)-3-(4-(3-fluoro- 2-(hydroxymethyl-d2)pyridine-4-yl)-1H-imidazole-2-yl )-2,3,8,8a-tetrahydroindridine-5(1H)-one as a white solid I got it.

[0269] LC / MS:C 24 H 17 Calculated mass for ClD2F2N8O2: 526.1 4. Measured value (ES, m / z): 527.05 [M+H] + . 1 1H NMR (400MHz) ,DMSO-d6)d 12.27(s,1H),9.85(s,1H),8.35(d ,J=5.0Hz,1H),7.98(t,J=8.0Hz,1H),7.90(t,J =5.4Hz,1H),7.72(dd,J=8.7,1.5Hz,1H),7.58( d,J=1.6Hz,1H),5.71(d,J=2.8Hz,1H),5.24(s, 1H),5.05(d,J=8.7Hz,1H),3.65-3.84(m,1H),2 .73(t,J=15.4Hz,1H),2.54-2.62(m,1H),2.17- 2.30(m,1H),2.06-2.16(m,1H),1.89-2.05(m,2 H). 19 F NMR(376MHz,DMSO-d6)d -112.85,-130 .twenty three

[0270] Example 8: Compound of formula (ID) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one-8a-d

[0271] [ka]

[0272] Step 1: 2-(2-((((tert-butyldimethylsilyl)oxy)methyl)-3 -Fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(3-chloro-2- Fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1,2,3 ,5,8,8a-Hexahydroindolidine-3-carboxylate-8a-d. (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl) Phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindridine-3- Carvone-8a-d acid (300 mg, 0.80 mmol, 1.0 equivalent) CH3CN(1 K2CO3 (142 mg, 1.03 mmol, 1.3 equivalents) was added to the solution in 0 mL. After stirring at room temperature for 0.5 hours, 2-bromo-1-(2-(((tert-butyldimethyl Lucilyl(oxy)methyl(3-fluoropyridine-4-yl)ethane-1-one(4 30 mg (1.20 mmol, 1.5 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The resulting mixture was purified using a silica gel column with MeOH / DCM (0→7%). And, 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-full Olopyridine-4-yl)-2-oxoethyl(3S,8aR)-7-(3-chloro-2) -Fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1,2, 3,5,8,8a-Hexahydroindolidine-3-carboxylate-8a-d is yellow Obtained as oil. LC / MS:C 30 H 32 The calculated quality for DClF2N6O5Si Quantity: 659.20, Measured value (ES, m / z): 660.15 [M+H] + .

[0273] Step 2: (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy )methyl)-3-fluoropyridine-4-yl)-1H-imidazole-2-yl)-7 -(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-2 ,3,8,8a-tetrahydroindolidine-5(1H)-one-8a-d. 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro Pyridine-4-yl)-2-oxoethyl(3S)-7-(3-chloro-2-fluoro- 6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1,2,3,5,8, 8a-Hexahydroindolidine-3-carboxylate-8a-d (380 mg, 0. A solution of 58 mmol, 1.0 equivalent of toluene (10 mL) and acetic acid (1 mL) is prepared by adding acetic acid. Ammonium (665 mg, 8.63 mmol, 15.0 equivalents) was added. Mixture 1 The mixture was stirred at 0°C for 1 hour. The solvent was removed under vacuum, and the residue was collected as MeOH / DCM(0→10 Purified by silica gel column using %), (3S)-3-(5-(2-(((t ert-butyldimethylsilyl(oxy)methyl(3-fluoropyridine-4-yl) -1H-imidazole-2-yl)-7-(3-chloro-2-fluoro-6-(1H-te Trazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindridine-5 (1H)-one-8a-d was obtained as a yellow oil. LC / MS:C 30 H 32 DClF2N Calculated mass for 8O2Si: 639.22, measured value (ES, m / z): 640. 20[M+H] + .

[0274] Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Loindridine-5(1H)-one-8a-d. (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl )-3-fluoropyridine-4-yl)-1H-imidazole-2-yl)-7-(3- Chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-2,3,8 ,8a-tetrahydroindolidine-5(1H)-one-8a-d(280mg, 0.4 In a 4 mmol (1.0 equivalent) solution in THF (5 mL), add triethylamine trihydrof 1.3 mL of ruolid was added. The mixture was stirred at 70°C for 1 hour. The solvent was then removed under vacuum. Remove and collect the residue in a C18 column [Condition: ACN-water-6.5 mM NH4HCO3+NH4] The second residue was purified with 3H2O (5 → 50%) to obtain a second residue. HPLC column: (R,R)WHELK-O1,4.6 * 50mm,3.5um; transfer [Dynamic phase: Hex(0.1%DEA):EtOH=55:45; Flow rate: 1mL / min] After purification, (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Loindolidine-5(1H)-one-8a-d was obtained as an off-white solid.

[0275] LC / MS:C 24 H 18 Calculated mass for ClDF2N8O2: 525.14 Measured value (ES, m / z): 526.10 [M+H] + . 1 1H NMR (400MHz, DMSO-d6)δ 12.25(s,1H),9.84(s,1H),8.34(d, J=5.1Hz,1H),7.94-8.00(m,1H),7.86-7.90(m, 1H),7.71(dd,J=8.6,1.5Hz,1H),7.57(d,J=3.8 Hz,1H),5.70(d,J=2.7Hz,1H),5.23-5.29(m,1H ),5.04(d,J=8.7Hz,1H),4.63(dd,J=6.0,2.3Hz ,2H),2.65-2.77(d,J=16.7Hz,1H),2.52-2.58( m,1H),2.16-2.29(m,1H),2.06-2.14(m,1H),2. 90-2.02 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ - 112.85, -130.16.

[0276] Example 9: Compound of formula (IE) (3S,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one-8a-d

[0277] [ka]

[0278] The title compound was isolated from the second fraction according to the procedure described in Example 8 above, and freeze-dried. The compound was prepared in this manner, and the title compound was obtained as a white solid.

[0279] LC / MS:C 24 H 18 Calculated mass for DClF2N8O2: 525.14 Measured value (ES, m / z): 526.10 [M+H] + . 1 1H NMR (400MHz, DMSO-d6)δ 12.52(s,1H),9.84(s,1H),8.34(d, J=5.1Hz,1H),7.94-8.01(m,1H),7.85-7.92(m, 1H),7.71(dd,J=8.7,1.5Hz,1H),7.62(d,J=3.7 Hz,1H),5.70(d,J=2.7Hz,1H),5.00-5.08(m,1H ),4.64(d,J=2.2Hz,2H),2.42-2.46(m,1H),2.3 1-2.41(m,1H),2.20-2.30(m,1H),1.95-2.08(m ,1H),1.64-1.78(m,1H),1.14-1.28(m,1H). 19 F NMR(376MHz,DMSO-d6)δ -113.06,-129.81.

[0280] Example 10: Compound of formula (IF) (3S,8aR * )-7-(3-chloro-2-fluoro-6-(1H-tetrazole- 1-Iyl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl-d2)py Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Loindridine-5(1H)-one-8a-d

[0281] [ka]

[0282] Step 1: 1-(tert-butyl)2-methyl(2S)-5-methoxypyrrolidine-1 ,2-dicarboxylate-5-d 1-(tert-butyl)2-methyl(2S)-5-hydroxypyrrolidine-1,2- Dicarboxylate-5-d (14g, 56.85 mmol, 1.0 equivalent) MeOH ( In a 140 mL solution, add p-toluenesulfonic acid monohydrate (2.7 g, 14.21 mmol) (1, 0.25 equivalents) was added. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was purified by silica gel column containing EA / PE (0%-35%), and 1- (tert-butyl)2-methyl(2S)-5-methoxypyrrolidine-1,2-dicarb Xylate-5-d was obtained as a yellow oil.

[0283] Step 2: 1-(tert-butyl)2-methyl(2S)-5-((2,2-dimethyl- 4-Oxo-4H-1,3-Dioxin-6-yl)methyl)pyrrolidine-1,2-Dica Luboxylate-5-d 1-(tert-butyl)2-methyl(2S)-5-methoxypyrrolidine-1,2-di Carboxylate-5-d (10g, 38.4mmol, 1.0 equivalent) and ((2,2- Dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy)trimethyl tert-butylmethyl ether (14.0g, 65.32 mmol, 1.7 equivalents) In a 100 mL solution, add BF3·Et2O (6.8 g, 47.91 mmol, 1.2 (5 equivalents) was added over 10 minutes at -40°C. The resulting mixture was stirred at -78°C for 40 minutes. The reaction mixture was heated overnight at ambient temperature. The reaction mixture was then mixed with saturated sodium bicarbonate solution (50 ml). Quenched with L). The resulting mixture was extracted with ethyl acetate (3 × 100 mL). Organic The layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was collected in silica gel. Purified by chromatography (0-40% ethyl acetate / petroleum ether), 1-(ter t-butyl)2-methyl(2S)-5-((2,2-dimethyl-4-oxo-4H-1, 3-Dioxin-6-yl)methyl)pyrrolidine-1,2-dicarboxylate-5-d It was obtained as a yellow oil. LC / MS:C18 H 26 Calculated mass for DNO7: 37 0.19, Measured value: 393.20 [M+H] + .

[0284] Step 3: Methyl(2S)-5-((2,2-dimethyl-4-oxo-4H-1,3-di Oxyn-6-yl)methyl)pyrrolidine-2-carboxylate-5-d 1-(tert-butyl)2-methyl(2S)-5-((2,2-dimethyl-4-oxy So-4H-1,3-dioxin-6-yl)methyl)pyrrolidine-1,2-dicarboxy Solution of Rate-5-d (8g, 21.60 mmol, 1.0 equivalent) in DCM (50 mL) TFA (10 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was then mixed with NaHC. The organic layer was washed with O3 solution (2 × 10 mL) and NaCl solution (1 × 10 mL). Then, dry with anhydrous sodium sulfate, filter, concentrate, and methyl(2S)-5-((2, 2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)methyl)pyrrolidine -2-carboxylate-5-d was obtained as a yellow oil. LC / MS:C 13 H 18 DNO Calculated mass for 5: 270.13, measured value: 213.05 [M+H-CO2Me ] + .

[0285] Step 4: Methyl(3S)-5-oxo-7-(((trifluoromethyl)sulfonyl) Oxy)-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate To-8a-d Methyl(2S)-5-((2,2-dimethyl-4-oxo-4H-1,3-dioxin -6-yl)methyl)pyrrolidine-2-carboxylate-5-d(6g, 22.20mg) The mixture was stirred at 100°C for 1 hour in 60 mL of toluene (mol, 1.0 equivalent). The medium is removed under vacuum, and the residue is collected using silica gel with MeOH / DCM (0%-20%). Purified by rum, methyl(3S)-5,7-dioxooctahydroindidine- 3-carboxylate-8a-d was obtained as a yellow oil.

[0286] Methyl(3S)-5,7-dioxooctahydroindolidine-3-carboxylate -8a-d (1g, 4.71 mmol, 1.0 equivalent) and triethylamine (1.4g, 1,1,1-Trifol (14.14 mmol, 3.0 equivalents) in a 10 mL solution of DCM Luoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfone D (1.7g, 4.71 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL). The resulting mixture was extracted using DCM (1 × 50 mL). The layers were removed and washed with water and NaCl solution (30 mL). The organic layers were combined and anhydrous sodium sulfate was added. The mixture was dried, filtered, and concentrated. The residue was analyzed using silica gel chromatography (0-20% vinegar). Purified by ethyl acid / petroleum ether, methyl(3S)-5-oxo-7-((( Trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydro Indoridine-3-carboxylate-8a-d was obtained as a yellow oil. LC / MS: C1 1H 11 Calculated mass for DF3NO6S: 344.04, measured mass: 345.00 [M+H] + .

[0287] Step 5: Methyl(3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-Oxo-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate ート-8a-d Methyl(3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy) -1,2,3,5,8,8a-Hexahydroindidine-3-carboxylate-8a -d (1g, 2.91 mmol, 1.0 equivalent) of 1,4-dioxane (15 mL) and H (6-amino-3-chloro-2-fluorophenyl)boronic acid in a 2O (2 mL) solution. (1.1g, 5.81 mmol, 1.0 equivalent) was added, followed by K2CO3 (803 mg) , 5.81 mmol, 2.0 equiv.), Pd(dppf)Cl2 (237 mg, 0.29 m (mol, 0.1 equivalent) was added. The resulting mixture was maintained under nitrogen and stirred at 90°C for 2 hours. The mixture was mixed. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL). The resulting mixture The substance was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and dried with anhydrous sodium sulfate. The solution was dried, filtered, and concentrated. The residue was analyzed by silica gel chromatography (0-20% MEOH). Purified by / DCM, methyl(3S)-7-(6-amino-3-chloro-2-flu) Olophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindridine- 3-carboxylate-8a-d was obtained as a brown solid. LC / MS:C 16 H 15 Cl Calculated mass for DFN2O3: 339.09, measured mass: 340.05 [M+H] + .

