Plasma kallikrein inhibitors

Abstract

The present invention provides compounds of formula (I), pharmaceutical compositions comprising one or more of the compounds, and methods of using the compounds to treat or prevent one or more disease states that can benefit from the inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein. [Case 1] TIFF2025503117000129.tif6182

Description

[Background technology]

[0001] Plasma kallikrein is a trypsin-like serine protease zymogen present in plasma. Its gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein shares 58% homology with factor XI. Proteolytic activation by factor XIIa at the internal I389-R390 bond generates 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 such as alpha-2 macroglobulin and Cl inhibitors. Interestingly, heparin significantly enhances 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 release bradykinin. The release of bradykinin 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) and Schmaier, AH, "Contact Activation," Thrombosis and Hemorrhage, pp. 105-128 (1998)).

[0002] Patients with a genetic deficiency in C1 inhibitor suffer from hereditary angioedema (HAE), a lifelong disease that causes intermittent swelling throughout the body, including the hands, feet, face, throat, genitals, and gastrointestinal tract. Analysis of blisters resulting from acute episodes has shown them to contain high levels of plasma kallikrein, and treatment with ecallantide (Kalbitor), a protein-based reversible plasma kallikrein inhibitor, has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L, et al., J. Allergy Clin. Immunol., 120: 416 (2007)). Recently, the oral plasma kallikrein inhibitor berotralstat was approved by the FDA for the prevention of HAE attacks (Zuraw, B., et al., J. Allergy Clin. Immunol. (2020)).

[0003] In addition, the plasma kallikrein-kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME). Recent publications have shown that plasma kallikrein contributes to the retinal vascular leakage and dysfunction observed in diabetic rodent models (A. Clermont, et al., Diabetes, 60:1590 (2011)), and that treatment with small molecule plasma kallikrein inhibitors improved the observed retinal vascular permeability and other abnormalities associated with retinal blood flow. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Coleman, R., “Contact Activation Pathway”, Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001) [Non-patent document 2] Schmaier AH, “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128 (1998) [Non-patent document 3] Schneider, L, et al., J.Allergy Clin.Immunol., 120: p.416 (2007) [Non-patent document 4] Zuraw, B., et al., J. Allergy Clin. Immunol.(2020) [Non-patent document 5] A. Clermont, et al., Diabetes, 60:1590 (2011) Summary of the Invention [Problem to be solved by the invention]

[0005] It would be desirable in the art to develop plasma kallikrein inhibitors that have utility in treating a wide range of disorders, including hereditary angioedema, diabetic macular edema, and diabetic retinopathy. [Means for solving the problem]

[0006] The present invention relates to a compound of formula I: [ka] The present invention relates to compounds of Formula I and pharmaceutically acceptable salts thereof. The compounds of Formula I are inhibitors of plasma kallikrein and, therefore, may be useful in the treatment, inhibition, or amelioration of one or more disease states that can benefit from the inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. The compounds of the present invention may also be used in combination with other therapeutically active agents, including, but not limited to, other agents useful for treating hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. The present invention further relates to methods for preparing the compounds of Formula I, as well as pharmaceutical compositions comprising the compounds of Formula I and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention relates to a compound of formula I: [ka] [During the ceremony, A is O or -CH2-; [ka] TIFF0007794991000004.tif19128; Q is -CH2- or absent; R 1 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 2 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 3 is hydrogen, halo, hydroxy, C 1-6 Alkyl and C 3-6 cycloalkyl; R 4 is hydrogen, halo, hydroxy and C1-6 selected from the group consisting of alkyl; R 5 is hydrogen, halo or C 1-6 alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo; R 6 is hydrogen, halo, hydroxy, cyclopropyl, C 1-6 Alkyl and (C 1-6 and (alkyl)cyclopropyl, wherein the alkyl group is independently selected from the group consisting of halo, phenyl, and OR. x and the cyclopropyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of OR x may be substituted with; R 7 is hydrogen, halo, hydroxy and C 1-6 alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo or hydroxy; Or R 6 and R 7 together with the carbon atom to which they are attached can form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group; R 8 is selected from the group consisting of phenyl or heteroaryl (which may be monocyclic or bicyclic); wherein the phenyl and heteroaryl groups are selected from the group consisting of oxo, halo, cyano, R x , OR x , N.R. 9 R 10 , (C=O)OR x , OCH2(C=O)OR x , SO2R x , SO2NR 9 R 10 , R y and CH2R y and optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 9 is hydrogen or C 1-3 is alkyl; R 10 is hydrogen or C 1-3 is alkyl; R x is hydrogen or C 1-6 alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halo and hydroxy; R y is heteroaryl, heterocyclyl or C 3-6 cycloalkyl, where the heteroaryl group is oxo or C 1-6 The heterocyclyl group is optionally substituted with one or two oxo groups, and the cycloalkyl group is C 1-6 may be substituted with alkyl. or a pharmaceutically acceptable salt thereof.

[0008] In one embodiment of the invention, Q is -CH2-. In another embodiment of the invention, Q is absent.

[0009] In one embodiment of the present invention, the present invention provides a compound of formula Ia: [ka] [During the ceremony, A is O or -CH2-; [ka] and; R 1 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 2 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 3 is hydrogen, halo, hydroxy, C 1-6 Alkyl and C 3-6 cycloalkyl; R 4 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 5 is hydrogen, halo or C1-6 alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo; R 6 is hydrogen, halo, hydroxy, cyclopropyl, C 1-6 Alkyl and (C 1-6 and (alkyl)cyclopropyl, wherein the alkyl group is independently selected from the group consisting of halo, phenyl, and OR. x and the cyclopropyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of OR x may be substituted with; R 7 is hydrogen, halo, hydroxy and C 1-6 alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo or hydroxy; Or R 6 and R 7 together with the carbon atoms to which they are attached can form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group; R 8 is selected from the group consisting of phenyl or heteroaryl (which may be monocyclic or bicyclic); wherein the phenyl and heteroaryl groups are selected from the group consisting of oxo, halo, cyano, R x , OR x , N.R. 9 R 10 , (C=O)OR x , OCH2(C=O)OR x , SO2R x , SO2NR 9 R 10 , R y and CH2R y and optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 9 is hydrogen or C 1-3 is alkyl; R 10 is hydrogen or C 1-3 is alkyl; R x is hydrogen or C 1-6alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halo and hydroxy; R y is heteroaryl, heterocyclyl or C 3-6 cycloalkyl, where the heteroaryl group is oxo or C 1-6 The heterocyclyl group is optionally substituted with one or two oxo groups, and the cycloalkyl group is C 1-6 may be substituted with alkyl. or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment of the invention, A is O. In another embodiment of the invention, A is -CH2-.

[0011] In one embodiment of the present invention, the present invention provides a compound of formula Ib: [ka] [During the ceremony, [ka] and; R 1 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 2 is hydrogen, halo, hydroxy and C 1-6 selected from the group consisting of alkyl; R 5 is hydrogen, halo or C 1-6 alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo; R 6 is hydrogen, halo, hydroxy, cyclopropyl, C 1-6 Alkyl and (C 1-6 and (alkyl)cyclopropyl, wherein the alkyl group is independently selected from the group consisting of halo, phenyl, and OR. xand the cyclopropyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of OR x may be substituted with; R 7 is hydrogen, halo, hydroxy and C 1-6 alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo or hydroxy; Or R 6 and R 7 together with the carbon atoms to which they are attached can form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group; R 8 is selected from the group consisting of phenyl or heteroaryl (which may be monocyclic or bicyclic); wherein the phenyl and heteroaryl groups are selected from the group consisting of oxo, halo, cyano, R x , OR x , N.R. 9 R 10 , (C=O)OR x , OCH2(C=O)OR x , SO2R x , SO2NR 9 R 10 , R y and CH2R y and optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 9 is hydrogen or C 1-3 is alkyl; R 10 is hydrogen or C 1-3 is alkyl; R x is hydrogen or C 1-6 alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halo and hydroxy; R y is heteroaryl, heterocyclyl or C 3-6 cycloalkyl, where the heteroaryl group is oxo or C 1-6The heterocyclyl group is optionally substituted with one or two oxo groups, and the cycloalkyl group is C 1-6 may be substituted with alkyl. or a pharmaceutically acceptable salt thereof.

[0012] In one embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] In another embodiment of the present invention, [ka] is.

[0013] In one embodiment of the present invention, R 1 In one class of embodiments, R is halo. 1 is chloro.

[0014] In one embodiment of the present invention, R 2 In one class of embodiments, R is halo. 2 is fluoro.

[0015] In one embodiment of the present invention, R 3 is hydrogen or methyl. In one class of this embodiment, R 3 is hydrogen. In one class of the embodiment, R 3 is methyl.

[0016] In one embodiment of the present invention, R 4 is hydrogen or methyl. In one class of this embodiment, R 4 is hydrogen. In one class of the embodiment, R 4 is methyl.

[0017] In one embodiment of the present invention, R 5 is hydrogen or halo. In one class of the embodiment, R 5 In a subclass of this embodiment, R is halo. 5 is fluoro.

[0018] In one embodiment of the present invention, R 6 is hydrogen, hydroxyl, C 1-6 -alkyl and (C 1-6 -alkyl)cyclopropyl, wherein the alkyl is halo or OR x In one class of the embodiments, R 6 is hydrogen, hydroxyl, C 1-6 -alkyl and -CH2 (cyclopropyl), where the alkyl is halo or OR x In a subclass of this embodiment, R 6 is C 1-6 In a further subclass of this embodiment, R is -alkyl. 6 In yet another subclass of this embodiment, R 6 In another subclass of this embodiment, R is ethyl. 6 is C 1-6-alkyl, where this is OR x or halo. In a further subclass of this embodiment, R 6 is C 1-6 -alkyl, which is substituted with fluoro, hydroxy or methoxy.

[0019] In one embodiment of the present invention, R 7 is hydrogen, hydroxyl or C 1-6 -alkyl, which may be substituted with hydroxy or halo. In one class of this embodiment, R 7 is hydrogen. In another class of this embodiment, R 7 is hydroxyl. In another class of this embodiment, R 7 is C 1-6 -alkyl, which may be substituted with hydroxy or halo.

[0020] In one embodiment of the present invention, R 6 and R 7 together with the carbon atoms to which they are attached form a six-membered heterocycle or C 3-6 Forms a cycloalkyl group.

[0021] In one embodiment of the present invention, R 8 is phenyl, where this is oxo, halo, cyano, -OCH2(C=O)OR x , -SO2R x and R y In a subclass of this embodiment, R 8 is phenyl, which is substituted with fluoro or chloro. In another embodiment of the present invention, R 8 is a monocyclic or bicyclic heteroaryl ring, where it is selected from halo, C 1-6 -Alkyl, R x and NR 9 R 10 may be substituted with.

[0022] Reference to preferred classes and subclasses described above is intended to encompass all combinations of particular groups and preferred groups unless otherwise indicated.

[0023] Specific embodiments of the present invention include, but are not limited to, the compounds identified herein as Examples 1 to 138, or pharmaceutically acceptable salts thereof.

[0024] Further included within the scope of the present invention are pharmaceutical compositions comprised of a compound of Formula I or Formula Ia, as described above, and a pharmaceutically acceptable carrier. The present invention is also intended to encompass pharmaceutical compositions comprised of a pharmaceutically 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.

[0025] The present invention encompasses compositions for treating diseases or conditions involving plasma kallikrein activity. Accordingly, the present invention encompasses compositions comprising a compound of the present invention in a pharmaceutically acceptable carrier for treating visual activity disorders, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood clotting during cardiopulmonary bypass surgery, and postoperative bleeding in mammals. One class of the present invention encompasses compositions for treating hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. These compositions may optionally contain anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents. To achieve the desired inhibition, the compositions can be added to blood, blood products, or mammalian organs.

[0026] The present invention further includes compositions for preventing or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in a mammal, comprising a compound of the present invention in a pharmaceutically acceptable carrier. These compositions can optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0027] The present invention further encompasses compositions for treating ocular inflammatory conditions, including, but not limited to, uveitis, posterior uveitis, macular edema, acute macular degeneration, wet age-related macular degeneration, retinal detachment, retinal vein occlusion, ocular tumors, fungal infections, viral infections, multifocal choroiditis, diabetic uveitis, diabetic macular edema, diabetic retinopathy, proliferative vitreoretinopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, histoplasmosis, and uveal diffusion. These compositions can optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0028] The present invention further encompasses compositions for treating posterior ocular diseases, including, but not limited to, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. These compositions can optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0029] It will be understood that the present invention is directed to the compounds of structural formula I or structural formula Ia described herein and to the pharmaceutically acceptable salts of the compounds of structural formula I or structural formula Ia, and further to salts that are not pharmaceutically acceptable when used as free compounds or precursors to their pharmaceutically acceptable salts or when used in other synthetic procedures.

[0030] The compounds 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 acids, including inorganic or organic bases and inorganic or inorganic acids. Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" are non-toxic salts of the compounds of the present invention, generally prepared by reacting the free base with a suitable organic or inorganic acid.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, diethylacetic acid, digluconate, dihydrochloride, dodecylsulfate, and the like. dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethoxybenzoate, benzoylsulf ... Tanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isothioate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucoate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), onate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelic acid, phenylpropionic acid, polygalacturonate, propionate, salicylate, stearate, sulfate, monoacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undecanoate, valerate, etc.Furthermore, when the compound of the present invention contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, salts of cyclic amines, dicyclohexylamine, 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, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also included are basic nitrogen-containing groups that can be quaternized with agents such as: lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, e.g., benzyl and phenethyl bromides; 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 or base, and then collecting the desired salt by filtering the salt or by 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 also simultaneously form acid addition salts and base salts depending on the type of substituents on its side chain.

[0032] When a compound of formula I or formula Ia contains both an acidic group and a basic group in the molecule, the present invention further encompasses inner salts or betaines (zwitterions) in addition to the above salt forms.

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

[0034] Unless a specific enantiomer or diastereomer is indicated, the present invention encompasses all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers in all ratios (e.g., mixtures of enantiomers and / or diastereomers). Thus, enantiomers in enantiomerically pure form (as both levorotatory and dextrorotatory enantiomers), in the form of racemates, and in the form of mixtures of the two enantiomers in all ratios are subject of the present invention. In the case of cis / trans isomerism, the present invention encompasses both the cis and trans forms and mixtures of these forms in all ratios. Individual stereoisomers can be prepared, if necessary, by separating the mixture by conventional methods (e.g., chromatography or crystallization) or by using stereochemically uniform starting materials in the synthesis or by stereoselective synthesis. Optionally, derivatization can be carried out prior to the separation of stereoisomers. Separation of a mixture of stereoisomers can be carried out at the stage of an intermediate during the synthesis of a compound of Formula I or Formula Ia, or can be carried out on the final racemic product. Absolute stereochemistry can be confirmed by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing a stereocenter of known configuration. Where the compounds of the present invention are capable of tautomerization, all individual tautomers and mixtures thereof are encompassed within the scope of the present invention. The present invention encompasses all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemates, enantiomers, diastereomers, and tautomers and mixtures thereof.

[0035] In the compounds of the present invention, the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but a different atomic mass or mass number from that predominantly found in nature. The present invention is intended to encompass all suitable isotopic variations of the compounds described specifically and generically. For example, various isotopic forms of hydrogen (H) include protium (H) and deuterium (H). Protium is the predominant hydrogen isotope found in nature. Enriching deuterium may provide certain therapeutic advantages, such as increased in vivo half-life or reduced required dosage, or may provide a compound useful as a standard for characterizing biological samples. Isotopically enriched compounds can be prepared without undue experimentation by conventional methods familiar to those skilled in the art, or by methods similar to those described in the general process schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0036] Any variable part (e.g., R x When any variable (such as ) occurs more than one time in any constituent, its definition at each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn from substituents into ring systems indicate 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 either ring of the bicyclic moiety.

[0037] It is understood that those skilled in the art can incorporate one or more silicon (Si) atoms into the compounds of the present invention in place of one or more carbon atoms to provide chemically stable compounds that can be easily synthesized from readily available starting materials using techniques known to those skilled in the art. Carbon and silicon have different covalent bond radii, which result in differences in bond distance and configuration when comparing bonds between similar C and Si elements. These differences result in subtle changes in the size and shape of silicon-containing compounds compared to carbon. Those skilled in the art will understand that size and shape differences 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 in the compounds of the present invention can be selected by one of ordinary skill in the art to provide chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and the methods described below. When a substituent itself is substituted with more than one group, it is understood that these multiple groups can be located on the same carbon or on different carbons, so long as a stable structure results. The expression "optionally substituted" (with one or more substituents) should be understood to mean that the group in question can be unsubstituted or substituted with one or more substituents.

[0039] Furthermore, the compounds of the present invention can exist in amorphous form and / or one or more crystalline forms, and all such amorphous and crystalline forms of the compounds of Formula I or Formula Ia, as well as mixtures thereof, are intended to be included within the scope of the present invention. Furthermore, 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 of the present invention, particularly pharmaceutically acceptable solvates and hydrates, are also included within the scope of the present invention, along with the unsolvated anhydrous forms of the compounds.

[0040] Furthermore, when a carboxylic acid (—COOH) or alcohol group is present in the compounds of the invention, pharmaceutically acceptable esters of such carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can also be used. Included are esters 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 within the scope of the present invention. For example, esters can optionally be made by esterification of available carboxylic acid groups or by forming an ester for available hydroxy groups in the compounds. Similarly, amides that are susceptible to conversion can also 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 to the acid form (or -COO- form, depending on the pH of the body fluid or tissue where the conversion occurs) or the hydroxy form, and as such are 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 Alkyl, etc.

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

[0043] Except where indicated herein, the terms "alkyl" and "alkylene" are intended to encompass both branched-chain saturated aliphatic hydrocarbon groups and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout this specification. For example, methyl may be represented by conventional abbreviations such as "Me" or CH3, or by a symbol that is an extended bond as a terminal group, e.g., [ka] Ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, butyl can be represented by "Bu" or CH2CH2CH2CH3, etc. 1-4 "Alkyl" (or "C1-C4 alkyl") means, for example, a straight or branched chain alkyl group having the specified number of carbon atoms, including all isomers. For example, the structure: [ka] have equivalent meanings. 1-4 Alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1 to 4 carbon atoms are intended for a straight or branched chain alkyl group.

