Plasma kallikrein inhibitors

Abstract

The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.

Description

PLASMA KALLIKREIN INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 713,618, filed October 30, 2024, the disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. Proteolyticactivation by factor Xlla at an internal I 389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors, including alpha 2 macroglobulin and Cl-inhibitor. Interestingly, heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of high molecular weight kininogen (HMWK). In blood, the majority of plasma kallikrein circulates in complex with HMWK. Plasma kallikrein cleaves HMWK to liberate bradykinin. Bradykinin release results in increase of vascular permeability and vasodilation (for review. Coleman, R.. "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier A. H., "Contact Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)).

[0003] Patients presenting genetic deficiency on C 1 -esterase inhibitor suffer from hereditary angioedema (HAE), a lifelong disease that results in intermittent swelling throughout the body, including the hands, feet, face, throat, genitals and gastrointestinal tract. Analysis of blisters arising from acute episodes have been shown to contain high levels of plasma kallikrein, and treatment with a protein-based reversible plasma kallikrein inhibitor, Ecallantide (Kalbitor), has been approved by the FDA for the treatment of acute attacks of HAE (Schneider. L, et al., J. Allergy Clin. Immunol., 120: p.416 (2007)).

[0004] Additionally, 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 observed retinal vascular leakage and dysfunction in diabetic rodent models (A. Clermont, et al., Diabetes, 60: 1590 (2011)), and that treatment with a small molecule plasma kallikrein inhibitor ameliorated the observed retinal vascular permeability and other abnormalities related to retinal blood flow.

[0005] It would be desirable in the art to develop plasma kallikrein inhibitors having utility to treat a wide range of disorders, including hereditary angioedema, diabetic macular edema and diabetic retinopathy.SUMMARY OF THE INVENTION

[0006] 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 as such may be useful in the treatment, inhibition or amelioration of one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary' angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds of this invention could further be used in combination with other therapeutically effective agents, including but not limited to, other drugs useful for the treatment of hereditary' angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I and pharmaceutically acceptable salts thereof.DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention relates to compounds of Formula I:A is C or N, provided that when A is N, R1does not exist;R1is F, Cl, NR5R6, Ci-C6alkyl, C3-C6cycloalkyl, or O-R4;R2is F, C1-C3alkyl, or C3-C6cycloalkyl;R3is H, F or Cl;is a heterocycle having up to 4 heteroatoms selected from N, S or O and optionally substituted with CH3, CHF2, CF3, or Cl; or a heteroaryl having up to 4 heteroatoms selected from N, S or O and optionally substituted with CHs, CHF2, CF3, or Cl;R4is H, C1-C6alkly, or C3-C6cycloalkyl;R5is H or C1-C4alkyl; andR6is H or C1-C4alkyl.

[0008] In an embodiment of the invention, A is C. In another embodiment of the invention, A is N.

[0009] In an embodiment of the invention. R1is F. In another embodiment of the invention, R1is Cl. In a further embodiment of the invention, R1is C1-C6alkyl. In an additional embodiment of the invention, R1is C3-C6 cycloalkyl. In a further embodiment of the invention R1is NR5R6. In a particular embodiment of the invention R1is O-R4. In embodiments where A is N, R1does not exist.

[0010] In an embodiment of the invention. R2is F. In another embodiment of the invention, R2is C1-C3 alkyl. In a further embodiment of the invention, R2is C3-C6 cycloalkyl

[0011] In an embodiment of the invention, R3is H. In another embodiment of the invention, R3is F. In a further embodiment of the invention, R3is Cl.( B )

[0012] In an embodiment of the invention. is a heterocycle having up to 4 heteroatoms selected from N, S or O and. In one embodiment of the invention, said heterocycle is substituted with CH3. In another embodiment of the invention, said heterocycle is substituted with CHF2. Ina further embodiment of the invention, said heterocycle is substituted with CF3. In an additional embodiment of the invention, said heterocycle is substituted with Cl. In certain embodiments of the invention the heterocycle has 4 heteroatoms selected from N, S or O. In some embodiments of the invention the 4 heteroatoms are N. In other embodiments of the invention the 4 heteroatoms are S. In further embodiments of the invention the 4 heteroatoms are O. In still further embodiments of the invention the 4 heteroatoms are a combination of N, S, or O. In certain embodiments of the invention the heterocycle has 3 heteroatoms selected from N, S or O. In some embodiments of the invention the 3 heteroatoms are N. In other embodiments of the invention the 3 heteroatoms are S. In further embodiments of the invention the 3 heteroatoms are O. In still further embodiments of the invention the 3 heteroatoms are a combination of N, S, or O.( B )