[0288] Step 6: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-O Kiso-1,2,3,5,8,8a-Hexahydroindolidine-3-Carvone-8a-d acid Methyl(3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxy So-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate-8 Tetrahydrofuran (20 mL) of ad (1.6 g, 4.71 mmol, 1.0 equivalent) And in a solution in water (4 mL), add LiOH (169 mg, 7.06 mmol, 1.5 equivalents) The reaction mixture was added and stirred at room temperature for 1 hour. The pH was adjusted to 2-5 with 2M HCl. The resulting mixture was extracted with ethyl acetate (2 × 50 mL). The organic layers were combined and anhydrous sodium sulfate was added. Dry with thorium, filter, concentrate, and obtain (3S)-7-(6-amino-3-chloro-2 -Fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolyl Zin-3-carbone-8a-d acid was obtained as a brown solid. LC / MS:C 15 H 13 Cl Calculated mass for DFN2O3: 325.07, measured mass: 326.20 [M+H] + .

[0289] Step 7: (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1 -yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol 3-carvone-8a-d acid (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-Hexahydroindolidine-3-Carvone-8a-d acid (1. TMSN3(3) is dissolved in a solution of 6g, 4.91 mmol, and 1.0 equivalent of AcOH (6 mL). (ml) and trimethoxymethane (3 mL) were added. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was collected using a C18 column with CH3CN / water (5%-35%). Purified by (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroyl Andridine-3-carbone-8a-d acid was obtained as a yellow solid. LC / MS:C 16 H1 Calculated mass for 2ClDFN5O3: 378.08, measured mass: 379.05 [M +H] + .

[0290] Step 8: 2-(2-((((tert-butyldimethylsilyl)oxy)methyl-d2 )-3-fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(3-chloro -2-Fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1, 2,3,5,8,8a-Hexahydroindolidine-3-carboxylate-8a-d (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl) Phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindridine-3- Carvone-8a-d acid (300 mg, 0.80 mmol, 1.0 equivalent) CH3CN(1 K2CO3 (142 mg, 1.03 mmol, 1.3 equivalents) was added to the solution in 0 mL. After stirring at room temperature for 0.5 hours, then 2-bromo-1-(2-(((tert-butyl Dimethylsilyl(oxy)methyl-d2)-3-fluoropyridine-4-yl)ethane 1-ONE (432 mg, 1.19 mmol, 1.5 equivalents) was added. The mixture was left at room temperature for 1 The mixture was stirred for a certain amount of time. The resulting mixture was subjected to silica gel chromatography (0-7% MeOH / DC). Purified by M), 2-(2-(((tert-butyldimethylsilyl)oxy) (Tyl-d2)-3-fluoropyridine-4-yl)-2-oxoethyl(3S)-7-( 3-Chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-O Kiso-1,2,3,5,8,8a-Hexahydroindolidine-3-carboxylate- 8a-d were obtained as yellow oil. LC / MS:C 30 H 30 For ClD3F2N6O5Si Calculated mass: 661.21, measured mass: 662.15 [M+H] + .

[0291] Step 9: (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy )methyl-d2)-3-fluoropyridine-4-yl)-1H-imidazole-2-yl )-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl )-2,3,8,8a-tetrahydroindolidine-5(1H)-one-8a-d 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-f Luoropyridine-4-yl)-2-oxoethyl(3S)-7-(3-chloro-2-flu) Oro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5 ,8,8a-Hexahydroindolidine-3-carboxylate-8a-d(280mg) Solution in toluene (10 mL) and glacial acetic acid (1 mL) (0.42 mmol, 1.0 equivalent) Ammonium acetate (489 mg, 6.34 mmol, 15.0 equivalents) was added to the mixture. The mixture was stirred at 100°C for 1 hour. The solvent was removed under vacuum, and the residue was treated with MeOH / DCM. (0%-10%) is used to purify by silica gel column, and (3S)-3-(5-( 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropropyl Lysine-4-yl)-1H-imidazole-2-yl)-7-(3-chloro-2-fluor Ro-6-(1H-tetrazole-1-yl)phenyl)-2,3,8,8a-tetrahydo Loindolidine-5(1H)-one-8a-d was obtained as a yellow oil. LC / MS:C 30 H 30 Calculated mass for ClD3F2N8O2Si: 641.23, measured mass: 64 2.20 [M+H] + .

[0292] Process 10:(3S,8aR * )-7-(3-chloro-2-fluoro-6-(1H-tetra Razole-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl -d2) Pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a- Tetrahydroindolidine-5(1H)-one-8a-d (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl -d2)-3-fluoropyridine-4-yl)-1H-imidazole-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-2, 3,8,8a-Tetrahydroindolidine-5(1H)-one-8a-d(140mg, In a 0.22 mmol (1.0 equivalent) solution in THF (4 mL), add triethylamine trimethylamine. Dihydrofluoride (1 mL) was added. The mixture was stirred at 70°C for 1 hour. The solvent was removed under vacuum. Remove below, and the residue is collected in a C18 column [Condition: ACN-water-6.5 mM NH4HCO3+] The residue was purified using NH3H2O ​​(5%-50%). The residue was then treated with chiral HPL. C[Column: (R,R)-Whelk-O1, 4.6 * 50mm, 3.5um; Mobile phase A :Hex(0.1%DEA):EtOH=50:50, Mobile phase B:;Flow rate: 1mL / min] Purified by (3S,8aR * )-7-(3-chloro-2-fluoro-6-(1H -Tetazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxy Methyl-d2)pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8, 8a-tetrahydroindolidine-5(1H)-one-8a-d is used as an off-white solid. I obtained it.

[0293] LC / MS:C 24 H 16 Calculated mass for D3ClF2N8O2: 527.1 5. Measured value (ES, m / z): 642.20 [M+H] + . 1 1H NMR (400MHz) ,DMSO-d6)(400MHz,DMSO-d6)δ 12.29(s,1H),9 .84(s,1H),8.34(d,J=5.1Hz,1H),7.93-8.02(m ,1H),7.84-7.92(m,1H),7.70-7.75(m,1H),7.5 8(d,J=4.0Hz,1H),5.69(d,J=2.7Hz,1H),5.12- 5.32(m,1H),5.04(d,J=8.7Hz,1H),2.63-2.80( m,1H),2.50-2.56(m,1H),2.17-2.31(m,1H),2. 05-2.15(m,1H),1.90-2.01(m,2H). 19 F-NMR:(3 76MHz,DMSO-d6)δ -112.86,-130.13.

[0294] Example 11: Compound of formula (IG) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one-1,1,8,8,8a-d5

[0295] [ka]

[0296] Step 1: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- Fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino-3-k (Lolo-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydro Indolinidine-3-carboxylate-1,1,8,8,8a-d5. (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-Hexahydroindolidine-3-Carvone-1,1,8,8, 8a-d5 acid (120 mg, 0.36 mmol, 1.0 equivalent) and Cs2CO3 (71 mg) Mixture (g, 0.22 mmol, 0.6 equivalents) in DMF (8 mL) and stir at room temperature for 30 minutes. Next, 2-bromo-1-(2-(((tert-butyldimethylsilyl)oxy )Methyl)-3-fluoropyridine-4-yl)ethane-1-one (185mg, 0.5 1 mmol (1.4 equivalents) was added to the mixture. The reaction mixture was stirred at room temperature for 4 hours. Next Then, dilute the resulting mixture with phenylethylamine (120 mL), add water (3 × 20 mL), and bran. Washed with 2 x 20 mL of water, dried with Na2SO4, and concentrated. The residue was collected as silica gel. Flash column chromatography (40g, MeOH / DCM: 1 / 20) Then, it is purified to obtain 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3 -Fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino-3- Chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Loindinidine-3-carboxylate-1,1,8,8,8a-d5 as a yellow solid Obtained. LC / MS:C 29 H 29 Calculated mass for ClD5F2N3O5Si: 6 10.22, Measured value (ES, m / z): 611.15 [M+H] + .

[0297] Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-( 5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoromethyl Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Loindridine-5(1H)-one-1,1,8,8,8a-d5. Under an inert atmosphere of nitrogen, 2-(2-(((tert-butyldimethylsilyl)oxy) Methyl)-3-fluoropyridine-4-yl)-2-oxoethyl(3S)-7-(6- (Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a -Hexahydroindoridine-3-carboxylate-1,1,8,8,8a-d5(1 (30 mg, 0.21 mmol, 1.0 equivalent) and NH4OAc (164 mg, 2.13 mg) Mixture of 11 mol / 10.0 equivalents of AcOH (2 mL) and toluene (20 mL) The mixture was stirred at 0°C for 30 minutes, then concentrated. The residue was subjected to flash column chromatography on silica gel. Purified by tography (40g, MeOH / DCM:1 / 15), (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert -Butyldimethylsilyl(oxy)methyl(3-fluoropyridine-4-yl)-1H -Imidazole-2-yl)-2,3,8,8a-tetrahydroindoridine-5(1H )-ON-1,1,8,8,8a-d5 was obtained as a yellow solid. LC / MS:C 29 H2 Calculated mass for 9D5ClF2N5O2Si: 590.25, measured value (ES, m / z):591.30[M+H] + .

[0298] Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Loindrindidine-5(1H)-one-1,1,8,8,8a-d5 (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2 -(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one-1,1,8,8,8a-d5 (80mg, 0.14mmol) (1.0 equivalent), TMSN3 (156 mg, 1.35 mmol, 10.0 equivalents) and Tri Methoxymethane (143 mg, 1.35 mmol, 10.0 equivalents) in AcOH (8 mL) The mixture was stirred overnight at 55°C. The solvent was removed under reduced pressure, and the residue was analyzed using a C18 reverse column (3 Apply 30g, ACN / H2O(0.05%NH4HCO3):5→50%), (3 S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phen (Lu)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)-1 H-imidazole-2-yl)-2,3,8,8a-tetrahydroindridine-5(1 H)-ON-1,1,8,8,8a-d5 was obtained as a white solid, and this was prep-chiralized. Further purification by HPLC yields (3S,8aR)-7-(3-chloro-2-fluoro- 6-(1H-tetrazole-1-yl)phenyl)-3-(5-(3-fluoro-2-( Hydroxymethyl)pyridine-4-yl)-1H-imidazole-2-yl)-2,3, 8,8a-Tetrahydroindolidine-5(1H)-one-1,1,8,8,8a-d5 It was obtained as a white solid.

[0299] LC / MS:C 24 H 14 Calculated mass for D5ClF2N8O2: 529.1 6. Measured value (ES, m / z): 530.10 [M+H] + . 1 1H NMR (400MHz) ,DMSO-d6)(400MHz,DMSO-d6)δ 12.26(s,1H),9 .84(s,1H),8.34(d,J=5.0Hz,1H),7.90-8.00(m ,1H),7.90(t,J=5.4Hz,1H),7.75-7.85(m,1H), 7.51-7.62(m,1H),5.70(s,1H),5.27(t,J=6.0H z,1H),5.04(d,J=8.7Hz,1H),4.58-4.69(m,2H) ,2.13-2.30(m,1H),1.84-2.00(m,1H). 19 F-NMR :(376MHz,DMSO-d6)δ -112.86,-130.15.

[0300] Example 12: Compound of formula (IH) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl-d2)pyri (Jin-4-yl)-1H-imidazole-2-yl-4-d)-2,3,8,8a-teto Lahydroindoridine-5(1H)-one

[0301] [ka]

[0302] (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl-d2)pyri (Zin-4-yl)-4-iodo-1H-imidazole-2-yl)-2,3,8,8a- Tetrahydroindolidine-5(1H)-one (25 mg, 0.038 mmol) and Z A mixture of n powder (25 mg, 0.38 mmol) and 1.5 g of CD3COOD (1.5 g The mixture was then stirred at room temperature for 4 hours after adding the ) and the precipitate was filtered off. filtrate The solution was concentrated under reduced pressure, and the residue was purified by Gilson HPLC to obtain 3S,8aR) -7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl) -3-(5-(3-fluoro-2-(hydroxymethyl-d2)pyridine-4-yl)- 1H-imidazole-2-yl-4-d)-2,3,8,8a-tetrahydroindol ¹⁵(1H)-ONE was obtained as a pale yellow solid.

[0303] LC / MS:C 24 H 19Calculated for ClF2N8O2: 527.1, measured value: 528 0.3(MH) + ); 1 H NMR(400MHz,METHANOL-d4)δ 9.62 (s,1H),8.56(s,1H),8.46(s,1H),7.85(dd,J=7 .83,8.80Hz,1H),7.58(dd,J=1.71,8.56Hz,1H) ,5.77-5.85(m,1H),5.21-5.30(m,1H),3.96-4. 13(m,1H),2.75-2.88(m,1H),2.66-2.73(m,1H) ,2.35-2.45(m,1H),2.27-2.33(m,1H),2.16-2. 24 (m, 1H), 2.02-2.12 (m, 1H).

[0304] Example 13: Compound of formula (IJ) (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl-d)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2) Pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroxy Droindolidine-5(1H)-one

[0305] [ka]

[0306] (3S,8aR)-7-[3-chloro-2-fluoro-6-(the) in the NMR tube Trazol-1-yl)phenyl]-3-[4-[2-[dijuterio(hydroxy) Methyl]-3-fluoro-4-pyridyl]-1H-imidazole-2-yl]-2,3, 8,8a-Tetrahydro-1H-Indolinidine-5-one (35 mg, 0.07 mmol) NaHCO3 was added to the solution in CD3OD of ) and the sample was 1 Analysis by 1H NMR Within a few minutes, the acidic proton in the tetrazole ring was exchanged for deuterium, (3R,8a S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl-d) Enyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyridine-4- Il)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindolide I obtained -5(1H)-on.