[0044] Unless otherwise indicated, the term "cycloalkyl" means a mono- or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0045] Unless otherwise indicated, the term "aryl," as used herein, refers to a stable monocyclic or bicyclic ring system having up to 10 carbon atoms in each ring, wherein at least one ring is aromatic. Bicyclic aryl ring systems include fused ring systems in which two rings share two atoms and spiro ring systems in which two rings share one atom. Aryl groups within this definition include, but are not limited to, phenyl, indene, isoindene, naphthalene, and tetralin.

[0046] Except where indicated, the term "heteroaryl," as used herein, refers to a stable monocyclic or bicyclic ring system having up to 10 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms and spiro ring systems in which two rings share one atom. Heteroaryl groups within this definition include, but are not limited to, azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphthipyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolinyl ... Azolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazolooxazinyl, dihydropyrazoliothiazinedioxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetrahydro quinoline, sulfonyl, 1,3-benzodioxolyl, 3-oxo-3,4-dihydro-2N-benzo[b][1,4]thiazine, imidazopyridinyl, 2-oxo-2,3-dihydroimidazolyl, 3,4-dihydrobenzoxazinyl, 2-oxo-2,3-dihydrooxazolyl, dihydroisobenzofuranyl, 1-oxoisoindolinyl, dioxide-2,3-dihydrobenzisothiazolyl, and 2-oxopyridyl.If the heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxides are also encompassed by this definition.

[0047] As used herein, the term "heterocycle" or "heterocyclyl," unless otherwise indicated, is intended to mean a stable, non-aromatic, monocyclic or bicyclic ring system containing one to four heteroatoms selected from the group consisting of O, N, S, SO, or SO, and up to ten atoms in each ring. Bicyclic heterocyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Thus, "heterocyclyl" includes, but is not limited to, azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, isochromanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides are also encompassed by this definition.

[0048] Except where indicated, the terms "halogen" or "halo" mean fluorine, chlorine, bromine, or iodine.

[0049] "Celite®" (Fluka) diatomite is a diatomaceous earth and may be referred to as "celite."

[0050] Except as indicated herein, the following structures, including substituent variables such as the variable "R": [ka] (where R is depicted as not being attached to any one particular bicyclic ring carbon atom). represents a structure in which the variable moiety can optionally be attached to any bicyclic ring carbon atom. For example, the variable moiety R shown in the above structure can be attached to any one of the six bicyclic ring carbon atoms (i, ii, iii, iv, v, or vi).

[0051] Except as otherwise provided 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.

[0052] The present invention further relates to medicaments comprising at least one compound of formula I or formula Ia and / or a pharmaceutically acceptable salt of a compound of formula I or formula Ia and / or an optional stereoisomeric form of a compound of formula I or formula Ia or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of formula I or formula Ia together with pharmaceutically suitable and pharmaceutically acceptable vehicles, additives and / or other active substances and adjuvants.

[0053] As used herein, the term "patient" is intended to mean a mammal, such as, for example, primates, humans, sheep, horses, cows, pigs, dogs, cats, rats, mice, and the like.

[0054] The medicaments according to the invention can be administered orally, by inhalation, rectally, or transdermally, or by subcutaneous, intraarticular, intraperitoneal, or intravenous injection. Oral administration is preferred. Stents and other surfaces in the body that come into contact with blood can be coated with the compounds of formula I.

[0055] The present invention further relates to a method for producing a medicament, which method comprises bringing at least one compound of formula I and formula Ia into a suitable dosage form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0056] Suitable solid or galenical formulations are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, solutions, suspensions, emulsions, drops or injectable solutions, and formulations with sustained release of the active substance, in which customary excipients are used, such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers, etc. Frequently used adjuvants that may be mentioned are 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 glycol, and solvents, such as sterile water and mono- or polyhydric alcohols, such as glycerol.

[0057] Dosage regimens utilizing plasma kallikrein inhibitors are selected according to a variety of factors, including the type, species, age, weight, sex, and medical 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 can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0058] The oral dosage of the plasma kallikrein inhibitor, when used for the indicated effects, ranges from about 0.01 mg / kg body weight / day (mg / kg / day) to about 30 mg / kg / day, preferably 0.025 mg / kg / day to 7.5 mg / kg / day, more preferably 0.1 mg / kg / day to 2.5 mg / kg / day, and most preferably 0.1 mg / kg / day to 0.5 mg / kg / day (unless otherwise specified, amounts of active ingredient are on a free base basis). For example, an 80 kg patient would be administered about 0.8 mg / day to 2.4 g / day, preferably 2 mg / day to 600 mg / day, more preferably 8 mg / day to 200 mg / day, and most preferably 8 mg / day to 40 mg / day. Thus, a suitably prepared medicament for once-daily administration will contain 0.8 mg to 2.4 g, preferably 2 mg to 600 mg, more preferably 8 mg to 200 mg, and most preferably 8 mg to 40 mg (e.g., 8 mg, 10 mg, 20 mg, and 40 mg). Advantageously, the plasma kallikrein inhibitor may be administered in divided doses two, three, or four times daily. For twice-daily administration, a suitably prepared medicament will contain 0.4 mg to 4 g, preferably 1 mg to 300 mg, more preferably 4 mg to 100 mg, and most preferably 4 mg to 20 mg (e.g., 4 mg, 5 mg, 10 mg, and 20 mg).

[0059] For intravenous injection, a patient will receive an amount of active ingredient sufficient to deliver 0.025 mg / kg / day to 7.5 mg / kg / day, preferably 0.1 mg / kg / day to 2.5 mg / kg / day, and more preferably 0.1 mg / kg / day to 0.5 mg / kg / day. Such an amount can be administered in many suitable ways (e.g., a large volume of low concentration active ingredient for a single extended period of time, or a small volume of high concentration active ingredient several times daily for a short period of time, e.g., once daily). Typically, a conventional intravenous formulation containing an active ingredient at a concentration of about 0.01 mg / mL to 1.0 mg / mL (e.g., 0.1 mg / mL, 0.3 mg / mL, and 0.6 mg / mL) can be prepared and administered at a daily dose of 0.01 mL / kg to 10.0 mL / kg of patient body weight (e.g., 0.1 mL / kg, 0.2 mL / kg, 0.5 mL / kg). In one example, an 80 kg patient would receive 8 mL of an intravenous formulation having an active ingredient concentration of 0.5 mg / mL twice daily, or 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid, or a pharmaceutically acceptable acid / conjugate base with adequate buffering capacity in the pH range acceptable for intravenous administration can be used as a buffer. Selection of an appropriate buffer and pH for the formulation can be readily performed by one skilled in the art, depending on the solubility of the drug to be administered.

[0060] The compounds of Formula I or Formula Ia can be administered as monotherapy and in combination with other therapeutic agents, including, but not limited to, anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0061] An "anti-inflammatory agent" is any agent that, when administered at therapeutically effective levels, is directly or indirectly effective in reducing inflammation. "Anti-inflammatory agents" include, but are not limited to, steroidal anti-inflammatory agents and glucocorticoids. Suitable anti-inflammatory agents include, but are not limited to, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

[0062] An "anti-VEGF agent" is any agent that is effective directly or indirectly in inhibiting the activity of VEGF (vascular endothelial growth factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, brolucizumab, and aflibercept.

[0063] An "immunosuppressant" is any agent that is effective directly or indirectly to suppress or reduce the strength of the body's immune system. Suitable immunosuppressants include, but are not limited to, corticosteroids (e.g., prednisone, budesonide, prednisolone), Janus kinase inhibitors (e.g., tofacitinib), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), mTOR inhibitors (e.g., sirolimus, everolimus), IMDH inhibitors (e.g., azathioprine, leflunomide, mycophenolate), biologics (e.g., abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), and monoclonal antibodies (e.g., basiliximab, daclizumab).

[0064] Suitable anticoagulants include, but are not limited to, 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 reocclusion and restenosis after angioplasty), other anticoagulants (e.g., aspirin), and thrombolytic agents (e.g., plasminogen activators or streptokinase) to achieve synergistic effects in the treatment of various vascular pathologies. 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 who have undergone angioplasty may benefit from co-administration of a fibrinogen receptor antagonist and a thrombin inhibitor.

[0065] In certain embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are used in conventional dosage ranges and regimens reported in the art, e.g., at dosages set forth in several editions of the Physicians' Desk Reference (e.g., 70th Edition (2016) and earlier editions). In other embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are used in dosages lower than their conventional dosage ranges.

[0066] Alternatively, or in addition, one or more additional pharmacologically active agents can be administered in combination with the compounds of the present invention. The additional active agent(s) is intended to mean one or more pharmaceutically active agents that exhibit activity in the body different from the compounds of the present invention (including prodrugs that are converted into pharmaceutically active forms after administration), and also includes the free acid, free base, and pharmaceutically acceptable salts of the additional active agent(s) if such forms are commercially available or otherwise chemically feasible. Generally, any suitable active agent(s) (including, but not limited to, antihypertensive agents, additional diuretics, antiatherosclerotic agents (e.g., lipid-modifying compounds), antidiabetic agents, and / or antiobesity agents) can be used in any combination with the compounds of the present invention in a single dosage formulation (fixed-dose drug combination), or can be administered to patients in one or more separate dosage formulations that allow for simultaneous or sequential administration of the active agents (co-administration of separate active agents). Examples of additional active agents that may be used include, but are not limited to, the following: 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 or ARBs, which may be in the free base form, free acid form, salt form, or prodrug form;For example, 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 medoximil (BENICAR®), telmisartan (MICARDIS®), valsartan (DIOVAN®), and any of these drugs used in combination with a thiazide-like diuretic (e.g., hydrochlorothiazide) (e.g., HYZAAR®, DIOVAN HCT®, ATACAND®). HCTZ®); potassium-sparing diuretics, such as 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; RO42-5892; A65317; CP80794; ES1005; ES8891; SQ34017; aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxybenzoates) -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 blocking agents (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha-adrenergic blocking agents (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, e.g., simvastatin and lovastatin (which are commercially available as lactone prodrugs ZOCOR® and MEVACOR® and function as inhibitors after administration), and pharmaceutically acceptable salts of dihydroxy open-acid HMG-CoA reductase inhibitors, such as atorvastatin (particularly the calcium salt sold under LIPITOR®), rosuvastatin (particularly CRESTOR®), and the like. (calcium salt sold under the trademark PRAVACHOL®), pravastatin (especially the sodium salt sold under the trademark LESCOL®) and fluvastatin (especially the sodium salt sold under the trademark LESCOL®); cholesterol absorption inhibitors, such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid-lowering agent (e.g., the HMG-CoA reductase inhibitors mentioned above), in particular ezetimibe (VYTORIN®) in combination with simvastatin or ezetimibe in combination with atorvastatin calcium; niacin in immediate-release or controlled-release form, in particular niacin in combination with a DP antagonist (e.g., laropiprant) and / or niacin in combination with an HMG-CoA reductase inhibitor; niacin receptor agonists, such as acipimox and acifran, and niacin receptor partial agonists;metabolic altering agents, including insulin sensitizers, and related compounds for treating diabetes, such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones, also known as glitazones (e.g., pioglitazone, rosiglitazone), alpha-glucosidase inhibitors (e.g., acal, bose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), concomitant medications, e.g., JANUMET® (sitagliptin with metformin), and injectable diabetes drugs, such as exenatide and pramlintide acetate; inhibitors of glucose uptake, such as sodium glucose transporter (SGLT) inhibitors and their various isoforms, e.g., 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 in preventing or treating the above-mentioned diseases, including, but not limited to, diazoxide; and, where chemically possible, free acid forms, free base forms, and pharmaceutically acceptable salt forms, prodrug forms (e.g., esters), and prodrug salts of the above-mentioned agents. The trade names of the pharmaceuticals set forth above are provided to exemplify the marketed forms of the active agent(s); such pharmaceuticals can be used in separate dosage forms for simultaneous or sequential administration with the compounds of the invention, or the active agent(s) therein can be used in fixed-dose drug combinations with the compounds of the invention;

[0067] A typical dose of a plasma kallikrein inhibitor of the present invention in combination with other suitable agents may be the same as the dose of the plasma kallikrein inhibitor administered without co-administration with additional agents, or may be substantially less than the dose of the plasma kallikrein inhibitor administered without co-administration with additional agents, depending on the therapeutic needs of the patient.

[0068] The compound is administered to a mammal in a therapeutically effective amount. A "therapeutically effective amount" means an amount of a compound of the present invention that, when administered to a mammal alone or in combination with additional therapeutic agents, is effective to treat (i.e., prevent, inhibit, or ameliorate) a disease state or treat the progression of that disease in a host.

[0069] The compounds of the present invention are preferably administered alone to a mammal 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 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, as described, for example, by Chou and Talalay, "Adv. Enzyme Regul. 1984, 22, 27-55." Generally, synergy is most clearly demonstrated at concentrations below the optimal concentration of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared to the individual components.

[0070] "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, the components can be administered simultaneously or sequentially in any order at different times. Thus, each component can be administered separately but sufficiently close in time to produce the desired therapeutic effect. Administration of each component need not be via the same route of administration; for example, one component can be administered orally and another component can be delivered to the vitreous of the eye.

[0071] The present invention is not limited in scope by the specific embodiments disclosed in the examples, which are intended as illustrations of only a few aspects of the invention, and any embodiments that 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 be apparent to those skilled in the art to which it pertains and are intended to be included within the scope of the appended claims.

[0072] General Method The compounds of the present invention can be prepared using conventional techniques or according to the methods outlined in the following general synthetic schemes. One of ordinary skill in the art can modify the procedures and reagents shown to arrive at similar intermediates and / or final compounds.

[0073] NMR spectra were recorded on VARIAN or Bruker NMR Systems (400, 500, or 600 MHz). Chemical shifts are reported in ppm downfield and upfield from tetramethylsilane (TMS) and are referenced to either the internal TMS or solvent resonances ( 1 H NMR: δ 7.27 for CDCl, δ 2.50 for (CD)(CHD)SO; and 13C NMR: δ 77.02 for CDCl3, δ 39.51 for (CD3)2SO. Coupling constants (J) are expressed in Hertz (Hz), and spin multiplicities are given as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), and br (broad line). Chiral separations can be performed on either a Waters Thar80 SFC or a Berger MGII preparative SFC system. LC-MS data can be recorded on a SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, Agilent 1100 Series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instrument (using a C18 column with a MeCN gradient in water (containing 0.02-0.1% TFA)). UV detection was performed at 220 and / or 254 nm and ESI ionization was used for MS detection.

[0074] When chiral resolution was achieved by chromatography using a chiral column, the chiral column used for the SFC chiral resolution is listed in the table. Some of the chiral columns used were CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK AD-H, and CHIRALPAK AS-H. Below, they are referred to by their two- or three-letter abbreviations. By convention, the table always lists the faster-eluting isomer from a chiral resolution first, followed immediately by the slower-eluting isomer from the same resolution. When three or more isomers were separated, they are always listed in the table in the order of their elution: Peak 1, followed by Peak 2, Peak 3, etc. An * symbol near a chiral center in a structure indicates that this chiral center was resolved by chiral resolution without unambiguously determining its stereochemical configuration.

[0075] Furthermore, UV is ultraviolet; W is watts; wt.% is weight percent; × g is times gravity; αD is the specific rotation of polarized light at 589 nm; % w / v is the weight percentage of the former agent relative to the volume of the latter agent; % v / v is the volume percentage of the former agent relative to the volume of the latter agent; cpm is counts per minute; δH is chemical shift, and mass spectra obtained by ES-MS are sometimes referred to as "LC-MS" in this specification; m / z is mass-to-charge ratio; n is normal; nm is nanometer; and nM is nanomole.

[0076] For purposes of this specification, the following abbreviations have the indicated meanings: [Table 1]

[0077] TIFF0007794991000021.tif240138

[0078] TIFF0007794991000022.tif240142

[0079] TIFF0007794991000023.tif93142

[0080] General description The starting materials used were obtained from commercial sources or prepared in other examples unless otherwise indicated. The methods used to prepare the compounds of the present invention are illustrated by the following schemes. Unless otherwise indicated, all starting materials used are commercially available.

[0081] Scheme Scheme A [ka]

[0082] Scheme A illustrates a synthetic sequence for preparing substituted spirocarbamates (e.g., A6) from Boc-protected anilines A1 and ketones (e.g., A2). Controlled lithiation of anilines A1 and addition to heterocyclic ketones A2 occurs in the presence of a Lewis acid (e.g., LaCl). The tertiary alcohol is cyclized in situ to the carbamate to give spirocarbamate derivatives (e.g., A3), which can be subjected to chiral separation, preferably using supercritical fluid chromatography (SFC), to give enantiomers A4 and A5. Deprotection of either enantiomer (e.g., A4) gives secondary amines A6, from which compounds of the present invention can be obtained.

[0083] Scheme B [ka]

[0084] Scheme B shows a synthetic sequence for preparing spirolactams such as B8. Difluorophenylacetonitrile B1 is reacted with charged bromoacetate under basic conditions to give 3-cyano-3-arylpropionate B2, which is further reacted with methyl acrylate to give mixed ester B3. The nitrile undergoes cobalt-catalyzed reduction and in situ cyclization to give lactam B4, which is reduced to piperidine and benzylated to give ester B5. Ester hydrolysis followed by formation of primary amide B6 generates a synthon, which is further reacted to give the orthofluorinated S-sulfonate. N Ar substitution can be performed to give the spirolactam scaffold (B7). This core structure can be subjected to further elaboration to give the desired aryl ring functionality (B8), the two enantiomers of which can be separated by chiral chromatography to give compounds of the invention.

[0085] Scheme C [ka]

[0086] Scheme C shows a synthetic sequence for preparing N-alkylpyrazoles such as C5. Pyrazole C1 can be subjected to a Mitsunobu reaction with alcohol C2 or reacted with alkyl halide C3 in the presence of a suitable weak base (e.g., CsCO3) to give N-alkylated esters of type C4, which can be deprotected under appropriate reaction conditions to give carboxylic acids (C5), from which compounds of the invention can be obtained.

