Factor XIa inhibitors

Abstract

The present invention provides compounds of formula I, pharmaceutical compositions comprising one or more of the above compounds, and methods of using the above compounds to treat or prevent thrombosis, embolism, hypercoagulability, or fibrotic changes. The compounds are selective factor XIa inhibitors or dual inhibitors of factor XIa and plasma kallikrein. TIFF2024504737000032.tif70131

Description

[Technical field]

[0001] Factor XIa is a plasma serine protease involved in the regulation of blood clotting. Although blood clotting is a necessary and important part of the regulation of homeostasis in an organism, abnormal blood clotting can also have deleterious effects. For example, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a clot may lodge in the blood vessel, block circulation, and induce a heart attack or stroke. Thromboembolic disorders are the leading cause of death and disability in industrialized societies.

[0002] Blood coagulation is a regulated process of blood flow that is essential for mammalian survival. The process of coagulation, and the subsequent dissolution of the clot after wound healing, begins after vascular injury and can be divided into four stages. The first stage, vasoconstriction or vasocontraction, allows to reduce blood loss in the injured area. The next stage is platelet activation by thrombin, where platelets adhere to the site of injury in the vessel wall and form platelet aggregates. In the third stage, the formation of the coagulation complex leads to the formation of a large amount of thrombin, which converts soluble fibrinogen into fibrin by the cleavage of two small peptides. In the fourth stage, after wound healing, the clot is dissolved by the action of plasmin, a key enzyme of the endogenous fibrinolytic system.

[0003] Two alternative pathways can lead to the formation of fibrin clots: the intrinsic pathway and the extrinsic pathway. Although these pathways are initiated by different mechanisms, at a later stage, they converge to lead to a common final pathway of the coagulation cascade. In this final pathway of coagulation, coagulation factor X is activated. Activated factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood. The formation of a clot on the bottom of a vessel wall abnormality without a wound is the result of the intrinsic pathway. Fibrin clot formation as a response to tissue damage or injury is the result of the extrinsic pathway. Both pathways involve a relatively large number of proteins known as clotting factors. The intrinsic pathway requires clotting factors V, VIII, IX, X, XI, and XII, as well as prekallikrein, high molecular weight kininogen, calcium ions, and platelet-derived phospholipids. Activation of factor XIa is the central intersection between the two activation pathways of coagulation. Factor XIa plays a key role in blood clotting.

[0004] Coagulation is initiated when blood is exposed to artificial surfaces (e.g., during hemodialysis, "on-pump" cardiovascular surgery, vascular grafts, bacterial sepsis), cell surfaces, cell receptors, cell debris, DNA, RNA, and extracellular matrix. This process is also called contact activation. Surface absorption of factor XII leads to a conformational change in the factor XII molecule, thereby facilitating its activation to proteolytically active factor XII molecules (factors XIIa and XIIf). Factor XIIa (or factor XIIf) has several target proteins, including plasma prekallikrein and factor XI. Active plasma kallikrein further activates factor XII, amplifying contact activation. Alternatively, the serine protease prolyl carboxyl peptidase can activate plasma kallikrein complexed with high molecular weight kininogen in multiprotein complexes formed on the surfaces of cells and matrices (Shariat-Madar et al., Blood, 108:192-199 (2006)). Contact activation is a surface-mediated process that is partially involved in the regulation of thrombosis and inflammation and is mediated at least in part by the fibrinolytic, complement, kininogen / kinin, and other humoral and cellular pathways (for reviews, see Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier, AH, "Contact Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)). The biological relevance of the contact activation system to thromboembolic disease is supported by the phenotype of factor XII-deficient mice. More specifically, factor XII-deficient mice were protected from thrombotic vascular occlusion in several models of thrombosis and stroke, and the phenotype of XII-deficient mice was identical to that of XI-deficient mice (Renne et al., J Exp. Med., 202:271-281 (2005); Kleinschmitz et al., J Exp. Med., 203:513-518 (2006)).The fact that factor XI is downstream of factor XIIa, together with the identical phenotype of XII- and XI-deficient mice, suggests that the contact activation system may play a major role in factor XI activation in vivo.

[0005] Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is similar to factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. Proteolytic activation by factor XIIa at an internal I 389-R390 bond yields a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors, including alpha2 macroglobulin and Cl inhibitors. Interestingly, heparin significantly promotes the inhibition of plasma kallikrein by antithrombin III in the presence of high molecular weight kininogen (HMWK). In blood, the majority of plasma kallikrein circulates in complex with HMWK. Plasma kallikrein cleaves HMWK to liberate bradykinin. Bradykinin release leads to increased vascular permeability and vasodilation (for reviews, see Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier AH, "Contact Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)).

[0006] Patients who present with a genetic deficiency of C1-esterase inhibitor suffer from hereditary angioedema (HAE), a lifelong disease that results in intermittent swelling of the entire body, including the hands, feet, face, throat, genitals and gastrointestinal tract. Analysis of blisters resulting from acute episodes has been shown to contain high levels of plasma kallikrein, and treatment with the protein-based reversible plasma kallikrein inhibitor ecallantide (Kalbitor) has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L, et al., J. Allergy Clin. Immunol., 120: p. 416 (2007)).

[0007] Furthermore, the plasma kallikrein-kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME). Recent publications have shown that in diabetic rodent models, plasma kallikrein contributes to the observed retinal vascular leakage and dysfunction (A. Clermont, et al., Diabetes, 60:1590 (2011)), and that treatment with a small molecule plasma kallikrein inhibitor improved the observed retinal vascular permeability, as well as other abnormalities associated with retinal blood flow. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Shariat-Madar et al.,Blood,108:192-199(2006) [Non-Patent Document 2] Coleman, R., “Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001) [Non-Patent Document 3] Schmaier, AH, “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128 (1998) [Non-Patent Document 4] Renne et al.,J Exp.Med.,202:271-281(2005) [Non-Patent Document 5] Kleinschmitz et al.,J Exp.Med.,203:513-518(2006) [Non-Patent Document 6] Schneider,L,et al.,J.Allergy Clin.Immunol.,120:p.416(2007) [Non-Patent Document 7] A. Clermont,et al.,Diabetes,60:1590(2011) Summary of the Invention

[0009] The present invention relates to compounds of formula I: [ka] and its pharmaceutically acceptable salts. The compound of formula I is a selective factor XIa inhibitor or a dual inhibitor of factor XIa and plasma kallikrein, and thus may be useful for treating, inhibiting or ameliorating one or more disease states that may benefit from the inhibition of factor XIa or plasma kallikrein, including thrombosis, embolism, hypercoagulability or fibrotic changes. The compound of the present invention may further be used in combination with other therapeutically effective agents, including but not limited to other drugs useful for treating thrombosis, embolism, hypercoagulability or fibrotic changes. The present invention further relates to a process for preparing the compound of formula I, and a pharmaceutical composition comprising the compound of formula I and its pharmaceutically acceptable salts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention relates to compounds of formula I: [ka] (In the formula, R 1 is pyrazole optionally substituted by hydrogen, OCHF2, or CF3, R 2 is chloro or fluoro, R 3 is hydrogen or fluoro, R 4 is hydrogen or C 1~3 is alkyl, X is CH or N); or a pharma- ceutically acceptable salt thereof.

[0011] Another embodiment of the present invention is a compound of formula Ia: [ka] (In the formula, R 2 is chloro or fluoro, R 4 is hydrogen, CH3 or CH2CH3); or a pharma- ceutically acceptable salt thereof.

[0012] One embodiment of the present invention is a compound of formula Ib: [ka] (In the formula, R 2 is chloro or fluoro, R 4 is hydrogen, CH3 or CH2CH3, X is CH or N); or a pharma- ceutically acceptable salt thereof.

[0013] Another embodiment of the present invention is a compound of formula Ic: [ka] (In the formula, R 2 is chloro or fluoro, R 4 is CH3 or CH2CH3); or a pharma- ceutically acceptable salt thereof.

[0014] In one embodiment of the present invention, R 1 is hydrogen. In another embodiment of the present invention, R 1 is OCHF2. In another embodiment of the present invention, R 1 is pyrazole optionally substituted by CF. In one class of embodiments, R 1 is a pyrazole substituted by CF3.

[0015] In one embodiment of the present invention, R 2 is chloro. In another embodiment of the present invention, R 2 is fluoro.

[0016] In one embodiment of the present invention, R 3 is hydrogen. In another embodiment of the present invention, R 3 is fluoro.

[0017] In one embodiment of the present invention, R 4 is CH3. In another embodiment of the present invention, R 4 is CH2CH3. In another embodiment of the present invention, R 4 is hydrogen.

[0018] In one embodiment of the invention, X is CH. In another embodiment of the invention, X is N.

[0019] In one embodiment of the invention, the compound of formula I is [ka] TIFF2024504737000008.tif94154 or a pharma- ceutically acceptable salt thereof.

[0020] Reference to the above preferred classes and subclasses is meant to include all combinations of particular and preferred groups, unless otherwise indicated.

[0021] Particular embodiments of the present invention include, but are not limited to, the compounds identified herein as Examples 1-9, or a pharma- ceutically acceptable salt thereof.

[0022] Pharmaceutical compositions comprising a compound of formula I, formula Ia, formula Ib or formula Ic above and a pharma- ceutically acceptable carrier are also included within the scope of the present invention. The present invention is also intended to encompass pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and any of the compounds specifically disclosed in this application. These and other aspects of the present invention will be apparent from the teachings contained herein.

[0023] The present invention also includes compositions for inhibiting platelet loss in mammals, compositions for inhibiting the formation of platelet aggregates, compositions for inhibiting the formation of fibrin, compositions for inhibiting thrombus formation, compositions for inhibiting embolism formation, compositions for treating inflammatory disorders, compositions for treating diabetic retinopathy, and compositions for treating hereditary angioedema, which comprise the compounds of the present invention in a pharma- ceutically acceptable carrier.These compositions may include anticoagulants, antiplatelet agents, and thrombolytic agents.The compositions may be added to blood, blood products, or mammalian organs to achieve the desired inhibition.

[0024] The present invention also includes compositions for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular accumulation of fibrin, and reclosure or restenosis of reopened blood vessels in a mammal comprising a compound of the present invention in a pharma- ceutically acceptable carrier. These compositions may also include anticoagulants, antiplatelet agents, and thrombolytic agents.

[0025] The invention also includes methods for treating unstable angina, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular accumulation of fibrin, and reclosure or restenosis of a reopened blood vessel comprising administering a composition of a compound of the invention to a mammal in need thereof.

[0026] The invention also includes a method of reducing the thrombogenicity of a surface in a mammal by covalently or non-covalently attaching a compound of the invention to the surface.

[0027] The invention also includes a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for inhibiting thrombin, inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal.Further, the invention includes a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0028] The compounds of the present invention are factor XIa inhibitors and may have therapeutic value, for example, in preventing coronary artery disease.Compared with known compounds in the art, the compounds of the present invention have improved pharmacokinetic profile.In addition, compared with known compounds, some of the compounds of the present invention have a good combination of potency, efficacy and pharmacokinetic properties.

[0029] As used herein, the compounds of the invention are understood to include pharma- ceutically acceptable salts of the compounds of structural formula I, formula Ia, formula Ib, and formula Ic, as well as salts that are not pharma- ceutically acceptable when used as free compounds or precursors to pharma- ceutically acceptable salts thereof, or in other synthetic operations.

[0030] The compound of the present invention can be administered in the form of pharmaceutically acceptable salts.The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or non-toxic acids, including inorganic or organic bases and inorganic or organic acids.The salts of basic compounds included in the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compound of the present invention, which are generally prepared by reacting free bases with suitable organic or inorganic acids.Representative salts of the basic compounds of the present invention include, but are not limited to, acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethylacetate, digluconate, dihydrochloride, dodecylsulfonate, edetate, edent ... Disylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinate, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate Salts include acetate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelate, phenylpropionate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate, etc. Additionally, when the compound of the present invention contains an acidic moiety, suitable pharma- ceutically acceptable salts thereof include salts derived from inorganic bases, including, but not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Also included are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharma-ceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also included are basic nitrogen-containing groups which can be quaternized with such agents as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, e.g., dimethyl, diethyl, dibutyl; and diamyl sulfate, long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chloride, bromide and iodides, aralkyl halides, e.g., benzyl and phenethyl bromide, and the like.

[0031] These salts can be obtained by known methods, for example, by mixing the compound of the present invention with a solution containing an equivalent amount of the desired acid, base, etc., and then recovering the desired salt by filtering the salt or evaporating the solvent. The compound of the present invention and its salt can form solvates with solvents such as water, ethanol, or glycerol. The compound of the present invention can simultaneously form acid addition salts and salts with bases depending on the type of substituents on the side chain.