[0307] LC / MS:C 24 H 16 Calculated for D3ClF2N8O2: 527.1, measured value: 5 28.3 (MH) + ). 1 H NMR(400MHz,METHANOL-d4)δ 8. 02(dd,J=8.31,9.78Hz,1H),7.78-7.88(m,1H), 7.54-7.61(m,1H),7.14(d,J=3.42Hz,1H),6.49 (dd,J=1.96,8.31Hz,1H),5.73(d,J=2.93Hz,1H ),5.16(d,J=8.80Hz,1H),3.84-3.96(m,1H),2. 89-3.04(m,1H),2.56-2.65(m,1H),2.28-2.39( m,1H),2.16-2.26(m,2H),1.99-2.12(m,1H).

[0308] Example 14: Compound of formula (IK) (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one-8,8,8a-d3

[0309] [ka]

[0310] Step 1: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-( 5-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)-1H-imidazo (-2-yl)-2,3,8,8a-tetrahydroindolidine-5(1H)-one- 8,8,8a-d3 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro Pyridine-4-yl)-2-oxoethyl(3S)-7-(6-amino-3-chloro-2 -Fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolyl Zin-3-carboxylate-8,8,8a-d 3 (0.51g, 0.837mmol) In a solution of 1.0 equivalent of toluene (10 mL), add NH4OAc (0.65 g, 8.4 ml). Add (mol, 10 equivalents) and AcOH (0.5 mL), and the resulting mixture at 100°C. The mixture was stirred for 1 hour. Then, the mixture was concentrated and subjected to reverse-phase chromatography (80g, M) using C18. Purified by eCN / H2O(0.05%CF3COOH):0>45%, (3S )-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluorinated Ro-2-(hydroxymethyl)pyridine-4-yl)-1H-imidazole-2-yl) -2,3,8,8a-tetrahydroindoridine-5(1H)-one-8,8,8a-d Solution 3 was obtained as a yellow solid (0.24 g, yield 60.4%). LC / MS:C 23 H 17 C Calculated mass for lD3F2N5O2: 474.15, measured mass: 476.20 [M +H] + .

[0311] Step 2: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)phenyl) Lysine-4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydro Loindrindidine-5(1H)-one-8,8,8a-d3 (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3 -Fluoro-2-(hydroxymethyl)pyridine-4-yl)-1H-imidazole-2 -yl)-2,3,8,8a-tetrahydroindridine-5(1H)-one-8,8, 8a-d3 (0.22g, 0.463mmol, 1.0 equivalent), trimethoxymethane (2 A mixture of azidotrimethylsilane (2 mL) and acetic acid (2 mL) was left at room temperature for 2 hours. The mixture was stirred. The solvent was evaporated under vacuum to obtain (3S)-7-(3-chloro-2-fluoro-6 -(1H-tetrazole-1-yl)phenyl)-3-(5-(3-fluoro-2-(H) Droxymethyl)pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8 ,8a-tetrahydroindridine-5(1H)-one-8,8,8a-d3 was obtained. The semi-product was subjected to chiral-HPLC (column: CHIRALPAK IF-3, 4.6). * 50 mm, 3μm; Mobile phase: MtBE(0.1%DEA):EtOH=70:30;Flow rate: 1 Separation by (mL / min) is performed, and (3S,8aR)-7-(3-chloro-2-fluoro-6 -(1H-tetrazole-1-yl)phenyl)-3-(5-(3-fluoro-2-(H) Droxymethyl)pyridine-4-yl)-1H-imidazole-2-yl)-2,3,8 ,8a-tetrahydroindolidine-5(1H)-one-8,8,8a-d3 is a white solid It was obtained as such.

[0312] LC / MS:C 24 H 16 Calculated mass for ClD3F2N8O2: 527.1 5. Measured value: 528.10 [M+H] + . 1 1H NMR (400MHz, DMSO-d6) )d 12.27(s,1H),9.85(s,1H),8.30-8.40(m,1H ),7.94-8.01(m,1H),7.86-7.93(m,1H),7.69-7 .75(m,1H),7.54-7.60(m,1H),5.70(s,1H),5.2 8(t,J=6.0Hz,1H),5.08-5.01(m,1H),4.64(dd, J=5.9,2.3Hz,2H),2.14-2.28(m,1H),1.91-2.0 0 (m, 2H).

[0313] Example 15: Compound of formula (II-A) 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl)-3-fluoropicolin acid

[0314] [ka]

[0315] (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridine- 4-yl)-1H-imidazole-2-yl)-2,3,8,8a-tetrahydroindopropyl Lysine-5(1H)-one (1.2g, 2.286 mmol, 1.00 equivalent) DCM ( A mixture of 60 mL of TEMPO (179 mg, 1.146 mg) and H2O (30 mL) is added. mmol, 0.50 equivalents) and PhI(OAc)2 (2.2 g, 6.830 mmol, 3 (0.0 equivalent) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated. Residue C 18 Reverse-phase column (330g, ACN / H2O (0.05%NH4HCO3): Applying 5%>>>23%>>>25%), 4-(2-((3S,8aR)-7-(3 -Chloro-2-fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-oxy So-1,2,3,5,8,8a-Hexahydroindolidine-3-yl)-1H-imida Zole-5-yl)-3-fluoropicolinic acid was obtained as a white solid.

[0316] 1 H NMR(400MHz,DMSO-d6)δ 12.30(br.,1H),9 .85(s,1H),8.28(d,J=8.0Hz,1H),7.93-8.01(m ,1H),7.84-7.92(m,1H),7.71(d,J=8.7Hz,1H), 7.55(d,J=4.0Hz,1H),5.69(d,J=2.7Hz,1H),5. 05(d,J=8.8Hz,1H),3.65-3.85(m,1H),2.63-2. 86(m,1H),2.52-2.62(m,1H),2.15-2.19(m,1H) ,2.05-2.14(m,1H),1.89-2.05(m,2H); 19 F NMR (376MHz,DMSO-d6)δ -112.81,-127.49;LC / MS: C 24 H 17 Calculated mass for ClF2N8O3: 538.11, measured mass: 539 .05[M+H] + ;

[0317] Example 16: Compound of formula (III-A) 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl)-3-fluoro-2-( Hydroxymethyl)pyridine 1-oxide

[0318] [ka]

[0319] Step 1: 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1- Ethoxyvinyl-3-fluoropyridine 2-((((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4 - Iodopyridine (0.80g, 2.178 mmol, 1.00 equivalent), tributyl (1 -Ethoxyvinyl) stanane (1.180 g, 3.267 mmol, 1.50 equivalents) and Pd(PPh3)4 (0.252g, 0.218 mmol, 0.10 equivalents) 1,4-di The mixture in oxane (10 mL) was stirred at 100°C for 4 hours. The reaction mixture was diluted with water and acetic acid was used. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried with sodium sulfate. , concentrated, 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1 Ethoxyvinyl-3-fluoropyridine was obtained as a pale yellow solid. LC / MS: C1 6H 26 Calculated mass for FNO2Si: 311.2, measured mass: 312.2 [M+ H] + .

[0320] Step 2: 1-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)ethane -1-on 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxy Vinyl-3-fluoropyridine (2.5g, 8.027mmol, 1 equivalent) THF ( 20 mL of 2 M HCl was added to the 15 mL solution. The mixture was stirred at room temperature for 5 hours. Next, the pH was adjusted to 8-10 with NaHCO3 solution. The resulting mixture was then treated with EA. Three extractions were performed. The combined organic layers were washed with brine, dried with Na2SO4, and then removed under vacuum. Concentrate to 1-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)ethane -1-one was obtained as a pale yellow solid.

[0321] Step 3: 4-Acetyl-3-fluoro-2-(hydroxymethyl)pyridine 1-oxy Do 1-(3-fluoro-2-(hydroxymethyl)pyridine-4-yl)ethane-1-ol In a solution of 1.25 g (7.390 mmol, 1 equivalent) in 20 mL of DCM, mC PBA (2.550 g, 14.780 mmol, 2.0 equivalents) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, and then quenched with NaHCO3 solution. The resulting mixture was DC-controlled. Extraction was performed three times with M. The combined organic layers were dried with Na2SO4 and concentrated under vacuum. Residual The substance is applied to a silica gel column containing EA / PE (0-100%), and 4-acetyl-3 -Fluoro-2-(hydroxymethyl)pyridine 1-oxide was obtained as a white solid. C / MS: Calculated mass for C8H8FNO3: 185.05, measured mass: 186. 05[M+H] + .

[0322] Step 4: 2-(acetoxymethyl)-4-(2-bromoacetyl)-3-fluoropyri Zin 1-oxide 4-Acetyl-3-fluoro-2-(hydroxymethyl)pyridine 1-oxide (0. A solution of 9g (4.861 mmol, 1 equivalent) in acetic acid (20 mL) is mixed with acetic acid (2.384 g Add a hydrogen bromide solution in a volume of 9.722 mmol (2 equivalents), followed by pyridinium tribromide. Mid (1.477 g, 4.618 mmol, 0.95 equivalents) was slowly added. Reaction mixture The mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum. The residue was mixed with water and EA. The organic phase was recovered, dried with Na2SO4, and concentrated under vacuum to obtain 2-(acetoxymethic acid). (Lu)-4-(2-bromoacetyl)-3-fluoropyridine 1-oxide is used as a pale yellow oil. Obtained. LC / MS:C 10 Calculated mass for H9BrFNO4: 304.97 Measured value: 306.00 [M+H] + ,308.00[M+2+H] + .

[0323] Step 5: 2-(acetoxymethyl)-4-(2-(((3S)-7-(3-chloro-2 -Fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1,2, 3,5,8,8a-Hexahydroindolidine-3-carbonyl)oxy)acetyl)- 3-Fluoropyridine 1-oxide (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazole-1-yl) Phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindridine-3- Dissolution of carboxylic acid (0.01 g, 0.026 mmol, 1.0 equivalent) in MeCN (1 mL) Potassium carbonate (0.007 g, 0.053 mmol, 2.0 equivalents) was added to the solution. After stirring the mixture for 30 minutes, 2-(acetoxymethyl)-4-(2-bromoacetyl)- 3-Fluoropyridine 1-oxide (0.012 g, 0.040 mmol, 1.5 equivalents) The reaction mixture was stirred at room temperature for 2 hours. LCMS was analyzed using 2-(acetoxymethyl )-4-(2-(((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazo (Il-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroyl Ndridine-3-carbonyl(oxy)acetyl(3-fluoropyridine-1-oxide This indicates that the product was generated, and the reaction mixture was used in the next step without further isolation or purification. LC / MS:C 26 H 21 Calculated mass for ClF2N6O7: 602.11 Measured value: 603.15 [M+H] + .

[0324] Step 6: 2-(acetoxymethyl)-4-(2-((3S)-7-(3-chloro-2- Fluoro-6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1,2,3 ,5,8,8a-Hexahydroindolidine-3-yl)-1H-imidazole-5-yl (Lu)-3-fluoropyridine 1-oxide 2-(acetoxymethyl)-4-(2-(((3S)-7-(3-chloro-2-fluor Ro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5, 8,8a-Hexahydroindolidine-3-carbonyl)oxy)acetyl)-3-Fur Toluene in olopyridine 1-oxide (0.34 g, 0.564 mmol, 1.0 equivalent) (15 mL) Solution contains ammonium acetate (0.870 g, 11.290 mmol, 20 An equivalent amount was added, followed by the addition of acetic acid (0.5 mL) under N2 conditions. The reaction mixture was heated to 100°C. The mixture was stirred for 1 hour, then cooled to room temperature and concentrated under vacuum. The residue was treated with MeOH / DCM. Purified by silica gel chromatography using (0-15%), 2-(acetoxy Methyl)-4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-teto Razole-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydr Roindidine-3-yl)-1H-imidazole-5-yl)-3-fluoropyridine 1-oxide was obtained as a pale yellow oil. LC / MS:C 26 H 21 For ClF2N8O4 Calculated mass: 582.13, measured mass: 583.10 [M+H] +

[0325] Step 7: 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-he Xahydroindolidine-3-yl)-1H-imidazole-5-yl)-3-fluoro -2-(hydroxymethyl)pyridine 1-oxide 2-(acetoxymethyl)-4-(2-((3S)-7-(3-chloro-2-fluoro -6-(1H-tetrazole-1-yl)phenyl)-5-oxo-1,2,3,5,8 ,8a-Hexahydroindolidine-3-yl)-1H-imidazole-5-yl)-3 - Fluoropyridine 1-oxide (0.16 g, 0.274 mmol, 1 equivalent) acetone In a nitrile solution (10 mL), add LiBr (0.119 g, 1.372 mmol, 5 equivalents). ), triethylamine (0.278g, 2.745 mmol, 10 equivalents) and water (0.2 5 mL was added. The reaction mixture was stirred at 60°C for 5 hours, and then concentrated under vacuum. Residue (Column: YMC-Actus Triart C18ExRS, 30mm x 1 50 mm, 5 μm; Mobile phase A: Water (10 mmol of NH4HCO3), Mobile phase B: ACN Purified by flow rate: 60 mL / min; gradient: 12 min from 20B to 30B), 4-(2- ((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 -yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol (-3-yl)-1H-imidazole-5-yl)-3-fluoro-2-(hydroxymethyl) (Tyl)pyridine 1-oxide was obtained as a white solid.