[0087] Scheme D [ka]

[0088] Scheme D shows a synthetic sequence for preparing epoxides such as D5 from carboxylic acids of type D1. D1 can be reacted with methoxymethylamine in the presence of a suitable coupling agent (e.g., CDI) to give Weinreb-type amides D2. This intermediate can be reacted with an aryllithium reagent (D3), which is generated by in situ lithium-halogen exchange by treating the corresponding aryl bromide with n-butyllithium at −78° C., to give aryl ketones of type D4. D4 can be further reacted with a sulfoxonium ylide, derived from trimethylsulfoxonium iodide and a strong base, to give epoxides (D5), which can then be used to give compounds of the present invention.

[0089] Scheme E [ka]

[0090] Scheme F [ka]

[0091] Scheme F shows a synthetic sequence for preparing imidazole ester F4 and carboxylic acid F5 from nitrile (F1). A nitrile such as F1 is treated with hydroxylamine hydrochloride to give a hydroxyamidine of type F2. Heating the hydroxyamidine (F2) with an alkynoate (F3) gives the desired imidazole ester (F4), which can be saponified to the corresponding carboxylic acid (F5), which can then give compounds of the invention.

[0092] Scheme G [ka]

[0093] Scheme G shows a synthetic sequence for preparing imidazophenone G4 from imidazolocarboxylate G1. Imidazole G1 can be protected with SEM chloride, which facilitates regiospecific acylation by the addition of an appropriate benzoyl chloride G3 to give the desired imidazolophenone G4, which can be saponified to give the carboxylic acid intermediate (G5), from which compounds of the invention can be obtained.

[0094] Scheme H [ka]

[0095] Scheme H shows a synthetic sequence for preparing imidazocarboxaldehyde H4. Bromoimidazole H1 can be protected by treatment with an appropriate reagent (e.g., SEM-Cl) and coupled with vinyl potassium tetrafluoroborate in the presence of a palladium catalyst to give vinyl imidazole H3. Oxidative cleavage of the olefin under Lemieux-Johnson conditions using sodium periodate and potassium osmate can give the desired imidazocarboxaldehyde H4, from which compounds of the invention can be obtained.

[0096] Scheme I [ka]

[0097] Scheme I shows a synthetic sequence for preparing substituted phenylacetates I4 from phenylacetic acid (I1) starting material. Treatment of I1 with a suitable base (e.g., LDA) followed by the addition of a suitable alkylating reagent (I2) can provide the desired mono-alkylated acid I3. Esterification by a number of methods known to those skilled in the art (e.g., reaction with TMS-CHN2) can provide the desired alkylated ester I4, from which compounds of the invention can be obtained.

[0098] Scheme J [ka]

[0099] Scheme J shows a method for generating α-spirophenylacetates J3, in which unsubstituted phenylacetate (J1) is reacted with a bifunctional alkylating agent (J2) in the presence of a suitable base (e.g., NaH) to provide the desired α,α-disubstituted phenylacetate (J3), from which compounds of the invention can be obtained.

[0100] Scheme K [ka]

[0101] Scheme K shows a synthetic sequence for preparing 1,2,4-triazoles K3 from esters such as I4 or J3. Reaction of I4 or J3 with hydrazine provides the hydrazide intermediate K1, which is subsequently condensed with an imidate (K2) to provide the aminocarbazone K3. Thermal cyclization of K3 in the presence of a suitable drying agent (e.g., molecular sieves) can provide the desired 1,2,4-triazole ester K4, from which compounds of the invention can be obtained.

[0102] Scheme L [ka]

[0103] Scheme L shows a synthetic sequence for converting a benzyl-substituted heterocycle (L1) to a phenone intermediate L2, which can be further functionalized at the benzylic carbon. Benzylic oxidation of an L1-type heterocycle with a suitable oxidizing agent (typically potassium permanganate) can directly provide the aforementioned phenone intermediate L2. L2 can be reacted in the presence of a fluorinating agent (e.g., DAST) to generate the α,α-gem-difluorobenzyl heterocycle L3. Alternatively, L2 can be treated with trimethylsilyltrifluoromethane, followed by a two-step process involving conversion of the hydroxyl to a reactive halide L4 (e.g., conversion to a chloride using thionyl chloride) followed by reduction with a suitable agent (e.g., lithium aluminum hydride) to provide the α-trifluoromethyl-substituted benzyl heterocycle L5, from which compounds of the present invention can be obtained. Additionally, any of the intermediate examples L2-L5 where X is defined to provide an ester functionality can be treated as described above to generate the corresponding carboxylic acid (not shown), which in turn can provide compounds of the invention.

[0104] Scheme M [ka]

[0105] Scheme M illustrates a preferred method for generating desired intermediates, such as triazolocarboxaldehydes (M5), from aminothioxoacetates M1. Reaction of M1 with Boc-hydrazine followed by treatment with benzyloxyacetyl chloride and heating afforded 5-substituted-3-carboxytriazoles (M3). SEM protection (M4) followed by debenzylation and oxidation of the resulting hydroxyl moiety using methods known to those skilled in the art affords triazolecarboxaldehydes M5. Treatment with an appropriate nucleophile (e.g., Grignard reagents (M6a) or alkyllithium species (M6b)) affords 2-alcohols M7. The alcohols M7 can themselves be carried on or further reacted in the presence of carbon tetrachloride and triphenylphosphine to afford chloromethyltriazolecarboxylates M8, which can directly afford compounds of the invention, or the chloromethyltriazolecarboxylates M8 can be saponified to carboxylic acids M9, which can then afford compounds of the invention.

[0106] Scheme N [ka]

[0107] Scheme N shows how a secondary alcohol M6 can be converted to the corresponding alkyl fluoride (N1) by reacting M6 in the presence of DAST, from which compounds of the present invention can be obtained.

[0108] Scheme O [ka]

[0109] Scheme O shows a synthetic sequence for converting heteroaryl ketones or aldehydes (O1) to benzyl-substituted heterocycles O4 and O5. A ketone or aldehyde such as O1 can be condensed with an arylsulfonyl hydrazide to give hydrazone O2, which can undergo a Barluenga-type coupling with an arylboronic acid (O3) in the presence of a suitable base (e.g., CsCO3) to give the desired benzyl-substituted heterocycle O4, which can directly provide compounds of the invention, or can be saponified to give carboxylic acids O5, which can provide compounds of the invention.

[0110] Scheme P [ka]

[0111] Scheme P shows a synthetic sequence for preparing sulfones such as P4 in two steps from an alcohol starting material (P1). Alcohol P1 can be reacted with thiobenzothiazole under Mitsunobu conditions to give the thioether intermediate P2, which can then be oxidized to give the substituted sulfone P3, from which compounds of the invention can be obtained.

[0112] Scheme Q [ka]

[0113] Scheme Q shows a synthetic sequence for preparing N-alkylpyrrolidines and piperidines (e.g., Q3). The heterocycle Q1 can be reacted with a suitable alkyl halide Q2 in the presence of a suitable non-nucleophilic base (e.g., NaH or Cs2CO3) to give an N-alkylated ester of type Q3, which can directly provide compounds of the invention, or the N-alkylated ester can be saponified to the carboxylic acid Q4, which can provide compounds of the invention.

[0114] Scheme R [ka]

[0115] Scheme R shows a synthetic sequence for preparing spirocarbamic acid amide R3 using the corresponding ester R1 and spirocarbamate A6 synthon. Ester R1 can be saponified to give carboxylic acid R2, which can then be reacted with spirocarbamate A6 in the presence of a suitable coupling agent (e.g., HATU or T3P) to give R3, which represents a compound of the present invention.

[0116] Scheme S [ka]

[0117] Scheme S shows a synthetic sequence for preparing trifluoroboryl alkyl-substituted pyrazole intermediate S2 from deprotected spirocarbamate synthon A6, which can undergo cross-coupling to generate S4. Amide formation can be achieved by reaction of spirocarbamate A6 with 4-pyrazolecarboxylic acid under the conditions described above to provide pyrazolyl amide precursor S1, which can be further reacted in the presence of a suitable strong base (e.g., KHMDS) and potassium bromomethyltrifluoroborate to provide alkyltrifluoroborate synthon S2. Cross-coupling with an appropriate aryl halide (S3) in the presence of a palladium catalyst (e.g., ClPd(dppf)) can provide S4, which can then be used to prepare compounds of the present invention.

[0118] Scheme T [ka]

[0119] Scheme T shows a synthetic sequence for converting heteroaryl aldehyde T1 to branched alkyl heteroaryl congeners T6, T8, and T9. Reaction of heteroaryl carboxaldehyde T1 with an appropriate Grignard reagent (T2) affords secondary alcohol T3, which can be oxidized to the corresponding ketone T4 by various known methods, most preferably using manganese dioxide as the oxidizing agent. Ketone T4 can be reacted with a second Grignard reagent (T5) to afford tertiary alcohol T6, which can function as a compound of the invention. Alternatively, both tertiary alcohol T6 and ketone T4 can be independently converted to the corresponding vinyl heteroaryl amide T8. In the case of tertiary alcohol T6, elimination in the presence of a suitable acid or Lewis acid source can produce vinyl amide T8. The olefin moiety can also be synthesized in one step from ketone T4 by treatment with sulfone reagent (O4) under Julia-Kociensky conditions or using a Wittig olefination reaction involving reaction with a phosphorus ylide reagent. Reduction of the olefin moiety of T8 can be carried out using a variety of conditions, particularly reaction with catalytic Raney nickel, to give amide T9, which represents a generic compound of the present invention.

[0120] Scheme U [ka]

[0121] Scheme U shows an alternative method for synthesizing compounds of the invention (U4). Cross-coupling of an SEM-protected triazoloalkyl chloride U1 with an appropriate aryl bromide (U2) can be carried out using a nickel-catalyzed reductive coupling procedure to give the protected benzyltriazole U3. SEM deprotection in the presence of a strong acid (e.g., TFA) can give benzyl-substituted triazolyl amides such as U4.

[0122] Scheme V [ka]

[0123] Scheme V shows an alternative method for synthesizing compounds of the present invention (V4). Direct coupling of an appropriate arylboronic acid (V2) with an SEM-protected triazolosulfonylhydrazone V1 can be carried out in the presence of a suitable weak inorganic base (e.g., potassium carbonate), thereby affording an SEM-protected benzyltriazole V3. SEM deprotection as described above affords the benzyltriazolylamide V4.

[0124] Scheme W [ka]

[0125] Scheme W shows a method for synthesizing the benzyl alcohol compound (W1) of the present invention. Various reducing agents (preferably sodium borohydride) can successfully reduce the T4-type intermediate ketone. Furthermore, many chiral reagents and biocatalytic ketoreductases can be used to perform the asymmetric reduction of the ketone moiety. All of these can provide the compounds of the present invention, as needed.

[0126] Scheme X [ka]

[0127] Scheme X shows an alternative method for synthesizing compounds of the present invention (X5). Following the procedures described above, A6 undergoes amide coupling to give intermediate X1, which can be reacted as described above in Scheme H to give triazolylcarboxaldehyde (X2). Reaction with aryl Grignard reagents (X3) or aryllithium reagents (X4), using methods known to those skilled in the art, gives benzyl alcohols from which compounds of the present invention can be prepared. [Example]

[0128] Intermediates Intermediate A6-a [ka]

[0129] 6-chloro-5-fluoro-5',5'-dimethylspiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: tert-butyl 6-chloro-5-fluoro-5',5'-dimethyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-carboxylate:Under a N atmosphere, THF (55 mL) was added to a round-bottom flask containing tert-butyl (4-chloro-3-fluorophenyl)carbamate (2.21 g, 9.00 mmol). The solution was cooled to −78 °C. To the stirring solution was added nBuLi (2.5 M in hexane, 11 mL, 27.9 mmol) over 40 min. The reaction mixture was stirred at −78 °C for an additional 45 min, at which point a solution of LaCl3·2LiCl (0.6 M in THF, 22.5 mL, 13.5 mmol) and tert-butyl 3,3-dimethyl-5-oxopiperidine-1-carboxylate (3.1 g, 13.5 mmol) was added over 40 min at −78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. To the reaction mixture was added KOtBu (1.7 M in THF, 5.3 mL, 9.0 mmol), and the resulting mixture was heated to 60 °C for 3 h. The mixture was cooled to room temperature, quenched with 1 M HCl, and diluted with EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. LCMS [M+Na] + = 421.1 (calculated value: 421.1).

[0130] Step 2: 6-chloro-5-fluoro-5',5'-dimethylspiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a round-bottom flask containing a suspension of tert-butyl 6-chloro-5-fluoro-5',5'-dimethyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-carboxylate (7.98 g, 20.0 mmol) in 1,4-dioxane (30 mL) was added HCl (4 M in dioxane, 25 mL, 100 mmol). The reaction mixture was heated to 90 °C and stirred vigorously for 12 h. The reaction was cooled to room temperature and concentrated under reduced pressure to provide the crude title compound. The crude product was carried on to the next step without further purification. LCMS [M+H] + = 299.1 (calculated value: 299.1).

[0131] The following compounds were prepared using procedures similar to those described above using the appropriate starting materials. [Table 2]

[0132] Intermediate B8-a [ka]

[0133] tert-Butyl 6'-chloro-5'-fluoro-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-3,4'-quinoline]-1-carboxylate Step 1. tert-butyl 3-cyano-3-(2,6-difluorophenyl)propanoate: A solution of 2-(2,6-difluorophenyl)acetonitrile (10.0 g, 65.3 mmol) in THF (15 mL) was added dropwise to a solution of KHMDS (1 M in THF, 65.3 mL, 65.3 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 minutes, at which point the reaction was warmed to 0° C. and stirred for 30 minutes. A separate flask containing tert-butyl 2-bromoacetate (12.7 g, 65.3 mmol) in THF (50 mL) was cooled to −48° C., and the parent solution was added dropwise. The resulting mixture was allowed to warm slowly to 0° C. over 1 hour, then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. LCMS [M+H] + = 268.3 (calculated value: 268.1).

[0134] Step 2. 1-(tert-butyl) 6-methyl 3-cyano-3-(2,6-difluorophenyl)hexanedioate:To a mixture of tert-butyl 3-cyano-3-(2,6-difluorophenyl)propanoate (15.0 g, 56.1 mmol) and methyl acrylate (4.83 g, 56.1 mmol) was added N,N,N-trimethyl-1-phenylmethanaminium hydroxide (2.35 g, 5.61 mmol). The resulting mixture was stirred at room temperature for 10 minutes, at which point the reaction was washed with EtOAc and brine. The organic layer was dried (MgSO4) and concentrated, and the crude residue was purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. LCMS [M+H] + = 354.3 (calculated value: 354.2).

[0135] Step 3. tert-Butyl 2-(3-(2,6-difluorophenyl)-6-oxopiperidin-3-yl)acetate To a solution of 1-(tert-butyl) 6-methyl-3-cyano-3-(2,6-difluorophenyl)hexanedioate (18.0 g, 50.9 mmol) in MeOH (50 mL) was added cobalt(II) chloride hexahydrate (18.2 g, 76.0 mmol). The resulting mixture was stirred at room temperature for 10 minutes, at which point NaBH (10.0 g, 264 mmol) was added in portions. After 1.5 hours, the reaction was diluted with water and extracted with EtOAc. The combined organics were dried (MgSO) and concentrated to give the title compound, which was carried forward without further purification. LCMS [M+H] + = 326.3 (calculated value: 326.2).

[0136] Step 4. tert-butyl 2-(1-benzyl-3-(2,6-difluorophenyl)piperidin-3-yl)acetate:To a solution of tert-butyl 2-(3-(2,6-difluorophenyl)-6-oxopiperidin-3-yl)acetate (11.0 g, 33.8 mmol) in THF (40 mL) at 0° C. was added borane-tetrahydrofuran complex (1 M THF solution, 80 mL, 80 mmol), and the mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was cooled to 0° C. and quenched with AcOH. The mixture was concentrated to give a crude residue. The crude residue was treated with ammonia (7 M MeOH solution, 4.8 mL, 33.8 mmol). The mixture was concentrated, and the crude residue was diluted with THF (50 mL). AcOH (4.41 mL, 77 mmol) and benzaldehyde (5.86 mL, 57.8 mmol) were added, followed by sodium triacetoxyborohydride (12.3 g, 57.8 mmol), and the mixture was stirred at room temperature. After 2 h, the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried (MgSO4) and evaporated, and the crude residue was purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. LCMS [M+H] + = 402.5 (calculated value: 402.2).

[0137] Step 5. 2-(1-benzyl-3-(2,6-difluorophenyl)piperidin-3-yl)acetamide: A mixture of tert-butyl 2-(1-benzyl-3-(2,6-difluorophenyl)piperidin-3-yl)acetate (5.61 g, 14.0 mmol) and HCl (4 M in dioxane, 17.5 mL, 69.9 mmol) was stirred at room temperature. After 12 h, the reaction was concentrated and the crude residue was dissolved in DMF (50 mL). Ammonium chloride (1.64 g, 30.7 mmol) was added, followed by EtN (4.3 mL, 31 mmol) and HATU (6.38 g, 16.8 mmol), and the reaction was stirred at room temperature. After 2 h, the reaction was filtered and concentrated to give the title compound as a crude residue, which was carried forward without purification. LCMS [M+H] + = 345.4 (calculated value: 345.2).

[0138] Step 6. tert-Butyl 5'-fluoro-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-3,4'-quinoline]-1-carboxylate: Crude 2-(1-benzyl-3-(2,6-difluorophenyl)piperidin-3-yl)acetamide (14.0 mmol) was dissolved in DMF (12 mL) and NaH (2.79 g, 69.9 mmol) was added portionwise. The resulting mixture was heated to 130° C. for 30 minutes, at which point the reaction was cooled to room temperature and neutralized with HCl. The reaction was concentrated, suspended in MeOH, and filtered. To the filtrate was added Pd—C (1.49 g, 1.40 mmol), and the mixture was degassed and stirred under an atmosphere of H. After 30 minutes, the reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to give the crude intermediate product, which was redissolved in DMF (5 mL). Di-tert-butyl dicarbonate (3.2 mL, 14 mmol) was added and the reaction was stirred at room temperature. After 3 h, the reaction was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried (MgSO), and concentrated. The crude residue was purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. LCMS [M+H] + = 335.4 (calculated value: 335.2).