[0032] When the compounds of formula I, formula Ia, formula Ib or formula Ic contain simultaneously acidic and basic groups in the molecule, the present invention includes, in addition to the salt forms mentioned, also inner salts or betaines (zwitterions).

[0033] The present invention encompasses all stereoisomeric forms of the compounds of formula I, formula Ia, formula Ib and formula Ic. Unless a specific stereochemistry is indicated, the present invention is meant to encompass all such isomeric forms of these compounds. Any asymmetric centers present in the compounds of formula I, formula Ia, formula Ib and formula Ic can have either (R) or (S) configurations, independently of one another. When a bond to a chiral carbon is shown as a straight line in the structural formula of the present invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and thus both the individual enantiomers and mixtures thereof, are encompassed by the formula. When a specific configuration is shown, that enantiomer (either (R) or (S) at that center) is intended. Similarly, when a compound name is listed without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and thus both the individual enantiomers and mixtures thereof, are encompassed by the name. The production of specific stereoisomers or mixtures thereof may be identified in the examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of the present invention.

[0034] Unless a specific enantiomer or diastereomer is indicated, the present invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers in any ratio. Thus, enantiomers in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates, as well as mixtures of the two enantiomers in any ratio, are subject of the present invention. In the case of cis / trans isomerism, the present invention includes both the cis form and the transformation, as well as mixtures of these forms in any ratio. The preparation of individual stereoisomers can be carried out, if desired, by conventional methods, for example, by separation of the mixture by chromatography or crystallization, by the use of stereochemically uniform starting materials for synthesis, or by stereoselective synthesis. Derivatization may be carried out before the separation of stereoisomers. Separation of the mixture of stereoisomers can be carried out at an intermediate stage during the synthesis of the compounds of formula I, formula Ia, formula Ib or formula Ic, or on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent that contains a stereocenter of known configuration.When the compounds of the present invention are capable of tautomerization, all individual tautomers and mixtures thereof are included within the scope of the present invention.The present invention includes all such isomers, as well as the salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers, and mixtures thereof.

[0035] In the compounds of the invention, atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that found predominantly in nature. The present invention is meant to include all suitable isotopic variations of the compounds specifically and generically described. For example, the various isotopic forms of hydrogen (H) include protium (1 H ) and deuterium (2 H) are included. Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds may be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described in the general process schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0036] When any variable occurs more than once in any constituent, its definition at each occurrence is independent of all other occurrences.Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds.Lines drawn from substituents into ring systems represent that the indicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on any of the rings of the bicyclic moiety.

[0037] It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the present invention in place of one or more carbon atoms by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art from readily available starting materials.Carbon and silicon have different covalent bond radii, which results in differences in bond distance and configuration when comparing the bonds of similar C elements with those of Si elements.These differences result in subtle changes in the size and shape of silicon-containing compounds when compared with carbon.Those skilled in the art will understand that the differences in size and shape can result in subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, etc. (Diass, JO et al. Organometallics (2006) 5: 1188-1198; Showell, GA et al. Bioorganic & Medicinal Chemistry Letters (2006) 16: 2555-2558).

[0038] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials by techniques known in the art and the methods described below.When a substituent itself is substituted with multiple groups, it is understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure is obtained.The phrase "optionally substituted" (by one or more substituents) should be understood to mean that the group in question can be unsubstituted or substituted by one or more substituents.

[0039] In addition, the compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and therefore, all amorphous and crystalline forms of the compounds of formula I, formula Ia, formula Ib and formula Ic and mixtures thereof are intended to be included within the scope of the present invention.In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents.Such solvates and hydrates of the compounds, particularly pharma-ceutically acceptable solvates and hydrates, are also included within the scope of the present invention, along with unsolvated and anhydrous forms.

[0040] Also, when a carboxylic acid (-COOH) or alcohol group is present in the compounds of the present invention, pharma- ceutically acceptable esters of the carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of the alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be used. Included are ester and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0041] Any pharmaceutically acceptable prodrug modification of the compounds of the present invention that results in in vivo conversion to a compound within the scope of the present invention is also within the scope of the present invention. For example, esters may be made by esterification of available carboxylic acid groups or by forming esters on available hydroxy groups in the compounds. Similarly, unstable amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs, particularly those that can be hydrolyzed in vivo back to the acid (or -COO- depending on the pH of the fluid or tissue where the conversion occurs) or hydroxy form, and are therefore included within the scope of the present invention. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1~6 -C substituted with alkyl esters and phenyl esters 1~6 Examples of such alkyl groups include alkyl.

[0042] Thus, the compounds within the general structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, their physical forms (e.g., amorphous and crystalline forms), solvates and hydrates, and any combination of these forms, as well as salts thereof, prodrug forms thereof, and salts of the prodrug forms thereof, which forms are possible unless otherwise specified.

[0043] Except as otherwise stated, the terms "halogen" or "halo" mean fluorine, chlorine, bromine, or iodine.

[0044] "Celite®" (Fluka) diatomite is a diatomaceous earth and may be referred to as "celite."

[0045] Except as noted herein, bicyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom.

[0046] The present invention also relates to medicinal products containing at least one compound of formula I, formula Ia, formula Ib or formula Ic, and / or of a pharma- ceutically acceptable salt of a compound of formula I, formula Ia, formula Ib or formula Ic, and / or of any stereoisomeric form of a compound of formula I, formula Ia, formula Ib or formula Ic, or of a pharma- ceutically acceptable salt of a stereoisomeric form of a compound of formula I, formula Ia, formula Ib or formula Ic, together with pharma- ceutically suitable and pharma- ceutically acceptable vehicles, excipients and / or other active substances and auxiliaries.

[0047] Anticoagulant therapy is indicated for the treatment and prevention of various thrombotic conditions, especially coronary artery disease and cerebrovascular disease.Those experienced in this field will easily recognize the situations that require anticoagulant therapy.The term "patient" as used herein is taken to mean a mammal, such as a primate, human, sheep, horse, cow, pig, dog, cat, rat and mouse.

[0048] The compound may be a selective factor XIa inhibitor or a dual inhibitor of factor XIa and plasma kallikrein. Factor XIa or dual factor XIa / plasma kallikrein inhibition is useful not only for anticoagulant therapy of individuals with thrombotic conditions, but also whenever inhibition of blood clotting is required, for example, to prevent clotting of stored whole blood and to prevent clotting of other biological samples for testing or storage. Thus, factor XIa or dual factor XIa / plasma kallikrein inhibitors may be added to or contacted with any medium that contains or is suspected to contain thrombin and where it is desired to inhibit blood clotting, for example, when contacting mammalian blood with a material selected from the group consisting of vascular grafts, stents, orthopedic prostheses, cardiac prostheses and extracorporeal circulation systems.

[0049] The compounds of the invention may be useful for treating or preventing venous thromboembolism in mammals (e.g., obstruction or occlusion of a vein by a detached thrombus; obstruction or occlusion of a pulmonary artery by a detached thrombus), cardiogenic thromboembolism (e.g., obstruction or occlusion of the heart by a detached thrombus), arterial thrombosis (e.g., formation of a thrombus in an artery which may cause infarction of tissue supplied by the artery), atherosclerosis (e.g., arteriosclerosis characterized by irregularly distributed lipid deposits), and for reducing the tendency of devices in contact with blood to clot blood.

[0050] Examples of venous thromboembolism that can be treated or prevented by the compound of the present invention include vein blockage, pulmonary artery blockage (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombogenic disease such as protein C deficiency, protein S deficiency, antithrombin III deficiency and factor V Leiden, and thrombosis caused by acquired thrombogenic disorder such as systemic lupus erythematosus (inflammatory connective tissue disease).With respect to venous thromboembolism, the compound of the present invention can also be useful in maintaining the patency of indwelling catheters.

[0051] Examples of cardiogenic thromboembolism that may be treated or prevented by the compounds of the invention include thromboembolic stroke (a detached blood clot causing neurological distress associated with impaired blood supply to the brain), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber myofibrils), cardiogenic thromboembolism associated with prosthetic heart valves, such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.

[0052] Examples of arterial thrombosis include unstable angina (severe constricting pain in chest originating from coronary artery), myocardial infarction (myocardial cell death due to insufficient blood supply), ischemic heart disease (ischemia due to occlusion of blood supply (e.g., due to arterial stenosis)), reclosure during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass graft, and occlusive cerebrovascular disease.With respect to arterial thrombosis, the compound of the present invention can also be useful for maintaining the patency of arteriovenous cannula.

[0053] Examples of atherosclerosis include arteriosclerosis.

[0054] The compounds of the invention may also be kallikrein inhibitors and may be particularly useful in the treatment of hereditary angioedema.

[0055] Examples of blood contacting devices include vascular grafts, stents, orthopedic prostheses, cardiac prostheses and extracorporeal circulatory systems.

[0056] The pharmaceutical agent according to the present invention can be administered orally, by inhalation, rectally or transdermally, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with the compounds of formula I, Ia, Ib and Ic, as well as other surfaces in the body that come into contact with blood, is possible.

[0057] The present invention also relates to a process for producing a medicinal product, which comprises bringing at least one compound of formula I, Ia, Ib and Ic into a suitable administration form using a pharma- ceutically suitable and pharma-ceutically acceptable carrier and, optionally, further suitable active substances, excipients or auxiliaries.

[0058] Suitable solid or galenic preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injection solutions and preparations with extended release of the active substances, for which customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used.Frequently used auxiliaries that may be mentioned include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycols and solvents, such as sterile water and mono- or polyhydric alcohols, such as glycerol.

[0059] Dosing regimens utilizing factor XIa inhibitors or dual factor XIa / plasma kallikrein inhibitors are selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof being used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of drug required to prevent, counter, or arrest the progression of the condition.

[0060] The compounds of Formula I, Formula Ia, Formula Ib and Formula Ic may be administered as monotherapy and in combination with other therapeutic agents including antithrombotic agents (anticoagulants and platelet aggregation inhibitors), thrombolytic agents (plasminogen activators), other profibrinolytic active substances, hypotensive agents, blood glucose regulators, lipid lowering agents and antiarrhythmic agents.

[0061] The factor XIa inhibitor or dual factor XIa / plasma kallikrein inhibitor can also be co-administered with suitable anticoagulants, including, but not limited to, other factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g., for treating or preventing unstable angina or for preventing reclosure after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects when treating various vascular lesions.Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban and semuloparin. For example, patients suffering from coronary artery disease and those undergoing angioplasty procedures may benefit from the co-administration of a fibrinogen receptor antagonist and a thrombin inhibitor. A factor XIa inhibitor may be administered first after thrombus formation, followed by tissue plasminogen activator or other plasminogen activators.