[0326] LC / MS:C 30 H 19 Calculated mass for ClF4N6O4: 540.12 Measured value: 541.15 [M+H] + . 1 1H NMR (400MHz, Methanol- d4)d 9.57(s,1H),8.29(d,J=6.9Hz,1H),8.10( t,J=7.9Hz,1H),7.81(dd,J=8.7,7.6Hz,1H),7. 60(d,J=4.1Hz,1H),7.55(dd,J=8.7,1.6Hz,1H) ,5.76(d,J=2.7Hz,1H),5.16(d,J=8.6Hz,1H),4 .94(d,J=3.2Hz,2H),3.88-4.01(m,1H),2.72-2 .89(m,1H),2.56-2.69(m,1H),2.14-2.39(m,3H ), 1.97-2.12 (m, 1H); 19 F NMR (376MHz, Methano l-d4)d -113.62,-124.02.

[0327] A person skilled in the art can identify the compound of formula (I), the compound of formula (II), the compound of formula (III), and the compound of formula (IV). Further stereoisomers of the compounds of formula (V) and formula (VI) (e.g., E (e.g., nantiomers, diastereomers) are preferably enantiomers and / or diastereomers. Omerally enriched (e.g., 90% ee or more, preferably 98% ee or more) reagent or By selecting and substituting the excipients, and / or preparing the corresponding racemic compounds, Next, for example, optimal recovery efficiency can be obtained using isocratic method conditions and stacked injection. Chiral separation and chiral division by preparative chiral supercritical fluid chromatography (SFC). The salts described herein are produced by crystallization, kinetic resolution, or other known methods using reagents. Recognize that it may be prepared in such a way.

[0328] Biological examples Biological Example 1: Factor XIa Inhibition Assay Use of fluorophore-quencher versus peptide substrate Inhibition of factor XIa was monitored using a fluorescence intensity-based assay. Tydosubstrate, 5Fam-KLTRAETV-K5Tamra (New England P (Purchased from eptide) was selected based on the FXI sequence. The activity of ZimogenFIX The conversion to the sexualized form FIXa occurs at two sites, Arg146 and Arg180, where FXIa This is caused by proteolytic cleavage. The custom peptide used in this assay is Based on the Arg146 cleavage site, FXIa cleaves the octameric peptide after the Arg residue. We designed a peptide substrate having a fluorophore-quencher pair whose fluorescence is quenched until [a certain time elapsed]. . Substrate K M When this was applied to the substrate inhibition model, k cat =0.86s -1 , K M =1 2.4 μM, K i = 61.6 μM, and the enzyme efficiency is k cat / K M =69523M -1 s -1 That was the case.

[0329] The Factor XIa FLINT assay was performed using the following 5Fam-KLTRAETV-K5Tam Used in the RA assay buffer: 50 mM Tris, pH 7.5, 100 mM Na Cl, 5 mM CaCl2, 0.1 mg / mL BSA, and 0.03% CHAPS were used. The assay buffer was prepared by mixing all fresh ingredients. 2X 5Fa The m-KLTRAETV-K5Tamra peptide substrate was first prepared in 100% DMSO. Then, it was diluted from 10 mM to 3 mM in 100% DMSO. Next, assay buffering was performed. Add the solution directly to the 3 mM stock of substrate to achieve a 30 μM 2X working concentration (15 μM final concentration). A 2X Factor XIa stock solution was prepared. The 2X Factor XIa stock solution was prepared using a 200 pM working stock solution (100 pM). Dilute the 6.562 μM stock with 1X assay buffer to achieve the final pM concentration. It was prepared by [method / method].

[0330] The test compound was subjected to 11 consecutive 3-fold dilutions at a final maximum compound concentration of 100 nM. The final DMSO concentration in the assay was 2% DMSO. FXIa and the compound were mixed for 30 minutes. The mixture was pre-incubated for 10 minutes, then the substrate was added to initiate the reaction. The assay was performed for 10 minutes. The assay was linear for longer than 30 minutes using 0 pM FXIa. More specifically, the assay was The following steps were taken: • 100 nL of 1 mM test compound in 384 black unbound Greiner Bio Dispense into One 784900 plates, adjust final concentration to 10 μM, and add 1% DMSO. This was defined as concentration. • Dispense 5 μL of 1X assay buffer into column 24 (low control), and add 5 μL of 2X assay buffer. Dispense the factor Ia solution into columns 1-23 (column 23 is high control), The plate is centrifuged at 500 rpm for 1 minute using the "cover" plate. Cover the plate and pre-incubate at room temperature for 30 minutes. • Pre-fill 5 μL of 2X 5Fam-KLTRAETV-K5Tamra peptide substrate Dispense into the entire sheet (columns 1-24), The plate is centrifuged at 500 rpm for 1 minute using a cover plate. • Using a fluorescent module F1485mm / 520mm, BMG PHER at room temperature The fluorescence intensity was kinetically monitored on AStar, and the plate was read.

[0331] Inhibition rate (IC) for each compound tested 50 ) Create a curve and GeneData Scr The data was analyzed using a 4-parameter logistic fit with ener. The relative fluorescence unit (RFU) values ​​were normalized to the inhibition percentage using the following formula. Inhibition %=(((HC-LC)-(Compound-LC)) / (HC-LC)) * 100 In the formula, LC, low control = mean signal without factor XIa or 100% inhibition of factor XIa. Harmful; HC, high control = Factor XIa + 5Fam-KLTRAET containing only DMSO This is the average signal of the V-K5 Tamra peptide substrate.

[0332] IC based on the following formula 50 To determine the value, use GENDATA to test the compound We created an 11-point dose-response curve for the substance. Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X ) * (ChoiceSlope)) In the formula, Y is the percentage inhibition in the presence of the X inhibitor concentration, and Top = high control = DMSO only. The average of factor XIa + 5Fam-KLTRAETV-K5Tamra peptide substrates including This is a signal. Bottom = mean signal or without low control and factor XIa This represents 100% inhibition of the factor. HillSlope coefficient; IC50 = highest / highest control. This is the concentration of the compound that exhibits 50% inhibition.

[0333] Biological Example 2: Kallikrein Inhibition Assay Utilization of quenching AMC peptide substrates We used fluorescence intensity-based assays to monitor the inhibition of human plasma kallikrein. The peptide substrate, Z-Gly-Pro-Arg-AMC (purchased from Bachem, Catalog) was used. Log number I-1150) uses a lower substrate concentration to control background fluorescence. Its relatively low K for kallikrein makes it possible to perform the assay. M Based on The kinetic parameters of this substrate were selected using the Michaelis-Menten equation based on the titration data. Determined by applying it to K M=40μM, k cat =0.76s -1 , and k cat / K M =18932M -1 s -1 I obtained it.

[0334] The kallikrein FLINT assay is performed using the following Z-Gly-Pro-Arg-AMC assay. The buffer solution used was: 50 mM Tris, pH 7.5, 100 mM NaCl, 5 ml M CaCl2, 0.1 mg / mL BSA, 0.03% CHAPS. All fresh ingredients. Assay buffer was prepared by mixing 2X Z-Gly-Pro-Arg. - AMC peptide substrate, 10 m for a working concentration of 100 μM (final concentration of 50 μM) M stock was prepared by diluting it in 1X assay buffer. 2X kallikreins Tok solution, use 1X assay buffer for 4nM working stock solution (2nM final concentration). It was prepared by diluting a 14.76 μM stock solution in it.

[0335] The test compound was subjected to 11 consecutive 3-fold dilutions at the final highest compound concentration of 1 nM. Final DMSO in the solution: 2% DMSO. 2nM kallikrein and the test compound were mixed for 30 minutes. The assay was incubated, then 50 μM substrate was added to initiate the reaction. The assay was linear for longer than 30 minutes using nM kallikrein. More specifically, the assay was The following steps were taken: • 100 nL of 1 mM test compound in 384 black unbound Greiner Bio Dispense into One 784900 plates, adjust final concentration to 10 μM, and add 1% DMSO. Concentration, • Dispense 5 μL of 1X assay buffer into column 24 (low control), and add 5 μL of 2X human Dispense the kallikrein enzyme solution into columns 1-23 (column 23 is a high-control column), The plate is centrifuged at 500 rpm for 1 minute using a cover plate. Cover the plate and pre-incubate at room temperature for 30 minutes. • Distribute 5 μL of 2X Z-Gly-Pro-Arg-AMC peptide substrate across the entire plate. Dispense into columns 1-24, The plate is centrifuged at 500 rpm for 1 minute using the "cover" plate. • Using a fluorescent module F1340mm / 440mm, BMG PHER at room temperature. The fluorescence intensity was kinetically monitored on AStar, and the plate was read.

[0336] Inhibition percentage (IC) for each compound tested 50 ) Create a curve and GeneData We used a 4-parameter logistic fit with Screener to analyze the data. The analysis was performed. The relative fluorescence unit (RFU) values ​​were normalized to the inhibition percentage using the following formula. did. Inhibition %=(((HC-LC)-(Compound-LC)) / (HC-LC)) * 100 In the formula, LC and low control = average signal of human kallikrein enzyme or human kallikrein enzyme It is a 100% inhibition of human kallikrein enzyme + Z- HC, high control = DMSO only This is the average signal of the Gly-Pro-Arg-AMC peptide substrate.

[0337] IC based on the following formula 50 To determine the value, use GENDATA to test the compound We created an 11-point dose-response curve for the substance. Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X ) *(ChoiceSlope)) In the formula, Y is the percentage inhibition in the presence of the X inhibitor concentration, and Top = high control = DMSO only. The average size of human kallikrein enzyme + Z-Gly-Pro-Arg-AMC peptide substrate This is a signal. Bottom = low control, average signal or without human kallikrein enzyme. This represents 100% inhibition of the tokalikrein enzyme. HillSlope coefficient; IC2 50 = This is the concentration of the compound that exhibits 50% inhibition compared to the highest / highest control.

[0338] A representative example of the present invention follows the procedures described in Biological Example 1 and Biological Example 2 above. The compounds were tested. The results are shown in Table B-1 below.

[0339] [Table 2]

[0340] Biological Example 3 Reactive metabolite study in human liver microsomes The compound of formula (IA) is used in HLM with GSH and KCN as scavenging agents. The biological activity was evaluated. The compound was administered to human liver supplemented with NADPH, KCN, and GSH. The samples were incubated in microsomes at 37°C for 60 minutes. The incubation area was 1m². g / mL protein, 10 μM substrate, 1 mM GSH (unlabeled:labeled = 3:1) and KC The test was performed using N 1 mM (unlabeled:labeled = 3:1) with a total volume of 1 mL. Nefazodone ( A 10 μM sample was used as a positive control and incubated under the same conditions. Then, by mixing with 5X volume of acetonitrile, the protein is extracted for metabolite extraction. Protein precipitation was performed. The protein was separated by centrifugation (3000 rpm, 10 minutes, 4°C). The mixture was reddened, the supernatant was transferred to a clean test tube, and evaporated to dryness under a gentle stream of nitrogen. The residue was mixed with 300 μL of water and acetonitrile (8:2v / v) containing 0.1% formic acid. After reconstitution with the solvent mixture, the solution was filtered using a 0.45 μm nylon filter. Filtered at 0×g for 3 minutes at room temperature. The filtrate was analyzed by liquid chromatography / tandem mass spectrometry (L). The contents were transferred to a 96-well plate for C-MS / MS analysis.

[0341] LC-MS / MS analysis: Agilent 1260 Infinity UHPLC B It was connected to a Ruker Q-TOF. The mass spectrometer uses positive electrospray ionization. The operation was performed using a dynamo. The column used was Phenomenex, Luna C8 (150 x 2.0 mm). The inner diameter was 3 μm. The mobile phase was A: 0.1% formic acid in water; mobile phase B: acetonitrile The solution contained 0.1% formic acid. The linear gradient of the 0.2 mL / min flow rate was used for the entire analysis as follows. I used it throughout.

[0342] [Table 3]

[0343] The compound of formula (IA) is obtained by the reactive metabolite in the HLM assay procedure described above. Tests showed that neither GSH nor KCN adducts were formed.

[0344] Biological Example 4 In vitro metabolism of human cryopreserved liver cells Human liver cells used for the in vitro metabolism of the compound of formula (IA) were Bioreclam Purchased from ation IVT (Westbury, NY); stored at low temperature. The cells were male human liver cells (lot number: UYG).

[0345] Liver cell incubation The liver cells, which had been stored at low temperatures, were rapidly thawed on ice, and the vials were placed in a 37°C water bath for about 90 seconds. The cells were then immediately added to preheated hepatocyte thawing medium. The cells were resuspended in the medium and then allowed to cool to room temperature. The cells were centrifuged at 700×g for 7 minutes. The supernatant was discarded, and the cells were treated with 12.5 mM HEPES. Re-suspension in 2 mL of Krebs-Henseleit buffer containing pH 7.4 (KHB). The solution was cloudy. Cell viability and yield were determined by trypan blue exclusion. Then, hepatocytes were... Dilute with KHB, 2 x 10 6 Cells / mL (500 μL / whey in a 10 mL glass tube) The cell concentration was adjusted to (L). The tube was rotated in a humidified incubator supplied with 5% CO2. Place in a shaker and allow to acclimate at 37°C for 15 minutes before use. Then, the formula (I- in KHB) was used. Add compound A) or the positive control diclofenac (10 μM) to hepatocytes. Final concentration in μM and 1 × 10⁻⁶ 6 Cells / mL (Final incubation volume of 1000 μL) The cell concentration was achieved. Cells were incubated for 0 or 3 hours. Incubation At the end of the period, the cells were citrated with 6 volumes of ice-cold acetonitrile containing 0.02% formic acid. The sample was churned, vortexed, and sonicated (5 minutes). The precipitated protein was centrifuged (3 Pelletize by (000 rpm, 10 minutes, 4°C), and transfer the supernatant to a borosilicate tube. It evaporated to dryness under a gentle flow of nitrogen.