[0013] In another embodiment of the invention is a heteroaryl having up to 4 heteroatoms selected from N, S or O and. In one embodiment of the invention, said heteroaryl is substituted with CH3. In another embodiment of the invention, said heteroaryl is substituted with CHF2. In a further embodiment of the invention, said heteroaryl is substituted with CF3. In an additional embodiment of the invention, said heteroaryl is substituted with Cl. In certain embodiments of the invention the heteroaryl has 4 heteroatoms selected from N. S or O. In some embodiments of the invention the 4 heteroatoms are N. In other embodiments of the invention the 4 heteroatoms are S. In further embodiments of the invention the 4 heteroatoms are O. In still further embodiments of the invention the 4 heteroatoms are a combination of N, S, or O. In certain embodiments of the invention the heteroaryl has 3 heteroatoms selected from N, S or O. In some embodiments of the invention the 3 heteroatoms are N. In other embodiments of the invention the 3 heteroatoms are S. In further embodiments of the invention the 3 heteroatoms are O. In still further embodiments of the invention the 3 heteroatoms are a combination of N, S, or O.

[0014] In an embodiment of the invention R4is H. In another embodiment of the invention R4is C1-C6alkly. In a further embodiment of the invention, R4is C3-C6 cycloalkyl.

[0015] In an embodiment of the invention R5is H. In another embodiment of the invention R5is C1-C4alkyl.

[0016] In an embodiment of the invention R6is H. In another embodiment of the invention R6is C1-C4alkyl.

[0017] Specific embodiments of the present invention include, but are not limited to the compounds identified herein as Examples 1 to 28, or pharmaceutically acceptable salts thereof.

[0018] Also included within the scope of the present invention is a pharmaceutical composition which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier. The invention is also contemplated to encompass a pharmaceutical composition which is comprised of a pharmaceutically acceptable carrier and any of the compounds specifically disclosed in the present application. These and other aspects of the invention will be apparent from the teachings contained herein.

[0019] The invention includes compositions for treating a diseases or condition in which plasma kallikrein activity' is implicated. Accordingly the invention includes compositions for treating impaired visual activity, 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 coagulation during cardiopulmonary’ bypass surgery, and bleeding from postoperative surgery in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. A class of the invention includes compositions for treating hereditary^ angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. These compositions may optionally include antiinflammatory’ agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.

[0020] The invention also 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 invention in a pharmaceutically acceptable carrier. These compositions may optionally include anti-inflammatory’ agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0021] The invention also includes compositions for treating inflammatory conditions of the eye, which includes, but is not limited to, uveitis, posterior uveitis, macular edema, acute macular degeneration, wet age related macular edema, retinal detachments, retinal vein occlusion, ocular tumors, fungal infections, viral infections, multifocal choroiditis, diabetic uveitis, diabetic macular edema, diabetic retinopathy, proliferative vitreoretinopathy, sympathetic opthalmia, Vogt Koyanagi-Harada syndrome, histoplasmosis and uveal diffusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0022] The invention also includes compositions treating posterior eye disease, which includes, but is not limited to, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0023] It will be understood that the invention is directed to the compounds of structural Formula I described herein, as well as the pharmaceutically acceptable salts of the compounds of structural Formula I and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

[0024] The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate. gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate and the like. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous,potassium, sodium, zinc, and the like. Also included are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also, included are the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[0025] These salts can be obtained by known methods, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol. The compounds of the present invention may form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.

[0026] If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).

[0027] The present invention encompasses all stereoisomeric forms of the compounds of Formula I. Unless a specific stereochemistry is indicated, the present invention is meant to comprehend all such isomeric forms of these compounds. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both each individual enantiomer and mixtures thereof, are embraced within the Formula. When a particular configuration is depicted, that entantiomer (either (R) or (S), at that center) is intended. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where suchstereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention.

[0028] Unless a specific enationmer or diastereomer is indicated, the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism the invention includes both the cis form and the transform as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary', with a reagent containing a stereogenic center of known configuration. Where compounds of this invention are capable of tautomerization, all individual tautomers as well as mixtures thereof are included in the scope of this invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0029] In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the specifically and generically described compounds. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the general process schemes and examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0030] When any variable (e.g., R4. etc.) occurs more than one time in any constituent, its definition on 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 into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.

[0031] It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0032] It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase '‘optionally substituted’’ (with one or more substituents) should be understood as meaning that the group in question is either unsubstituted or may be substituted with one or more substituents.

[0033] Furthermore, compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are intended to be included within the scope of the present invention. In addition, some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms.

[0034] Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxy lic acidderivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0035] Any pharmaceutically acceptable pro-drug modification of a compound of this invention which results in conversion in vivo to a compound within the scope of this invention is also within the scope of this invention. For example, esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of this invention may be prepared to act as pro-drugs which can be hydrolyzed back to an acid (or -COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of this invention. Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -C1-6alkyl esters and -C1-6alkyl substituted with phenyl esters.

[0036] Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise.