[0139] Step 7. tert-Butyl 6'-chloro-5'-fluoro-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-3,4'-quinoline]-1-carboxylate: To a solution of tert-butyl 5'-fluoro-2'-oxo-2',3'-dihydro-1'H-spiro[piperidine-3,4'-quinoline]-1-carboxylate (900 mg, 2.69 mmol) in DMF (6 mL) was added N-chlorosuccinimide (359 mg, 2.69 mmol), and the mixture was heated to 80 °C. After 10 min, the reaction was diluted with EtOAc and washed with a 1:1 mixture of saturated aqueous NaHCO and brine. The organic layer was dried (MgSO) and concentrated, and the crude residue was purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. LCMS [M+H] + = 369.4 (calculated value: 369.1).

[0140] The title compound was separated by SFC (instrument: SFC-80 Method Column AS-H (250 mm x 21 mm); conditions: 35% EtOH, time (min); flow rate (mL / min) 50, pressure (Bar) 120). The faster eluting isomer of the title compound was obtained (B8-a1): LCMS [M+H] + = 369.4 (calculated value: 369.1). The slower eluting isomer of the title compound was obtained (B8-a2): LCMS [M+H] + = 369.4 (calculated value: 369.1).

[0141] Intermediate C4-a [ka]

[0142] Ethyl (rac)-1-(1-(3-chlorophenyl)ethyl)-1H-pyrazole-4-carboxylate To a mixture of 1-(1-bromoethyl)-3-chlorobenzene (4.40 g, 20.0 mmol) and CsCO (19.6 g, 60.1 mmol) in DMF (50 mL) was added ethyl 1H-pyrazole-4-carboxylate (3.09 g, 22.1 mmol). The mixture was stirred at 60 °C for 3 h. The mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc / petroleum ether) to provide the title compound. LCMS [M + H] + = 279.1, (calculated value: 279.0). 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 4.2 Hz, 2H), 7.26 (d, J = 4.5 Hz, 2H), 7.18 (s, 1H), 7.04-7.11 (m, 1H), 5.48 (q, J = 7.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.88 (d, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0143] The following compounds were prepared using procedures similar to those described above using the appropriate starting materials. [Table 3]

[0144] Intermediate C5-a [ka]

[0145] 1-Benzyl-1H-pyrazole-4-carboxylic acid A 10 mL vial was charged with tert-butyl 1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazole-4-carboxylate (100 mg, 0.306 mmol) and TFA (230 μL, 39 mmol). The reaction was stirred at room temperature for 12 h. The crude reaction mixture was concentrated to dryness and then triturated with ether to afford the title compound, which was carried forward for further purification. LCMS [M+H] + = 272.0, calculated value: 272.2

[0146] Intermediate C5-b [ka]

[0147] 1-(2-cyclopropyl-1-phenylethyl)-1H-pyrazole-4-carboxylic acid Step 1: 2-Cyclopropyl-1-phenylethanone:To a solution of phenylmagnesium bromide (3.0 M in THF, 2.70 mL, 8.01 mmol) in THF (5 mL) was added 2-cyclopropylacetonitrile (500 mg, 6.16 mmol) in THF (2 mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 h, at which time the reaction was quenched with 1 M HCl and extracted with EtOAc. The combined organic fractions were washed with brine, dried (NaSO), filtered, and the solvent was evaporated under reduced pressure to give a crude residue which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. 1 H NMR (500 MHz, CDCl3) δ 7.93-7.99 (m, 2H), 7.53-7.61 (m, 1H), 7.42-7.50 (m, 2H), 2.89 (d, J = 6.9 Hz, 2H), 1.10-1.26 (m, 1H), 0.55-0.66 (m, 2H), 0.15-0.25 (m, 2H).

[0148] Step 2: 2-Cyclopropyl-1-phenylethanol: To a solution of 2-cyclopropyl-1-phenylethanone (100 mg, 0.624 mmol) in MeOH (5 mL) was added NaBH (35 mg, 0.94 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h, at which point the mixture was concentrated to give a residue. The residue was suspended in water and extracted with EtOAc. The combined organic fractions were dried (NaSO), filtered, and the solvent was evaporated under reduced pressure to give the crude title compound, which was carried forward without purification. 1 H NMR (500 MHz, CDCl3,) δ 7.22-7.30 (m, 4H), 7.18 (dt, J = 6.9, 2.2 Hz, 1H), 4.69 (t, J = 6.6 Hz, 1H), 1.97 (br s, 1H), 1.52-1.64 (m, 2H), 0.57-0.67 (m, 1H), 0.27-0.43 (m, 2H), 0.03 (dq, J = 9.2, 4.7 Hz, 1H), -0.12--0.02 (m, 1H).

[0149] Step 3: Ethyl 1-(2-cyclopropyl-1-phenylethyl)-1H-pyrazole-4-carboxylate: To a stirred mixture of triphenylphosphine (155 mg, 0.592 mmol), 2-cyclopropyl-1-phenylethanol (80 mg, 0.493 mmol), and ethyl 1H-pyrazole-4-carboxylate (69 mg, 0.49 mmol) in toluene (2 mL) was added di-tert-butyl azodicarboxylate (170 mg, 0.740 mmol), and the resulting mixture was heated to 80 °C for 2 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic fractions were washed with brine, dried (NaSO), filtered, and the solvent was evaporated under reduced pressure to give a crude residue, which was purified by preparative TLC (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 285.2 (calculated value: 285.2).

[0150] Step 4: 1-(2-cyclopropyl-1-phenylethyl)-1H-pyrazole-4-carboxylic acid: To a stirred solution of ethyl 1-(2-cyclopropyl-1-phenylethyl)-1H-pyrazole-4-carboxylate (80 mg, 0.28 mmol) in MeOH (1 mL) and water (0.2 mL) was added lithium hydroxide hydrate (59 mg, 1.41 mmol) and the reaction was heated to 40° C. for 2 h. The reaction was cooled to room temperature and concentrated to give a crude residue, which was suspended in water and acidified with 1 M HCl to pH=6. The mixture was extracted with EtOAc and the combined organic layers were concentrated to give the crude title compound, which was carried forward without further purification. LCMS [M+H] + = 257.1 (calculated value: 257.1).

[0151] Intermediate D5-a [ka]

[0152] 2-(cyclopropylmethyl)-2-(4-fluorophenyl)oxirane Step 1: 2-Cyclopropyl-N-methoxy-N-methylacetamide:To a mixture of 2-cyclopropylacetic acid (5.0 g, 49.9 mmol) in DCM (20.0 mL) was added CDI (9.00 g, 55.5 mmol) at room temperature under N. The mixture was stirred at room temperature for 1 h. N,O-dimethylhydroxylamine hydrochloride (5.50 g, 56.4 mmol) was then added. The mixture was stirred at room temperature for an additional 15 h. The reaction was quenched with 1 N HCl, and the aqueous layer was extracted with DCM. The combined organic layers were washed with 50% saturated aqueous NaCO and brine, dried over anhydrous NaSO, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 143.1 (calculated value: 144.1). 1 H NMR (400 MHz, CDCl3) δ 3.66 (d, J = 1.9 Hz, 3H), 3.19 (d, J = 1.9 Hz, 3H), 2.35 (br d, J = 6.9 Hz, 2H), 1.03-1.15 (m, 1H), 0.51-0.59 (m, 2H), 0.12-0.21 (m, 2H).

[0153] Step 2: 2-cyclopropyl-1-(4-fluorophenyl)ethenone: To a solution of 1-bromo-4-fluorobenzene (4.89 g, 27.9 mmol) in anhydrous THF (20 mL) was added dropwise a solution of n-BuLi (11.2 mL, 27.9 mmol, 2.5 M in hexane) at −78 °C under N. After stirring at −78 °C for 1 h, a solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (4.00 g, 27.9 mmol) in anhydrous THF (5 mL) was added dropwise. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction was quenched with saturated aqueous NH.sub.4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M + H] + = 178.2 (calculated value: 178.1).1 H NMR (400 MHz, CDCl3) δ 8.00-8.11 (m, 2H), 7.15-7.29 (m, 2H), 2.92 (d, J = 6.7 Hz, 2H), 1.03-1.19 (m, 1H), 0.49-0.62 (m, 2H), 0.10-0.26 (m, 2H).

[0154] Step 3: 2-(cyclopropylmethyl)-2-(4-fluorophenyl)oxirane: Trimethylsulfonium iodide (1.15 g, 5.61 mmol) was suspended in THF (15 mL). The mixture was cooled to 0 °C, and potassium tert-butoxide (630 mg, 5.61 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 15 minutes. 2-Cyclopropyl-1-(4-fluorophenyl)ethanone (500 mg, 2.81 mmol) was added, and the mixture was continued to stir at room temperature for 30 hours. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the title compound, which was used without further purification. LCMS [M+H] + = 192.2 (calculated value: 193.1).

[0155] Intermediate E3-a [ka]

[0156] Ethyl 1-(2-hydroxy-1-phenylethyl)-1H-pyrazole-4-carboxylate To a mixture of ethyl 1H-pyrazole-4-carboxylate (1.50 g, 10.7 mmol) in 2-phenyloxirane (1.29 g, 10.7 mmol) in a round-bottom flask was added yttrium(III) nitrate hydrate (0.031 mL, 0.214 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was directly purified by silica gel chromatography (EtOAc / petroleum ether) to afford the title compound. LCMS [M+H] += 261.1, (calculated value: 261.1). 1 H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.81-7.86 (m, 1H), 7.34-7.39 (m, 3H), 7.17-7.23 (m, 2H), 5.42 (dd, J = 8.4, 3.5 Hz, 1H), 4.45 (dd, J = 12.2, 8.2 Hz, 1H), 4.24-4.30 (m, 2H), 4.13-4.17 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H).

[0157] The following compounds were prepared using procedures similar to those described above using the appropriate starting materials. [Table 4]

[0158] Intermediate E4-a [ka]

[0159] Ethyl 1-((1S,2R)-2-methoxy-1-phenylpropyl)-1H-pyrazole-4-carboxylate To ethyl 1-((1S,2R)-2-hydroxy-1-phenylpropyl)-1H-pyrazole-4-carboxylate (79 mg, 0.29 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (11.5 mg, 0.288 mmol), and the resulting mixture was stirred at 0° C. for 15 minutes. Iodomethane (18 μL, 0.29 mmol) was added, and the reaction mixture was allowed to warm to room temperature for 4 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M+H] + = 289.1 (calculated value: 289.3). 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 22.3 Hz, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.46 - 7.30 (m, 2H), 5.13 (dd, J = 16.5, 7.2 Hz, 0H), 4.85 - 4.10 (m, 1H), 3.26 (d, J = 11.8 Hz, 2H), 1.35 (td, J = 7.1, 3.0 Hz, 2H), 1.12 (dd, J = 15.7, 6.2 Hz, 2H).

[0160] Intermediate E4-b [ka]

[0161] Ethyl 1-((1R,2S)-2-methoxy-1-phenylpropyl)-1H-pyrazole-4-carboxylate Intermediate E4-b was prepared using a procedure similar to that described for the preparation of intermediate E4-a above. LCMS [M+H] + = 289.1 (calculated value: 289.3).

[0162] Intermediate F5-a [ka]

[0163] 2-(4-Fluorobenzyl)-1H-imidazole-5-carboxylic acid Step 1: 2-(4-fluorophenyl)-N-hydroxyacetimidamide: To a mixture of 2-(4-fluorophenyl)acetonitrile (1.0 g, 7.4 mmol) in MeOH (10 mL) was added hydroxylamine hydrochloride (617 mg, 8.88 mmol) and DIEA (3.2 mL, 19 mmol), and the reaction mixture was heated to 60° C. and stirred overnight. The reaction was cooled to room temperature and concentrated to give a crude residue, which was purified by silica gel chromatography (MeOH / DCM) to give the title compound. LCMS [M+Na] + = 168.9 (calculated value: 169.1)

[0164] Step 2: Ethyl 2-(4-fluorobenzyl)-1H-imidazole-5-carboxylate: A solution of ethyl propiolate (660 μL, 6.54 mmol) and 2-(4-fluorophenyl)-N-hydroxyacetimidamide (1.00 g, 5.95 mmol) in EtOH was heated to 70° C. overnight. The reaction mixture was concentrated, at which point xylene was added, and the resulting mixture was heated to 200° C. for 30 minutes and concentrated to give a crude residue which was purified by silica gel chromatography (MeOH / DCM) to give the title compound. LCMS [M+H] + = 249.1 (calculated value: 249.3).

[0165] Step 3: 2-(4-fluorobenzyl)-1H-imidazole-5-carboxylic acid: The title compound was prepared following a procedure similar to that described in Intermediate C5-b, Step 4.

[0166] Intermediate G5-a [ka]

[0167] 2-(4-Fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylic acid Step 1: Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate: To a stirred solution of methyl 1H-imidazole-5-carboxylate (5.00 g, 39.6 mmol) and KCO (11.0 g, 79.0 mmol) in ACN (50 mL) was added SEM-Cl (8.4 mL, 48 mmol), and the resulting mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (NaSO), filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 257.1 (calculated value: 257.1).

[0168] Step 2: Methyl 2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate:To a solution of methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (3.50 g, 13.7 mmol) and TEA (2.3 mL, 16 mmol) in ACN (30 mL) was added 4-fluorobenzoyl chloride (1.94 mL, 16.4 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was concentrated to give a crude residue which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M-57] + = 321.0 (calculated value: 321.0).

[0169] Step 3: 2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylic acid: The title compound was prepared following a procedure similar to that described in Intermediate C5-b, Step 4. LCMS [M+H] + = 365.1 (calculated value: 365.1).

[0170] Intermediate H [ka]

[0171] (R)-2-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbaldehyde Step 1: Ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate: To a solution of ethyl 4-bromo-1H-imidazole-2-carboxylate (3.00 g, 13.7 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (657 mg, 16.4 mmol, 60% w / w dispersion in mineral spirits) over 30 min. (2-(Chloromethoxy)ethyl)trimethylsilane (3.43 g, 20.5 mmol) was added, and the resulting mixture was warmed to 30° C. for 10 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 349.1 (calculated value: 349.0).1 H NMR (CDCl3, 400MHz) δ 7.26 (s, 1H), 5.77 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.49-3.64 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 0.91-0.98 (m, 2H), 0.00 (s, 9H).

[0172] Step 2: Lithium 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate: The title compound was prepared following a procedure similar to that described in Intermediate C5-b, Step 4. LCMS (acid) [M + H] + = 321.0 (calculated value: 321.0).

[0173] Step 3: (R)-1′-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a solution of lithium 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (1.88 g, 5.73 mmol) and EDCI (2.20 g, 11.5 mmol) in pyridine (8 mL) in a round-bottom flask was added (R)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one (2.53 g, 6.88 mmol), and the reaction mixture was heated at 30° C. for 16 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with 1 M HCl and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 573.07 (calculated value 573.0).

[0174] Step 4: (R)-6-chloro-5-fluoro-1′-(1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:To a solution of (R)-1'-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (2.00 g, 3.48 mmol) in EtOH (20 mL) was added potassium vinyltrifluoroborate (607 mg, 4.53 mmol), Pd(dppf)Cl (510 mg, 6.97 mmol), and TEA (1.46 mL, 10.5 mmol), and the mixture was stirred at 90 °C for 6 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated, and the organic layer was concentrated to give the crude residue. It was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 521.2 (calculated value: 521.3).

[0175] Step 5: (R)-2-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidine]-1′-ylcarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbaldehyde: To a solution of (R)-6-chloro-5-fluoro-1'-(1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (1.30 g, 2.50 mmol) in acetone (5 mL) and water (5 mL) was added potassium osmate(VI) dihydrate (37 mg, 0.10 mmol), and the mixture was stirred at 0° C. for 10 minutes. Sodium periodate (2.14 g, 9.98 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was directly purified by silica gel chromatography (EtOAc / petroleum ether) to provide the title compound. LCMS [M+H] + = 523.2 (calculated value: 523.2).

[0176] Intermediate H4-a [ka]

[0177] Ethyl 4-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate Step 1: Ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate: To a solution of ethyl 4-bromo-1H-imidazole-2-carboxylate (1.00 g, 4.57 mmol) in DMF (8 mL) at 0° C. was added sodium hydride (219 mg, 5.48 mmol, 60 wt% dispersion in mineral spirits) in several portions. After 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (1.14 g, 6.85 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography (EtOAc / petroleum ether) to provide the title compound. LCMS [M+H] + = 348.9 / 350.9 (calculated values: 349.1, 351.1).

[0178] Step 2: Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole-2-carboxylate: To a solution of ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (1.10 g, 3.15 mmol) in EtOH (15 mL) was added potassium vinyltrifluoroborate (548 mg, 4.09 mmol), Pd(dppf)Cl (691 mg, 0.945 mmol), and TEA (1.3 mL, 9.5 mmol). The resulting mixture was heated to 90 °C for 12 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography (EtOAc / petroleum ether) to provide the title compound. LCMS [M+H] + = 297.2 (calculated value: 297.2).

[0179] Step 3: Ethyl 4-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate:To a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-1H-imidazole-2-carboxylate (600 mg, 2.02 mmol) in acetone (5 mL) and water (5 mL) was added potassium osmate(VI) dihydrate (32 mg, 0.086 mmol) at 0 °C. After 10 min, NaIO (864 mg, 4.04 mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with water and extracted with EtOAc. The combined organics were concentrated and purified by silica gel chromatography (EtOAc / petroleum ether) to provide the title compound. LCMS [M+H] + = 299.2 (calculated value: 299.1).