[0346] Sample preparation The residue obtained after evaporation is mixed with 250 μL of water and acetonitrile containing 0.01% formic acid. Reconstruction at (9:1v / v) and sonication and vortexing are used to make drug-derived materials more pliable. After aiding in dissolution, rinse at 10,000 × g using a 0.45 μm nylon filter at room temperature for 10 The solution was filtered for several minutes. The filtrate was then subjected to liquid chromatography / ultraviolet / mass spectrometry (LC-UV / MS). The sample was transferred to a 96-well plate for analysis.

[0347] LC / UV / MS (Liquid Chromatography / Ultraviolet / Mass Spectrometry) LTQ / Orbitrap (Thermo Scientific, Inc., Bre Men, Germany) under single ion-lock mass mode, full scan MS Regarding this, 15,000, MS 2 (Also known as MS / MS or tandem mass spectrometry) This was performed by data-dependent precision mass measurements with a resolution of 7,500. Chromatographic separation of drugs and metabolites is performed at 35°C and in a solution containing 0.1% formic acid. Phenom elutes in a nonlinear gradient consisting of water (solvent A) and acetonitrile (solvent B). Kinetex Phenyl manufactured by enex, Inc. (Torrance, CA, US) - This was achieved using a hexyl column (150 × 2.1 mm inner diameter, 1.7 μm).

[0348] Quantification of unchanged drugs and their metabolites by UV spectroscopy, separated by individual chromatography The integral was performed using the -c method to obtain the percentage of the total peak area.

[0349] result: The compound of formula (IA) was tested according to the in vitro metabolite assay procedure described above. The compound of formula (IA) exhibits low metabolic turnover in human hepatocytes and produces three oxidative metabolites. The substance and two glucuronide metabolites were produced from incubation. Diclofenac Using as a positive control for the test, the turnover of diclofenac from human hepatocytes was 89%. Yes, and the incubation system was shown to be effective. (3-Fluoropyridine-2- The methanol moiety was the primary metabolic soft spot of the compound of formula (IA). Compound (II-A) which is a carboxylic acid metabolite

[0350] [ka] It was a metabolite in human liver cells.

[0351] Biological Example 5: PK Test Animal: Male Sprague-Dawley rat (7-8 weeks old, weighing 250-300g) ) with standard rat feed (Keaoxieli, Beijing, China) and water The animals were placed in plastic cages that allowed them free access to the environment. Before the experiment, the animals were heated to 20-25°C. Temperature was maintained at a 12-hour light / dark cycle and relative humidity of 40% to 70%.

[0352] Pharmacokinetics in rats: Jugular vein cannula insertion was performed on rats 2-3 days prior to the experiment. The test compound was treated by dissolving it in PEG400 / water (1:1) or suspending it in 0.5% HPMC. Three rats were forcibly orally administered the test compound (20%) at a dose of 5 or 10 mg / kg. 3 animals (dissolved in HPbCD or PEG400 in water (1:1)) at a dose of 1 or 2 mg / kg The rats were injected via tail vein.

[0353] Blood samples (approximately 0.2 ml each) were taken at 0 (before administration) and 5 (at the time of IV administration). (Only in combination), at 15, 30, 60, 120, 240, 360, 480 and 1440 minutes, cervical suction The blood was collected from the pulse. To prevent blood clotting and compensate for fluid loss, immediately after obtaining each blood sample, 0 Each crab was treated with 0.2 mL of heparinized 0.9% NaCl injection solution (50 U / mL). The urea was washed away. The blood sample was separated by centrifugation, and approximately 0.1 mL of plasma was extracted. The sample was stored at -80°C until analysis.

[0354] LC-MS / MS analysis: Analysis of the analyte using liquid chromatography combined with tandem mass spectrometry. The assay was performed using the LC-MS / MS method. The LC-MS / MS system used was Sh imadzu HPLC system (Kyoto) and turbo electrospray ionization (ES) I) API 5500 with a source (AB Sciex, Toronto, Canada) It consisted of a triple quadrupole mass spectrometer. The LC conditions were as follows: Column, Syn ergi 2.5μ Polar-RP 100A (50 * 3.0mm)(Phenome nex, Torrance, CA); 5% acetonitrile in water containing 0.1% formic acid or This was a gradient dissolution test using 95% acetonitrile in water containing 0.1% formic acid at a rate of 0.5 mL / min. Discharge and injection volume: 10 μL. Multiple reaction monitoring (MRM) method selected for quantitative analysis. The optimized transitions were Q1→Q3 and M1→ for the analyte and internal standard, respectively. The setting was M3. The instrument parameters were set as follows: Ion spray voltage: 5500 V; Curtain gas: 30 psi; Nebulizer gas: 50 psi; Turbo gas: 50 ps i; Collision gas: 10 psi; Temperature: 450°C.

[0355] Data analysis: Non-compartmental analysis (WinNonlin) using standard methods. Using this method, the total area (AUC) under the plasma concentration-time curve from time 0 to infinity is calculated. 0-t ) and Calculate pharmacokinetic parameters such as terminal half-life and peak plasma concentration (C max ) and C ma x Time to reach (T max This was determined directly from experimental data.

[0356] Results: The rat PK of the compound of formula (IA) was measured according to the assay procedure described above, and the results were These are listed in Table B-2 below.

[0357] [Table 4]

[0358] Biological Example 6: hERG Assay HERG (human ether-a-go-go related gene) rapidly develops in cardiomyocytes. Activated delayed rectifier K + Current (I Kr Potassium has similar biophysical properties to ) Code the channel. This I Kr The current is involved in the repolarization phase of the cardiac action potential. + Current This contributes to the interruption of this current, which prolongs the action potential duration and causes long-term QT ​​syndrome. It is possible. The occurrence of QT prolongation may indicate the onset of ventricular arrhythmias such as torsades de pointes. This could lead to a sudden death.

[0359] Experimental procedure: The effect of the test compound on HERG current was examined using single-electrode and whole-cell voltage clamping. The technology was used to perform tests at the single-cell level.

[0360] Cells: Human embryonic kidney cell line (HEK29) capable of stable transfection with HERG. 3) was used. Cells were continuously cultured. Before use, the cells were coated with poly-L-lysine. Cells were seeded in small plated petri dishes. 1-2 days after plating, the cells were treated with An experiment was conducted.

[0361] Solution: The bath solution consists of 150 NaCl, 4 KCl, 5 glucose, and 10 HEPE (in mM). It contained S, 1.8CaCl2, and 1MgCl2 (pH 7.4 using NaOH). The pipette solution is (mM) 120 KCl, 5 EGTA, 10 HEPES, 4 Mg ATP It contained 0.5 CaCl2 and 2 MgCl2 (pH 7.2 using KOH). Test Dissolve the compound in DMSO, 10 -2 M or 10 -1 A stock solution of M was obtained. Control ( The bath solution (=bath solution + DMSO) and the test solution (=bath solution + DMSO + test compound) are 0.3% or It contained 0.03% DMSO. Using a Y-tube system, it was dissolved in the cells under test. The solution was applied, rapidly altering the solution near the cells (in less than 0.5 seconds).

[0362] Electrophysiological measurement: Cell membrane current is measured using an EPC-9 patch-clamp amplifier. Measurements were taken at different membrane potentials using lamp technology. The holding potential was -80mV. HER G current (K + -Selective outward current) to -40mV after 2 seconds of depolarization to +60mV This was determined as the maximum tail current. The pulse cycle speed was 15 seconds. Each test pulse Before the pulse, a short pulse (0.5 seconds) from the holding potential down to -60mV is applied (linearly). Leakage current was determined. After establishing the total cell composition, a 5-minute equilibrium period was followed by pipetting. This allowed for internal perfusion of the cells with the solution. Then, a test pulse was applied for 5 minutes, and the control conditions were met. The HERG current was quantified. While continuing the pulse protocol, perfusion was performed using either the control solution or the HERG current. Then, the solution containing the test compound was switched to. The effect of the test compound was measured 5 minutes after drug application. Test compounds were tested at concentrations of 1-3 per cell.

[0363] Measurement: The HERG current starts from a holding potential of -80mV and rises to +60mV over 2 seconds. This was determined as the maximum tail current at -40mV after depolarization.

[0364] The amplitude of the HERG current gradually decreased over time, even under control conditions. To accurately quantify the degree of blockage by the test compound, a continuous rundown of the HERG current was performed. This needs to be taken into consideration. Therefore, the time course of the HERG current is the first 5 minutes in the control solution. The results were exponentially fitted to the period and extrapolated for the remainder of the experiment. These extrapolations were then applied to the experiment. Provides an estimated amplitude of current when the compound is not administered. The degree of blockage by the test compound. To determine the degree, the measured current and the fitted current in the control solution extrapolated at the same time point are used. The ratio between them was calculated.

[0365] Standard conditions: The test compound was dissolved in DMSO (final DMSO concentration: 0.3 or 0.03). %). The effect of the test compound on HERG current was measured 5 minutes after drug application.

[0366] Criteria for all or none: If a decrease of more than 5% in HERG current can be observed, R compound This is thought to (partially) block the HERG current.

[0367] Results: The compound of formula (IA) was tested in the hERG assay according to the procedure described above. Upon measurement, the IC was >30μM 50 This was shown.

[0368] Biological Example 7: AMES II Assay The purpose of this study is to determine the histidine requirement in the absence and presence of the mammalian metabolic activation system. By inducing a revertant mutation in the genes of the Salmonella typhimurium strain Regarding the ability of these bacteria to produce histidine-independent strains, compounds and / or those The objective was to evaluate the metabolites. The Ames reverse mutation test involves mutations in a wide range of chemical classes. It has been shown to be a rapid and highly sensitive indicator of heteroactivity.

[0369] Ames II mutagen manufactured by Xenometrics (Boulder, CA, USA) Mutagenic performance (mutagenic ability) is evaluated by using in-house adapted sex assay kits. The strains TA98 and TA mixed (a combination of six strains) used in this study were Frameshift mutations and base pair substitutions were detected, respectively.

[0370] Experimental procedure: Dissolve the test compound in DMSO, always taking precautions against accidental exposure to staff and the environment. It was handled in a way that reduced risk.

[0371] In in vitro gene reversion tests, Salmonella typhyllum (Salmonella typ The effects were determined by exposing mutant strains of *Himurium* to various concentrations of test compounds. Normally, Salmonella typhimurium requires histidine to reproduce. It is possible to synthesize it, but the mutant strain used in this test was unable to perform this function. No. When many of these bacteria are exposed to the mutagen, they revert to their original histidine-independent form. The mutation occurs in a portion of the bacterial population. These colonies (reverted mutants) are histidine-deficient cultures. Their ability to grow on land makes them easily detectable. Many compounds are found in bacterial cells. Because it does not exert its mutagenic effect until it is metabolized by an enzyme system that is not available to it, the test The compound and bacteria were pre-treated with a compound known to induce a higher level of enzyme activity. Incubate in the presence of supplemental liver fractions collected from the treated animals. Bacterial reverse mutation test. To detect spot mutations involving the substitution, addition, or deletion of one or more DNA base pairs, We will use an amino acid-requiring strain of Salmonella typhimurium. The principle of this bacterial reverse mutation test is to reverse the mutation present in the test strain and synthesize essential amino acids. The goal is to detect mutations that restore the functional ability of the bacteria. Revertant mutant bacteria are then compared to the parent strain. They are detected by their ability to grow in the absence of amino acids required by the test strain. The bacterial reverse mutation test is a highly sensitive, rapid, and accurate test for mutagenic activity across a wide range of chemical classes. It was shown to be an indicator. Mixed S. typhimurium strain TA98 And TA were used in this study. They are histidine-dependent (his-) and mutations Therefore, they revert to histidine prototrophy (his+). These strains are the mutagens of those It has further mutations that increase susceptibility. In bacteria, the mutagen causes changes in the DNA. Almost all of the primary damage was repaired by the excision and repair system, resulting in a slight Only a fraction of the potential mutational damage is expressed. The uvrB mutation is a deletion in the uvrB gene. This is a loss, and it results in a DNA excision repair system that makes the strain more susceptible to the mutagens. The uvrB deletion is a bio gene that, just as bacteria also need biotin for growth, It extends through. RFA mutations (deep RFA) affect the cell membrane, and as a result, normal ri The cell wall lacks polysaccharide (LPS). The RFA mutation, in other cases, affects the normal cell wall. This increases the permeability of the cell wall to large molecules, such as those containing large ring systems that are excluded. To cause this. Strains containing plasmid pKM101 are weaker in parental strains that do not possess the plasmid. It is reactivated by numerous mutagens, some of which are detected and some are not detected at all. This pKM101 Plasmids enhance the error-prone DNA repair system, thereby inducing chemical mutagenesis and Increases spontaneous mutagenesis.

[0372] The genotypes of S. typhimurium used in the assay are shown in Table B below. As listed in section 3,

[0373] [Table 5]

[0374] The test strains used were frozen strains stored at -70°C or below, and fresh overnight oxygenated water. Prepared from nutrient broth cultures. Bacterial cultures for testing were frozen in oxoid nutrient broth. It was obtained by inoculating the cultured material and incubating it overnight at 37°C.