[0037] Except where noted herein, the terms "alkyl" and "alkylene" are intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g., methyl, may be represented by conventional abbreviations including ‘’Me” or CH3or a symbol that is an extended bond as the terminal group, e.g.,, ethyl may be represented by “Et” or CH2CH3, propyl may be represented by “Pr” or CH2CH2CH3, butyl may be represented by “Bu” or CH2CH2CH2CH3, etc. “C1-4 alky l” (or “C1-C4 alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. For example, the structureshave equivalent meanings. C1-4 alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1-4 carbon atoms are intended for linear or branched alkyd groups.

[0038] Except where noted, the term “cycloalkyl” means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, “cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on.

[0039] Except where noted, the term “aryl”, as used herein, represents a stable monocyclic or bicyclic ring system of up to 10 carbon atoms in each ring, wherein at least one ring is aromatic. Bicyclic aryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Aryl groups within the scope of this definition include, but are not limited to: phenyl, indene, isoindene, naphthalene, and tetralin.

[0040] Except where noted, the term “heteroaryl”, as used herein, represents a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotri azolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl. naphthalenyl, naphthpyridinyl. oxadiazolyl, oxazolyl. oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazoloxazinyl, dihydropyrazolyothiazinedi oxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetra-hydroquinoline and 3-oxo-3, 4dihydro-2N-benzo[b][l,4]thiazine. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0041] Except where noted, the term "halogen" or “halo” means fluorine, chlorine, bromine or iodine.

[0042] “Celite®” (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0043] Except where noted herein, structures containing substituent variables such as variable R" below:which are depicted as not being attached to any one particular bicyclic ring carbon atom, represent structures in which the variable can be optionally attached to any bicyclic ring carbon atom. For example, variable R shown in the above structure can be attached to any one of 6 bicyclic ring carbon atoms i, ii, iii, iv, v or vi.

[0044] Except where noted herein, bicyclic ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.

[0045] The invention also relates to medicaments containing at least one compound of the Formula I and / or of a pharmaceutically acceptable salt of the compound of the Formula I and / or an optionally stereoisomeric form of the compound of the Formula I or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formula I, together with a pharmaceutically suitable and pharmaceutically acceptable vehicle, additive and / or other active substances and auxiliaries.

[0046] The term “patient” used herein is taken to mean mammals such as primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.

[0047] The medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with compounds of the Formulas I and other surfaces which come into contact with blood in the body is possible.

[0048] The invention also relates to a process for the production of a medicament, which comprises bringing at least one compound of the Formula I into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0049] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having prolonged release of active substance, in whose preparation customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used.Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives,animal and plant oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

[0050] The dosage regimen utilizing the plasma kallikrein inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0051] Oral dosages of the plasma kallikrein inhibitors, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg / kg / day) to about 30 mg / kg / day, preferably 0.025-7.5 mg / kg / day, more preferably 0.1-2.5 mg / kg / day, and most preferably 0.1-0.5 mg / kg / day (unless specificed otherwise, amounts of active ingredients are on free base basis). For example, an 80 kg patient would receive between about 0.8 mg / day and 2.4 g / day, preferably 2-600 mg / day, more preferably 8-200 mg / day, and most preferably 8-40 mg / kg / day. A suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g.. 8 mg. 10 mg. 20 mg and 40 mg.Advantageously, the plasma kallikrein inhibitors may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg. 5 mg, 10 mg and 20 mg.

[0052] Intravenously, the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg / kg / day, preferably 0.1-2.5 mg / kg / day, and more preferably 0.1-0.5 mg / kg / day. Such quantities may be administered in a number of suitable ways, e.g., large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g., once a day. Typically, a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg / mL, e.g., 0.1 mg / mL, 0.3 mg / mL, and 0.6 mg / mL, and administered in amounts per day of between 0.01 mL / kg patient weight and 10.0 mL / kg patient weight, e.g., 0.1 mL / kg, 0.2 mL / kg, 0.5 mL / kg. In one example, an 80 kg patient, receiving 8 mL twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg / mL, receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptableacid / conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.

[0053] Compounds of Formula I can be administered both as a monotherapy and in combination with other therapeutic agents, including but not limited to anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0054] An "anti-inflammatory agent" is any agent which is directly or indirectly effective in the reduction of inflammation w hen administered at a therapeutically effective level. “Antiinflammatory agent” includes, but is 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.

[0055] An “anti-VEGF agent” is any agent which is directly or indirectly effective in inhibiting the activity of VEGF (Vascular Endothelial Growth Factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab and aflibercept.