[0062] Alternatively or additionally, one or more additional pharmacologically active agents may be administered in combination with the compound of the present invention. By one or more additional active agents, it is intended to mean one or more pharmacologic active agents active in the body, including prodrugs that are converted into pharmacologic active forms after administration, and one or more additional active agents also include free acids, free bases and pharmacologic acceptable salts of said additional active agents, if such forms are commercially available or chemically possible, different from the compound of the present invention. In general, any suitable one or more additional active agents, including but not limited to antihypertensive agents, additional diuretics, antiatherosclerotic agents, such as lipid-modifying compounds, antidiabetic agents and / or antiobesity agents, may be used in any combination with the compound of the present invention in a single dosage formulation (fixed dose drug combination), or may be administered to a patient in one or more separate dosage formulations that allow for simultaneous or sequential administration of active agents (co-administration of separate active agents). Examples of additional active agents that may be used include, but are not limited to, angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril);Angiotensin II receptor antagonists, also known as angiotensin receptor blockers, i.e. ARBs, which may be in the form of a free base, free acid, salt or prodrug, such as azilsartan, e.g. azilsartan medoxomil potassium (EDARBI®), candesartan, e.g. candesartan cilexetil (ATACAND®), eprosartan, e.g. eprosartan mesylate (TEVETAN®), irbesartan (AVAPRO®), losartan, e.g. losartan potassium (COZAAR®), olmesartan, e.g. olmesartan medoxomil (BENICAR®), telmisartan (MICARDIS®), valsartan (DIOVAN®), and thiazide-like diuretics, e.g. hydrochlorothiazide (e.g. HYZAAR®, DIOVAN HCT®, ATACAND®). any of these drugs used in combination with HCTZ; potassium-sparing diuretics, e.g., amiloride HCl, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017;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]-octanamide hemifumarate) SPP600, SPP630 and SPP635;endothelin receptor antagonists;vasodilators (e.g., nitroprusside);calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine);potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam);sympatholytics; beta-adrenergic blockers (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha-adrenergic blockers (e.g., doxazosin, prazosin or alpha-methyldopa); central alpha-adrenergic agonists; peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors, such as simvastatin and lovastatin, which are marketed in lactone prodrug form as ZOCOR® and MEVACOR® and function as inhibitors after administration, and pharma- ceutically acceptable salts of dihydroxy open-acid HMG-CoA reductase inhibitors, such as atorvastatin (particularly the calcium salt sold under LIPITOR®), Rosuvastatin (especially the calcium salt sold under the trademark CRESTOR®), pravastatin (especially the sodium salt sold under the trademark PRAVACHOL®) and fluvastatin (especially the sodium salt sold under the trademark LESCOL®); cholesterol absorption inhibitors, for example ezetimibe (ZETIA®), and any other lipid-lowering agent such as the above-mentioned HMG-CoA reductase inhibitors, in particular ezetimibe in combination with simvastatin (VYTORIN®) or atorvastatin calcium; immediate or controlled release niacin, in particular niacin in combination with a DP antagonist, for example laropiprant and / or an HMG-CoA reductase inhibitor; niacin receptor agonists, for example acipimox and acifran, and niacin receptor partial agonists;Metabolic altering agents, e.g., insulin sensitizers and related compounds for the treatment of diabetes, e.g., biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones, also called glitazones (e.g., pioglitazone, rosiglitazone), alpha-glucosidase inhibitors agents (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), concomitant medications, e.g., JANUMET® (method sitagliptin with luminin), and injectable diabetes drugs, such as exenatide and pramlintide acetate; inhibitors of glucose uptake, such as sodium glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1, SGLT-2 (e.g., ASP-1941, TS-071, BI-10773, tofogliflozin, LX-4211, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, remogliflozin and sotagliflozin) and SGLT-3; or other drugs useful for the prevention or treatment of the above diseases, including, but not limited to, diazoxide, and, where chemically possible, free acid, free base and pharma- ceutically acceptable salt forms, prodrug forms, such as esters, and salts of prodrugs of the above drugs. The trade names of the above pharmaceutical products are provided to illustrate the marketed form of the active agent(s). Such pharmaceutical agents may be used in separate dosage forms for simultaneous or sequential administration with the compounds of the invention, or the active agent(s) therein may be used in a fixed dose drug combination with the compounds of the invention;

[0063] Typical doses of the factor XIa inhibitors or factor XIa / plasma kallikrein inhibitors of the present invention in combination with other suitable antiplatelet, anticoagulant or thrombolytic agents may be the same as the dose of the factor XIa inhibitor administered without the concomitant administration of an additional antiplatelet, anticoagulant or thrombolytic agent, or may be substantially less than the dose of the thrombin inhibitor administered without the concomitant administration of an additional antiplatelet, anticoagulant or thrombolytic agent, depending on the therapeutic needs of the patient.

[0064] The compound is administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of a compound of the invention that, when administered to a mammal, alone or in combination with an additional therapeutic agent, is effective to treat (i.e., prevent, inhibit or ameliorate) a thromboembolic and / or inflammatory disease state or treat disease progression in the host.

[0065] The compounds of the present invention are preferably administered to a mammal alone in a therapeutically effective amount. However, the compounds of the present invention can also be administered to a mammal in a therapeutically effective amount in combination with an additional therapeutic agent as defined below. When administered in combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect of the compounds when administered in combination (in this case, inhibition of the desired target) is greater than the additive effect of each of the compounds when administered individually as single agents. In general, synergy is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of reduced cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared to the individual components.

[0066] "Administered in combination" or "combination therapy" means that a compound of the present invention and one or more additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component can be administered simultaneously at different times or sequentially in any order. Thus, each component can be administered separately but sufficiently close in time to provide the desired therapeutic effect.

[0067] The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of some aspects of the invention, and any embodiments which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to be included within the scope of the appended claims.

[0068] Common methods Several methods for preparing the compounds of the present invention are shown in the following schemes and examples. Starting materials and necessary intermediates are in some cases commercially available or can be prepared according to literature procedures or as shown herein. The compounds of the present invention can be prepared by using the reactions shown in the following schemes in addition to other standard operations known in the literature or exemplified in the experimental procedures. The numbering of the substituents shown in the schemes does not necessarily correlate to that used in the claims, and in many cases, for clarity, a single substituent is shown attached to the compound, with multiple substituents being allowed under the above definition. The reactions used to generate the compounds of the present invention are carried out by using the reactions shown in the schemes and examples herein in addition to other standard operations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. The starting materials are made according to procedures known in the art or as shown herein.

[0069] The compounds of the present invention can be prepared in various ways. In some cases, the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions that are commonly known to those skilled in the art. In some cases, the order of carrying out the above-mentioned reaction schemes may be changed to facilitate the reaction or to avoid undesired reaction products. Since the schemes are illustrative, the present invention should not be construed as being limited by the chemical reactions and conditions shown. The preparation of the various starting materials used herein is well within the skill of those skilled in the art. The following examples are provided so that the present invention may be more fully understood. These examples are merely illustrative and should not be construed as limiting the present invention in any way. The absolute stereochemistry of the separate stereoisomers in the examples and intermediates is not determined unless otherwise stated in the examples or explicitly stated in the nomenclature.

[0070] Abbreviations are used and defined as follows: S-(+)-DTBM-Segphos® is (S)-(+)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole, xphos-G2 is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), and cataCXium® A Pd G2 is chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), available from Sigma Aldrich.

[0071] Ac Acetyl Ar Aryl aq Water-based Bn Benzyl Boc tert-Butyloxycarbonyl t-Bu tert-Butyl 18-Crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane DAST Diethylaminosulfur trifluoride DCE Dichloroethane DCM Dichloromethane DEA Diethylamine DIAD Diethyl azodicarboxylate DIEA or DIPEA N,N-Diisopropylethylamine DMA Dimethylacetamide DME 1,2-Dimethoxyethane DMF Dimethylformamide DMPU 1,3-Dimethyl-tetrahydropyrimidin-2(1H)-one DMSO Dimethyl sulfoxide DPPA Diphenylphosphoryl azide EDC or EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide ESMS Electrospray Mass Spectrometry Et Ethyl EtOAc Ethyl acetate Et3N Triethylamine h hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate Hex HOBt Hydroxybenzotriazole hydrate HPLC High Performance Liquid Chromatography IPA Isopropanol LCMS Liquid Chromatography Mass Spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide m-CPBA m-Chloroperbenzoic acid Me Methyl MeCN Acetonitrile MeOH Methanol mg milligram min(one or more) minutes μL microliter mL Milliliters mmol NMR nuclear magnetic resonance NIS N-iodosuccinimide MS mass spectrometry MTBE Methyl tert-butyl ether Pd / C Palladium Carbon Ph Phenyl Py Pyridine Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PPh3 Triphenylphosphine TBAI Tetrabutylammonium iodide TEA Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin Layer Chromatography TMEDA Tetramethylethylenediamine TMS Tetramethylsilane rt room temperature SEM 2-(trimethylsilyl)ethoxy)methyl SFC Supercritical Fluid Chromatography

[0072] NMR spectra were measured using VARIAN NMR systems (400, 500 or 600 MHz) and BRUKER NMR systems (400, 500 MHz). Chemical shifts are reported in ppm downfield and upfield from TMS and are referenced to either the internal TMS or the solvent resonance ( 1 H NMR: δ 7.27 for CDCl3, δ 2.50 for (CD3)(CHD2)SO, and 13C NMR: δ 77.02 for CDCl3, δ 39.51 for (CD3)2SO. Coupling constants (J) are given in Hertz (Hz) and spin multiplicities are given as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet) and br (broad). Chiral separations were performed using either a Waters Thar 80 SFC system or a Berger MG II system, a Thar 80 SFC system, a Waters 80 SFC system, a Sepiatec 100 SFC system, a Waters 200 SFC system, a Thar 350 SFC system, or a Berger MG III preparative SFC system. LCMS data were recorded using a SHIMADAZU LCMS-2020 instrument, a SHIMADAZU LCMS-2010EV instrument, an Agilent 1100 series LCMS instrument, or a Waters Acquity LCMS instrument, using a C18 column with a MeCN gradient in water containing 0.02-0.1% TFA. UV detection was at 220 and / or 254 nm, and ESI ionization was used for MS detection.

[0073] In cases where the chiral resolution was achieved by chromatography using a chiral column, the chiral column used for the SFC chiral resolution is as indicated.

[0074] Also, TLC is thin layer chromatography. UV is ultraviolet. W is watts. wt% is weight percent. xg is times gravity. α D is the specific rotation of polarized light at 589 nm. °C is degrees Celsius. %w / v is the percentage of the weight unit of the former agent compared to the volume of the latter agent. Hz is hertz. cpm is counts per minute. δ His the chemical shift. d is a doublet. dd is a doublet of a doublet. MHz is megahertz. MS is mass spectrum, and herein mass spectra obtained by ESMS may be designated by "LCMS". m / z is mass to charge ratio. n is normal. N is normal. nm is nanometer. nM is nanomolar.

[0075] "Human FXIa Ki(nM)" is human factor XIa Ki(nM).

[0076] Scheme Scheme 1 shows one synthetic sequence for preparing compounds of the invention. Macrocycles of general formula 8 can be prepared as described in Scheme 1. Preparation of intermediate macrocyclic cores 2 is described in detail in the intermediates section and general methods related to such systems are described in WO 2017 / 074832. Compounds such as 1, where Y is a suitable reactive halide, can be coupled with an appropriate boronic acid 2 or boronic ester using Suzuki reaction. Methyl or ethyl esters can be introduced to the imidazole of compound 3 by iodination followed by a carbonation reaction in the presence of methanol or ethanol. Subsequent reduction of the olefin of compound 5 to compound 6 can be performed by an asymmetric hydrogenation process where enantiomeric enrichment can be obtained by use of the Rh catalyst / S-(+)-DTBM-segphos® reagent system. Formation of the N-oxide in 7 can be achieved by oxidation of the pyridine of 6 with an oxidizing agent such as oxone or peracetic acid. Finally, removal of the SEM protecting group of 7 by treatment with TFA can be performed to obtain compounds of general formula 8.

[0077] Scheme 1 [ka]

[0078] Intermediate 1 Methyl (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate [ka]

[0079] Step 1: (4-Bromo-3-nitrophenyl)carbamate To a solution of 4-bromo-3-nitroaniline (500.0 g, 2.30 mol, 1 equiv) in 2-Me-THF (2.5 L) was added DIEA (655.0 g, 5.07 mol, 883.0 mL, 2.2 equiv) in one portion. Methyl carbonochloridate (261.0 g, 2.76 mol, 214.0 mL, 1.2 equiv) was then added to the reaction over 0.5 h while maintaining the temperature between 20-48 °C. The reaction was heated to 50 °C and aged for 1 h. It was then cooled to 20 °C. The reaction was poured into water and extracted with EtOAc. The combined organic portions were washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under vacuum. The product was slurried with petroleum ether. The product was then collected by filtration and dried under vacuum to give methyl (4-bromo-3-nitrophenyl)carbamate. 1H NMR: (400 MHz, CDCl3) 8.03 (s, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.45-7.47 (m, 1 H), 6.99 (s, 1 H), 3.81 (s, 3 H).

[0080] Step 2: Methyl (3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate In a 3 L three-neck flask equipped with a magnetic stirrer, add a 25 °C solution of methyl (4-bromo-3-nitrophenyl)carbamate (450.0 g, 1.64 mol, 1.0 equiv.) in dioxane (2.7 L), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (456.9 g, 1.80 mol, 1.1 equiv.), KOAc (353.2 g, 3.60 mol, 2.2 equiv.) and Pd(dppf)Cl2 (59.8 g, 0.08 mol, 0.05 equiv.) to the reaction. The mixture was purged with N2 three times, then heated to 80 °C and aged for 7 h. The reaction was concentrated under vacuum. The residue was suspended in MTBE. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 50:1 to 4:1). Fractions containing the desired product were combined and concentrated under vacuum to give methyl (3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. 1HNMR: 400 MHz CDCl3 δ: 8.18(s,1 H), 7.69-7.71(d,J=7.2 Hz,1 H), 7.46-7.48(d,J=8.0 Hz,1 H), 6.96(s,1 H), 3.80(s,3 H), 1.42(s,12 H).