[0375] The in vitro metabolic activation system uses rat liver enzymes (S9 fraction) and nicotinamide. Denine dinucleotide phosphate (NADP) and glucose-6-phosphate (G-6-P) It was composed of the energy-generating system (core) it contained. In short, the enzyme was produced 5 days before slaughter. Prepared from adult male Wistar rats treated with 500 mg / kg Aroclor1254. It was found in the 9000 x g supernatant of liver homogenate. (According to Aroclor1254) A mixed-function oxidizer that can metabolize chemicals into a more active form using this treatment. The enzyme was induced. The S9 fraction was frozen and stored at approximately -70°C until use. Thaw immediately before use, and combine with the core and the activation system (S9-mix) listed in Table B-4 below. It was formed.

[0376] [Table 6]

[0377] Standard conditions: The test compound concentrate and S9 mixture were prepared immediately before use. All concentration levels The test compound, negative control, and positive control were plated in a triple row in a 24-well plate in the presence of bacteria. Rating completed. 90-minute incubation (37°C) process (orbital shaker) After 250 rpm, add 2.75 ml of indicator medium to each well, then 50 μl The volume was transferred to a 384-well plate according to a fixed pattern. The samples were incubated in the dark at 37°C for 48 hours. After incubation, the positive wells (yellow) were observed. The plates are divided by scoring the number of bacterial colonies (either by color or visible at the bottom of the wells). Analysis was performed. Information on possible precipitation of compounds in the wells was also recorded. Individual plate counts were recorded. By directly inputting data into a computer, the bacterial strain and metabolic activation system can be used as a control or a compound. It has become possible to appropriately present the plate count for each item.

[0378] Criteria for all or none: The number of yellow wells on the solvent control plate is used to test the variation background. The return value is considered positive in the following cases: (a) The test compound is Compared to a parallel solvent control, at one or more concentration levels, of the strains (TA98 or mixed) This resulted in an average increase of at least three times the number of revertant mutants having one variant. This was due to the nature of the strain. A low spontaneous mutation rate can, in some cases, lead to an extremely low number of revertant mutant wells in the solvent control. It can be reduced. At this point, past background levels need to be taken into consideration. (b) A dose-response relationship is observed.

[0379] These criteria were applied in most cases. If uncertain results were obtained, the test compound... More tests were needed to evaluate the mutagenic potential of the substance. The test compound required additional If a positive response that cannot be reproduced in a run occurs in a single test, the first positive test The data was ignored.

[0380] Control experiment: Before the test is considered valid, a positive control is tested against the mixed strain and TA9. This showed at least a threefold increase in the number of reverted mutant wells that exceeded the solvent control value for 8. .

[0381] PIR observation: Recorded as follows. PIR1 = No increase in reverted mutant colonies. PIR2 = Uncertain increase (no clear dose response or reproducibility). PIR3 = Clear dose-related and reproducible increase in revert mutant colonies.

[0382] Reference compounds: Positive control items exhibit metabolic activation, as listed in Table B-5 below. 2-aminoanthracene for experiments, and 2-aminoanthracene for experiments without metabolic activation. These were trofluorene and 4-nitroquinoline-N-oxide.

[0383] [Table 7]

[0384] Control items are always handled in a manner that minimizes the risk of accidental exposure to staff and the environment. The solution of the positive control was prepared immediately before use, and the final 2% DMSO solvent solution was used for each culture. It is present in the solution. The stability of the positive control substance in the solution was unknown, but it recovered within the expected range. An increase in the number of transient mutant colonies indicates biological stability.

[0385] Results: The compound of formula (IA) was tested according to the procedure above and subjected to the AMES II assay. The result was determined to be negative.

[0386] Biological Example 8: In vitro micronucleus assay The in vitro micronucleus test (MNT) is used to detect micronuclei (MNs) in the cytoplasm of interphase cells. This is a genotoxicity test. Micronuclei are acentrose chromosome fragments (i.e., lacking centromeres) or These may originate from all chromosomes that cannot move to the poles during the later stages of cell division. Compounds and and / or their metabolites, in the absence and presence of the mammalian metabolic activation system, TK6H We evaluate their ability to induce chromosomal / genomic abnormalities in trimphoblastoid cell lines. Human TK6 cells are often used in in vitro micronucleus studies, and It is noteworthy that these cells possess the wild-type p53 state, and several groups The features that are inferred may help reduce the frequency of false positive results. The evaluation is manual and / Alternatively, it is performed by semi-automated microscopic analysis. In vitro MNT is performed on primary cells and cell lines. This is a highly sensitive test for evaluating the potential genotoxicity of chemical and physical factors. It has been shown that the micronucleus (MN) is smaller than the main nucleus within the cell, and therefore is called a "micronucleus". It has the same form as the interperitoneal nucleus, except that it contains words.

[0387] The in vitro micronucleus test using TK6 cells is an approved controlled genotoxicity assay. The micronucleus assay in TK6 follows the OECD 487 guidelines. and to meet the requirements of the current international guidelines issued by ICH S2(R1) It is designed to be so.

[0388] Reference compound: A parallel positive control drug is used to ensure the responsiveness of the test system and to activate promutagen. The potential of the metabolic pathway to convert to sex metabolites was demonstrated, but the standard for comparison with the test item was not met. The following conditions were not provided. The conditions used in this study were as follows: The positive control chemicals were as shown in Table B-5 below. The solvents and final test concentrations under each condition were as listed in Table B-6 below.

[0389] [Table 8]

[0390] Parallel negative (containing dimethyl sulfoxide (DMSO; CAS number 67-68-5)) Vehicle control included (final DMSO concentration is 1%).

[0391] Assay principle: Cell cultures are tested with and without an external source of metabolic activation. Exposure to the substance. Parallel negative, solvent / vehicle, and positive controls were included in all tests. Test compounds During or after exposure to the substance, damage to chromosomes or spindles can impair the formation of micronuclei in interphase cells. The cells were grown for a sufficient period to produce the desired result. The harvested and stained interphase cells were examined for the presence of micronuclei. The cells were analyzed. The analyzed cells underwent cell division during or after exposure to the test compound. It was important to demonstrate that the probability was high. For all protocols, cells It is important to demonstrate that growth occurred in both the control and treated cultures, and the test compound The degree of substance-induced cytotoxicity and / or cell division arrest was scored for micronuclei. The evaluation was performed in cultures. The total duration was defined as the time it took for the cell to complete at least one division. This enabled the expression of lesions induced as micronuclei (i.e., 1 (A cell doubling of ~5 to 2.0 was possible.)

[0392] In vitro micronucleus studies were performed using two treatment schedules; rat liver S9 Treatment for 3 hours in the presence of the base metabolic activation system (S9mix) and in the absence of S9mix. Continuous treatment for approximately 24 hours under the following conditions. If necessary, a second trial to confirm the findings of the first trial. We conducted an exam.

[0393] Equipment used for the assay: Freezer (approx. -10°C to -30°C); Freezer (approx. -80°C) Refrigerator (approx. 2°C to 8°C); Centrifugal separator (capable of centrifuging 96-well plates); CO 2-stage adjustable, 37°C incubator; Z1 Coulter Counter; Shandon Cytospin 4Thermo; Vortex Mixer; Ultrasonic Bath (Grant Water Bath OLS 200); Microscope (Axio Imager 2-Ze iss); and microscope (GXML3201-GX microscope)

[0394] Test-specific material used in the assay: Cell line TK6 (ATTC CRL-8015); R10P culture medium; RPMI 1640+Glutamax(TM)-I(Gibco( Trademark) 61870044) + Equine inactivated serum (Gibco 16050-122) + Penicillin Sylin / Streptomycin (Gibco 15140-122) + Sodium Pyruvate Mu (Gibco 11360-039) + Pluronic Acid (Gibco 24040-032) ) Culture medium containing; centrifuge tubes (15 mL / 50 mL) - 5 mL round-bottom tubes (C orning / falcon 352054); Micropipette / Multichannel - Cell culture flask T75 (Falcon, BD-catalog number 353136); 96W U-shaped base plate, sterile, polystyrene (Star Lab E2996-1700); Breath Easy Sealing Membranes (Sigma Aldr. ich / Merck 2380059); 96-well flat-bottom plate, sterile with lid - 96 well V-shaped base gel plate, sterile, polystyrene (Thermo Fisher 249662) );DMSO (Fisher BP231-100)

[0395] Method and Procedure: The test compound was solubilized in DMSO (dimethyl sulfoxide). To facilitate the process, vortex mixing, ultrasonic treatment, and heating up to 37±2℃ are performed as needed. The test compound was used as follows. The test compound was stored at room temperature, protected from light. It was formulated in DMSO and then... After use in the initial experiment, the remaining formulated test compound was protected from light along with a desiccant. It was stored at room temperature in a ventilated storage cabinet.

[0396] The test compound formulation is related to the Gentronix Standard Operati Prepared immediately before administration according to the ng Procedures. In short, the test compound in the solvent A stock solution of the substance was prepared, and then diluted in the same solvent to formulate the required concentration. Dosages for any subsequent trials were based on the findings from the initial trial.

[0397] The TK6 cell line is from the European Collection of Authenti. I purchased it from cated Cell Cultures. Then, I used it to create TK6 fine We created an in-house master stock of cells, and then created a working stock from that. All stock The cells were stored in liquid nitrogen. The cells were maintained in the logarithmic phase and 10% heat-inactivated horse serum (Gibc). o, Life Technologies, UK), antibiotics and Pluronic F The cells were subculturised every 1-4 days in RPMI 1640 containing 68.

[0398] TK6 culture wells were treated with 2.2 μl of test compound solution or positive control solution. Negative control The culture was treated with the same volume of solvent. Cells in 218 μl were added to the wells. Final overall The product was 220 μl.

[0399] Assay procedure: Day 1: Seed TK6 cells into T75 culture flasks at a density of approximately 200,000 cells / ml. Seeds were planted (5% CO2, 37°C).

[0400] Day 2: On the processing day, 200,000 cells / ml were densely packed into a flat-bottomed 96-well plate. The culture was prepared at [temperature]. The cells were treated three times with test compounds at concentrations of at least 24. (The final concentration of DMSO was 1%). This included parallel negative, vehicle, and positive controls. At the very least, two possible processing designs were created. The cells were treated for 3 hours in the presence of a rat metabolic activation system. After processing, the culture was centrifuged (in a U-shaped bottom 96-well plate), washed with the culture medium, and then... Then, the samples were resuspended in fresh culture medium for a recovery period after processing (in a U-shaped bottom 96-well plate). The cells were counted using a Z1 Coulter Counter. The continuous processing (23-28 hours) is carried out in the absence of metabolic activation.

[0401] The post-mitochondrial fraction (S9 homogenate) of mammalian liver used for metabolic activation was: Molecular Toxicology I, induced by Aroclor 1254 A male Sprague Dawley rat purchased from nc. (MOLTOX, USA) The following preparations were made. Batch S9 was frozen (-80°C) and thawed immediately before use. Each batch was sterility, protein content, cytochrome P450 catalytic enzyme activity, and known promutogens The ability to convert into a bacterial mutagen was certified by the manufacturer. The S9 fraction is activated Therefore, an exogenous cofactor is required. The cofactor used was NAD purchased from Apollo. It consisted of a pH regeneration system. The cofactor reagents were prepared in R10P culture medium as follows: (a) Add 7.0 g / L of glucose-6-phosphate to the final 25 mM solution (min (b) 3.8 g / L of NADP (min) in the final 5 mM solution (a) molecular weight 743.41).

[0402] Equal volumes of the two solutions were mixed and the pH was adjusted to 7.2 with a 1M sodium hydroxide solution. The solution was filtered and sterilized, and approximately 5.5 mL aliquots were dispensed into suitable containers. The entire solution was then dissolved in approximately - Stored at 80°C and used within 6 months.

[0403] The S9 homogenate was adjusted to a protein content of 30 mg / mL before being added to the culture medium. The final concentration of liver homogenate (S9) in the test system was 2.0%.

[0404] Day 3: Cytotoxicity Profile: After treatment, the number of viable cells was measured in Z1Coulter C Determined by the cell count in one cell of the replication culture well using Ounter, population multiplication The number of additions (PD) and relative population doublings (RPD) were calculated. PD = [log(Ni / N0)] / log2 In the formula, N0 is the baseline count at time 0; Ni is the given time point (i, i). This is the cell concentration at the end of incubation. For treated cultures, PD was performed in parallel. This was expressed as a percentage of the number of PDs in the vehicle control group. RPD = [Number of PDs in treated culture / Number of PDs in control culture] × 100

[0405] Based on the obtained cytotoxicity profile, the concentration of the test compound is selected for MN analysis. (per processing arm). The objective is to cover at least 55±5% of cytotoxicity. The task was to select one of the concentrations. If no cytotoxicity or precipitate was observed, then the most The higher test concentration should be either 1 mM or 500 μg / mL, whichever is lower (ICH S2(R1) This was selected as the equivalent of (2011). When solubility is the limiting factor, the maximum concentration is Under the condition that there is no interference with scoring, the lowest concentration in the culture is when the smallest precipitate is observed. The result was [degree]. At the end of the process, the precipitate was evaluated using an optical microscope.

[0406] Microscopic analysis: After processing, cells are centrifuged on a glass slide (cytospin), and methylamine is extracted. Fix in a solution and stain with acridine orange (manual analysis) or DAPI (semi-automated analysis). For all selected test conditions (test compound and positive control), the cell slides were separated. It was prepared from two cultures, each intended for microscopic analysis.