[0056] An “immunosuppressant agent” is any agent which is directly or indirectly effective in suppressing, or reducing, the strength of the body’s immune system. Suitable immunosuppressant agents include, but are not limited to, corticosteroids (for example, prednisone, budesonide, prednisolone), janus kinase inhibitors (for example, tofacitinib), calcineurin inhibitors (for example, cyclosporin, tacrolimus), mTOR inhibitors (for example, sirolimus. everolimus), IMDH inhibitors (for example, azathioprine, leflunomide, mycophenolate), biologies (for example, abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), and monoclonal antibodies (for example, basiliximab, daclizumab).

[0057] Suitable anticoagulants include, but are not limited to. Factor Xia inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor Vila inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor Xlla inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g., to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as 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 patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors.

[0058] In certain embodiments the anti-inflammatory agents, anti-VEGF agents, immunosuppressant agents, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in editions of the Physicians' Desk Reference, such as the 70th edition (2016) and earlier editions. In other embodiments, the anti-inflammatory agents. anti-VEGF agents, immunosuppressant agents, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in lower than their conventional dosage ranges.

[0059] Alternatively or additionally, one or more additional pharmacologically active agents may be administered in combination with a compound of the invention. The additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which is different from the compound of the invention, and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible. Generally, any suitable additional active agent or agents, including but not limited to anti-hypertensive agents, additional diuretics, anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and / or antiobesity agents may be used in any combination with the compound of the invention in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents). Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g.. alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril. imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists also known as angiotensin receptor blockers or ARBs, which may be in free-base, free-acid, salt or pro-drug form, such as azilsartan, e.g.. azilsartan medoxomil potassium (ED ARBI®), 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 such as hydrochlorothiazide (e.g.,HYZAAR®, DIOVAN HCT®, ATACAND HCT®), etc.); potassium sparing diuretics such as amiloride HC1, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid 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); sympatholitics; beta-adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazosin, prazosin or alpha methyldopa); central alpha adrenergic agonists; peripheral vasodilators (e.g., hydralazine); lipid lowering agents, e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant and / or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents including insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), combination medications such as JANUMET® (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; inhibitors of glucose uptake,such as sodium-glucose transporter (SGLT) inhibitors and its various isoforms, such as SGLT-1, SGLT-2 (e.g., ASP-1941, TS-071, BI-10773, tofogliflozin, LX-4211, canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, remogliflozin and sotagliflozin), and SGLT-3; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including but not limited to diazoxide; and including the free-acid, free-base, and pharmaceutically acceptable salt forms, pro-drug forms, e.g., esters, and salts of pro-drugs of the above medicinal agents, where chemically possible. Trademark names of pharmaceutical drugs noted above are provided for exemplification of the marketed form of the active agent(s); such pharmaceutical drugs could be used in a separate dosage form for concurrent or sequential administration with a compound of the invention, or the active agent(s) therein could be used in a fixed dose drug combination including a compound of the invention.

[0060] Typical doses of the plasma kallikrein inhibitors of the invention in combination with other suitable agents may be the same as those doses of plasma kallikrein inhibitors administered without coadministration of additional agents, or may be substantially less that those doses of plasma kallikrein inhibitors administered without coadministration of additional agents, depending on a patient’s therapeutic needs.

[0061] The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount” it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e., prevent, inhibit or ameliorate) the disease condition or treat the progression of the disease in a host.

[0062] The compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of each of the compounds when administered individually as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components.

[0063] By ‘'administered in combination” or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. The administration of each component does not need to be via the same route of administration; for example, one component can be administered orally, and another can be delivered into the vitreous of the eye.

[0064] The present invention is not limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to fall within the scope of the appended claims.GENERAL METHODS

[0065] Compounds of the present invention may be prepared using conventional techniques or according to the methodology outlined in the following general synthetic schemes. One skilled in the art can vary the procedures and reagents shown to arrive at similar intermediates and / or final compounds.

[0066] NMR spectra were measured on VARIAN or Bruker NMR Systems (400, 500 or 600 MHz). Chemical shifts are reported in ppm downfield and up field from tetramethylsilane (TMS) and referenced to either internal TMS or solvent resonances (1H NMR: 5: 7.27 for CDCh, 5: 2.50 for (CDS)(CHD2)SO. Coupling constants (J) are expressed in hertz (Hz), and spin multiplicities are given as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet), and br (broad). Chiral resolutions were performed on either Waters Thar 80 SFC or Berger MG II preparative SFC systems. LC-MS data were recorded on SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, or Agilent 1100 series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instruments using C18 columns employing a MeCN gradient in water containing 0.02 to 0.1% TFA. UV detections were at 220 and / or 254 nm and ESI ionization was used for MS detection.