[0180] Intermediate I4-a [ka]

[0181] Methyl 2-(4-fluorophenyl)butanoate Step 1: 2-(4-fluorophenyl)butanoic acid: To a solution of 2-(4-fluorophenyl)acetic acid (1.00 g, 6.49 mmol) in THF (10 mL) was added LDA (7.10 mL, 14.3 mmol, 2 M THF solution) at −78° C. The resulting mixture was allowed to warm to room temperature over 30 minutes, at which point iodoethane (1.21 g, 7.79 mmol) was added in one portion and the reaction was stirred at room temperature for 4 hours. The reaction was concentrated and the crude residue was partitioned between EtOAc and water. The layers were separated and the aqueous layer was acidified by the addition of 1 M HCl and extracted with EtOAc. The combined organics were dried (NaSO) and concentrated to give the title compound, which was carried forward without further purification. 1H NMR (500 MHz, CD3OD) δ 7.31 - 7.35 (m, 2H), 7.03 - 7.07 (m, 2H), 3.59 (s, 1H), 2.00 - 2.02 (m, 1H), 1.69 - 1.78 (m, 1H), 0.89 (t, J = 7.4Hz, 3H).

[0182] Step 2: Methyl 2-(4-fluorophenyl)butanoate: To a stirred solution of 2-(4-fluorophenyl)butanoic acid (1.1 g, 6.0 mmol) in DCM (7.5 mL) and MeOH (1.5 mL) at 0 °C was added (diazomethyl)trimethylsilane (4.5 mL, 9.1 mmol, 2.0 M in toluene), and the resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by the addition of 5% aqueous AcOH, followed by neutralization by the addition of saturated aqueous NaHCO. The mixture was extracted with DCM, and the combined organic fractions were washed with brine, dried (NaSO), filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound.

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.27 - 7.29 (m, 1H), 7.24 - 7.27 (m, 1H), 6.97 - 7.03 (m, 2H), 4.12 (q, J = 7.3 Hz, 1H), 3.66 (s, 3H), 3.36 - 3.50 (m, 1H), 2.03 - 2.12 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).

[0184] Intermediate K4-a [ka]

[0185] Ethyl 5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate The title compound was prepared following a procedure similar to that described above for intermediate K5-a, steps 1-3. 1 H NMR (500MHz, CD3OD) δ 7.30 (dd, J = 8.5, 5.4 Hz, 2H), 6.99-7.10 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 1.39 (t, J= 7.2 Hz, 3H).

[0186] Intermediate K5-a [ka]

[0187] 5-(1-(4-fluorophenyl)propyl)-4H-1,2,4-triazole-3-carboxylic acid Step 1: 2-(4-fluorophenyl)butanehydrazide: To a stirred solution of methyl 2-(4-fluorophenyl)butanoate (300 mg, 1.53 mmol) in EtOH (3 mL) was added hydrazine hydrate (781 mg, 15.3 mmol) and the resulting mixture was heated to 80° C. for 12 h. The reaction was cooled to 0° C. and filtered to give the crude title compound, which was carried forward without further purification. LCMS [M+H] + = 197.1 (calculated value: 197.1).

[0188] Step 2: (Z)-ethyl 2-amino-2-(2-(2-(4-fluorophenyl)butanoyl)hydrazono)acetate: To a stirred solution of 2-(4-fluorophenyl)butanehydrazide (100 mg, 0.510 mmol) in EtOH was added ethyl 2-ethoxy-2-iminoacetate (148 mg, 1.02 mmol), and the resulting mixture was heated to 80° C. for 12 h. The reaction was cooled to room temperature and concentrated to give the title compound, which was carried forward without further purification. LCMS [M+H] + = 296.2 (calculated value: 296.1).

[0189] Step 3: Ethyl 5-(1-(4-fluorophenyl)propyl)-4H-1,2,4-triazole-3-carboxylate:To a stirred solution of (Z)-ethyl 2-amino-2-(2-(2-(4-fluorophenyl)butanoyl)hydrazono)acetate (110 mg, 0.372 mmol) in xylene (1.5 mL) was added 4 Å molecular sieves and the resulting mixture was heated to 150° C. for 24 h. The reaction was cooled to room temperature and concentrated to give a crude residue which was purified by preparative TLC (EtOAc / petroleum ether) to give the title compound.

[0190] 1 H NMR (500 MHz, CD3OD) δ 7.31 - 7.38 (m, 2H), 7.00 - 7.08 (m, 2H), 4.36 - 4.48 (m, 2H), 4.09 (br t, J = 7.9 Hz, 1H), 2.21 - 2.32 (m, 1H), 2.03 - 2.11 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 0.83 - 0.95 (m, 3H). LCMS [M+H] + = 278.2 (calculated value: 278.1).

[0191] Step 6: 5-(1-(4-fluorophenyl)propyl)-4H-1,2,4-triazole-3-carboxylic acid: The title compound was prepared following a procedure similar to that described above for Intermediate C5-b, Step 4. LCMS [M+H] + = 250.1 (calculated value: 250.1).

[0192] Intermediate L2-a [ka]

[0193] 5-(4-fluorobenzoyl)-4H-1,2,4-triazole-3-carboxylic acid Step 1: Ethyl 5-(4-fluorobenzoyl)-4H-1,2,4-triazole-3-carboxylate:To a stirred solution of ethyl 5-(4-fluorobenzyl)-4H-1,2,4-triazole-3-carboxylate (850 mg, 3.41 mmol) in DCM (15 mL) was added potassium permanganate (1.08 g, 6.82 mmol), and the mixture was stirred at room temperature. After 12 h, the reaction was diluted with 1 M HCl and extracted with EtOAc. The layers were separated, and the organic layer was concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 264.1 (calculated value: 264.1).

[0194] Step 2: 5-(4-fluorobenzoyl)-4H-1,2,4-triazole-3-carboxylic acid: The title compound was prepared following a procedure similar to that described above for Intermediate C5-b, Step 4. LCMS [M+H] + = 236.0 (calculated value: 236.0).

[0195] Intermediate L2-b [ka]

[0196] 5-Benzoyl-4H-1,2,4-triazole-3-carboxylic acid: The title compound was prepared following a procedure similar to that described above for intermediate L2-a. LCMS [M+H] + = 218.0 (calculated value: 218.1).

[0197] Intermediate M9-a [ka]

[0198] 3-(1-chloropropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carboxylic acid Step 1: tert-butyl 2-(2-ethoxy-1-imino-2-oxoethyl)hydrazine-1-carboxylate:The Boc-hydrazide (19.8 g, 150 mmol) was combined with ethyl 2-amino-2-thioxoacetate (20.0 g, 150 mmol) in EtOH (80 mL) and the mixture was stirred at room temperature. After 23 h, the reaction was filtered, and the filter cake was washed with EtOH and dried under reduced pressure to give the title compound. LCMS [M+H] + = 232.15 (calculated value: 232.3).

[0199] Step 2: Ethyl 5-((benzyloxy)methyl)-4H-1,2,4-triazole-3-carboxylate: A solution of tert-butyl 2-(2-ethoxy-1-imino-2-oxoethyl)hydrazine-1-carboxylate (45.0 g, 195 mmol) and benzyloxyacetyl chloride (9.3 mL, 59 mmol) in pyridine (100 mL) was heated to 105 °C. After 5 h, the reaction was cooled to room temperature, diluted with EtOAc, and acidified with 1 M HCl. The mixture was neutralized by the addition of saturated aqueous NaHCO3, and the layers were separated. The organic layer was dried (Na2SO4) and concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M+H] + = 262.0 (calculated value: 262.3).

[0200] Step 3: Ethyl 5-(hydroxymethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate:To a stirred solution of ethyl 5-((benzyloxy)methyl)-4H-1,2,4-triazole-3-carboxylate (12.1 g, 46.3 mmol) in THF (93 mL) maintained under a positive N pressure was added sodium hydride (2.04 g, 50.9 mmol, 60% w / w dispersion in mineral spirits) in several portions at 0 °C. After 15 min, SEM-Cl (9.9 mL, 56 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction was quenched by the addition of several portions of ice, at which point the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried (NaSO), filtered, and concentrated to give the crude product. The crude product was dissolved in EtOH (120 mL). The reaction vessel was evacuated and flushed with nitrogen three times. At that time, palladium hydroxide on carbon (51 g, 73 mmol) was added, and the mixture was degassed again as above, followed by one degassing cycle in which the reaction atmosphere was replaced with hydrogen. The reaction mixture was stirred under hydrogen (1 atm) at room temperature for 48 hours, at which point the reaction was filtered through Celite® and the filtrate was concentrated to give the crude title compound, which was carried forward without further purification. LCMS [M+H] + = 302.1 (calculated value: 302.4).

[0201] Step 4: Ethyl 5-(1-hydroxypropyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate:To a stirred solution of ethyl 5-(hydroxymethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate (1.86 g, 6.17 mmol) in DCM (19 mL) was added DMP (3.93 g, 9.26 mmol), and the mixture was stirred at room temperature. After 1.5 h, the reaction was quenched with saturated aqueous NaHCO and saturated aqueous NaSO. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO, dried (MgSO), and concentrated to give a crude residue, which was dissolved in toluene (19 mL) and cooled to 0 °C. Diethylzinc (15% in toluene, 7.2 mL, 8.02 mmol) was added dropwise, and the reaction was continued stirring at 0 °C. After 1 h, the reaction was quenched with saturated aqueous NH4Cl, warmed to room temperature, diluted with water and EtOAc, and stirred at room temperature overnight. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M+H] + = 330.2 (calculated value: 330.5).

[0202] Step 5: Ethyl 5-(1-chloropropyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate: To a stirred solution of ethyl 5-(1-hydroxypropyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate (4.00 g, 12.1 mmol) and carbon tetrachloride (18.7 g, 121 mmol) in DCM (40 mL) at room temperature was added triphenylphosphine (3.50 g, 13.4 mmol). After 4 h, the reaction was concentrated to give a crude residue which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M+H] + 348.2 (calculated value: 348.2).

[0203] Step 6: 3-(1-chloropropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carboxylic acid:The title compound was prepared following a procedure similar to that described above for Intermediate C5-b, Step 4. [M-CO2+H] + = 276.2 (calculated value: 276.1)

[0204] Intermediate Ma [ka]

[0205] 3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carboxylic acid The title compound was prepared from ethyl 3-bromo-1H-1,2,4-triazole-5-carboxylate following procedures similar to those described above for Intermediate M9-a, Step 3 and Intermediate C5-b, Step 4. LCMS [M+H] + = 322.2 (calculated value: 322.0).

[0206] Intermediate O5-a [ka]

[0207] 4-benzyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylic acid Step 1: (Z)-ethyl 4-((2-((4-methoxyphenyl)sulfonyl)hydrazono)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate: To a solution of intermediate H4-a (400 mg, 1.340 mmol) in MeOH (6 mL) was added 4-methoxybenzenesulfonyl hydrazide (271 mg, 1.34 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated to give the crude title compound, which was carried forward without purification. LCMS [M+H] + = 483.1 (calculated value: 483.2).

[0208] Step 5: Ethyl 4-benzyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate:To a stirred mixture of (Z)-ethyl 4-((2-((4-methoxyphenyl)sulfonyl)hydrazono)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (250 mg, 0.518 mmol) and phenylboronic acid (95 mg, 0.78 mmol) in dioxane (5 mL) was added potassium carbonate (107 mg, 0.777 mmol). The reaction mixture was heated to 100° C. and stirred at 100° C. for 12 h. The mixture was cooled to room temperature and diluted with water and EtOAc. The combined organic layers were concentrated and purified by preparative TLC (EtOAc:petroleum ether) to provide the title compound. LCMS [M+H] + = 361.3 (calculated value: 361.2).

[0209] Step 6: 4-benzyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylic acid: The title compound was prepared following a procedure similar to that described in Intermediate C5-b, Step 4. LCMS [M+H] + = 333.2 (calculated value: 333.2).

[0210] Intermediate P3-a [ka]

[0211] 2-(((1-methoxycyclopropyl)methyl)sulfonyl)benzo[d]thiazole Step 1: 2-(((1-methoxycyclopropyl)methyl)thio)benzo[d]thiazole: To a solution of (1-methoxycyclopropyl)methanol (300 mg, 2.94 mmol), benzo[d]thiazole-2-thiol (590 mg, 3.52 mmol), and triphenylphosphine (925 mg, 3.52 mmol) in THF (5 mL) at 0° C. was added DEAD (930 μL, 5.87 mmol). The mixture was stirred at 0° C. for 2 h, at which time the reaction was diluted with water and extracted with EtOAc. The combined organic layers were concentrated and purified by preparative TLC (EtOAc / petroleum ether) to provide the title compound. LCMS [M+H] + = 252.0 (calculated value: 252.0).

[0212] Step 2: 2-(((1-methoxycyclopropyl)methyl)sulfonyl)benzo[d]thiazole: To a solution of 2-(((1-methoxycyclopropyl)methyl)thio)benzo[d]thiazole (350 mg, 1.39 mmol) in EtOH (5 mL) was added ammonium molybdate tetrahydrate (172 mg, 0.139 mmol) and HO (5.7 mL, 56 mmol, 30% v / v aqueous solution). The resulting mixture was stirred at room temperature. The reaction was concentrated and the crude residue was purified by preparative TLC (EtOAc / petroleum ether) to afford the title compound. LCMS [M+H] + = 284.0 (calculated value: 284.0).

[0213] Intermediate Q4-a [ka]

[0214] 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)pyrrolidine-3-carboxylic acid Step 1: Methyl pyrrolidine-3-carboxylate hydrochloride: To a mixture of pyridin-2(1H)-one (721 mg, 7.58 mmol) and TBAI (280 mg, 0.758 mmol) in THF (30 mL) was added NaH (303 mg, 7.58 mmol, 60% w / w dispersion in mineral spirits) at 0 °C. The resulting mixture was stirred at room temperature for 30 min, at which point 1,4-bis(bromomethyl)benzene (2.00 g, 7.58 mmol) was added. After 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M+H] + = 278.0, (calculated value: 278.0). 1H NMR (400 MHz, CDCl3): δ 7.42 -7.20 (m, 6H), 6.67-6.59 (m, 1H), 6.21 - 6.13 (m, 1H), 5.15 (s, 2H), 4.48 (s, 2H).

[0215] Step 2: Methyl 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)pyrrolidine-3-carboxylate: To a mixture of methyl pyrrolidine-3-carboxylate hydrochloride (119 mg, 0.719 mmol) in DMF (2 mL) was added NaH (60 mg, 1.51 mmol, 60 wt% dispersion in mineral spirits) at 0 °C. The mixture was allowed to warm to room temperature with stirring for 30 min, at which point a solution of 1-(4-(bromomethyl)benzyl)pyridin-2(1H)-one (200 mg, 0.719 mmol) in DMF (0.2 mL) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to provide the crude title compound. LCMS [M+H] + 327.3 (calculated value: 327.16).

[0216] Step 3: 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)pyrrolidine-3-carboxylic acid: To a mixture of methyl 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)pyrrolidine-3-carboxylate (300 mg, 0.643 mmol) in DMF (1 mL) was added lithium hydroxide hydrate (135 mg, 3.22 mmol) in water (0.2 mL), and the resulting mixture was stirred at room temperature for 2 h. The reaction was acidified with 1 M HCl to pH 5 and purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide the title compound.

[0217] LCMS [M+H] += 313.2, (calculated value. 313.2). 1H-NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 7.86 - 7.79 (m, 1H), 7.53 - 7.41 (m, 3H), 7.37 (d, J = 7.9 Hz, 2H), 6.44 (d, J = 9.1 Hz, 1H), 6.31 - 6.23 (m, 1H), 5.14 (s, 2H), 4.36 (d, J = 12.3 Hz, 2H), 3.41 (s, 2H), 3.18 (s, 2H), 2.72-2.55 (m, 1H), 2.40 - 1.94 (m, 2H).

[0218] The following compounds were prepared using procedures similar to those described above using the appropriate starting materials. [Table 5]

[0219] Intermediate S2-a [ka]

[0220] Potassium (R)-((4-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-ylcarbonyl)-1H-pyrazol-1-yl)methyl)trifluoroborate Step 1: (R)-6-chloro-5-fluoro-1'-(1H-pyrazole-4-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a stirred solution of intermediate A6-d (500 mg, 1.628 mmol), 1H-pyrazole-4-carboxylic acid (192 mg, 1.71 mmol), and DIEA (0.85 mL, 4.9 mmol) in DMF (16 mL) was added HATU (743 mg, 1.95 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO), filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography ((30% EtOH:EtOAc) / hexanes) to provide the title compound. LCMS [M+H] + = 364.9 (calculated value: 365.1).

[0221] Step 2: Potassium (R)-((4-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidine]-1′-ylcarbonyl)-1H-pyrazol-1-yl)methyl)trifluoroborate: To a solution of (R)-6-chloro-5-fluoro-1'-(1H-pyrazole-4-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (30 mg, 0.082 mmol) in THF (2 mL) was added potassium (bromomethyl)trifluoroborate (17 mg, 0.082 mmol) and KHMDS (16 mg, 0.082 mmol), and the resulting mixture was heated to 60 °C. After 2 h, the reaction was cooled to room temperature, quenched by the addition of MeOH, and concentrated to give a crude residue, which was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound.

[0222] LCMS [M-39] + = 445.1 (calculated value: 445.1) 1 H NMR (500 MHz, DMSO- d6) δ 10.58 (br s, 1H), 7.76 (br s, 1H), 7.49-7.58 (m, 1H), 6.87-7.24 (m, 1H), 6.73 (br d, J = 8.6 Hz, 1H), 4.17-4.84 (m, 2H), 3.67-3.84 (m, 1H), 3.15-3.32 (m, 1H), 3.02 (br s, 2H), 2.24-2.35 (m, 1H), 2.19 (br s, 1H), 1.85 (br s, 1H), 1.61 (br d, J = 11.5 Hz, 1H).

[0223] Example Example 1 and Example 2 [ka]

[0224] (R)-6-chloro-1'-(1-((S)-2-cyclopropyl-1-phenylethyl)-1H-pyrazole-4-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one and (R)-6-chloro-1'-(1-((R)-2-cyclopropyl-1-phenylethyl)-1H-pyrazole-4-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one To a stirred mixture of intermediate C5-b (60 mg, 0.23 mmol), intermediate A6-d (104 mg, 0.280 mmol), and HATU (134 mg, 0.351 mmol) in DCM (1 mL), TEA (65 μL, 0.47 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction was filtered, and the filtrate was concentrated to give a crude residue. It was purified by preparative reverse-phase HPLC (ACN / water + 0.05% TFA) to give the title compound as a mixture of diastereomers. The title compound was separated by SFC (Instrument SFC-17 Method Column DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); Conditions 0.1% NH₃H₂O EtOH Start B 15%; End B 15% Gradient Time (min); 100% B).