[0407] Microscopic analysis (of blind-coded cell slides) was performed to determine the micronuclei (MNCs). The number was determined. The presence of micronuclei was confirmed by at least 2000 mononuclear cells per test condition (culture). The evaluation was performed using at least 1000 cells per culture (2 cultures per concentration). Genotoxicity As a measure of sex, the number of MNCs was used to calculate the percentage of MNCs. MNC% = [Number of MNCs / Number of mononuclear cells analyzed] × 100

[0408] Furthermore, the multiplier of increase in MNC in treated cultures compared to parallel vehicle controls was calculated. The ratio of increase in MNC = MNC% in treated culture / MNC% in VC culture.

[0409] In semi-automated analysis, the acquired images (Metafer) are used to eliminate false positives. Versions 4.0.8 and Neon 1.1.6 were also evaluated manually. Check the results obtained. Therefore, ad hoc concentrations were verified by manual microscopy. Manual microscopy was performed to analyze the binucleus ( Further cellular effects such as induction of BN, polynucleated (POLY), and apoptotic (APO) cells; This enabled the quantification of endpoints that are typically not quantifiable by semi-automated analysis.

[0410] Microscopic examination scoring criteria: The analyst selected a suitable area of ​​the slide (i.e., (Not too thin, nor too densely spread.) Cells should not overlap, and the cytoplasm should surround the nucleus. It must be clearly visible. Suspicious MNs were confirmed or rejected according to the following criteria. (a) The MN diameter is less than one-third of the diameter of the main nucleus and is located within the intact cytoplasm of the cell. (b) The MN is uniformly stained, the same color, and located in the same focal plane as the main nucleus. (c) (d) The MN was nonrefractory, spherical, and had a clear outline. They were not aligned. They had an irregular shape, or the two nuclei were significantly different in size. Care was taken not to score the cells. Both were mixed with multinucleated cells that were not very spread out. It was not a binucleated cell. Multinucleated cells were analyzed for their micronuclei.

[0411] Test pass criteria: The treatment conditions are (a) at least 1.5 cell population doublings per vehicle control. (b) When observed in cultures, it was considered acceptable for the evaluation of genotoxic effects. The frequency of MNCs in vehicle control cultures is compared with the Gentronix historical control database. (c) Positive control compounds are, A biologically significant increase in the frequency of MNCs above the control value for the row vehicle (statistically significant, (d) The maximum concentration was (i) approximately 55 ± 5%. (ii) cytotoxicity limit (RPD = 45 ± 5%), (ii) lysis limit, or (iii) 500 μ The test reached the lower of g / mL or 1 mM. The passing criteria for the test are not absolute. Please note that other mitigating factors may be taken into consideration in the final pass / fail decision. To meet the criteria, experiments were repeated independently as needed.

[0412] Exam evaluation criteria: If the exam pass criteria are met, the OECD 487 Exam Guidelines ( The following criteria were used to evaluate the results based on the 2016 (2016) standard.

[0413] Clearly positive (score 3): (a) At least one test concentration is the same as that of a parallel vehicle control. Compared to the previous example, it induced a statistically significant increase (Fisher's exact test, p-value < 0.05). (b) The increase in MNC was observed in the trend test (Cochran Armitage test, p-value < When evaluated at 0.05), it was dose-related in at least one experimental condition. c) Any statistically significant increase in MNC is outside the distribution of past laboratory vehicle control data. (95% confidence interval based on Poisson). At least one experimental condition (processing arm) ) Test compounds that meet all of the above criteria are biologically relevant stains in this system. It was thought that this could induce chromosome breakage and / or an increase or decrease in chromosomes.

[0414] Clearly negative (score 1): (a) All test concentrations compared to the parallel vehicle control. (b) Trend test (c) No concentration-related increase in MNC was observed (p-value < 0.05). The data was within the distribution of past vehicle control data (95% limit of control). All of the above criteria were met. The test compound induces chromosome breakage and / or increase or decrease in this test system. I thought it was impossible.

[0415] Uncertain (Score 2): How many of the above criteria apply to clearly positive or clearly negative responses? Test compounds that meet only one of the following criteria should be selected based on expert judgment and / or further investigation (e.g., existing experiments) (Analyzing more cells or repeating the test within a modified concentration range) Therefore, it was evaluated. Rarely, even after further investigation, the dataset may not show positive or negative results. If the argument could not be made feasible, it was concluded that the results were uncertain.

[0416] Uncertain (Score 0): The test pass criteria were not met, and further tests will be required before the final compound classification. It was necessary.

[0417] Please note that there was no need to verify clearly positive or clearly negative results. The aforementioned criteria are not absolute, and other mitigating factors may be incorporated into the final evaluation. The trend test is considered valid only for experiments in which statistically significant MN inductions were observed. I did it.

[0418] Results: The compound of formula (IA) was tested according to the in vitro MNT assay procedure described above. The result was negative (score 1).

[0419] Biological Example 9 I C 50 Evaluation of TDI potential using the shift method To establish the potential TDI of specific P450 isozymes, test compounds were selected. In the presence of the cofactor NADPH, along with HLM, it is present in a certain concentration range (typically 0.04 to 10 μL). Pre-incubate for 30 minutes over M). After pre-incubation, during the investigation... Prossex is known to be metabolized specifically to certain metabolites depending on the isoform. Add the substrate at a fixed concentration. Allow a predetermined incubation period (e.g., CYP3A4 test). After 10 minutes in the sterol assay, a suitable organic solvent containing an internal standard (typically) The reaction is stopped by adding acetonitrile. For LC-MS / MS analysis... Before analysis, the sample was centrifuged, and the IC50TDI value was obtained using curve fitting. Calculate this when the pre-incubation process is performed in the absence of the test compound. Compare the obtained IC50 (IC50Rev) for reversible inhibition. The leftward shift of IC50 during oxidative stimulation (i.e., increased inhibition) indicates the isozyme's This demonstrates the potential of TDI. The IC50 shift value is the ratio of IC50Rev / IC50TDI. It is calculated as follows.

[0420] The assay was performed using a fully automated Tecan robotic system. Sample analysis was performed using probes. The analysis was performed by LC-MS / MSMS using a stable labeled internal standard of the substrate metabolite.

[0421] The final incubation conditions were as listed in Table B-7 below.

[0422] [Table 9]

[0423] Results: CYP3A4 (testosterone): Compound of formula (IA) under standard solvent conditions Below, the tests were conducted according to the TDI potential assay described above. No pre-incubation was performed. So, the measured IC 50 The concentration was 12.2 ± 1.4 μM (68.2% maximum concentration). The IC measured by rain incubation 50 The concentration was 17.5 ± 2.5 μM (6 2.8% maximum concentration). I C 50 The shift is 0.70.

[0424] Biological Example 10 Human liver microsomal CYP450 cocktail inhibition assay Using a cocktail DDI assay, clinically important P450 isolators in early detection Inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 The test compounds were evaluated for their potential to cause drug-drug interactions. The identification of the inhibitory activity of the test compound against the isoform is determined by the isoform being investigated. A cocktail of specific probe substrates known to be selectively metabolized to the metabolites of [substance name] is used. This was achieved by doing so. For example, dextromethorphan is 2D6 isoform It is known that it is exclusively demethylated by human liver microsomes (HLM). ) Co-incubation of a probe substrate in a certain range of inhibitor concentrations with a test compound. This is an IC for multiple CYP isoforms. 50 It enables simultaneous calculation of values, and therefore This provides higher throughput compared to conventional single-probe assays.

[0425] Method and procedure: The final protein concentration during incubation was 0.2 mg / ml. The incubation time was 10 minutes. The final total solvent during incubation was 0 The reagents were 0.15% DMSO and 0.8% acetonitrile. The assay was performed using a multichannel assay. Petting tools (8-channel and 96-channel), deck reagent cooling capacity and plates An integrated automated Cytomat incubator (37°C) equipped with a shaking device (Kendro) The process was automated using the Beckman Biomek FX automated liquid handler.

[0426] The test compound was supplied as a 5 mM DMSO stock solution. (0.1 M phosphate buffer) (pH 7.4) was prepared in-house using Na2HPO4·12H2O and KH2PO4. Ta.

[0427] Frozen human liver microsomes (HLMs) are stirred regularly until the entire volume is thawed. Thawed at 7°C and then kept on ice. Based on the protein concentration of the HLM batch, suspension The liquid is an assay buffer and probe substrate mixture (substrate for each CYP isoform). Further dilution was performed to obtain a final protein concentration of 0.2 mg / mL.

[0428] The probe substrate is added to the assay buffer (phenacetin, tolbutamide, S-mephenytoin, This was prepared separately with dextrometrophan or water (amodiaquine, midazolam). Combine these (at appropriate concentrations for each substrate) with HLM and assay buffer to form the final enzyme / substrate. A mixture was obtained.

[0429] The final total solvent during incubation was 0.15% DMSO and 0.8% acetonitrile. The solution was prepared using NADPH (5.27 mM) in assay buffer (room temperature). Quenching containing deuterated analogs of each of the seven probe substrate metabolites. The solution was dissolved in acetonitrile at the appropriate concentration.

[0430] Assay procedure: Prepare an appropriate volume of enzyme / substrate mixture (80 μl) and the test or reference inhibitor. By combining stock solutions (1 μl solutions added from the dilution series), the ink A sample for incubation was prepared. Pre-incubation period (typically 10 minutes) Subsequently, the reaction was initiated by adding NADPH solution (19 μl, 5.27 mM). The mixture was incubated at 37°C for 10 minutes. 1.6 volumes of cooled quenching solution were added. By doing so, the incubation was quenched. Then the incubation The mixture was centrifuged at 4°C and 4000 rpm for 10 minutes. The specified amount of supernatant (S / N) was transferred to a separate container. Transferred and diluted with water (S / N: water = 60 μL / 180 μL). All 7 probe substrates were used. Selective LC / MS method is used for simultaneous measurement of the product (and associated deuterated internal standards). Each sample was then injected into the UPLC / MS system.

[0431] Calculation and formula: The activity percentage was calculated as follows. Activity%=(Ri / R) * 100 In the formula, Ri and R represent metabolite vs. internal label in the presence and absence of TC, respectively. It was a quasi-peak area ratio. Next, the percentage activity data was plotted logarithmically (TC concentration). Plot the curve, apply it to the data, and use the data reduction tool in 3DX to reduce the IC 50 It returned the following. Specifically, the algorithm used in the tool was the four sigmoid functions. Parameter relationship: Based on the response as a function of concentration (% activity), with four parameters Ta is IC 50 These are hill gradient, baseline and range, and the relationship between them is as follows: That's right. Response = Range / (1 + (Concentration / IC50)^Hill) + Baseline.

[0432] The best-fitting line using the above relationship is Marquardt-Levenberg. This was achieved using a nonlinear fitting algorithm. A curve created from seven single-point concentrations was used. Using IC 50 I calculated it.

[0433] Results: The compound of formula (IA) was tested according to the TDI potential assay procedure described above. IC against human liver microsomes 50 The measured values ​​are listed in Table B-8 below.

[0434] [Table 10]

[0435] Biological Example 11: Seahorse Assay The purpose of this assay is to use the Agilent Seahorse XFe96 analyzer. Using this method, we investigated the effect of the compound of formula (IA) on mitochondrial respiration in HepG2 cells. The objective was to investigate the process in parallel with the Seahorse assay, specifically focusing on the detailing of HepG2 cells. The cell survival rate was also determined.

[0436] Measurement of mitochondrial respiration in HepG2 cells: Compound dose in 100% DMSO The solution was prepared and then diluted in assay medium to achieve a final solvent concentration of 0.10%. epG2 cells are contained in 10% HI FBS and 1X Pen / Strep cell cultures. In EMEM, cells were incubated at a density of 40,000 cells / well in a Seahorse plate (Agil ent Technologies,Santa Clara,California) Plated overnight. Seahorse XF basic medium (Agilent, part number) (No. 103334-100), 16 mM glutamine, 5.5 mM glucose and 8 mM pill The culture was washed twice with assay medium containing bait. After washing, 175 μl of assay medium was used. Add the culture medium and place the plate in an incubator at 37°C (without CO2) to open the assay. It began. Mitochondrial respiration, quantified as the oxygen consumption rate (OCR), was developed by the manufacturer. Using the Seahorse Mito Stress Test assay according to Rotol Measurements were taken using a Gilent Seahorse XFe 96 analyzer. In short, Mitoco To evaluate the compound-specific effect on ndoria function, each test compound (0.3, 1, (at concentrations of 3, 10, 30, and 100 μM) or vehicle control (0.1% DMSO) Add one component, followed by three mitochondrial regulators in sequence, each with its own unique properties. The metabolic parameters were shifted. First, a complex V (ATP synthase) inhibitor was used. μM oligomycin, followed by the uncoupling reagent 1 μM FCCP (carbonyl cyanide- p-trifluoromethoxyphenylhydrazone), and finally, complex I and III inhibitors, respectively. A 0.5 μM combination of the harmful agents rotenone / antimycin A.

[0437] Cell viability measurement: HepG2 cells were tested using 10% HI FBS and 1X Pen / Stre In EMEM containing p, cells were collected at a density of 40,000 cells / well in a black-walled 96-well plate. Seeds were sown on top and left to adhere overnight. The next day, the test compound was prepared and diluted with EMEM. Test material After a one-hour incubation with the product, follow the manufacturer's protocol for Cell Tit Using the er Fluor Assay (Promega, catalog number G6081) Cell viability was evaluated. The viability assay used ubiquitous proteases found in living cells. The activity of cathepsin is monitored.