[0067] When chiral resolution was achieved by chromatography using chiral columns, the chiral columns used for SFC chiral resolutions are listed in tables. Some of the chiral columns used were CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY,CHIRALPAK IA, CHIRALPAK AD-H, and CHIRALPAK AS-H. Henceforth, they will be referred by their two or three letter abbreviations. As a convention, the fast-eluting isomer from a chiral resolution is always listed first in this table followed immediately by the slower-eluting isomer from the same resolution. If more than two isomers were separated, they will be always listed in the tables in order they were eluted, such as Peak 1 followed by Peak 2, Peak 3 and so on. A* symbol near a chiral center in a structure denotes that this chiral center was resolved by chiral resolution without its stereochemical configuration unambiguously determined. Also, TLC is thin layer chromatography; UV is ultraviolet; Wis watts; wt. % is percentage by weight; x g is times gravity; ao is the specific rotation of polarized light at 589 nm: °C is degrees Celsius; % wt. is percentage in weight of the former agent relative to the volume of the latter agent; Hz is hertz; cpm is counts per minute; δH is chemical shift; d is doublet; dd is doublet of doublets; MHz is megahertz; MS is mass spectrum, and a mass spectrum obtained by ES-MS may be denoted herein by "LC-MS"; mlz is mass to charge ratio; n is normal; N is normal; nm is nanometer; nM is nanomolar.

[0068] Several catalysts and ligands are used in the following procedures. "XANTPHOS" is also known as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. "XANTPHOS Pd G3" is also known as [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2- (2'-amino-l, 1'-biphenyl)]palladium(II) methanesulfonate. "BrettPhos" is also known as 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-l,r-biphenyl and the "BrettPhos Pd G3" is also known as [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1, 1'- biphenyl)-2-(2'-amino-l, 1' -biphenyl)]palladium(II) methanesulfonate. "cataCXium APd G2" is also know as chloro[(di(l-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II). These catalysts and ligands are available from Millipore Sigma.

[0069] For purposes of this specification, the following abbreviations have the indicated meanings:Ac acetylACN acetonitrileAcOH or HOAc acetic acidAc2O Acetic anhydrideaq. aqueousAr arylBn benzylBoc or BOC tert-butoxycarbonylbr broadn-Bu butylt-Bu tertiarybutylcalcd. calculatedd doubletdba dibenzylideneacetoneDBAD Di-tertebutyl azodicarboxylateDBU 1,8-Diazabicyclo(5.4.0)undec-7-eneDCE 1,2-dichloroethaneDCM dichloromethanedd doublet of doubletsDIAD diisopropyl azodicarboxylateDIBAL diisobutylaluminum hydrideDIEA or Htinig’s base / V. A-diisopropvIethylamineDMA N,N-dimethylacetamideDMAP 4-dimethylaminopyridineDME dimethoxyethaneDMF dimethylformamideDMP Dess-Martin periodinane ( 1,1,1 -triacetoxy)- 1,1- dihydro-l,2-benziodoxol-3(177)-one DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMS dimethylsulfideDMSO dimethyl sulfoxideDPPA Diphenylphosphoryl azidedppf 1, 1 '-bis(diphenylphosphino)ferrocene dt doublet of tripletsDTT dithiothreitolEDC or EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTA ethylenediamine tetraacetic acidequiv equivalentsESI electrospray ionizationEt ethylEtOH ethanolEtOAc ethyl acetateg gramsGST glutathione S-transferaseh hourHATUN,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HMDS 1,1,1,3,3,3-hexamethyldisilazaneHOBt 1 -hydroxybenzotriazoleHPLC high-performance liquid chromatography Hz hertzICso concentration at which 50% inhibition exists IPA isopropanol / Pr isopropylJ coupling constantL litersLAH lithium aluminum hydrideLC liquid chromatographyLCMS liquid chromatography mass spectrometry LDA lithium diisopropylamideLED light emitting diodeM massM molarM multipletmCPBA meta-chloroperoxy benzoic acidMeCN acetonitrileMeOH methanolmg milligramsMHz megahertzmin minutemL microlitersmL millilitersmm micrometersmmol millimolesMPLC medium pressure liquid chromatographyMS mass spectrometryMs methanesulfonyl (mesyl)MTBE methyl tert-butyl etherN normalNADP Nicotinamide adenine dinucleotide phosphate NBS N-bromosuccinimideNCS N-chlorosuccinimidenm nanometernM nanomolarNMP 1-methylpyrrolidinoneNMR nuclear magnetic resonance spectroscopyPet. ether Petroleum etherpH measure of acidity or basicitv of aq. or other solutions Ph phenylpin pinacolPMB 4-methoxy benzylPr propylprep preparativepsi pounds per square inchq quartetrac racemic mixtureRT or rt room temperature (ambient, about 25 °C) s singletsatd. saturatedSFC supercritical fluid chromatographyt tripletT3P propylphosphonic anhydrideTBAF tert-butyl ammonium fluorideTBS or TBDMS tert-butyldimethyl silylTBDPS tert-butyldiphenylsilylTBDPSC1 tert-butyldiphenylsilyl chlorideTBSC1 tert-butyldimethylsilyl chloride / Bu tert-butylTEA triethylamine (Et3N)TEMED tetramethylethylenediamineTf trifl ateTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTLC thin layer chromatographyTMS trimethylsilylTris tris(hydroxymethyl)aminomethaneTs toluenesulfonyl (tolyl)UPLC ultra performance liquid chromatographywt. weightXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene(9,9-dimethyl-977-xanthene-4,5- diyl)bis(diphenylphosphine)General

[0070] Starting materials used were obtained from commercial sources or prepared in other examples, unless otherwise noted.