[0081] Step 3: Methyl (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate To a dried hydrogenation bottle was added Pd / C (3.0 g, 10.0% purity), MeOH (1.5 L) and methyl (3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (60.0 g, 0.18 mol, 1.0 equiv). The vessel was degassed under vacuum and purged with H2 three times. The reaction was then aged under H2 (20 Psi) at 25 °C for 2 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum to give methyl (3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. LCMS (ES, m / z): 292.9 [M+H]+ . 1HNMR:(400 MHz,CDCl3)7.51(d,J=8.0 Hz,1H),6.91(s,1H),6.55(s,1H),6.46-6.49(m,1H),4.80(s,2H),3.76(s,3H),1.33(s,12H)

[0082] Intermediate 2 (5-Bromopyridin-2-yl)(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanone [ka]

[0083] Step 1: 4-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole To a suspension of NaH (4.21 g, 105 mmol, 60% wt) in DMF (200 mL) at 0° C., 4-iodo-1H-imidazole (17 g, 88 mmol) was added portionwise. This was stirred for 1 h and SEM-Cl (16.07 g, 96 mmol) was added to the reaction. The mixture was stirred at room temperature for 12 h and poured into ice water (200 mL). The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with petroleum ether: EtOAc=10:1 to 3:1 v / v) to give the title compound. MS (ES) + )m / z:325(M+H).

[0084] Step 2: 5-Bromo-N-methoxy-N-methylpicolinamide To a solution of 5-bromopicolinic acid (15 g, 74.3 mmol) in DCM (200 mL) at 0° C., EDC (21.35 g, 111 mmol), N,O-dimethylhydroxylamine hydrochloride (10.86 g, 111 mmol) and pyridine (15.01 mL, 186 mmol) were added. The mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was diluted with EtOAc (250 mL) and washed with 1N HCl (50 mL) and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS (ES) + ) m / z: 245, 247 (M+H).

[0085] Step 3: (5-bromopyridin-2-yl)(4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanone To a solution of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (15.88 g, 49.0 mmol) in THF (100 mL) at −78° C. was added LDA solution (26.5 mL, 53.0 mmol, 2 M in THF) dropwise. The reaction was stirred for 1 h and a solution of 5-bromo-N-methoxy-N-methylpicolinamide (10 g, 40.8 mmol) in THF (20 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h and was quenched with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with EtOAc (150 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with petroleum ether: EtOAc = 10:1 v / v) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.85(s,1H),8.23(m,1H),8.02(m,1H),7.52(s,1H),5.81(s,2H),3.65(m,2H),0.96(m,2H),-0.01(s,9H).

[0086] Intermediate 3 Methyl (3-amino-4-(2-(5-bromopicolinoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)carbamate [ka]

[0087] A mixture of intermediate 2 (40 g, 79 mmol), intermediate 1 (25.3 g, 87 mmol), tetrakis(triphenylphosphine)palladium(0) (4.55 g, 3.94 mmol), DMF (354 mL), and tripotassium phosphate (50.1 g, 236 mmol) was stirred at 60° C. for 3.5 h. It was cooled to room temperature and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with water (3×100 mL) and then with brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with a gradient of 0-60% EtOAc / hexanes) to give the title compound. MS (ES) + )m / z:546,548 [M+H].

[0088] Intermediate 4 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoic acid [ka]

[0089] Step 1: Methyl 5-(benzo[d]thiazol-2-ylthio)pentanoate Benzo[d]thiazole-2-thiol (220 g, 1.32 mol) and methyl 5-bromopentanoate (282.2 g, 1.45 mol) were combined with acetone (2.0 L) in a three-neck round bottom flask equipped with a magnetic stirrer at 20° C. To this was added K2CO3 (181.8 g, 1.32 mol) in one portion at 20° C. The reaction was stirred at 20° C. for 12 hours. The reaction was filtered and concentrated in vacuo to give methyl 5-(benzo[d]thiazol-2-ylthio)pentanoate, which was used in the next step without further purification.

[0090] Step 2: Methyl 5-(benzo[d]thiazol-2-ylthio)-2-methylpentanoate A three-necked round bottom flask equipped with a magnetic stirrer was charged with a solution of methyl 5-(benzo[d]thiazol-2-ylthio)pentanoate (300.0 g, 1.07 mol) and CHI (151.3 g, 1.07 mol) in dry THF (1.5 L) at 20° C. After cooling the reaction to −70° C., LiHMDS (2 M in THF, 746.3 ml) was added to the mixture over 2 h while maintaining the temperature below −60° C. The reaction was aged at −60° C. for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (8.0 L) and extracted with ethyl acetate. The organic layer was washed with brine and then concentrated under vacuum. The residue was purified by silica gel chromatography. Fractions containing the desired product were combined and concentrated under vacuum to give methyl 5-(benzo[d]thiazol-2-ylthio)pentanoate.

[0091] Step 3: Methyl 5-(benzo[d]thiazol-2-ylthio)-2,2-dimethylpentanoate A three-necked round bottom flask equipped with a magnetic stirrer was charged with a solution of methyl 5-(benzo[d]thiazol-2-ylthio)-2-methylpentanoate (200.0 g, 0.68 mol) and CHI (283.5 g, 2.0 mol) in dry THF (1.0 L) at 20° C. After cooling the reaction to −70° C., LDA (2 M, 0.88 L) was added to the mixture over 2 h while maintaining the temperature below −60° C. The reaction was aged at −60° C. for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (4.0 L) and extracted twice with ethyl acetate (5.0 L, 4.0 L). The organic layer was washed with brine (5.0 L) and then concentrated under vacuum to give methyl 5-(benzo[d]thiazol-2-ylthio)-2,2-dimethylpentanoate, which was used in the next step without further purification.

[0092] Step 4: 5-(benzo[d]thiazol-2-ylthio)-2,2-dimethylpentanoic acid A three-necked round bottom flask equipped with a magnetic stirrer was charged with a solution of methyl 5-(benzo[d]thiazol-2-ylthio)-2,2-dimethylpentanoate (200.0 g, 0.64 mol) in 2-methyltetrahydrofuran (0.2 L) at 20 °C. Aqueous NaOH (3.75 M, 1.0 L) was added in one portion to the mixture at 20 °C. The mixture was aged at reflux at 80 °C for 15 h. After cooling to room temperature, the reaction was extracted with ethyl acetate and the aqueous layer was adjusted to pH = 2 with aqueous HCl (4 M, 1.0 L) to precipitate a solid. The solid was filtered and the filter cake was washed with petroleum ether to give 5-(benzo[d]thiazol-2-ylthio)-2,2-dimethylpentanoic acid, which was used in the next step without further purification.

[0093] Step 5: 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoic acid A three-necked round bottom flask equipped with a magnetic stirrer was charged with a solution of 5-(benzo[d]thiazol-2-ylthio)-2,2-dimethylpentanoic acid (730.0 g, 2.48 mol) in EtOH (3600 ml) at 20 °C. To this, ammonium molybdate (73 g) was added in one portion at 20 °C. H2O2 (1403 g, 12.4 mol, 30% purity) was added to the mixture over 0.2 h at 20 °C. The reaction was aged at about 20-30 °C for 2 h, at which point water (15 L) was added at 20 °C. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous Na2SO3 (4.0 L x 3) and then dried over Na2SO4. The mixture was filtered and the filtrate was concentrated under vacuum. The product was triturated with petroleum ether:ethyl acetate=1:1 to give 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoic acid. LCMS (ES, m / z): 328.0 [M+H] + .

[0094] Intermediate 5 Methyl ((1 2 Z,8Z)-9-(5-bromopyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate [ka]

[0095] Step 1: 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoyl chloride To a mixture of 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoic acid (200 g, 0.61 mol) in acetonitrile (1000 ml) at 25° C. was added sulfurous dichloride (109 g, 0.12 mol) over 10 minutes. The reaction mixture was stirred at 25° C. for 2 hours and then it was concentrated in vacuo to give 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoyl chloride, which was used without further purification.

[0096] Step 2: Methyl (3-(5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanamido)-4-(2-(5-bromopicolinoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)carbamate To a mixture of methyl (3-amino-4-(2-(5-bromopicolinoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)carbamate (276 g, 0.51 mol) in DCM (850 ml) at 25° C. was added a solution of 5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanoyl chloride (180 g, 0.52 mol) in DCM (1100 ml) over 5 minutes followed by triethylamine (144.9 ml, 1.04 mol) over 10 minutes. The reaction mixture was stirred at 25° C. for 2 hours. The two reactions were combined for workup. The reaction mixture was poured into water (4.4 L). The organic layer was washed with 1N HCl (4.4 L x 2), saturated NaHCO3 (4.4 L), brine (4.4 L) and concentrated to dryness in vacuo to give the title compound, which was used without further purification. LCMS (ES, m / z): 855.2, 857.3 [M+H] + .

[0097] Step 3: Methyl ((1 2 Z,8Z)-9-(5-bromopyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate To a solution of LiHMDS (1.0M, 818 ml, 0.82 mol) in THF (1250 ml) at -20°C was added dropwise a solution of methyl (3-(5-(benzo[d]thiazol-2-ylsulfonyl)-2,2-dimethylpentanamido)-4-(2-(5-bromopicolinoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenyl)carbamate (250 g, 0.20 mol) in THF (1250 mL). The reaction mixture was stirred at -30°C to -20°C for 2 h. The four reactions were combined for workup. The reaction mixture was poured into saturated NH4Cl (10 L) at 0-10°C. The organic layer was washed with 5% NaOH (10 L, 9 L and 8 L). The aqueous layer was extracted with ethyl acetate (5 L, 3 L). The combined organic layers were washed with brine (5 L, 4 L), dried over anhydrous sodium sulfate, and filtered. After concentration in vacuum, the product was purified by recrystallization from MeOH to give the title compound. LCMS (ES, m / z): 640.2, 642.2 [M+H] + .1H NMR(400 MHz,CDCl3):δ 8.71(d,J=2.4 Hz,1H),7.96-7.89(m,2H),7.64(br s,1H),7.54(d,J=8.4 Hz,1H),7.40(d,J=8.6 Hz,1H),7.34(s,1H),6.94(br dd,J=6.4,10.4 Hz,1H),6.81(br s,1H),5.09(d,J=10.8 Hz,1H),4.85(d,J=10.6 Hz,1H),3.85(s,3H),3.37-3.24(m,2H),2.52-2.26(m,3H),1.86(dt,J=6.0,13.8 Hz,1H),1.42(s,3H),1.27(s,3H),0.83(t,J=8.3 Hz,2H),0.00(s,9H).

[0098] Intermediate 6 (6-((1 2 Z,8Z)-2 4-((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-en-9-yl)pyridin-3-yl)boronic acid [ka]

[0099] Methyl ((1 2 Z,8Z)-9-(5-bromopyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a stirred mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.761 g, 3.00 mmol), potassium acetate (0.735 g, 7.49 mmol) in dioxane (20 mL) was added xphos-G2, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.197 g, 0.250 mmol) under N2 at 25 °C and the mixture was stirred at 100 °C under N2 for 1 h. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic fractions were washed with brine (20 mL×2), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (6-((1 2 Z,8Z)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-en-9-yl)pyridin-3-yl)boronic acid was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 606.2 [M+H] + .

[0100] [Example 1] (R,Z)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine 1-oxide [ka]

[0101] Step 1: Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5-bromopyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4To a stirred mixture of xphos-G2 (0.393 g, 0.499 mmol), 1-(4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)-1H-pyrazole (2.67 g, 7.49 mmol) in THF (60 mL) was added 2M potassium phosphate (9.37 mL, 18.7 mmol) at 25° C. under N2, and the mixture was stirred at 80° C. under N2 for 16 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (80 mL×2). The combined organic fractions were washed with brine (80 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-60% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 790.4 (M+H) + .

[0102] Step 2: Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a stirred mixture of 1-iodopyrrolidine-2,5-dione (1.44 g, 6.41 mmol) in CH3COOH (25 mL) was added 1-iodopyrrolidine-2,5-dione (1.44 g, 6.41 mmol) at 25 °C and the reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was carefully added dropwise to Na2CO3 solution at 0 °C until PH = 7. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic fractions were washed with brine (200 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-50% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 916.2 (M+H) + .

[0103] Step 3: Ethyl (1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -Carboxylate Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of PdCl2(dppf) (2.037 g, 2.78 mmol) and TEA (10.35 mL, 74.3 mmol) in EtOH (60 mL) and DMSO (60 mL) was added PdCl2(dppf) (2.037 g, 2.78 mmol) and TEA (10.35 mL, 74.3 mmol) and the mixture was stirred at 70 °C under CO atmosphere at 50 psi for 16 h. The reaction mixture was concentrated. The mixture was cooled, diluted with ethyl acetate (200 mL), washed with brine (200 mL x 4), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography (C18; eluent 0-50% MeCN / H2O) to give ethyl (1H-yl) carbamate. 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -carboxylate was obtained. LCMS (ES, m / z): 862.5 (M+H) + .