[0438] Data analysis: Mitochondrial SRC (Reserve Respiratory Capacity) is calculated from maximum respiratory rate to basal respiratory rate. The SRC value was calculated by subtracting the degree. Automatically by Agilent Technologies (version 4.0) It was generated. All experiments were performed in triplicate, and the mean and standard deviation were calculated for each test concentration. All data was normalized relative to the vehicle control.

[0439] I C 50 The values ​​are applied to a two-parameter equation with nonlinear regression and variable gradient (Hill coefficient). This was determined by fitting a dose-response curve.

[0440]

number

[0441] Results: The compound of formula (IA) was tested according to the Seahorse assay procedure described above. However, as measured by respiratory reserve capacity, IC50 is greater than 100 μM. 50 de Mitoko It showed no direct effect on ndorian respiration. It also had no effect on cell viability, and IC5 The value of 0 exceeded 100 μM.

[0442] Biological Example 12: Rabbit AV shunt (thrombosis) assay and ex vivo coagulation time A male New Zealand White (NZW) rabbit, Charles River La The kittens were purchased at a weight range of 2.45-3.22 kg (CRL) and approximately 10-14 weeks of age. The animals are housed in standard rabbit cages, with one animal per cage, in the animal room. The temperature was maintained at 22°C with a 12-hour daylight cycle. Standard rabbit feed and water were provided, along with fruits and other nutrients. It was provided with a concentrated ginseng solution. Green leaves were not provided to avoid interference with the anticoagulation test. It was.

[0443] The rabbit AV shunt model is described in the literature (Wong, PC, et al., Nonpe ptide factor Xa inhibitors III:effects o f DPC423, an orally-active pyrazole antit hrombotic agent,on arterial thrombosis i n rabbits,J Pharmacol Exp Ther,2002;pp 9 It was established as described in 93-1000, Vol 303(3). Rabbits The subjects were intentionally divided into different experimental groups, and the group size (n=2-5) was determined according to the availability of the test compound. I changed it.

[0444] Ketamine HCl (20.0-50.0 mg / kg, IM) and xylazine (2.0-1 0.0 mg / kg (IM) was used for anesthesia induction. Anesthesia maintenance thereafter was performed throughout the study period. Then, as needed (i.e., every 30-50 minutes), ketamine HCl (22.7-25%) 0.0 mg / kg / ~0.5 hours, IM) and xylazine (2.27~5.0 mg / kg The procedure was performed using IM over a period of approximately 0.5 hours. Alternatively, rabbits were induced, followed by isoflu. Langus anesthetic (2-4% isoflurane and 0.9-1.2 L / min via the nose cone) The flow rate (of O2) was maintained.

[0445] After anesthesia, two incisions are made in each thigh to expose the femoral artery and vein from the opposite thigh. A cm incision was made. PE-100 tubes were cannula-inserted into the veins and arteries. After cannula insertion, the rabbit was allowed to equilibrate for 20 minutes. Then, the AV shunt device was moved to the femoral artery. It is connected between the cannula for the pulse (one thigh) and the cannula for the femoral vein (the opposite thigh). The shunt device consists of the outer piece of the TYGON tube (length 8 cm; inner diameter 7.9 mm) and The shunt consisted of an inner section of the tube (length 2.5 cm; inner diameter 4.8 mm). Furthermore, an 8cm long 2-0 silk thread was included as a trigger for thrombus formation. Forty minutes after the blood flow began, the shunt was cut, the silk thread was removed along with the blood clot, and weighed. .

[0446] The following test compounds and vehicles were used in the rabbit AV shunt study. • 35% hydroxypropyl β-cyclodex in 10 mM phosphate buffer (pH 7) Compounds of formula (IA) containing the vehicle of torin (HPβCD); • A vehicle containing 70 / 20 / 10PEG / water / ethanol.

[0447] The administration solution was prepared fresh daily in the vehicle at various doses. Vehicle or test compound This was administered 20 minutes before the start of the AV shunt thrombosis trial (initial dose or loading dose) and thereafter. The drug was administered intravenously via the marginal aural vein in a continuous 40-minute infusion (maintenance dose). .

[0448] Statistical analysis: All data is expressed as mean ± SEM. GraphPad Prism Statistical analysis was performed using software (v8.0). Significance was determined using one-way ANOVA. The p-value was defined as p<0.05 so that it would be determined accordingly. Tukey's test was used for multiple comparisons. .

[0449] result: Compared to the vehicle, the reduction in thrombus weight for the compound of formula (IA) is shown in Table B below. As listed in -9,

[0450] [Table 11]

[0451] Ex vivo coagulation assay: The following coagulation reagents are used in Diagnostica Stago (Parsippany, NJ) I purchased it from ). For thrombin time (TT), see Thrombin10 (catalog number Regarding the prothrombin time (PT), (item number: 00611, lot number: 251851) Neoplastine (registered trademark) Cl 5 (Catalog number: 00666, Lot number) :01504), activated partial thromboplastin time (aPTT) is CKP rest(registered trademark)5 (catalog number: 00597, lot number: 112768) and CaCl2 (0.025M, catalog number: 00367, lot number: 254158). For ex vivo analysis of coagulation time, a coagulation analyzer STA rt4 (Diagnostic Stag) is used. I used o).

[0452] Before and after shunt placement via femoral artery cannula, blood samples (1 mL each) were taken in 3.2% citrate. Sodium phosphate (BD Biosciences, Franklin Lakes, NJ) The sample was collected and centrifuged at 2500g at 20°C for 15 minutes. The resulting platelet-poor plasma (PP) P) was transferred to a clean tube and stored at -80°C until use.

[0453] The coagulation assay uses a 4-channel coagulation analyzer, STA rt 4 (Diagnosia Sta The procedure was performed using PPP in (go). For the aPTT assay, 50 μl of CK was used. Incubate Preset reagent in a cuvette with 50 μl of PPP at 37°C for 3 minutes. Coagulation was initiated by adding 50 μl of 25 mM CaCl2. The start time was recorded as the coagulation time.

[0454] Statistical analysis: All data is expressed as mean ± SEM. GraphPad Prism Statistical analysis was performed using software (v8.0). Significance was determined using one-way ANOVA. The p-value was defined as p<0.05 so that it would be determined accordingly. Tukey's test was used for multiple comparisons. .

[0455] result: Compared to the vehicle, the onset of coagulation measured for the compound of formula (IA) was as follows: The results were as listed in Tables B-10 and B-11.

[0456] [Table 12] a The trial period was after the first dose.

[0457] [Table 13] a The trial period was after the first dose.

[0458] Formulation Example 1 Solid oral formulation - Predicted examples As a specific embodiment of the oral composition, 100 mg prepared as in Example 5 above A compound of formula (IA), or a compound of formula (II-A) prepared in Example 13 above. Formulated with finely divided lactose, into size O hard gel capsules. It provides a total amount of 580-590 mg to fill.

[0459] The above specification, along with the examples given for illustrative purposes, teaches the principles of the present invention. However, the implementation of this invention is included within the scope of the following claims and equivalents. It will be understood that this includes all common variations, adaptations, and / or modifications.

[0460] Throughout this application, various publications are cited. The disclosures in these publications constitute the present invention. To provide a more detailed explanation of the latest technologies related to this, the present invention is incorporated by reference.

Claims

1. Compound of formula (I) 【Chemistry 1】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts It is a solvate.

2. Compound according to claim 1 having formula (I-A) 【Chemistry 2】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts It is a solvate.

3. (a) Compound of formula (I-B) 【Transformation 3】 (b) Compound of formula (I-C) 【Chemistry 4】 (c) Compounds of formula (I-D) 【Transformation 5】 (d) Compounds of formula (I-E) 【Transformation 6】 (e) Compounds of formula (I-F) 【Transformation 7】 (f) Compounds of formula (I-G) 【Transformation 8】 (h) Compounds of formula (I-H) 【Chemistry 9】 (j) Compound of formula (I-J) 【Chemistry 10】 (k) Compounds of formula (I-K) 【Chemistry 11】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts The compound according to claim 1, wherein is selected from the solvates.

4. Compound of formula (II) 【Chemistry 12】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts It is a solvate.

5. Compound according to claim 4 having formula (II-A) 【Chemistry 13】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts It is a solvate.

6. Compound of formula (III) 【Chemistry 14】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts It is a solvate.

7. Compound according to claim 6 having formula (III-A) 【Chemistry 15】 or its tautomers, stereoisomers, isotope substitutions, or pharmaceutically acceptable salts It is a solvate.

8. (a) Compound of formula (IV-A) 【Chemistry 16】 or its stereoisomers, isotope substitutions, or salts; (b) Compound of formula (V-A) 【Chemistry 17】 or its stereoisomers, isotope substitutions, or salts; and (c) Compounds of formula (VI-A) [Chemistry 18] or its stereoisomers, isotope substitutions, or salts, A compound selected from the group consisting of the following.

9. A pharmaceutically acceptable carrier and the compound according to claim 1, 2, 3, 4, 5, 6, or 7 A pharmaceutical composition containing pharmaceutical ingredients.

10. (a) thromboembolic disorders; (b) inflammatory disorders or disorders; or (c) plasma kallikrein activity A method for the treatment or prevention of a disease or condition involving, and which is necessary for the target This includes administering a therapeutically effective amount of the compound according to claim 1, 2, 3, 4, 5, 6, or 7 to the patient. Hmm, a method.

11. The aforementioned thromboembolic disorders include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and arterial thromboembolic disorders. A claim selected from the group consisting of cerebrovascular thromboembolic disorders and venous cerebrovascular thromboembolic disorders. The method described in item 10.

12. The aforementioned thromboembolic disorders include unstable angina, acute coronary syndrome, atrial fibrillation, the first myocardial infarction, and recurrent myocardial infarction. Myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, terminal Peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery Thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and artificial valves or other implants People who have runts, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, or other conditions that promote thrombosis. A claim is made from a group of conditions consisting of thrombosis resulting from other procedures in which blood is exposed to the surface of the workpiece. The method described in item 10.

13. The aforementioned thromboembolic disorders are hereditary angioedema (HAE) and diabetic macular edema (DME). The method according to claim 10, selected from the group.

14. The aforementioned inflammatory disorders consist of sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome. The method according to claim 10, selected from the group.

15. Diseases or conditions involving plasma kallikrein activity include visual impairment, diabetic retinopathy, and diabetes. Macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, Arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation The method according to claim 10, selected from the group consisting of, and cardiopulmonary bypass surgery.

16. (a) thromboembolic disorders, (b) inflammatory disorders, or (c) plasma kallikrein activity is involved. To prepare medicines for the treatment or prevention of a disease or condition, which requires Use of the compound according to claim 1, 2, 3, 4, 5, 6, or 7 in the subject.

17. The aforementioned thromboembolic disorders include (a) arterial cardiovascular thromboembolic disorders and (b) venous cardiovascular thromboembolic disorders. (c) arterial cerebrovascular thromboembolic disorder, or (d) venous cerebrovascular thromboembolic disorder. , the use described in claim 16.

18. (a) thromboembolic disorders, (b) inflammatory disorders, or (c) plasma kallikrein activity is involved. In methods for treating or preventing a disease or condition, use is permitted for those who require it. The compound according to claim 1, 2, 3, 4, 5, 6, or 7 for the purpose of

19. In the subjects requiring it, the thromboembolic disorder is (a) arterial cardiovascular thromboembolic (b) venous cardiovascular thromboembolic disorders, (c) arterial cerebrovascular thromboembolic disorders, and (d) The compound according to claim 18, selected from the group consisting of venous cerebrovascular thromboembolic disorders.

20. Compounds according to claim 1, 2, 3, 4, 5, 6, or 7 for use as pharmaceuticals 。

21. (a) thromboembolic disorders, (b) inflammatory disorders, or (c) plasma kallikrein activity is involved. For use in individuals who require it for the treatment or prevention of a disease or condition. The compound according to claim 1, 2, 3, 4, 5, 6, or 7.

22. (a) Arterial cardiovascular thromboembolic disorder, (b) Venous cardiovascular thromboembolic disorder, (c) Arterial cerebral blood A thrombus selected from the group consisting of (d) vascular thromboembolic disorders and (d) venous cerebrovascular thromboembolic disorders. Claim 2, for use in subjects requiring the treatment or prevention of embolic disorders. The compound described in 1.

23. (a) thromboembolic disorders, (b) inflammatory disorders, or (c) plasma kallikrein activity is involved. Claims 1, 2, 3, 4 for use in the treatment or prevention of a disease or condition A composition comprising the compound described in 5, 6, or 7.

24. (a) Arterial cardiovascular thromboembolic disorder, (b) Venous cardiovascular thromboembolic disorder, (c) Arterial cerebral blood A thrombus selected from the group consisting of (d) vascular thromboembolic disorders and (d) venous cerebrovascular thromboembolic disorders. A compound comprising the compound described in claim 1 for use in the treatment or prevention of embolic disorders, The composition described in item 23.

25. Claims 1, 2 for use in the method according to any one of claims 10 to 15 , the compounds described in 3, 4, 5, 6, or 7.

26. A claim for manufacturing a pharmaceutical product for the method according to any one of claims 10 to 15 Use of the compounds described in item 1, 2, 3, 4, 5, 6, or 7.

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