[0225] The faster eluting isomer of the title compound was obtained (Example 1): 1 H NMR (CD3OD, 500 MHz) δ 7.90-8.42 (m, 1H), 7.58-7.87 (m, 1H), 7.12-7.50 (m, 6H), 6.73 (br d, J = 12.1 Hz, 1H), 5.34-5.63 (m, 1H), 4.53-4.77 (m, 1H), 4.30 (br s, 1H), 2.94 (br s, 1H), 2.23-2.68 (m, 3H), 1.93-2.21 (m, 2H), 1.73 (br d, J = 11.7 Hz, 1H), 1.22-1.42 (m, 1H), 0.55 (br s, 1H), 0.39 (br s, 2H), 0.09 (br s, 2H). LCMS [M+H] + = 509.1 (calculated value: 509.2). The slower eluting isomer of the title compound was obtained (Example 2): 1H NMR (CD3OD, 500 MHz) δ 7.81-8.23 (m, 1H), 7.49-7.79 (m, 1H), 7.03-7.40 (m, 6H), 6.60 (br s, 1H), 5.19-5.62 (m, 1H), 4.51 (s, 1H), 4.22 (br s, 1H), 2.85 (br s, 1H), 2.13-2.54 (m, 3H), 1.82-2.11 (m, 2H), 1.63 (br d, J = 12.1 Hz, 1H), 1.06-1.32 (m, 1H), 0.11-0.55 (m, 3H), 0.00 (br s, 2H). LCMS [M+H] + = 509.1 (calculated value: 509.2).

[0226] Following procedures similar to those described above for Examples 1 and 2, using the appropriate starting materials, the following compounds were prepared. [Table 6]

[0227] TIFF0007794991000078.tif213170

[0228] TIFF0007794991000079.tif217170

[0229] TIFF0007794991000080.tif211170

[0230] TIFF0007794991000081.tif219170

[0231] TIFF0007794991000082.tif218170

[0232] TIFF0007794991000083.tif209170

[0233] TIFF0007794991000084.tif219170

[0234] TIFF0007794991000085.tif31170

[0235] Example 47 [ka]

[0236] (R)-2-chloro-4-((4-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-carbonyl)-1H-pyrazol-1-yl)methyl)benzonitrile To a stirred solution of intermediate S2-a (13 mg, 0.028 mmol) in dioxane (0.3 mL) and water (0.1 mL) was added 4-bromo-2-chlorobenzonitrile (5.0 mg, 0.023 mmol), CsCO (30 mg, 0.092 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3 mg, 0.003 mmol). The resulting mixture was degassed with a stream of N, the reaction vessel was sealed, and the reaction mixture was heated to 90 °C and stirred overnight. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO), and concentrated under reduced pressure to give the crude residue, which was purified by preparative TLC (MeOH / DCM) to give the title compound.

[0237] 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.33 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 5.33 (s, 2H), 4.80 (s, 1H), 4.37 (bs, 1H), 3.25 (s, 1H), 2.46 (s, 1H), 2.39 (s, 1H), 2.34 (d, J = 12.0 Hz, 1H), 1.72 (m, 1H), 1.24 (s, 1H). LCMS [M+H] + = 514.0 (calculated value: 514.1).

[0238] Following procedures similar to those described above for Example 47, using the appropriate starting materials, the following compounds were prepared: [Table 7]

[0239] TIFF0007794991000088.tif237164

[0240] TIFF0007794991000089.tif236164

[0241] TIFF0007794991000090.tif178164

[0242] Example 65 [ka]

[0243] (R)-1'-(4-benzyl-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (R)-1′-(4-benzyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:To a solution of intermediate O5-a (74 mg, 0.22 mmol) and EDC (84 mg, 0.44 mmol) in pyridine (4 mL) at 0 °C, intermediate A6-d (105 mg, 0.284 mmol) was added. The resulting mixture was warmed to 30 °C and stirred for 16 h. The reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1 M HCl and concentrated to give a crude residue, which was purified by preparative TLC (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 585.4 (calculated value: 585.2).

[0244] Step 2: (R)-1'-(4-benzyl-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a solution of (R)-1'-(4-benzyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (90 mg, 0.154 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 11 hours, at which time the mixture was concentrated to give a crude residue which was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound.

[0245] 1 H NMR (400 MHz, CD3OD) δ 7.11-7.59 (m, 7H), 6.63-6.88 (m, 1H), 4.47-4.70 (m, 1H), 3.87-4.33 (m, 3H), 3.47 (br d, J = 12.8 Hz, 1H), 2.97-3.27 (m, 0.5H), 2.57 (br s, 0.5H), 2.32 (br s, 2H), 2.01-2.22 (m, 1H), 1.77 (br d, J = 13.4 Hz, 1H). LCMS [M + H] + = 455.2 (calculated value: 455.1).

[0246] Following procedures similar to those described above for Example 65, using the appropriate starting materials, the following compounds were prepared: [Table 8]

[0247] TIFF0007794991000093.tif33170

[0248] Example 75 [ka]

[0249] (R)-6-chloro-5-fluoro-1'-(4-((R or S)-2-(1-methoxycyclopropyl)-1-phenylethyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (3'R)-6-chloro-5-fluoro-1'-(4-(hydroxy(phenyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: (R)-2-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidine]-1′-ylcarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbaldehyde. To a stirred solution of Intermediate H (580 mg, 1.11 mmol) in THF (8.0 mL) was added phenylmagnesium bromide (3.0 M in THF, 0.74 mL, 2.218 mmol) at −15° C. The reaction was allowed to warm to 0° C. and stirred for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated to give the crude residue. It was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 601.3 (calculated value: 601.2).

[0250] Step 2: (R)-1′-(4-benzoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:To a stirred solution of (3'R)-6-chloro-5-fluoro-1'-(4-(hydroxy(phenyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (520 mg, 0.865 mmol) in DCM (3.0 mL) was added manganese(IV) oxide (376 mg, 4.33 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered and concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 599.1 (calculated value: 599.2).

[0251] Step 3: (R,Z)-6-chloro-5-fluoro-1′-(4-(2-(1-methoxycyclopropyl)-1-phenylvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a solution of (R)-1'-(4-benzoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (160 mg, 0.267 mmol) and 2-(((1-methoxycyclopropyl)methyl)sulfonyl)benzo[d]thiazole (91 mg, 0.320 mmol) in THF (4 mL) in a glovebox, LHMDS (1.07 mL, 1.07 mmol, 1.0 M in THF) was added, and the mixture was sealed and stirred at room temperature for 16 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and water, and the mixture was extracted with EtOAc. The combined organic extracts were concentrated to give a crude residue. It was purified by preparative TLC (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 667.1 (calculated value: 667.2).

[0252] Step 4: (4R)-6-chloro-5-fluoro-1′-(4-(2-(1-methoxycyclopropyl)-1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:To a solution of (R,Z)-6-chloro-5-fluoro-1'-(4-(2-(1-methoxycyclopropyl)-1-phenylvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (10 mg, 0.015 mmol) in THF (4 mL) was added Raney Ni (0.4 mg, 0.007 mmol). The resulting mixture was stirred under H (balloon) at room temperature for 16 h. The reaction mixture was filtered and concentrated to give the crude title compound, which was carried forward without purification. LCMS [M+H] + = 635.2 (calculated value: 635.3).

[0253] Step 5: (3'R)-5-fluoro-1'-(4-(2-(1-methoxycyclopropyl)-1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a solution of (4R)-6-chloro-5-fluoro-1'-(4-(2-(1-methoxycyclopropyl)-1-phenylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (10 mg, 0.015 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.3 mL) at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 10 hours. The reaction was concentrated and purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to afford the title compound as a stereochemical mixture. LCMS [M+H] + = 539.2 (calculated value: 539.2).

[0254] The title compound was resolved by SFC (Method Column DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); Mobile phase A: water (0.1% NH 3 H 2 O), Mobile phase B: EtOH; Gradient: 25% B → 25% B).

[0255] The faster eluting isomer of the title compound was obtained (Example 75): 1H NMR (400 MHz, CD3OD) δ 7.40-7.51 (m, 1H), 7.14-7.40 (m, 3H), 7.05 (br s, 1H), 6.83-7.00 (m, 1H), 6.75 (br t, J = 9.3 Hz, 1H), 6.20 (br d, J = 13.7 Hz, 1H), 4.51-4.78 (m, 1H), 4.12-4.44 (m, 1H), 3.60-3.90 (m, 1H), 3.12-3.30 (m, 3H), 2.94 (br t, J = 12.7 Hz, 1H), 1.89-2.80 (m, 6H), 1.55-1.79 (m, 1H), 0.90 (br t, J = 6.6 Hz, 1H), 0.35-0.66 (m, 1H), -0.09-0.31 (m, 1H). LCMS [M + H] + = 539.2 (calculated value: 539.2).

[0256] Example 76 [ka] (R)-6-chloro-5-fluoro-1'-(2-(4-fluorobenzyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: The title compound was prepared following a procedure similar to that described in Example 1.

[0257] LCMS [M+H] + = 473.0 (calculated value: 473.1). 1 H NMR (600MHz, CDCl3) δ 1H NMR (600 MHz, CDCl3) δ 9.85 - 9.42 (br m, 1H), 8.18 (s, 1H), 7.43 (s, 1H), 7.29 (m, 3H), 7.15 (m, 1H), 6.89 (m, 1H), 6.76 - 6.54 (m, 1H), 5.06 (br m, 1H), 4.93 - 4.69 (m, 1H), 4.01 (br m, 1H), 2.65 - 2.42 (m, 1H), 2.41 - 2.10 (m, 2H), 1.80 - 1.61 (m, 1H), 1.40 - 1.21 (m, 2H).

[0258] Examples 77 and 78 [ka]

[0259] (R)-6-chloro-5-fluoro-1'-(2-((S)-(4-fluorophenyl)(hydroxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one and (R)-6-chloro-5-fluoro-1'-(2-((R)-(4-fluorophenyl)(hydroxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one Step 1: (R)-6-chloro-5-fluoro-1′-(2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: The title compound was prepared following a procedure similar to that described in Example 1. LCMS [M+H] + = 617.2 (calculated value: 617.2).

[0260] Step 2: (3'R)-6-chloro-5-fluoro-1'-(2-((4-fluorophenyl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a stirring mixture of (R)-6-chloro-5-fluoro-1'-(2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (1.00 g, 1.62 mmol) in THF (10 mL) was added sodium borohydride (61 mg, 1.6 mmol) at 0° C., and the resulting mixture was continued to stir at 0° C. for 12 h. The reaction was concentrated, and the crude residue was purified by silica gel chromatography (EtOAc / petroleum ether) to afford the title compound. LCMS [M+H] + = 619.2 (calculated value: 619.2).

[0261] Step 3: (3'R)-6-chloro-5-fluoro-1'-(2-((4-fluorophenyl)(hydroxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: The title compound was prepared as a stereochemical mixture following a procedure similar to that described above in Example 75, Step 5.

[0262] The title compound was resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); flow rate: 60 mL / min; gradient 45% B → 45% B).

[0263] The faster eluting isomer of the title compound was obtained (Example 77): 1 H NMR (400MHz, CD3OD) δ 8.30-8.60 (m, 2H), 8.18 (br s, 1H), 7.93 (s, 1H), 7.66 (br d, J = 8.3 Hz, 1H), 7.60 (br s, 1H), 7.44-7.44 (m, 1H), 7.41 (br d, J = 8.3 Hz, 1H), 5.26 (s, 2H), 4.47-4.65 (m, 2H), 4.30-4.45 (m, 1H), 4.02-4.22 (m, 1H), 3.62-3.98 (m, 3H), 3.34-3.62 (m, 4H), 3.04-3.28 (m, 1H), 2.91 (br d, J = 7.6 Hz, 2H), 2.32-2.52 (m, 1H), 2.19-2.30 (m, 2H), 1.82-2.18 (m, 5H), 1.34 (br d, J = 6.8 Hz, 2H), 1.19-1.31 (m, 1H).LCMS [M + H] + = 489.1 (calculated value: 489.1) The slower eluting isomer of the title compound was obtained (Example 78): 1H NMR (400MHz, CD3OD) δ 8.30-8.60 (m, 2H), 8.18 (br s, 1H), 7.93 (s, 1H), 7.66 (br d, J = 8.3 Hz, 1H), 7.60 (br s, 1H), 7.44-7.44 (m, 1H), 7.41 (br d, J = 8.3 Hz, 1H), 5.26 (s, 2H), 4.47-4.65 (m, 2H), 4.30-4.45 (m, 1H), 4.02-4.22 (m, 1H), 3.62-3.98 (m, 3H), 3.34-3.62 (m, 4H), 3.04-3.28 (m, 1H), 2.91 (br d, J = 7.6 Hz, 2H), 2.32-2.52 (m, 1H), 2.19-2.30 (m, 2H), 1.82-2.18 (m, 5H), 1.34 (br d, J = 6.8 Hz, 2H), 1.19-1.31 (m, 1H).LCMS [M + H] + = 489.1 (calculated value: 489.1).

[0264] Examples 79 and 80 [ka]

[0265] (R)-6-chloro-5-fluoro-1'-(2-((S)-1-(4-fluorophenyl)propyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one and (R)-6-chloro-5-fluoro-1'-(2-((R)-1-(4-fluorophenyl)propyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one Step 1: (R)-6-chloro-5-fluoro-1′-(2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: The title compound was prepared following a procedure similar to that described in Example 1. [M + H] + , 617.2, (calculated value: 617.2).

[0266] Step 2: (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)-1-hydroxypropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one:To a solution of (R)-6-chloro-5-fluoro-1'-(2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (500 mg, 0.810 mmol) in THF (6 mL) was added ethylmagnesium bromide (0.324 mL, 0.972 mmol, 3 M THF solution), and the mixture was stirred at room temperature. After 1 h, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 647.2, (calculated value: 647.2).

[0267] Step 3: (R,E)-6-chloro-5-fluoro-1′-(2-(1-(4-fluorophenyl)prop-1-en-1-yl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a stirred solution of (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)-1-hydroxypropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (120 mg, 0.185 mmol) and triethylsilane (0.15 mL, 0.93 mmol) in CHCl3 (3 mL) at room temperature was added BF3.OEt2 (0.14 mL, 1.1 mmol), and the resulting mixture was heated to 50 °C for 12 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were concentrated to give the crude title compound, which was carried forward without further purification. LCMS [M+H] + = 499.1, (calculated value: 499.1).

[0268] Step 4: (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)propyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one:To a stirred solution of (R,E)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)prop-1-en-1-yl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (80 mg, 0.16 mmol) in THF (5 mL) at room temperature was added Raney Ni (0.94 mg, 0.016 mmol). The resulting mixture was stirred at room temperature for 1 hour, at which time the reaction was filtered through a pad of Celite® and concentrated to give a crude residue which was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound as a stereochemical mixture.

[0269] LCMS [M+H] + = 501.2 (calculated value: 501.14). The title compound was resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); flow rate: 60 mL / min; gradient 60% B → 60% B).

[0270] The faster eluting isomer of the title compound was obtained (Example 79): 1 H NMR (400 MHz, CD3OD) δ 7.34-7.63 (m, 4H), 6.98 (br s, 2H), 6.71 (br s, 1H), 5.79 (br s, 1H), 5.50 (br s, 0.5H), 4.70 (br s, 0.5H), 3.75 (br s, 0.5H), 2.93 (br s, 0.5H), 2.41-2.59 (m, 1H), 2.27 (br d, J = 13.2 Hz, 1H), 1.91-2.37 (m, 1H), 1.73 (br s, 1H), 1.20-1.41 (m, 1H).LCMS [M+H] + = 501.2 (calculated value: 501.1)

[0271] The slower eluting isomer of the title compound was obtained (Example 80): 1H NMR (400 MHz, CD3OD,) δ 7.66-8.04 (m, 1H), 7.22-7.57 (m, 3H), 7.10 (br s, 2H), 6.70 (br s, 1H), 4.63 (br s, 0.5H), 4.50 (br d, J = 8.1 Hz, 0.5H), 4.26 (br s, 0.5H), 4.07 (br s, 1H), 3.34-3.56 (m, 1H), 3.00 (br d, J = 18.1 Hz, 0.5H), 2.02-2.63 (m, 5H), 1.74 (br d, J = 12.5 Hz, 1H), 0.93 (br s, 3H). LCMS [M+H] + = 501.2 (calculated value: 501.1).

[0272] Example 81 [ka]

[0273] (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)-1-hydroxypentyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)-1-hydroxypentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a stirred solution of (R)-6-chloro-5-fluoro-1'-(2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (11 μL, 0.032 mmol) in THF (2 mL) at −78° C. was added n-butyllithium (0.016 mL, 0.039 mmol, 2.5 M in hexanes). After 10 min, the reaction was allowed to warm to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the combined organics were concentrated to give the crude title compound, which was carried forward without further purification. LCMS [M+H] + = 675.3 (calculated value: 675.3).

[0274] Step 2: (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)-1-hydroxypentyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a solution of (3'R)-6-chloro-5-fluoro-1'-(2-(1-(4-fluorophenyl)-1-hydroxypentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (21 mg, 0.031 mmol) in DCM (2 mL) was added TFA (0.2 mL) and the resulting mixture was stirred at room temperature. After 12 h, the reaction was concentrated to give a crude residue which was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound.