[0104] Step 4: Ethyl (R,Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-24 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate To a stirred mixture of bis(norbornadiene)rhodium(I) tetrafluoroborate (0.195 g, 0.522 mmol) in 1,2-dichloroethane (15 mL) was added (S)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole (0.616 g, 0.522 mmol) in a glove box at 25° C., and the mixture was stirred at 25° C. for 1 h under N2 atmosphere. 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 To a stirred mixture of 5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2-carboxylate (4.5 g, 5.2 mmol) in trifluoroethanol (80 mL) was added the above mixture at 25° C., and the reaction mixture was stirred at 50 psi of H2 at 50° C. for 48 h. The reaction mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-60% EtOAc / petroleum ether) to give ethyl (R,Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2-methylpyridine. 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-15 -carboxylate was obtained. LCMS (ES, m / z): 864.3 (M+H) + .

[0105] Step 5: (R,Z)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine 1-oxide Ethyl (R,Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 A mixture of (R,Z)-2-(1H-carboxylate (2.0 g, 2.3 mmol) in CH3COOOH (30 mL) was stirred at 30 °C for 3 h under N2 atmosphere. The mixture was added to aqueous sodium bicarbonate (saturated, 200 mL) and aqueous Na2SO3 (saturated, 500 mL) at 0 °C, and the mixture was extracted with ethyl acetate (500 mL × 2). The combined organic fractions were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (R,Z)-2-(1H-carboxylate). 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine 1-oxide was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 880.3 (M+H). + .

[0106] Step 6: (R,Z)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine 1-oxide (R,Z)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine 1-oxide (2.0 g, 2.3 mmol), 2-amino-3-mercaptopropanoic acid (0.826 g, 6.82 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (20 mL, 2.3 mmol) and the mixture was stirred at 40 °C under N2 atmosphere for 3 h. Volatiles were evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-65% CHCl / EtOAc). This was further purified by chiral SFC (DAICEL CHIRALCEL OD, 40% 0.1% NH3H2O ​​EtOH / CO2) to give (R,Z)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-11 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine 1-oxide was obtained. LCMS (ES, m / z): 750.3 (M+H) + .1H NMR(400 MHz,DMSO-d6):δ 12.90(s,1H),10.93(s,1H),9.74(s,1H),8.71-8.47(m,2H),8.22-8.12(m,1H),8.07(br d,J=4.3 Hz,1H),7.94-7.69(m,3H),7.68-7.60(m,1H),7.56-7.48(m,1H),7.42-7.28(m,1H),7.05-6.92(m,1H),4.92-4.71(m,1H),4.23-4.03(m, 2H),3.72-3.62(m,3H),2.24-1.78(m,4H),1.58-1.36(m,1H),1.29-1 .21(m,3H),1.19-1.11(m,3H),1.07-0.92(m,3H),0.33-0.42(m,1H).

[0107] [Example 2] (R,Z)-5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide [ka]

[0108] Step 1: 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-pyrazole To a solution of 2-bromo-4-chloro-1-fluorobenzene (8.32 g, 39.7 mmol) and 4-(trifluoromethyl)-1H-pyrazole (3.20 g, 23.5 mmol) in DMA (40 mL) was added Cs2CO3 (15.32 g, 47.0 mmol). The mixture was heated to 80 °C for 20 h. Water (80 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 2). The combined organic fractions were washed with brine (40 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-20% EtOAc / petroleum ether) to give 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-pyrazole.

[0109] Step 2: Methyl ((1 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate (6-((1 2 Z,8Z)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-en-9-yl)pyridin-3-yl)boronic acid (1.50 g, 2.48 mmol), 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-pyrazole (0.766 g, 2.35 mmol), potassium phosphate (2.477 mL, 4.95 mmol) in THF (15 mL) was added cataCXium® A Pd G2 (0.166 g, 0.248 mmol) and the mixture was stirred at 80° C. under N2 atmosphere for 2 h. LCMS showed the reaction was complete. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic fractions were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 806.3 (M+H) + .

[0110] Step 3: Methyl ((1 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a stirred mixture of 1-iodopyrrolidine-2,5-dione (0.381 g, 1.69 mmol) in CH3COOH (10 mL) was added 1-iodopyrrolidine-2,5-dione (0.381 g, 1.69 mmol) at 25 °C and the mixture was stirred at 40 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was carefully added dropwise to NaHCO3 solution at 0 °C until PH = 7. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic fractions were washed with brine (50 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 932.1 (M+H) + .

[0111] Step 4: Ethyl (1 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -Carboxylate Methyl ((1 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of 1-phenyl-yl)carbamate (1.10 g, 1.18 mmol) in EtOH (10 mL) and DMSO (10 mL) was added PdCl2(dppf) (0.259 g, 0.354 mmol) and TEA (1.645 mL, 11.8 mmol) and the mixture was stirred at 70 °C under CO atmosphere at 50 psi for 16 h. LCMS showed the reaction was complete. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica (0-50% EtOAc / petroleum ether) to give ethyl (1-phenyl-yl)carbamate. 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -carboxylate was obtained. LCMS (ES, m / z): 878.3 (M+H) + .

[0112] Step 5: Ethyl (R,Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1-((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate To a stirred mixture of 5,5'-bis(bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino)-4,4'-bibenzo[d][1,3]dioxole (102 mg, 0.087 mmol) in 1,2-dichloroethane (1 mL) was added (S)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole (32.4 mg, 0.087 mmol) at room temperature in a glove box, and the mixture was stirred at 25°C for 1 h under N2 atmosphere. 2 Z,8Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 A stirred mixture of 9-carboxylate (760 mg, 0.865 mmol) in 2,2,2-trifluoroethan-1-ol (5 mL) was added to the above catalyst mixture at room temperature, and the mixture was stirred under H2 atmosphere (50 psi) at 45 °C for 36 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give ethyl (R,Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2-yl)-pyridine-2-yl (R,Z)-9-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-pyridine-2-yl (R,Z)-9-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridine ...)-pyridine-2-yl (R,Z)-9-(5-chloro-2- 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5-carboxylate was obtained. LCMS (ES, m / z): 880.4 (M+H) + .

[0113] Step 6: (R,Z)-5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide Ethyl (R,Z)-9-(5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 A solution of the -carboxylate (640 mg, 0.727 mmol) in CH3COOOH (5 mL, 10% wt) was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was carefully added dropwise to a cooled (0 °C) mixture of 20 g ice, saturated NaHCO3 (80 mL), and saturated Na2SO3 (80 mL). The mixture was extracted with EtOAc (200 mL x 2). The combined organic fractions were washed with brine (200 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (R,Z)-5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 896.3 (M+H) + .

[0114] Step 7: (R,Z)-5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (R,Z)-5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1To a mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (640 mg, 0.714 mmol), 2-amino-3-mercaptopropanoic acid (260 mg, 2.14 mmol) in CHCl (6 mL), TFA (6 mL) was added and the mixture was stirred at 40 °C under N atmosphere for 2 h. The solvent was removed under reduced pressure. Aqueous NaHCO (saturated, 5 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic fractions were washed with brine (15 mL × 2), dried over NaSO, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-60% EtOAc / petroleum ether). This was further purified by chiral SFC (DAICEL CHIRALPAK AS, 40% 0.1% NH3H2O ​​EtOH / CO2) and then by reverse phase HPLC (ACN / water with 0.04% NH3H2O ​​+ 10 mM NH4HCO3 modifier) ​​to give (R,Z)-5-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained. LCMS(ES,m / z):766.2(M+H)+.1H NMR(500 MHz,CDCl3):δ 12.39-11.97(m,1H),11.70(br s,1H),8.30(s,1H),7.91(br d,J=8.5 Hz,1H),7.82(s,1H),7.77(br s,1H),7.70(s,1H),7.64-7.48(m,4H),7.33(br d,J=8.1 Hz,1H),6.97-6.77(m,2H),4.87-4.72(m,1H),4.29(q,J=6.9 Hz,2H),3.76(s,3H),3.03-2.63(m,1H),2.37-2.11(br s,1H),1.98-1.78(m,1H),1.61-1.46(m,2H),1.39-1.13(m,10H).

[0115] [Example 3] (R,Z)-5-(2-(difluoromethoxy)-5-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide [ka]

[0116] Step 1: 2-Bromo-1-(difluoromethoxy)-4-fluorobenzene To a stirred mixture of 2-bromo-4-fluorophenol (20.0 g, 105 mmol) in DMF (250 mL) was added K2CO3 (43.4 g, 314 mmol) and sodium 2-chloro-2,2-difluoroacetate (19.16 g, 126 mmol) and the reaction mixture was stirred at 70 °C under N2 for 15 h. Water (500 mL) was added and the mixture was extracted with petroleum ether (500 mL x 3). The combined organic fractions were washed with brine (500 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-10% EtOAc / petroleum ether) to give 2-bromo-1-(difluoromethoxy)-4-fluorobenzene. 1H NMR (400 MHz, CD3OD): δ 7.52-7.45(m,1H),7.35-7.25(m,1H),7.20-7.10(m,1H),6.76(t,J=72 Hz,1H).

[0117] Step 2: Methyl ((1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate (6-((1 2 Z,8Z)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-en-9-yl)pyridin-3-yl)boronic acid (11.3 g, 18.7 mmol) and PdCl2(dppf) (0.956 g, 1.31 mmol) in dioxane (120 mL) was added 2-bromo-1-(difluoromethoxy)-4-fluorobenzene (6.75 g, 28.0 mmol) and potassium phosphate (2 M, 28.0 mL, 56.0 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 4 h. Water (150 mL) was added and the mixture was extracted with ethyl acetate (250 mL x 2). The combined organic fractions were washed with brine (250 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-50% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 722.6 (M+H) + .

[0118] Step 3: Methyl ((1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1-((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a stirred mixture of 1-iodopyrrolidine-2,5-dione (2.244 g, 9.97 mmol) in CH3COOH (60 mL) was added 1-iodopyrrolidine-2,5-dione (2.244 g, 9.97 mmol) at 25 °C and the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was carefully added dropwise to NaHCO3 solution at 0 °C until PH = 7. The mixture was extracted with ethyl acetate (500 mL x 2). The combined organic fractions were washed with brine (500 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-60% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 848.3 (M+H) + .

[0119] Step 4: Ethyl (1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4-((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -Carboxylate Methyl ((1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of Pd(dppf)Cl2 (1.958 g, 2.68 mmol) in EtOH (90 mL) and DMSO (90 mL) was added Pd(dppf)Cl2 (1.958 g, 2.68 mmol) and Et3N (7.99 mL, 57.3 mmol) under N2. The suspension was degassed under vacuum and purged with CO several times. The reaction mixture was stirred at 70 °C under CO (50 psi) for 23 h. The reaction mixture was cooled to 25 °C, water (150 mL) was added, and the mixture was extracted with ethyl acetate (250 mL × 2). The combined organic fractions were washed with brine (250 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (10-40% EtOAc / petroleum ether) to give ethyl (1 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -carboxylate was obtained. LCMS (ES, m / z): 794.2 (M+H) + .

[0120] Step 5: Ethyl (R,Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate To a stirred mixture of bis(norbornadiene)rhodium(I) tetrafluoroborate (0.313 g, 0.838 mmol) in 1,2-dichloroethane (5 mL), (S)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole (0.988 g, 0.838 mmol) was added at room temperature in a glove box, and the mixture was stirred at 25°C under N2 atmosphere for 1 h. 2 Z,8Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 A stirred mixture of 2,2,2-trifluoroethane-1-ol (60 mL) was added to the above catalyst mixture at room temperature and the reaction mixture was stirred at 50 °C under H2 atmosphere (50 psi) for 48 h. The mixture was concentrated. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give ethyl (R,Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2-pyridin-2-yl). 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -carboxylate was obtained. LCMS (ES, m / z): 796.2 (M+H) + .

[0121] Step 6: (R,Z)-5-(2-(difluoromethoxy)-5-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide Ethyl (R,Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 To a stirred mixture of 18-Crown-6 (5.58 g, 21.1 mmol) and oxone (12.98 g, 21.11 mmol) in MeOH (30 mL) was added water (8 mL) at 25 °C and the reaction mixture was stirred at 25 °C for 2 h under N2 atmosphere. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic fractions were washed with aqueous Na2SO3 (100 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give (R,Z)-5-(2-(difluoromethoxy)-5-fluorophenyl)-2-(1H-pyridinyl ... 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 812.1 (M+H). + .