[0071] The methods used for the preparation of the compounds of this invention are illustrated by the following schemes. Unless specified otherwise, all starting materials used are commercially available.Scheme 1.

[0072] Compounds of formula (I) and (II) are prepared from a cyano intermediate such as la. Cycloaddition of la with sodium azide provides lb. Alkylation of la with an alkylhalide followed by deprotection afford intermediate I and II.Scheme 2.

[0073] Compounds of formula (III) are prepared from la via hydrolysis of la to give amide 2b. Curtius rearrangement of 2b followed by deprotection afford 2c. Treatment of aniline 2c with trimethyl orthoformate and azidotrimethylsilane followed by acidic deprotection provide intermediate III.Scheme 3.

[0074] Compounds of formula (IV) and (V) are prepared from 2c. Treatment of 2c with 4-methylbenzenesulfonohydrazide and 2,2-dimethoxyacetaldehyde under modified Sakai reaction conditions afforded IV. Alternatively, azide 3b is prepared from 2c via the formation of diazonium intermediates. Copper catalyzed cycloaddition of 3b with alkyne 3c followed by deprotection afford intermediate V.Scheme 4.

[0075] General synthesis of multiple embodiments of the present invention are summarized in Scheme 4 which depicts the preparation of compounds VI from intermediate 4a. 4a is converted to 4c via treatment with DPPA to form an azide intermediate followed by copper catalyzedcycloaddition with alkyne 4b. Oxidation with a reagent such as mCPBA followed by coupling with lactam 4d under basic conditions provides 4e. Hydrolysis of the ester in 4e affords 4f.Amide coupling betw een acid 4f and amine such as 4g provides VI.Scheme 5.

[0076] General synthesis of multiple embodiments of the present invention are summarized in Scheme 5 which depicts the preparation of compounds VII from intermediate 5a. Formation of azide 5b can be achieved by treatment of 5 a with methanesulfonylchloride followed by sodium azide or treatment of 5a with DPP A. Copper catalyzed cycloaddition of azide 5b with alkyne 5c affords triazole 5d. Treatment of 5d with lactam 4d under palladium catalyzed C-N bond formation conditions gives 5e. Hydrolysis of the ester 5e under either acidic or basic conditions generates acid 5f. Amide coupling between acid 5f and amine such as 4g provides VII.INTERMEDIATES1-((S)-1-(4,5-dimethyl-6-((1R,5lSy2-oxo-3-azabicyclo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-lH- 1.2.3-triazole-4-carboxylic acid

[0077] Intermediate A was prepared according to the procedure described in W02022010828 which is hereby incorporated by reference.Intermediate Bl and B2Ethyl 1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate and ethyl 1-((R)-1-(4-methyl-6-((1R,51S,)-2-oxo-3-azabicyclo[3.1, 0]hexan-3-y l)py ridin-3-yl)ethyl)- 177- 1.2.3-triazole-4-carboxylate

[0078] Intermediate Bl and B2 was prepared according to the procedure described in W02022010828.Intermediate Cl and C2l-(( )-l-(5-chloro-4-methyl-6-(-2-oxo-3-azabicvclo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-17 / -1.2.3-triazole-4-carboxylic acid and l-((A)-l-(5-chloro-4-methyl-6-(oxo-3-azabicyclo[3, 1.01hexan-3-yl)pyridin-3-yl)ethyl)- 1, 2.3-triazole-4-carboxylic acidStep 1. Ethyl 1-((S)-1-(4-methyl-6-((1R,5S,)-2-oxo-3-azabicvclo[3.1.01hexan-3-yl)pyridin-3-yDethyl)- 177- 1.2.3 -tri azol e-4-carboxylate.

[0079] To a solution of ethyl l-((S)-l-(4-methyl-6-((lA.5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-17 / -l,2,3-triazole-4-carboxylate (100 mg, 0.281 mmol) in MeCN (3 mL) was added trichloroisocyanuric acid (131 mg, 0.563 mmol). The mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (40 g ISCO), eluting with (0-30% CH3CN / DCM) to give the title compound. MS (ESI) m / z: 390.2 [M+H]+.Step 2, l-((S)-l-(5-chloro-4-methyl-6-(-2-oxo-3-azabicvclo|3.1.0|hexan-3-yl)pyridin-3-yl)ethyl)-17 / -1.2.3-triazole-4-carboxylic acid.