[0275] 1 H NMR (400 MHz, CD3OD) δ 7.67-8.04 (m, 1H), 7.35-8.00 (m, 3H), 7.12 (br dd, J = 17.4, 8.6 Hz, 2H), 6.59-6.90 (m, 1H), 4.48-4.75 (m, 1H), 4.31 (br s, 0.5H), 4.10 (br s, 0.5H), 3.37-3.59 (m, 1H), 3.37-3.59 (m, 1H), 3.34-3.57 (m, 1H), 3.03 (br s, 0.5H), 2.59 (br s, 0.5H), 2.21-2.49 (m, 4H), 2.01-2.20 (m, 1H), 1.69-1.84 (m, 1H), 1.08-1.51 (m, 4H), 0.76-0.98 (m, 3H). LCMS [M+H] + = 545.2 (calculated value: 545.2).

[0276] Example 82 and Example 83 [ka] (R)-6-chloro-5-fluoro-1'-(2-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one and (R)-6-chloro-5-fluoro-1'-(2-((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one Step 1: (3'R)-6-chloro-5-fluoro-1'-(2-(2,2,2-trifluoro-1-(4-fluorophenyl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a solution of (R)-6-chloro-5-fluoro-1'-(2-(4-fluorobenzoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (700 mg, 1.13 mmol) in THF (10 mL) were added trimethyl(trifluoromethyl)silane (194 mg, 1.36 mmol) and CsF (258 mg, 1.70 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / petroleum ether) to give the title compound. LCMS [M -58] + = 629.2 (calculated value: 687.2).

[0277] Step 2: (3'R)-6-chloro-1'-(2-(1-chloro-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole-5-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a solution of (3'R)-6-chloro-5-fluoro-1'-(2-(2,2,2-trifluoro-1-(4-fluorophenyl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (180 mg, 0.262 mmol) in DCM (5 mL) was added SOCl (0.50 mL, 6.9 mmol) and the mixture was stirred at room temperature for 12 h. The reaction was concentrated to give the crude product, which was carried forward without further purification. LCMS [M+H] + = 575.1 (calculated value: 575.1).

[0278] Step 3: (3'R)-6-chloro-5-fluoro-1'-(2-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a solution of (3'R)-6-chloro-1'-(2-(1-chloro-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole-5-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (15 mg, 0.026 mmol) in THF (1 mL) was added LiAlH (1.5 mg, 0.039 mmol) at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was concentrated to give a crude residue, which was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound as a stereochemical mixture. LCMS [M+H] + = 541.1, (calculated value: 541.1)

[0279] The title compound was resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); flow rate: 60 mL / min; gradient 50% B → 50% B).

[0280] The faster eluting isomer was obtained (Example 82): LCMS [M+H] + = 541.1, (calculated value: 541.1). 1 H NMR (400MHz, CD3OD) δ 7.34-7.78 (m, 4H), 6.86-7.21 (m, 2H), 6.51-6.83 (m, 1H), 6.11 (br d, J = 13.2 Hz, 0.5H), 5.26-5.54 (m, 0.5H), 4.99 (br s, 1H), 4.76 (br d, J = 10.3 Hz, 1H), 3.72 (br d, J = 14.2 Hz, 0.5H), 2.93 (br s, 0.5H), 2.45-2.60 (m, 1H), 1.87-2.40 (m, 3H), 1.74 (br d, J = 12.2 Hz, 1H).

[0281] The slower eluting isomer of the title compound was obtained (Example 83): LCMS [M + H] + = 541.1, (calculated value: 541.1). 1 H NMR (400 MHz, CD3OD) δ 7.36-7.76 (m, 4H), 6.94-7.25 (m, 2H), 6.74 (br s, 1H), 5.71 (br d, J = 2.9 Hz, 0.5H), 5.12 (br s, 2H), 4.74 (br s, 0.5H), 3.76 (br s, 0.5H), 3.33-3.44 (m, 1H), 2.97 (br d, J = 16.9 Hz, 0.5H), 2.54 (br s, 1H), 2.16-2.37 (m, 2H), 1.75 (br d, J = 14.4 Hz, 1H).

[0282] Example 84 and Example 85 [ka]

[0283] (R)-6-chloro-5-fluoro-1'-(5-((S)-1-(4-fluorophenyl)propyl)-4H-1,2,4-triazole-3-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one and (R)-6-chloro-5-fluoro-1'-(5-((R)-1-(4-fluorophenyl)propyl)-4H-1,2,4-triazole-3-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one Step 1: (3'R)-6-chloro-5-fluoro-1'-(5-(1-(4-fluorophenyl)propyl)-4H-1,2,4-triazole-3-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: The title compound was prepared as a mixture following a procedure similar to that described in Example 1. LCMS [M+H] + = 502.4 (calculated value: 502.1)

[0284] The title compound was resolved by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm) (conditions: mobile phase A: CO2, mobile phase B: 0.1% NH3H2O ​​EtOH, starting 20% ​​B, ending 20% ​​B gradient time: min), retention time: 100% B, flow rate: (L / min)).

[0285] The faster eluting isomer of the title compound was obtained (Example 84): 1H NMR (500 MHz, CD3OD) δ 7.41 - 7.49 (m, 1H), 7.37 (dd, J = 8.6, 5.4 Hz, 1H), 7.30 (br s, 1H), 7.05 (br s, 1H), 6.94 (br s, 1H), 6.64 - 6.79 (m, 1H), 4.90 (br s, 2H), 3.95 - 4.14 (m, 1H), 3.77 (br d, J = 14.8 Hz, 1H), 3.33 - 3.46 (m, 1H), 2.99 (br t, J = 12.7 Hz, 1H), 2.47 - 2.60 (m, 1H), 2.10 - 2.36 (m, 3H), 1.85 - 2.09 (m, 1H), 1.78 (br d, J = 14.3 Hz, 1H), 1.19 - 1.44 (m, 2H), 0.78 - 0.97 (m, 3H). LCMS [M+H] + = 502.2 (calculated value. 502.1).

[0286] The title compound was dissolved and the opposite body was obtained (Example 85): 1 H NMR (500 MHz, CD3OD) δ 7.45 (br t, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.5, 5.5 Hz, 1H), 7.29 (br d, J = 5.3 Hz, 1H), 7.06 (br d, J = 7.8 Hz, 1H), 6.92 (br s, 1H), 6.75 (br dd, J = 18.0, 8.5 Hz, 1H), 4.91 - 5.05 (m, 1H), 4.74 - 4.86 (m, 1H), 3.96 - 4.12 (m, 1H), 3.39 - 3.79 (m, 1H), 2.99 (br t, J = 11.9 Hz, 1H), 2.53 (br d, J = 13.7 Hz, 1H), 2.11 - 2.35 (m, 3H), 1.93 - 2.10 (m, 1H), 1.68 - 1.82 (m, 1H), 0.79 - 0.95 (m, 3H). LCMS [M+H] + = 502.2 (calculated value. 502.1).

[0287] Following procedures similar to those described above for Example 84 and Example 85, using the appropriate starting materials, the following compounds were prepared. [Table 9]

[0288] TIFF0007794991000102.tif232170

[0289] TIFF0007794991000103.tif229170

[0290] TIFF0007794991000104.tif233170

[0291] TIFF0007794991000105.tif113169

[0292] Examples 109 and 110 [ka]

[0293] (R)-6-chloro-5-fluoro-1'-(3-((S)-1-(4-methyl-1H-benzo[d]imidazol-6-yl)propyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one and (R)-6-chloro-5-fluoro-1'-(3-((R)-1-(4-methyl-1H-benzo[d]imidazol-6-yl)propyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidine]-2(1H)-one Step 1: (R)-6-chloro-1′-(3-((S)-1-chloropropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a stirred solution of intermediate M9-a (468 mg, 1.437 mmol), intermediate A6-d (419 mg, 1.37 mmol), and TEA (600 μL, 4.31 mmol) in DCM (9 mL) at room temperature was added 1-propanephosphonic anhydride (680 μL, 2.30 mmol). After 1 h, the reaction mixture was diluted with DCM, quenched with water, and washed with saturated aqueous NH4Cl. The organics were separated, dried (Na2SO4), and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M + Na] + = 594.1 (calculated value: 594.1).

[0294] Step 2: (4R)-6-chloro-5-fluoro-1′-(3-(1-(4-methyl-1H-benzo[d]imidazol-6-yl)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: In a glove box, to a stirred solution of (4R)-6-chloro-1'-(5-(1-chloropropyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (50 mg, 0.087 mmol) in DMI (0.9 mL) was added 6-bromo-4-methyl-1H-benzo[d]imidazole hydrochloride (65 mg, 0.26 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (12 mg, 0.044 mmol), and nickel(II) bromide ethylene glycol dimethyl ether complex (14 mg, 0.044 mmol) at room temperature. Zinc (17 mg, 0.26 mmol) was added, and the mixture was heated to 50° C. for 1 h. A second portion of nickel(II) bromide ethylene glycol dimethyl ether complex (13.5 mg, 0.044 mmol) and zinc (17 mg, 0.26 mmol) was added, and the reaction was continued stirring at 50° C. for 1 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO), and concentrated to give a crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M+H] + = 668.1 (calculated value: 668.3).

[0295] Step 3: (4R)-6-chloro-5-fluoro-1′-(3-(1-(4-methyl-1H-benzo[d]imidazol-6-yl)propyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:To a stirred solution of (4R)-6-chloro-5-fluoro-1'-(5-(1-(4-methyl-1H-benzo[d]imidazol-6-yl)propyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (20 mg, 0.030 mmol) in dioxane (0.5 mL) at room temperature was added HCl (60 μL, 0.24 mmol, 4 M in dioxane). After 3 h, the reaction was concentrated and the crude residue was purified by preparative reverse-phase HPLC (ACN / water with 0.05% TFA) to afford the title compound as a stereochemical mixture. LCMS [M+H] + = 538.4 (calculated value: 538.0).

[0296] The title compound was separated by SFC (column DAICEL CHIRALCEL AS-H (250 mm x 21 mm), (conditions: mobile phase A: CO2, mobile phase B: 0.2% DIPA EtOH, initial B 35%, final B 35%).

[0297] The faster eluting isomer of the title compound was obtained (Example 109): LCMS [M + H] + = 537.9 (calculated value: 538.0). 1¹H NMR (400 MHz, CD₃OD) δ 8.09 (d, J = 9.0 Hz, 1H), 7.50 - 7.29 (m, 1H), 7.04 (d, J = 35.9 Hz, 1H), 6.70 (dd, J = 41.0, 8.6 Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 4.17 - 4.01 (m, 1H), 3.79 (d, J = 14 Hz, 0.5H, revertor 1), 3.40 (d, J = 14 Hz, 0.5H, revertor 2), 3.08 - 2.90 (m, 1H), 2.49 (m, 3H), 2.39 - 1.97 (m, 2H), 1.81 - 1.64 (m, 1H), 1.63 - 1.46 (m, 1H), 1.28-1.23 (m, 3H), 1.16 (d, J = 6.2 Hz, 1H), 0.89 (m, 3H).

[0298] The title compound was dissolved and the opposite body was obtained (Example 110): LCMS [M + H] + = 537.9 (calculated value. 538.0). 1 ¹H NMR (400 MHz, CD₃OD) δ 8.09 (d, J = 9.0 Hz, 1H), 7.50 - 7.29 (m, 1H), 7.04 (d, J = 35.9 Hz, 1H), 6.70 (dd, J = 41.0, 8.6 Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 4.17 - 4.01 (m, 1H), 3.79 (d, J = 14 Hz, 0.5H, revertor 1), 3.40 (d, J = 14 Hz, 0.5H, revertor 2), 3.08 - 2.90 (m, 1H), 2.49 (m, 3H), 2.39 - 1.97 (m, 2H), 1.81 - 1.64 (m, 1H), 1.63 - 1.46 (m, 1H), 1.28-1.23 (m, 3H), 1.16 (d, J = 6.2 Hz, 1H), 0.89 (m, 3H).

[0299] Following procedures similar to those described above for Example 109 and Example 110, using the appropriate starting materials, the following compounds were prepared. [Table 10]

[0300] Example 113 [ka]

[0301] (R)-6-chloro-1'-(3-(3-methylbenzyl)-1H-1,2,4-triazole-5-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (R)-6-chloro-5-fluoro-1′-(5-(hydroxymethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: The title compound was prepared in two steps from ethyl 5-(hydroxymethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate (Intermediate M9-a, prepared as described above in Steps 1-3). Ethyl 5-(hydroxymethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carboxylate was treated under conditions similar to those described above for Intermediate C5-b, Step 4, followed by treatment of the resulting crude product with Intermediate A6-d under conditions similar to those described in Examples 1 and 2. LCMS [M+H] + = 526.1 (calculated value: 526.0).

[0302] Step 2: (R,E)-N'-((5-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-carbonyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methylene)-4-methoxybenzenesulfonohydrazide: To a stirred mixture of (R)-6-chloro-5-fluoro-1'-(5-(hydroxymethyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole-3-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (6.93 g, 13.2 mmol) and NaHCO3 (1.11 g, 13.2 mmol) in DCM (66 mL) at room temperature was added DMP (6.15 g, 14.5 mmol). After 12 h, the reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, and the mixture was filtered through Celite®. The layers were separated, and the organic layer was dried (Na2SO4), filtered, and concentrated to give the crude residue, which was dissolved in MeOH (30 mL). To the solution was added 4-methoxybenzenesulfonohydrazide (1.33 g, 6.57 mmol), and the mixture was stirred at room temperature. After 12 h, the reaction was concentrated to dryness, and the crude residue was dissolved in EtOAc. The organics were washed with saturated aqueous NH4Cl, water, and brine, then dried (Na2SO4), filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. LCMS [M + Na] + = 730.1 (calculated value: 730.2).

[0303] Step 3: (R)-6-chloro-1′-(3-(3-methylbenzyl)-1H-1,2,4-triazole-5-carbonyl)-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:A mixture of (R,E)-N'-((5-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3'-piperidine]-1'-carbonyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methylene)-4-methoxybenzenesulfonohydrazide (71 mg, 0.10 mmol), (3-methyl)boronic acid (20 mg, 0.15 mmol), and potassium carbonate (35 mg, 0.25 mmol) was suspended in dioxane (0.5 mL), and the mixture was heated to 110°C. After 12 h, the reaction was cooled to room temperature, and excess HCl (4 M in dioxane) was added. The mixture was heated to 60°C for 1 h, cooled to room temperature, and concentrated to give a crude residue. It was purified by reverse phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound.

[0304] 1 H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 0.5H), 10.57 (s, 0.5H), 7.55 (m, 1H), 7.21-6.98, (m, 3H), 6.78 (m, 1H), 4.79 (d, J = 15 Hz, 1H), 4.57 (d, J = 15 Hz, 1H), 4.07 (m, 1H), 3.97 (M, 1H), 3.77 (d, J = 15 Hz, 1H), 2.93 (m, 2H), 2.28 (s, 3H), 1.97-1.85 (m, 2H) 1.69 (m, 1H).LCMS [M + H] + = 470.0 (calculated value: 469.9).

[0305] Following procedures similar to those described above for Example 113, using the appropriate starting materials, the following compounds were prepared: [Table 11]

[0306] TIFF0007794991000110.tif152168

[0307] Example 127 [ka]

[0308] (4R)-6-chloro-5-fluoro-1'-(3-((4-fluorophenyl)(hydroxy)methyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (R)-1′-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a stirred solution of intermediate Ma (2.34 g, 7.14 mmol) and intermediate A6-d (2.63 g, 7.14 mmol) in pyridine (25 mL) was added EDC (1.64 g, 8.57 mmol), and the mixture was stirred at room temperature. After 12 h, the reaction was concentrated, and the crude residue was purified by silica gel chromatography (silica, EtOAc:petroleum ether) to provide the title compound. LCMS [M-57] + =516.0 (calculated value. M+H=574.1).

[0309] Step 2: (R)-5-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidine]-1′-ylcarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carbaldehyde: The title compound was prepared in two steps following procedures similar to those described for Intermediate H, Steps 4 and 5. LCMS [M+H] + = 524.2 (calculated value: 524.2).

[0310] Step 3: (3'R)-6-chloro-5-fluoro-1'-(3-((4-fluorophenyl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one:To a stirred solution of 1-bromo-4-fluorobenzene (300 mg, 1.71 mmol) in THF (10 mL) at −78° C. was added n-butyllithium (820 μL, 2.06 mmol, 2.5 M in hexane) dropwise. After 30 min, (R)-5-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidine]-1′-ylcarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole-3-carbaldehyde (800 mg, 1.527 mmol) was added, and the mixture was stirred at −78° C. for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were concentrated to give a crude residue. It was purified by preparative TLC (EtOAc / petroleum ether) to give the title compound. LCMS [M+H] + = 620.2 (calculated value: 620.2).

[0311] Step 4: (3'R)-6-chloro-5-fluoro-1'-(3-((4-fluorophenyl)(hydroxy)methyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: The title compound was prepared following a procedure similar to that described above for Example 75, Step 5.

[0312] 1H NMR (400 MHz, CD3OD) δ 7.50 (dd, J = 8.1, 5.6 Hz, 1H), 7.39-7.45 (m, 2H), 7.08 (br t, J = 8.6 Hz, 1H), 6.97 (td, J = 8.8, 2.4 Hz, 1H), 6.66-6.79 (m, 1H), 5.96 (s, 0.5H), 5.90 (s, 0.5H), 5.41-5.58 (m, 0.5H), 4.97 (br d, J = 13.9 Hz, 1H), 4.75 (br d, J = 12.7 Hz, 0.5H), 3.79 (dd, J = 14.2, 4.9 Hz, 0.5H), 3.40 (br d, J = 14.2 Hz, 0.5H), 2.91-3.03 (m, 1H), 2.38-2.57 (m, 1H), 2.13-2.35 (m, 2H), 1.63-1.84 (m, 1H), 1.62-1.82 (m, 1H).LCMS [M + H] + = 490.2 (calculated value: 490.1).

[0313] Example 128 [ka]

[0314] (R)-6-chloro-5-fluoro-1'-(3-((R or S)-1-(4-fluorophenyl)-1-hydroxypropyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (R)-6-chloro-5-fluoro-1′-(3-(4-fluorobenzoyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: The title compound was prepared following procedures similar to those described above in Examples 1 and 2. LCMS [M+H] + = 488.1 (calculated value: 488.1).