[0122] Step 7: (R,Z)-5-(2-(difluoromethoxy)-5-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (R,Z)-5-(2-(difluoromethoxy)-5-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (4.0 g, 4.9 mmol) and 2-amino-3-mercaptopropanoic acid (2.98 g, 24.6 mmol) in CHCl (15 mL) was added TFA (30 mL) at 25 °C and the mixture was stirred at 25 °C under N atmosphere for 2 h. The solvent was removed, NaHCO (200 mL) was added and the mixture was extracted with ethyl acetate (250 mL x 2). The combined organic fractions were washed with brine (200 mL), dried over NaSO, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-70% EtOAc / petroleum ether). This was further purified by chiral SFC (DAICEL CHIRALCEL OD, 45% 0.1% NH3H2O ​​MeOH / CO2) to give (R,Z)-5-(2-(difluoromethoxy)-5-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4-((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained. LCMS (ES, m / z): 682.0 (M+H) + .1H NMR(400 MHz,CD3OD):δ 8.46(br s,1H),8.02-7.51(m,4H),7.40-7.22(m,4H),6.85(t,J=54.6 Hz,1H),4.95-4.85(m,1H),4.29-4.08(m,2H),3.73(s,3H),2.22-2.14(m,2H),1.90-1.78(m,1H),1.50-1.42(m,1H),1.33-0.99(m,11H)

[0123] [Example 4] (R,Z)-5'-chloro-2'-(difluoromethoxy)-6-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenecyclononaphan-9-yl)-[3,3'-bipyridine] 1-oxide [ka]

[0124] Step 1: 3-Bromo-5-chloro-2-(difluoromethoxy)pyridine To a mixture of 3-bromo-5-chloropyridin-2-ol (1.85 g, 8.88 mmol) and Na2CO3 (1.88 g, 17.8 mmol) in MeCN (20 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.581 g, 8.88 mmol). The reaction mixture was stirred at 25 °C for 15 h. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica (0-30% EtOAc / petroleum ether) to give 3-bromo-5-chloro-2-(difluoromethoxy)pyridine. 1H NMR (400 MHz, CDCL3): δ 8.08(s,1H),7.95(s,1H),7.38(t,J=72.0 Hz,1H).

[0125] Step 2: Methyl ((1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate (6-((1 2 Z,8Z)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1To a mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-en-9-yl)pyridin-3-yl)boronic acid (0.945 g, 1.56 mmol) and 3-bromo-5-chloro-2-(difluoromethoxy)pyridine (0.565 g, 2.19 mmol) in dioxane (20 mL) was added Pd(dppf)Cl2 (0.115 g, 0.140 mmol) and K3PO4 (2M, 2.34 mL, 4.68 mmol) under N2. The reaction mixture was stirred at 80 °C for 5 h. The reaction was then diluted with EtOAc (30 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica (20-50% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 739.2 (M+H) + .

[0126] Step 3: Methyl ((1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-5,5-dimethyl-4-oxo-1 1-((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of methyl (1-yl)carbamate (1.23 g, 1.66 mmol) in acetic acid (20 mL) was added N-iodosuccinimide (0.356 g, 1.58 mmol). The reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated in vacuo to remove AcOH and the residual oil was diluted with EtOAc (30 mL) and poured into 2N aqueous K2CO3 until pH = 8. It was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica (10-45% EtOAc / petroleum ether) to give methyl (1-yl)carbamate (1.23 g, 1.6 ... 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 865.0 (M+H) + .

[0127] Step 4: Ethyl (1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -Carboxylate Methyl ((1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-15 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of Pd(dppf)Cl2 (0.254 g, 0.347 mmol) and Et3N (1.611 mL, 11.56 mmol) in EtOH (15 mL) and DMSO (15 mL) was added Pd(dppf)Cl2 (0.254 g, 0.347 mmol) and Et3N (1.611 mL, 11.56 mmol) under N2. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred at 70 °C under CO (50 psi) for 20 h. The reaction mixture was cooled to 25 °C and concentrated in vacuo to remove EtOH. The residue was diluted with EtOAc (20 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica (10-45% EtOAc / petroleum ether) to give ethyl (1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -carboxylate was obtained. LCMS (ES, m / z): 811.2 (M+H) + .

[0128] Step 5: Ethyl (R,Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate To a stirred mixture of (S)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole (118 mg, 0.100 mmol) in 1,2-dichloroethane (2.0 mL) was added bis(norbornadiene)rhodium(I) tetrafluoroborate (37.3 mg, 0.100 mmol) in a glove box at 25° C., and the mixture was stirred at 25° C. for 1 h under N2. Ethyl (1 2 Z,8Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 To a mixture of 2,2,2-trifluoroethan-1-ol (20 mL) was added the above mixture under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 50 °C under H2 (50 psi) for 48 h. The reaction mixture was cooled to 25 °C and concentrated to dryness. The residue was purified by column chromatography on silica (10-50% EtOAc / petroleum ether) to give ethyl (R,Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2-yl ester. 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -carboxylate was obtained. LCMS (ES, m / z): 813.2 (M+H) + .

[0129] Step 6: (R,Z)-5'-chloro-2'-(difluoromethoxy)-6-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenecyclononaphan-9-yl)-[3,3'-bipyridine] 1-oxide Ethyl (R,Z)-9-(5'-chloro-2'-(difluoromethoxy)-[3,3'-bipyridin]-6-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 A mixture of 1-carboxylate (690 mg, 0.848 mmol) in CH3COOOH (12 mL) (8-10%) was stirred at 25 °C for 4 h. The reaction mixture was diluted with EtOAc (20 mL) and poured into saturated aqueous Na2SO3 / NaHCO3 (v / v, 1:1) until pH = 8. It was then extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give (R,Z)-5'-chloro-2'-(difluoromethoxy)-6-(1H-pyridinium)-2-(4-methyl-1H-pyridinium). 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-[3,3'-bipyridine] 1-oxide was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 829.2 (M+H). + .

[0130] Step 7: (R,Z)-5'-chloro-2'-(difluoromethoxy)-6-(15 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenecyclononaphan-9-yl)-[3,3'-bipyridine] 1-oxide (R,Z)-5'-chloro-2'-(difluoromethoxy)-6-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 To a mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-[3,3'-bipyridine]1-oxide (700 mg, 0.844 mmol) in TFA (10 mL) and DCM (5.0 mL) was added 2-amino-3-mercaptopropanoic acid (307 mg, 2.53 mmol). The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (30 mL) and poured into 2N aqueous K2CO3 until pH = 8. It was then extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica (25-65% EtOAc / petroleum ether). This was further purified by chiral SFC (DAICEL CHIRALCEL OD, 40% 0.1% NH3H2O ​​EtOH / CO2) to give (R,Z)-5'-chloro-2'-(difluoromethoxy)-6-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-[3,3'-bipyridine] 1-oxide was obtained. LCMS (ES, m / z): 699.2 (M+H) +.1H NMR(400MHz,CD3OD):δ 8.61(s,1H),8.30(s,1H),8.14(s,1H),8.07-7.27(m,6H),5.07-4.90(m,1H),4.31- 4.04(m,2H),3.73(s,3H),2.30-2.01(m,2H),1.72-1.39(m,2H),1.31-0.97(m,11H).

[0131] [Example 5] (R,Z)-5-(3-chloro-2-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide [ka]

[0132] Step 1: Methyl ((1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5-bromopyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4To a stirred mixture of PdCl2(dppf) (0.114 g, 0.156 mmol) in THF (15 mL) was added (3-chloro-2-fluorophenyl)boronic acid (0.354 g, 2.03 mmol) and potassium phosphate (2 M, 2.341 mL, 4.68 mmol). The reaction mixture was stirred at 85 °C under N2 atmosphere for 16 h. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 690.2 (M+H) + .

[0133] Step 2: Methyl ((1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-24 To a stirred mixture of 1-iodopyrrolidine-2,5-dione (0.352 g, 1.57 mmol) in CH3COOH (10 mL) was added 1-iodopyrrolidine-2,5-dione (0.352 g, 1.57 mmol) at 25 °C and the reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was carefully added dropwise to NaHCO3 solution at 0 °C until pH = 7. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give methyl ((1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 816.1 (M+H) + .

[0134] Step 3: Ethyl (1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -Carboxylate Methyl ((1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of PdCl2(dppf) (134 mg, 0.184 mmol) and TEA (0.256 mL, 1.84 mmol) in EtOH (20 mL) and DMSO (20 mL) was added PdCl2(dppf) (134 mg, 0.184 mmol) and TEA (0.256 mL, 1.84 mmol) and the mixture was stirred at 70 °C under CO atmosphere at 50 psi for 16 h. Water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give ethyl (1 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -carboxylate was obtained. LCMS (ES, m / z): 762.2 (M+H) + .

[0135] Step 4: Ethyl (R,Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate To a stirred mixture of (S)-(+)-5,5'-bis(bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino)-4,4'-bibenzo[d][1,3]dioxole (132 mg, 0.111 mmol) in 1,2-dichloroethane (4 mL) was added bis(norbornadiene)rhodium(I) tetrafluoroborate (41.7 mg, 0.111 mmol) in a glove box at 25° C. and the mixture was stirred at 25° C. for 1 h under N2. 2 Z,8Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 To a mixture of ethyl (R,Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2-carboxylate (850 mg, 1.12 mmol) in 2,2,2-trifluoroethan-1-ol (40 mL) was added the above mixture under N2. The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was stirred at 50 °C under H2 (50 psi) for 16 h. The reaction mixture was cooled to 25 °C and concentrated to dryness. The residue was purified by column chromatography on silica (0-40% EtOAc / petroleum ether) to give ethyl (R,Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2-methyl-p-tolyl. 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -carboxylate was obtained. LCMS (ES, m / z): 763.9 (M+H) + .

[0136] Step 5: (R,Z)-5-(3-chloro-2-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4-((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide Ethyl (R,Z)-9-(5-(3-chloro-2-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 To a stirred mixture of 18-CROWN-6 (1798 mg, 6.80 mmol) and oxone (4182 mg, 6.80 mmol) in MeOH (30 mL), water (8 mL) was added at 25 °C, and the mixture was stirred at 25 °C for 2 h under N2 atmosphere. Water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic fractions were washed with aqueous Na2SO3 (50 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (R,Z)-5-(3-chloro-2-fluorophenyl)-2-(1H-pyridine). 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 780.2 (M+H) + .

[0137] Step 6: (R,Z)-5-(3-chloro-2-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4-((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (R,Z)-5-(3-chloro-2-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (650 mg, 0.833 mmol), (R)-2-amino-3-mercaptopropanoic acid (303 mg, 2.50 mmol) in DCM (3 mL) was added TFA (6 mL) and the mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated to dryness. Water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic fractions were washed with aqueous NaHCO3 (50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-90% EtOAc / petroleum ether). This was further purified by chiral SFC (DAICEL CHIRALPAK OD, 60% 0.1% NH3H2O ​​EtOH / CO2) to give (R,Z)-5-(3-chloro-2-fluorophenyl)-2-(1 5 -(ethoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained. LCMS (ES, m / z): 650.2 (M+H) +.1H NMR(400 MHz,CD3OD):δ 8.54(s,1H),7.95(br d,J=7.4 Hz,1H),7.81(br d,J=8.6 Hz,1H),7.71-7.55(m,3H),7.52(br t,J=6.7 Hz,1H),7.36-7.28(m,2H),4.99-4.93(m,1H),4.26-4.08(m,2H),3.73(s,3H),2.17(br s,2H),1.87(br s,1H),1.49(br d,J=7.0 Hz,1H),1.38-1.24(m,4H),1.21(br t,J=7.0 Hz,3H),1.15(s,3H),0.90-0.86(m,1H).

[0138] [Example 6] (R,Z)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(Methoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide [ka]

[0139] Step 1: Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5-bromopyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-11 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a stirred mixture of xphos-G2 (0.295 g, 0.375 mmol), 1-(4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)-1H-pyrazole (2.168 g, 6.09 mmol) in THF (60 mL) was added K3PO4 (2 M, 7.0 mL, 14 mmol) at 25 °C under N2, and the mixture was stirred at 80 °C under N2 for 3 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic fractions were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-60% EtOAc / petroleum ether). It was suspended in 20 mL of a mixed solvent (1:2 EtOAc / petroleum ether) and the suspension was stirred for 30 min. The mixture was filtered and the filter cake was dried under vacuum to give methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 790.5 (M+H) + .

[0140] Step 2: Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a stirred mixture of methyl ((1-yl)carbamate (8.50 g, 10.8 mmol) in CHCl3 (100 mL) was added 1-iodopyrrolidine-2,5-dione (2.421 g, 10.76 mmol) at 25 °C and the mixture was stirred at 30 °C for 24 h. The mixture was concentrated. The residue was purified by column chromatography on silica (0-35% EtOAc / petroleum ether) to give methyl ((1-yl)carbamate. 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 -yl)carbamate. LCMS (ES, m / z): 916.5 (M+H) + .