[0080] To a solution of ethyl l-((5)-l-(5-chloro-4-methyl-6-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-17 / -l,2,3-triazole-4-carboxylate (72 mg. 0.185mmol) in MeOH (4 ml) was added 1.0 M LiOH in H2O (230 µL, 0.230 mmol). The mixture was soncated at room temperature for 2 h before 1.0 M HC1 in H2O (231 pl, 0.231 mmol) was added. It was concentrated in vacuo. The residue was washed with MeOH / DCM (1 / 1) and filtered. The filtrate was concentrated in vacuo to give the title compound. MS (ESI) m / z: 362.1 [M+H]+.

[0081] Using similar procedure, 1-((R)-1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid was prepared starting from ethyl 1-((R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate.Intermediate D1-((S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acidStep 1. 2-chloro-3-fluoro-5-iodo-4-methylpyridine.

[0082] To a stirred solution of LDA (299.63 g, 2796.87 mmol) in THF (6000 mL) was added a solution of 2-chloro-3-fluoro-4-iodopyridine (600 g, 2330.73 mmol) in THF (1200 mL) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 5 h at -30 °C. To the above mixture was added Mel (363.90 g, 2563.80 mmol) dropwise at -78 °C. The resulting mixture was stirred for additional 30 min at -78 °C. The reaction was quenched with sat. NH4CI (aq.) (12 L). The resulting mixture was extracted with EtOAc (3 x 3 L). The combined organic layers were washed with brine (2 x 4 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Pet. ether / EtOAc (100: 0) to afford 2-chloro-3-fluoro-5-iodo-4-methylpyridine. MS (ESI) m / z: 271.9 [M+H]+.Step 2, l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanone.

[0083] A solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (410 g, 1510.35 mmol) in THF (8200 mL) was treated with iPrMgCL LiCl (285.15 g. 1963.45 mmol) for 1 h at -30 °C under nitrogen atmosphere followed by the addition of AC2O (200.45 g, 1963.45 mmol) in THF (2000 mL) dropwise at -20 °C. The resulting mixture was stirred for 1 h at -15 °C. The reaction wasquenched with NH4CI at 0 °C. The resulting mixture was extracted with EtOAc (3 x 4000 mL). The combined organic layers were washed with brine (3 x 2000 mL), dried overanhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Pet. ether / EtOAc (10:1-4:1) to afford l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanone. MS (ESI) m / z: 229.2 |M+H+ACN|.Step 3, (lR)-l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanol.

[0084] Water (10000 mL) was charged to a 30 L reactor, followed by the addition of KH2PO4 (72.49 g. 533.04 mmol, 0.5 equiv) at 25 °C. After 30 min. NaOH (61.2 g) was added dropwise until the pH was 7. Then enzyme KRED PIBO2 (40 g, 20% wt.) and NADP (20 g, 10% wt.) were added. After 30 min, l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanone (200 g, 1066.09 mmol, 1.0 equiv) in IP A (4000 mL) was added drop wise at 30 °C and the mixture was aged at 35 °C for 36 h. The mixture was partitioned between brine (20 L) and EtOAc (20 L). The water layer was back extracted with EtOAc (6 L). The combined organic layers were washed with brine (6 L), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with Pet. ether / EtOAc (100:0-60:40) to afford (lR)-l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanol. MS (ESI) m / z: 190.1 [M+H]+.Step 4, (S)-5-(l-azidoethyl)-2-chloro-3-fluoro-4-methylpyridine.

[0085] To a stirred solution of (lR)-l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanol (180 g, 949.31 mmol) in THF (1800 mL) was treated with DPPA (391.89 g, 1423.97 mmol) and DBU (216.78 g, 1423.97 mmol) at 25 °C under nitrogen atmosphere. The final reaction mixture was stirred for 12 h at 70 °C. The reaction was then quenched by the addition of ice water. The resulting solution was extracted with ethyl acetate (3 x 2000 mL) and the organic layers was combined. The resulting mixture was washed with brine (3 x 2000 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to afford (S)-5-(l-azidoethyl)-2-chloro-3-fluoro-4-methylpyridine. MS (ESI) m / z: 215.0 [M+H]+.Step 5, tert-butyl 1-[(S)-1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethyl]-1,2,3-triazole-4-carboxylate.