[0315] Step 2: (3'R)-6-chloro-5-fluoro-1'-(3-(1-(4-fluorophenyl)-1-hydroxypropyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one:To a stirred solution of (R)-6-chloro-5-fluoro-1'-(3-(4-fluorobenzoyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (233 mg, 0.450 mmol) in THF (6 mL) at room temperature was added ethylmagnesium bromide (0.31 mL, 0.92 mmol, 3 M THF solution). After 3 h, the reaction was diluted with water and extracted with a 10% MeOH:DCM mixture. The combined organics were concentrated, and the crude residue was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound as a stereochemical mixture. LCMS [M+H] + = 518.0 (calculated value: 518.1).

[0316] The title compound was resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase A: CO2, mobile phase B: EtOH (0.1% NH3H2O); flow rate: 60 mL / min; gradient 50% B → 50% B).

[0317] The faster eluting isomer of the title compound was obtained (Example 128): 1 H NMR (400 MHz, CD3OD) δ 7.50-7.67 (m, 2H), 7.44 (q, J = 8.2 Hz, 1H), 7.04 (t, J = 8.6 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H), 6.66-6.79 (m, 1H), 5.45 (s, 0.5H), 5.01 (br d, J = 14.1 Hz, 0.5H), 4.80 (br d, J = 14.5 Hz, 1H), 3.78 (d, J = 14.5 Hz, 1H), 3.41 (d, J = 13.7 Hz, 0.5H), 2.93-3.05 (m, 0.5H), 2.09-2.45 (m, 4H), 2.02-2.70 (m, 1H), 1.67-1.82 (m, 1H), 0.75-0.89 (m, 3H). LCMS [M + H]+ = 518.0 (calculated value: 518.1).

[0318] Example 129 [ka]

[0319] (3'R)-6-chloro-5-fluoro-1'-(3-(1-fluoro-1-(4-fluorophenyl)propyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (3'R)-6-chloro-5-fluoro-1'-(3-(1-fluoro-1-(4-fluorophenyl)propyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one: To a stirred mixture of (3'R)-6-chloro-5-fluoro-1'-(3-(1-(4-fluorophenyl)-1-hydroxypropyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (30 mg, 0.058 mmol) in DCM (0.8 mL) at 0° C. was added DAST (23 μL, 0.17 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 12 hours, at which point the reaction was diluted with water and extracted with DCM. The combined organics were concentrated, and the crude residue was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide the title compound.

[0320] The title compound was resolved by SFC (column: DAICEL CHIRALCEL AD-H (250 mm × 30 mm, 5 μm), mobile phase A: CO , mobile phase B: MeOH (0.1% NH H O); flow rate: 60 mL / min; gradient 20% B → 20% B).

[0321] The faster eluting isomer of the title compound was obtained (Example 129): 11H NMR (400 MHz, CD3OD) δ 7.49 - 7.56 (m, 1H), 7.48 - 7.55 (m, 1H), 7.34 - 7.48 (m, 2H), 7.12 (t, J = 9.0 Hz, 1H), 6.92 - 7.04 (m, 1H), 6.64 - 6.81 (m, 1H), 5.48 - 5.67 (m, 0.5H), 5.00 (br d, J = 13.7 Hz, 1H), 4.77 (br d, J = 12.9 Hz, 0.5H), 3.75 (dd, J = 14.1, 4.7 Hz, 1H), 3.42 (d, J = 13.7 Hz, 0.5H), 2.93 - 3.05 (m, 0.5H), 2.43 - 2.65 (m, 2H), 2.07 - 2.38 (m, 3H), 1.69 - 1.83 (m, 1H), 0.92 (t, J = 7.4 Hz, 1H), 0.85 (q, J = 7.0 Hz, 2H). LCMS [M + H] + = 520.2 (calculated. 520.1).

[0322] Example 130

Chem.

[0323] (4R)-6-chloro-5-fluoro-1'-(3-(2-methoxy-1-phenylethyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (R,Z)-6-chloro-5-fluoro-1′-(3-(2-methoxy-1-phenylvinyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one:To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (219 mg, 0.638 mmol) in THF (5 mL) at −78° C. was added LHMDS (0.57 mL, 0.75 mmol, 1.4 M THF solution). After 30 min, (R)-1′-(3-benzoyl-1H-1,2,4-triazole-5-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one (250 mg, 0.532 mmol) was added, and the mixture was warmed to 0° C. and stirred for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were concentrated to give a crude residue, which was purified by silica gel chromatography (MeOH / DCM) to give the title compound. LCMS [M+H] + = 498.1 (calculated value: 498.1).

[0324] Step 2: 6-chloro-5-fluoro-1′-(3-(2-methoxy-1-phenylethyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a stirred solution of (Z)-6-chloro-5-fluoro-1'-(3-(2-methoxy-1-phenylvinyl)-1H-1,2,4-triazole-5-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one (30 mg, 0.036 mmol) in THF (2 mL) was added Raney Ni (106 mg, 0.181 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through a pad of Celite®, and the filtrate was concentrated to give a crude residue, which was purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to give the title compound.

[0325] 1H NMR (400MHz, CD3OD) δ 7.40-7.49 (m, 1H), 7.26-7.39 (m, 3H), 7.15-7.26 (m, 2H), 6.64-6.84 (m, 1H), 5.50-5.69 (m, 0.5H), 5.00 (br d, J = 14.2 Hz, 0.5H), 4.79 (br d, J = 13.0 Hz, 1H), 4.38-4.57 (m, 1H), 3.99-4.16 (m, 1H), 3.70-3.96 (m, 0.5H), 3.41-3.50 (m, 1H), 3.36 (s, 1H), 3.26 (d, J = 2.94-3.08 (m, 0.5H), 2.45-2.60 (m, 1H), 2.10-2.38 (m, 2H), 1.68-1.83 (m, 1H). + = 500.2 (calculated value: 500.1).

[0326] Example 131 [ka]

[0327] (R)-1'-((S or R)-1-benzyl-3-fluoropyrrolidine-3-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3'-piperidin]-2(1H)-one Step 1: (4R)-1′-(1-benzyl-3-fluoropyrrolidine-3-carbonyl)-6-chloro-5-fluorospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-2(1H)-one: To a stirred solution of intermediate A6-d (100 mg, 0.326 mmol), potassium 1-benzyl-3-fluoropyrrolidine-3-carboxylate (100 mg, 0.383 mmol), and HATU (161 mg, 0.423 mmol) in DMF (2.5 mL) was added DIEA (0.171 mL, 0.977 mmol), and the resulting mixture was stirred at room temperature. After 12 h, the reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO), filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (25% EtOH:EtOAc / hexanes) to give the title compound as a mixture of isomers.

[0328] The title compound was resolved by SFC (column OJ-H 50 x 250 mm, conditions: mobile phase A: CO2, mobile phase B: 0.1% DIPA MeOH).

[0329] The slower eluting isomer was obtained as the title compound (Example 131): 1 H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.37 - 7.22 (m, 5H), 6.79 (t, J = 9.2 Hz, 1H), 4.14-4.66 (dd, 2H), 3.57 - 3.76 (m, 4H), 2.96 - 3.27 (m, 2H), 2.69 - 2.91 (m, 2H), 2.33 - 2.58 (m, 2H), 2.05 - 2.26 (m, 2H), 1.64 - 1.90 (m, 2H). LCMS [M+H] + = 476.1 (calculated value: 476.2).

[0330] Example 132 [ka]

[0331] (S)-6-Chloro-5-fluoro-1'-(1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carbonyl)spiro[benzo[d][1,3]oxazine-4,3'-pyrrolidin]-2(1H)-one Step 1: (S)-6-chloro-5-fluoro-1′-(1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carbonyl)spiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one: To a stirred solution of intermediate A6-c (38 mg, 0.10 mmol) and DIEA (90 μL, 0.51 mmol) in DMF (2 mL) was added 1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (48 mg, 0.15 mmol). HATU (59 mg, 0.15 mmol) was added, and the resulting mixture was stirred at room temperature. After 2 h, the reaction was filtered and purified by reverse-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide the title compound.

[0332] LCMS [M+H] + = 548.1 (calculated value: 548.2). 1H NMR (600 MHz, DMSO-d6) δ 10.73 (d, J = 19.7 Hz, 1H), 8.41 (d, J = 35.2 Hz, 1H), 7.88 (s, 1H), 7.83 - 7.65 (m, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.23 (dd, J = 21.4, 10.2 Hz, 3H), 6.80 (t, J = 8.1 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 6.22 (d, J = 6.4 Hz, 1H), 5.32 (d, J = 31.3 Hz, 2H), 5.07 (d, J = 9.4 Hz, 2H), 4.21 (d, J = 15.0 Hz, 1H), 4.03 (t, J = 12.0 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.80 (t, J = 10.1 Hz, 1H), 3.67 (d, J = 7.1 Hz, 1H), 2.72 - 2.57 (m, 1H).

[0333] Following procedures similar to those described above for Example 132, using the appropriate starting materials, the following compounds were prepared: [Table 12]

[0334] Factor XIa assay The efficacy of the compounds of the present invention as inhibitors of coagulation factor XIa can be confirmed 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 presence of the compounds of the present invention. Assays were performed at room temperature or 37°C. Substrate hydrolysis released aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by exciting at 405 nm and measuring the increase in emission at 510 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 are reported as the 50% inhibitory concentration (IC 50 ) or the inhibition constant (K i )

[0335] Compounds were preincubated with human factor XIa (0.04 nM) in 50 mM HEPES buffer, pH 7.4, containing 150 mM sodium chloride, 5 mM calcium chloride, and 0.1% PEG 8000, for 30 minutes 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 minutes of incubation at 25°C. The percent inhibition for each data point was calculated from the data and analyzed using a four-parameter equation of log(inhibitor) versus response to determine the 50% inhibitory concentration (IC). 50 ) was determined. 50 was converted to an equilibrium inhibition constant (Ki) using the Cheng-Prusoff equation.

[0336] Activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful for the treatment or prevention of a variety of cardiovascular and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndromes, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, stroke (e.g., thrombotic or embolic stroke), venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.

[0337] Plasma kallikrein assay The effectiveness of the compounds of the present invention as inhibitors of plasma kallikrein can be confirmed 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 presence of the compounds of the present invention. Assays were performed at room temperature or 37°C. Substrate hydrolysis released aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by exciting at 405 nm and measuring the increase in emission at 510 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 are reported as the 50% inhibitory concentration (IC 50 ) or the inhibition constant (K i )

[0338] Plasma kallikrein measurements were performed in 50 mM HEPES buffer (pH 7.4) containing 150 mM NaCl, 5 mM CaCl, and 0.1% PEG8000 (polyethylene glycol; Fisher Scientific). Measurements 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.

[0339] Activity assays were performed by diluting the substrate stock solution at least 10-fold with a solution containing enzyme or enzyme equilibrated with inhibitor to a final concentration ≤ 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 increase in fluorescence was measured at 405Ex / 510Em (nm). Values ​​were converted to percent inhibition of the control reaction (after subtracting the 100% inhibition value). IC 50 was determined by the inflection point from a four-parameter logistic curve fit. Ki was calculated using the Cheng Prusoff equation: Ki = IC50 / (1 + ([S] / Km)).

[0340] Activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful for the treatment or prevention of a variety of ophthalmic, cardiovascular, and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndromes, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, stroke (e.g., thrombotic or embolic stroke), venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, reocclusion or restenosis of recanalized vessels, hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion.

[0341] Plasma kallikrein (PKal) IC of selected compounds 50 (nM) and factor XIa IC 50 (nM) is as follows: [Table 13]

[0342] TIFF0007794991000119.tif245143

[0343] TIFF0007794991000120.tif246143

[0344] TIFF0007794991000121.tif13145

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, A is O or —CH ２ - and; 【Chemistry 2】 and Q is -CH ２ - or absent; R １ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ２ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ３ is hydrogen, halo, hydroxy, C １－６ Alkyl and C ３－６ cycloalkyl; R ４ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ５ is hydrogen, halo or C １－６ alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo; R ６ is hydrogen, halo, hydroxy, cyclopropyl, C １－６ Alkyl and C １－６ alkyl-cyclopropyl, wherein the alkyl group is selected from the group consisting of halo, phenyl, and OR ｘ and the cyclopropyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of OR ｘ optionally substituted with; R ７ is hydrogen, halo, hydroxy and C １－６ alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo or hydroxy; Or, R ６ and R ７ together with the carbon atoms to which they are attached can form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group; R ８ is selected from the group consisting of phenyl or heteroaryl (which can be monocyclic or bicyclic); wherein the phenyl and heteroaryl groups are selected from the group consisting of oxo, halo, cyano, R ｘ , OR ｘ , N.R. ９ R １０ , (C=O)OR ｘ , OCH ２ (C=O)OR ｘ , S.O. ２ R ｘ , S.O. ２ NR ９ R １０ , R ｙ and CH ２ R ｙ optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R ９ is hydrogen or C １－３ is alkyl; R １０ is hydrogen or C １－３ is alkyl; R ｘ is hydrogen or C １－６ alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halo and hydroxy; R ｙ is heteroaryl, heterocyclyl or C ３－６ cycloalkyl, where the heteroaryl group is oxo or C １－６ The heterocyclyl group may be optionally substituted with one or two oxo groups, and the cycloalkyl group may be optionally substituted with one or two oxo groups. １－６ may be substituted with alkyl. or a pharmaceutically acceptable salt thereof.

2. Q is -CH ２ The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

3. Formula Ia: 【Transformation 3】 [During the ceremony, A is O or —CH ２ - and; 【Chemistry 4】 and R １ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ２ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ３ is hydrogen, halo, hydroxy, C １－６ Alkyl and C ３－６ cycloalkyl; R ４ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ５ is hydrogen, halo or C １－６ alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo; R ６ is hydrogen, halo, hydroxy, cyclopropyl, C １－６ Alkyl and C １－６ alkyl-cyclopropyl, wherein the alkyl group is selected from the group consisting of halo, phenyl, and OR ｘ and the cyclopropyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of OR ｘ optionally substituted with; R ７ is hydrogen, halo, hydroxy and C １－６ alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo or hydroxy; Or, R ６ and R ７ together with the carbon atoms to which they are attached can form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group; R ８ is selected from the group consisting of phenyl or heteroaryl (which can be monocyclic or bicyclic); wherein the phenyl and heteroaryl groups are selected from the group consisting of oxo, halo, cyano, R ｘ , OR ｘ , N.R. ９ R １０ , (C=O)OR ｘ , OCH ２ (C=O)OR ｘ , S.O. ２ R ｘ , S.O. ２ NR ９ R １０ , R ｙ and CH ２ R ｙ optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R ９ is hydrogen or C １－３ is alkyl; R １０ is hydrogen or C １－３ is alkyl; R ｘ is hydrogen or C １－６ alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halo and hydroxy; R ｙ is heteroaryl, heterocyclyl or C ３－６ cycloalkyl, where the heteroaryl group is oxo or C １－６ The heterocyclyl group may be optionally substituted with one or two oxo groups, and the cycloalkyl group may be optionally substituted with one or two oxo groups. １－６ may be substituted with alkyl.

3. The compound according to claim 1 or 2, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof.

4. 2. The compound of claim 1, wherein A is O, or a pharmaceutically acceptable salt thereof.

5. Formula Ib: 【Transformation 5】 [During the ceremony, 【Transformation 6】 and R １ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ２ is hydrogen, halo, hydroxy and C １－６ selected from the group consisting of alkyl; R ５ is hydrogen, halo or C １－６ alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo; R ６ is hydrogen, halo, hydroxy, cyclopropyl, C １－６ Alkyl and C １－６ alkyl-cyclopropyl, wherein the alkyl group is selected from the group consisting of halo, phenyl, and OR ｘ and the cyclopropyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of OR ｘ optionally substituted with; R ７ is hydrogen, halo, hydroxy and C １－６ alkyl, wherein the alkyl group is optionally substituted with 1 to 3 halo or hydroxy; Or, R ６ and R ７ together with the carbon atoms to which they are attached can form a 3- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclyl group; R ８ is selected from the group consisting of phenyl or heteroaryl (which can be monocyclic or bicyclic); wherein the phenyl and heteroaryl groups are selected from the group consisting of oxo, halo, cyano, R ｘ , OR ｘ , N.R. ９ R １０ , (C=O)OR ｘ , OCH ２ (C=O)OR ｘ , S.O. ２ R ｘ , S.O. ２ NR ９ R １０ , R ｙ and CH ２ R ｙ optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R ９ is hydrogen or C １－３ is alkyl; R １０ is hydrogen or C １－３ is alkyl; R ｘ is hydrogen or C １－６ alkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halo and hydroxy; R ｙ is heteroaryl, heterocyclyl or C ３－６ cycloalkyl, where the heteroaryl group is oxo or C １－６ The heterocyclyl group may be optionally substituted with one or two oxo groups, and the cycloalkyl group may be optionally substituted with one or two oxo groups. １－６ may be substituted with alkyl. The compound according to claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof.

6. R １ is a halo, and R ２ or a pharmaceutically acceptable salt thereof, of claim 1 , wherein: is halo.

7. R ３ is hydrogen or methyl, and R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or methyl.

8. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halo.

9. R ８ is phenyl, where this is oxo, halo, cyano, —OCH ２ (C=O)OR ｘ , -SO ２ R ｘ and R ｙ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with:

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from any one of Compounds 1 to 138 shown below: 【Transformation 7】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

11. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11 for the treatment of visual activity disorders, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood clotting during cardiopulmonary bypass surgery and bleeding from post-operative surgery in mammals.

13. 12. The pharmaceutical composition of claim 11 for the treatment of uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal.

14. 12. The pharmaceutical composition of claim 11 for the treatment of diabetic retinopathy or diabetic macular edema in a mammal.

15. 12. The pharmaceutical composition of claim 11 for the treatment of retinal vein occlusion in a mammal.

16. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal in need thereof.

17. 10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

18. 12. The composition of claim 11, further comprising another agent selected from the group consisting of an anti-inflammatory agent, an anti-VEGF agent, an immunosuppressant, an anticoagulant, an antiplatelet agent, and a thrombolytic agent.

19. 13. The pharmaceutical composition of claim 12 for use in combination with another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents and thrombolytic agents.

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