[0141] Step 3: Methyl (1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -Carboxylate Methyl ((1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-1 5 -Iodo-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-2 4 To a mixture of Pd(dppf)Cl2 (0.959 g, 1.31 mmol) and TEA (6.09 mL, 43.7 mmol) in MeOH (30 mL) and DMSO (30 mL) was added Pd(dppf)Cl2 (0.959 g, 1.31 mmol) and TEA (6.09 mL, 43.7 mmol) and the mixture was stirred at 70 °C under CO atmosphere at 50 psi for 16 h. The mixture was concentrated, cooled, and then diluted with ethyl acetate (500 mL). It was washed with brine (200 mL x 4), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-35% EtOAc / petroleum ether) to give methyl (1 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 -carboxylate was obtained. LCMS (ES, m / z): 916.5 (M+H) + .

[0142] Step 4: Methyl (R,Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-24 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate To a stirred mixture of bis(norbornadiene)rhodium(I) tetrafluoroborate (0.132 g, 0.354 mmol) in 1,2-dichloroethane (5 mL), (S)-(+)-5,5'-bis(bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino)-4,4'-bibenzo[d][1,3]dioxole (0.417 g, 0.354 mmol) was added at room temperature in a glove box, and the mixture was stirred at 25° C. for 1 h under a N2 atmosphere. 2 Z,8Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-8-ene-1 5 A stirred mixture of 5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2-carboxylate (3.00 g, 3.54 mmol) in 2,2,2-trifluoroethan-1-ol (50 mL) was added to the above catalyst mixture at room temperature, and the mixture was stirred under H2 atmosphere (50 psi) at 50 °C for 48 h. The residue was purified by column chromatography on silica (0-35% EtOAc / petroleum ether) to give methyl (R,Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2-methylpyridine. 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5-carboxylate was obtained. LCMS (ES, m / z): 851.6 (M+H) + .

[0143] Step 5: (R,Z)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(Methoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide Methyl (R,Z)-9-(5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 To a stirred mixture of 5-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1H-pyrazol-1-yl)phenyl)-2-carboxylate (5.00 g, 5.88 mmol) in CH3COOOH (30 mL, 10% wt) was added at 25° C. for 3 h. This was carefully added dropwise to a cooled mixture of 20 g of ice, saturated NaHCO3 (80 mL), and saturated Na2SO3 (80 mL) at 0° C. The mixture was extracted with EtOAc (200 mL×2). The combined organic fractions were washed with brine (200 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give (R,Z)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-( ... 5 -(Methoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained, which was used in the next step without further purification. LCMS (ES, m / z): 866.6 (M+H) + .

[0144] Step 6: (R,Z)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(Methoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (R,Z)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(Methoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide (5.00 g, 5.77 mmol), 2-amino-3-mercaptopropanoic acid (3.50 g, 28.9 mmol) in DCM (20 mL) was added 2,2,2-trifluoroacetic acid (40 mL, 5.77 mmol) and the mixture was stirred at 40 °C for 2 h. The mixture was concentrated to dryness. The residue was dissolved in 200 mL of ethyl acetate. This was carefully added dropwise to aqueous sodium bicarbonate at 0 °C. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic fractions were washed with brine (200 mL × 2), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (0-80% EtOAc / petroleum ether). This was further purified by chiral SFC (DAICEL CHIRALCEL OD, 55% 0.1% NH3H2O ​​EtOH / CO2) to give (R,Z)-5-(5-fluoro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2-(1 5 -(Methoxycarbonyl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)pyridine 1-oxide was obtained. LCMS (ES, m / z): 736.2 (M+H) +.1H NMR(400 MHz,DMSO-d6):δ 12.93(s,0.5H),12.19(br s,0.5H),10.89(br s,0.5H),9.96-9.65(m,1H),8.64(br d,J=11.2 Hz,1H),8.57(br s,0.5H),8.25-8.10(m,1H),8.07(br s,1H),7.94(br d,J=8.1 Hz,0.5H),7.82-7.68(m,2H),7.64-7.63(m,1.5H),7.55-7.53(m,1.5H),7.46-7.35(m,1H),7.32(br d,J=8.3 Hz,0.5H),7.06-6.92(m,1H),4.95-4.69(m,1H),3.77-3.55(m,6H),2.27-1.71(m,3H),1.59-1.30(m,1H),1.29-0.23(m,8H).

[0145] [Example 7] Ammonium (R,Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)-1-oxidepyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-aza-1(4,2)-imidazola-2(1,2)benzenacyclononaphane-1 5 -Carboxylate [ka]

[0146] Step 1: (Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylic Acid Ethyl (Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-24 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 A mixture of -carboxylate (2 g, 2.51 mmol), lithium hydroxide hydrate (0.527 g, 12.56 mmol) in THF (20 mL), water (6 mL) and MeOH (5 mL) was stirred at 40° C. for 16 h. The reaction was quenched with HCl (1M) to pH=3, water (10 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic portions were washed with brine (saturated, 2×50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound. LCMS (ES, m / z): 768.5 (M+H). + .

[0147] Process 2:(Z)-2-(1 5 -Carboxy-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(2-(difluoromethoxy)-5-fluorophenyl)pyridine 1-oxide (Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)pyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5A mixture of the -carboxylic acid (1 g, 1.302 mmol) in CH3COOOH (10 mL, 10% wt) was stirred at 25° C. for 6 h. The reaction was carefully added dropwise to a cooled 0° C. mixture of 5 g ice, saturated NaHCO3 (50 mL) / saturated Na2SO3 (50 mL). The mixture was extracted with EtOAc (2×150 mL). The combined organic portions were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the title compound. The residue was used in the next step without further purification. LCMS (ES, m / z): 784.4 (M+H). + .

[0148] Process 3:(Z)-2-(1 5 -Carboxy-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(2-(difluoromethoxy)-5-fluorophenyl)pyridine 1-oxide (Z)-2-(1 5 -Carboxy-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 -((2-(trimethylsilyl)ethoxy)methyl)-1 1To a stirred mixture of H-3-aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(2-(difluoromethoxy)-5-fluorophenyl)pyridine 1-oxide (1.1 g, 1.403 mmol) and DL-cysteine ​​(0.850 g, 7.02 mmol) in DCM (5 mL) was added TFA (10 mL, 130 mmol) at room temperature and the mixture was stirred at 40° C. for 1 h. The mixture was concentrated and the residue was diluted with EtOAc (50 mL). The mixture was poured into 100 mL of NaHCO3 solution at 0° C. and then extracted with ethyl acetate (2×100 mL). The combined organic portions were washed with brine (50 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Agela® Silica Flash Column, eluent 0-3% MeOH / DCM gradient @ 30 mL / min, 35 min, dry loading) to give the title compound. LCMS (ES, m / z): 654.3 (M+H). + .

[0149] Step 4: Ammonium (R,Z)-9-(5-(2-(difluoromethoxy)-5-fluorophenyl)-1-oxidepyridin-2-yl)-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphane-1 5 -Carboxylate (Z)-2-(1 5 -Carboxy-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(2-(difluoromethoxy)-5-fluorophenyl)pyridine 1-oxide (480 mg, 0.734 mmol) was separated using SFC (Column DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um), conditions 0.1% NH3H2O, EtOH. Start B 50, end B 50, gradient flow rate (mL / min) 80, injection 150) to give peak 1 (S)-isomer (RT = 0.868 min) and peak 2 (R)-isomer (RT = 3.819 min). The peak 1 residue was further purified by preparative HPLC (Column YMC-Actus Triart C18 150×30 mm×5 um, Conditions: Water (0.1% TFA)-ACN start B 36, end B 56, gradient time (min) 11, 100% B hold time (min) 2, flow rate (ml / min) 25, injection 7), and the solution was lyophilized to give (S,Z)-2-(1 5 -Carboxy-2 4 -((Methoxycarbonyl)amino)-5,5-dimethyl-4-oxo-1 1 H-3-Aza-1(4,2)-imidazola-2(1,2)-benzenacyclononaphan-9-yl)-5-(2-(difluoromethoxy)-5-fluorophenyl)pyridine 1-oxide was obtained. LCMS (ES, m / z): 654.2 (M+H) + .1H NMR(MeOD,400MHz)δ 8.53(d,J=1.2 Hz,1H),7.89(d,J=8.4 Hz,1H),7.84-7.79(m,1H),7.72(br d,J=8.5 Hz,1H),7.62(s,1H),7.44-7.33(m,3H),7.33-7.25(m,1H),6.83(t,J=58 Hz,1H),4.95-4.90(m,1H),3.77(s,3H),2.46-2.15(m,2H),1.83-1.55(m,2H),1.50-1.25(m,4H),1.13(s,3H),1.10-0.80(m,1H).

[0150] Peak 2 was lyophilized to give the title compound. LCMS (ES, m / z): 654.2 (M+H) +.1H NMR(MeOD,500MHz)δ 8.51(br s,1H),7.86-7.63(m,3H),7.44-7.19(m,5H),6.80(t,J=58 Hz,1H),5.00-4.93(m,1H),3.75(s,3H),2.39-1.84(m,2H),1.56-1.33(m,2H),1.32-1.21(m,4H),1.17-1.12(m,4H).

[0151] By using a similar procedure as above and appropriate starting materials, the following compounds were synthesized and characterized by LC / MS. [Table 1]

[0152] Factor XIa assay The effectiveness of the compounds of the present invention as inhibitors of coagulation factor XIa can be determined using the relevant purified serine protease and a suitable synthetic substrate. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and in the presence of the compounds of the present invention. The assay was performed at room temperature or at 37°C. Hydrolysis of the substrate resulted in the release of aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm upon excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of an inhibitor indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of this assay were reported as the 50% inhibitory concentration (IC50) or the inhibition constant K i It is expressed as:

[0153] Compounds were preincubated with human (0.04 nM) factor XIa in 50 mM HEPES buffer containing 150 mM sodium chloride, 5 mM calcium chloride, 0.1% PEG 8000, pH 7.4 for 30 min at 25°C. Factor XIa enzyme activity was determined by adding the substrate glycine-proline-arginine-7-amido-4-trifluoromethylcoumarin (GPR-AFC) and measuring fluorescence at 400 / 505 nm after 60 min incubation at 25°C. The % inhibition for each data point was calculated from the data and analyzed using the log(inhibitor) vs. response four parameters equation to determine the 50% inhibitory concentration (IC50). The Cheng-Prusoff equation was used to convert the IC50 to an equilibrium inhibition constant (Ki).

[0154] Activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful for treating or preventing a variety of cardiovascular and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndromes, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, stroke such as thrombotic or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, and reclosure or restenosis of reopened blood vessels.

[0155] Kallikrein Assay The effectiveness of the compounds of the present invention as inhibitors of kallikrein can be determined using the relevant purified serine protease and an appropriate synthetic substrate. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and in the presence of the compounds of the present invention. The assay was performed at room temperature or at 37°C. Hydrolysis of the substrate resulted in the release of aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm upon excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of an inhibitor indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of this assay were reported as the 50% inhibitory concentration (IC50) or the inhibition constant K i It is expressed as:

[0156] Kallikrein determinations were performed in 50 mM HEPES buffer at pH 7.4 containing 150 mM NaCl, 5 mM CaCl2, and 0.1% PEG 8000 (polyethylene glycol; Fisher Scientific). Determinations were performed using purified human plasma kallikrein (Enzyme Research Laboratories) at a final concentration of 0.5 nM and the synthetic substrate, Acetyl-KPR-AFC (Sigma #C6608), at a concentration of 100 mM.

[0157] Activity assays were performed by diluting stock solutions of substrate at least 10-fold into solutions containing enzyme or enzyme equilibrated with inhibitor to a final concentration of ≦0.2 Km. The time required to achieve equilibrium between enzyme and inhibitor was determined in control experiments. Reactions were performed under linear progress curve conditions and the fluorescence increase was measured at 405 Ex / 510 Em nm. Values ​​were converted to percent inhibition of the control reaction (after subtraction of the 100% inhibition value). IC was calculated by the inflection point from a four parameter logistic curve fit. 50 The Cheng Prusoff equation, Ki=IC 50Ki was calculated using / (1+([S] / Km)).

[0158] Activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful for treating or preventing a variety of cardiovascular and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndromes, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, stroke such as thrombotic or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, and reclosure or restenosis of reopened blood vessels.

[0159] Activated partial thromboplastin time (aPTT) assay The activated partial thromboplastin time (aPTT) is a coagulation test that measures the intrinsic coagulation cascade. The test is performed in sodium citrate plasma. Human plasma is made by collecting blood obtained from healthy donors of both sexes into sodium citrate tubes (Sarstedt coagulation 9NC / 10ml). The blood is centrifuged at 1500×g and the plasma is collected. The aPTT is checked for each individual donor and those within the normal range (28-40 seconds) are pooled, aliquoted and stored at -80°C. Test samples are prepared by adding inhibitors or vehicle to the plasma. These spiked samples are then run on a coagulation analyzer (STA-R Evolution, Stago Diagnostica). In general, the analyzer performs the following steps: activating factor XII by adding ellagic acid (Pacific Hemostasis) and then measuring the clotting time after remineralization of the sample. Inhibition of FXI prolongs the aPTT clotting time. Data are expressed as the percentage increase over the clotting time of the vehicle control and the concentration that caused a 50% (1.5-fold) increase in clotting time.

[0160] Norepinephrine transporter functional antagonist uptake assay Human norepinephrine transporter (NET) functional antagonist uptake assay was performed on a Panlabs Cerep (assay #302100). Human recombinant norepinephrine transporter expressed in MDCK cells was seeded overnight. Test compounds and / or vehicle were pre-incubated with cells (2x10E5 / ml) in modified Tris-HEPES buffer pH 7.1 for 20 minutes at 25°C, then 25 nM [3H]norepinephrine was added for an additional 15 minute incubation period. Lysates were obtained from solubilized cells and counted to determine [3H]norepinephrine uptake. A reduction in [3H]norepinephrine uptake of 50% or more (>=50%) compared to 10 μM desipramine indicates significant inhibitory activity. Compounds are screened at 10, 3, 1, 0.3, 0.1, 0.03, 0.01 and 0.003 μM. These same concentrations are applied simultaneously to separate groups of untreated cells, and only if significant inhibition of uptake is observed are compounds evaluated for possible compound-induced cytotoxicity. IC50 values ​​were determined by nonlinear least-squares regression analysis using MathIQ™ (IDBusiness Solutions Ltd., UK).

[0161] Inhibition of tissue kallikrein enzyme activity Compounds were assayed using human tissue kallikrein (RayBiotech, Cat. No. 228-10996 or Evotec, final concentration 5 nM) in 50 mM HEPES, 150 mM NaCl, 5 mM CaCl2, 0.1% PEG-8000, pH 7.4 at 25 °C in Corning 3575 non-binding surface microplates. Compounds were tested in a 10-point dose titration starting at 166.67 uM using a 3-fold dilution series. Tissue kallikrein enzyme activity was determined by measuring the rate of cleavage of N-acetyl-KPR-AFC substrate (Sigma, Cat. No. C6608, final concentration 100 uM) by continuously monitoring fluorescence at 400 / 505 nm using a Tecan Safire plate reader. Initial reaction rates (0-20 min) were used to determine percent inhibition. The % inhibition for each data point was recalculated from the RFU / min data and analyzed using the log(inhibitor) vs. response 4-parameter equation with GraphPad Prism software.

[0162] High Throughput (HT) Solubility Determination The chromatography system consists of an Agilent 1290 UPLC / DAD system and ChemStation software, both from Agilent Technologies, USA. Separation is performed using a Supelco Ascentis Express C18, 30 mm x 3.0 mm ID, 2.7 μm HPLC column. The mobile phase consists of potassium phosphate buffered at pH 7 (mobile phase A) and acetonitrile (mobile phase B). The column oven temperature is set at 30°C and the UPLC analysis consists of a gradient. The injection volume is 2 μL and the spectrophotometric detection is set at 215 and 238 nm.

[0163] A 10 mM stock solution of the compound in DMSO is provided for analysis. 2.5 μL of the stock solution (10 mM) was diluted into 247.5 μL of organic co-solvent (10% MeCN / 80% MeOH / 10% DMSO, v / v / v) to create a 100 μM standard solution. To create the solubility solutions, 4.1 μL of the 10 mM DMSO stock solution was diluted into 247.5 μL of phosphate buffered saline (PBS) (pH 7) solution. A second 4.1 μL aliquot of the 10 mM DMSO stock solution was added to 196 μL of PBS (pH 2) solution. A third 4.1 μL aliquot of the 10 mM DMSO stock solution was added to 196 μL of FaSSIF (pH 6.5) solution. Each solubility solution was sealed and shaken at 25 °C for 24 h. The equilibrated solubility solutions were filtered by centrifugation using a filter (0.45 μm, polypropylene). 50 μL each of the 100 μM standard solutions and the filtered equilibrated solubility solutions were placed in a 384-well plate, and the plate was then heat-sealed.

[0164] Each standard solution and solubility solution was analyzed by UPLC / DAD. The solubility values ​​were calculated according to the following formula: Solubility = (sample peak area / standard peak area) (standard concentration)

[0165] Table 1 The following table shows the representative data of the compounds of the examples.In this table, FXIa Ki is a measure of the ability of test compound to inhibit the action of FXIa enzyme.Such results show the inherent activity of the compound for use as FXIa enzyme inhibitor.Furthermore, plasma kallikrein (pKal) inhibition, tissue kallikrein inhibition (tKal) and norepinephrine transporter functional antagonist uptake activity (NET) are shown.

[0166] [Table 2]

[0167] Pharmacokinetic General Procedure: Rat Cassette General Procedure: Plasma pharmacokinetic parameters for clearance, volume of distribution, half-life and mean residence time (MRT) were determined in rats from an IV cassette dosing study. Two male rats, typically weighing 225-260 grams, were fasted overnight prior to dosing. Compounds were prepared for IV dosing by adding to the vehicle depending on the dose used. In a typical preparation, up to five test compounds were added at 1 mg / mL (IV) to a vehicle composed of 20% dimethyl sulfoxide (DMSO), 60% polyethylene glycol 400 (PEG400) and 20% water. Two rats were administered the IV formulations via a pre-cannulated jugular vein. Blood was collected by a pre-cannulated artery, typically at pre-dose, 2, 8, 15, 30 min, 1, 2, 4, 6 and 8 h post-dose. Samples were collected in K2EDTA tubes, stored on ice and centrifuged. Plasma was transferred to a microtiter plate and stored at -70°C until analysis. Plasma samples were extracted using protein precipitation and analyzed by liquid chromatographic separation followed by mass spectrometry detection (LCMS / MS) using standard curves for each compound. Plasma pharmacokinetic parameters were calculated by noncompartmental methods.

[0168] Rat Screening IV / PO General Procedure: Plasma pharmacokinetic parameters for clearance, volume of distribution, half-life, mean residence time (MRT) and oral bioavailability (%F) were determined in rats from oral and IV dosing studies. Four male rats, typically weighing 225-260 grams, were fasted overnight prior to dosing. Compounds were prepared for oral and IV dosing by adding to the vehicle depending on the dose used. A typical preparation contained 1 mg / mL (IV) or 1.5 mg / mL (oral) test compound in a vehicle composed of 20% dimethyl sulfoxide (DMSO), 60% polyethylene glycol 400 (PEG400) and 20% water. Two rats were administered the IV formulation via a previously cannulated jugular vein and two rats were administered the oral dose via oral gavage. Typically, blood was collected via a pre-cannulated artery at pre-dose, 2 min, 8 min, 15 min, 30 min, and 1, 2, 4, 6, and 8 h post-dose for IV and pre-dose, 15 min, 30 min, and 1, 2, 4, 6, and 8 h post-dose for oral administration. Samples were collected in K2EDTA tubes, stored on ice, and centrifuged. Plasma was transferred to microtiter plates and stored at -70°C until analysis. Plasma samples were extracted using protein precipitation and analyzed by liquid chromatographic separation followed by mass spectrometry detection (LCMS / MS) using standard curves for each compound. Plasma pharmacokinetic parameters were calculated for IV and oral administration data by noncompartmental methods. Oral bioavailability was determined as the ratio of dose-normalized plasma area under the curve (AUC) after oral vs. IV administration.

[0169] Canine Screening IV / PO General Procedure: Plasma pharmacokinetic parameters for clearance, volume of distribution, half-life, mean residence time (MRT) and oral bioavailability were determined in dogs from oral and IV dosing studies. Four male dogs, typically weighing 8-12 kilograms, were fasted overnight prior to dosing. Compounds were prepared for oral and IV dosing by adding to the vehicle depending on the dose used. A typical preparation contained 1 mg / mL (IV) or 1.5 mg / mL (oral) test compound in a vehicle composed of 20% dimethyl sulfoxide (DMSO), 60% polyethylene glycol 400 (PEG400) and 20% water. Two dogs were administered the IV formulation via the saphenous or cephalic vein, and two dogs were administered the oral dose via oral gavage. Typically, blood was collected via the cephalic or jugular vein at pre-dose, 2 min, 8 min, 15 min, 30 min, and 1, 2, 4, 6, 8, and 24 h post-dose for IV and pre-dose, 15 min, 30 min, and 1, 2, 4, 6, 8, and 24 h for oral dosing. Samples were collected in K2EDTA tubes, stored on ice, and centrifuged. Plasma was transferred to microtiter plates and stored at -70°C until analysis. Plasma samples were extracted using protein precipitation and analyzed by liquid chromatographic separation followed by mass spectrometry detection (LCMS / MS) using standard curves for each compound. Plasma pharmacokinetic parameters were calculated for IV and oral dosing data by noncompartmental methods. Oral bioavailability was determined as the ratio of dose-normalized plasma area under the curve (AUC) after oral vs. IV dosing.

[0170] Canine Cassette General Procedure: Plasma pharmacokinetic parameters for clearance, volume of distribution, half-life and mean residence time (MRT) were determined in dogs from an IV cassette dosing study. Two male dogs, typically weighing 8-12 kilograms, were fasted overnight prior to dosing. Compounds were prepared for IV dosing by adding to the vehicle depending on the dose used. In a typical preparation, up to five test compounds were added at 1 mg / mL (IV) to a vehicle composed of 20% dimethyl sulfoxide (DMSO), 60% polyethylene glycol 400 (PEG400) and 20% water. Two dogs were administered the IV formulations via the saphenous or cephalic vein. Blood was typically collected via the cephalic or jugular vein at pre-dose, 2, 8, 15, 30 min, 1, 2, 4, 6, 8 and 24 h post-dose. Samples were collected in K2EDTA tubes, stored on ice and centrifuged. Plasma was transferred to microtiter plates and stored at -70°C until analysis. Plasma samples were extracted using protein precipitation and analyzed by liquid chromatographic separation followed by mass spectrometry detection (LCMS / MS) using standard curves for each compound. Plasma pharmacokinetic parameters were calculated by noncompartmental methods.

[0171] Table 2 The following table shows representative data for the compounds of the examples. This table shows selected pharmacokinetic data (MRT = mean residence time) for both rats and dogs. In addition, high-throughput solubility in pH 2 phosphate buffer (PBS) and pH 6.5 FaSSIF (fasted state simulated intestinal fluid) is shown.

[0172] [Table 3]

Claims

1. Compounds of Formula I: 【Chemistry 1】 (In the formula, R １ is hydrogen, OCHF ２ , or C.F. ３ is a pyrazole optionally substituted by R ２ is chloro or fluoro, R ３ is hydrogen or fluoro, R ４ is hydrogen or C １～３ is alkyl, X is CH or N; or a pharma- ceutically acceptable salt thereof.

2. The compound according to claim 1 of formula Ia: 【Chemistry 2】 (In the formula, R ２ is chloro or fluoro, R ４ is hydrogen, CH ３ or CH ２ CH ３ ) or a pharma- ceutically acceptable salt thereof.

3. Compound according to claim 1 of formula Ib: 【Chemistry 3】 (In the formula, R ２ is chloro or fluoro, R ４ is CH ３ or CH ２ CH ３ and X is CH or N; or a pharma- ceutically acceptable salt thereof.

4. Compound according to claim 3 of formula Ic: 【Chemistry 4】 (In the formula, R ２ is chloro or fluoro, R ４ is CH ３ or CH ２ CH ３ ) or a pharma- ceutically acceptable salt thereof.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein X is CH.

6. 2. The compound of claim 1, wherein X is N; or a pharma- ceutically acceptable salt thereof.

7. R １ OCHF ２ 2. The compound of claim 1, wherein:

8. R ４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is methyl or ethyl.

9. R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

10. R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is chloro.

11. R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

12. R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

13. The compound of claim 1 selected from the following: 【Chemistry 5】 【change】 or a pharma- ceutically acceptable salt thereof.

14. 14. A pharmaceutical composition comprising a compound according to claim 1 or 13, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

15. 15. The composition of claim 14 for inhibiting or treating thrombus formation in blood.

16. The composition according to claim 14 for preventing thrombus formation in blood.

17. 15. The composition of claim 14 for treating venous thromboembolism and pulmonary embolism in a mammal.

18. 15. The composition of claim 14 for treating deep vein thrombosis in a mammal.

19. 15. The composition of claim 14 for treating thromboembolic stroke in a mammal.

20. 20. Use of a compound according to claim 1 or 13, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombin, inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal in need thereof.

21. 20. A compound according to claim 1 or 13, or a pharma- ceutically acceptable salt thereof, for use in therapy.

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