[0086] To a stirred mixture of 5-[(lS)-l-azidoethyl]-2-chloro-3-fluoro-4-methylpyridine (200 g, 931.83 mmol). CuSCU (14.87 g, 93.18 mmol) and / e / 7-butyl prop-2-ynoate (117.56 g, 931.83 mmol) in f-BuOH (2000 mL) and H2O (2000 mL) were added sodium ascorbate (55.66 g, 279.55 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with NaHCCh (aq.)(1000 mL). The resulting mixture was extracted with EtOAc (3 x 2000 mL). The combined organic layers were washed with brine (2 x 1000 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Pet. ether / EtOAc (100:0-50:50). The resulting impure product containing fractions were combined and concentrated under vacuum. The residue was purified by trituration with MTBE (1000 mL). The precipitated solids were collected by filtration and washed with MTBE (300 mL). The resulting mixture was dried under vacuum to afford tert-butyl l-[(l< S)-l-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethyl]-l,2,3-triazole-4-carboxylate. This material was used in the next step without further purification. MS (ESI) m / z: 341.2 [M+H]+. Step 6. tert-butyl 1-[(1S)-1-{5-fluoro-4-methyl-6-[(1R,5tSf)-2-oxo-3-azabicvclo|3. 1. O|hexan-3-yl1pyridin-3-yl}ethyl]-1.2.3-triazole-4-carboxylate.

[0087] A solution of tert-butyl 1-[(1S)-1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethyl]-1,2,3-triazole-4-carboxylate (175 g, 513.52 mmol, 1.0 equiv) and (17?,5S)-3-azabicyclo[3.1.0]hexan-2-one (69.82 g, 718.93 mmol) in dioxane (2975 mL) was treated with CS2CO3 (334.63 g, 1027.05 mmol), Xantphos (29.71 g, 51.353 mmol) and Pd2(dba)s (47.03 g, 51.35 mmol). The mixture was stirred at 100 °C for 16 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (2 x 1500 mL). The combined organic layers were washed with brine (3 x 800 mL). dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Pet. ether / EtOAc (1:4-0:100) to afford terf-butyl l-[(15)-l-{5-fluoro-4-methyl-6-[(17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl]pyridin-3-yl}ethyl]-l,2,3-triazole-4-carboxylate. MS (ESI) m / z: 402.2 [M+H]+.Step 7, l-(tiS)-l-(5-fluoro-4-methyl-6-((17?.5X)-2-oxo-3-azabicvclo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-177-1.2.3-triazole-4-carboxylic acid.

[0088] To a solution of te / 7-butyl l-((S)-l-(5-fluoro-4-methyl-6-((17?,55)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-l / 7-l,2,3-triazole-4-carboxylate (1.00 g. 2.49 mmol) in DCM (3.11 mL) was added HC1 (6.23 mL, 4.00 molar, 24.9 mmol). The reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give the title compound. MS (ESI) m / z: 346.3 [M+H]+.Intermediate El, E2 and E3l-(1-(1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid, 1-((S)-1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid and 1-((R)-l-(5-methoxy-4-methyl-6-((17?,51S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acidStep 1. 2-chloro-3-fluoro-5-iodo-4-methylpyridine.

[0089] To a solution of 2-chloro-3-fluoro-4-iodopyridine (50 g, 194 mmol) in THF (500 mL) stirred at -78 °C was added a solution of 2 M LDA in THF (117 mL, 233 mmol). The reaction solution was stirred at -78 °C for 2 h. To this solution was added Mel (97 mL, 1554 mmol) and the resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched by water (200 mL) at -78 °C and the resulting mixture was warmed to 0 °C. It was diluted with water (60 mL), extracted with EtOAc (50 mL x 3). The combined organics were concentrated under vacuum and the residue was purified by column chromatography (SiCh, Pet. ether / EtOAc = 30: 1) to afford the title compound. 'H NMR (400 MHz, CDCh) 8: 8.47 (s, 1H), 2.44 (d, J = 2.0 Hz, 3H).Step 2, 2-chloro-5-iodo-3-methoxy-4-methylpyridine.

[0090] To a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (9.0 g, 33.2 mmol) in MeOH (150 mL) was added sodium methanolate (3.58 g. 66.3 mmol). The resulting mixture was stirred at 85 °C under N2 for 48 h. The reaction mixture was poured into water (150 mL), extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed under vacuum, the residue was purified by flash silica gel chromatography MPLC (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-3% ethyl acetate / petroleum ether gradient @ 35 mL / min) to give the title compound. MS (ESI) m / z: 283.9 [M+H]+.Step 3, l-(6-chloro-5-methoxy-4-methylpyridin-3-yl) ethan-l-one.

[0091] Dichlorobis (triphenylphosphine) palladium (II) (0.743 g, 1.058 mmol) was dissolved in toluene (30 mL). Tributyl(l-ethoxyvinyl)stannane (3.58 mL, 10.58 mmol) and 2-chloro-5-iodo-3-methoxy-4-methylpyridine (2.0 g, 7.05 mmol) were then added. The resulting mixture was stirred at 90 °C under N2 for 16 h. It was cooled to 25 °C and 6 N HC1 (20 mL) aqueous solution was added and the mixture was stirred at 25 °C for 1 h. NaHCCh (aq. 40 mL) was added and the mixture was washed with saturated aqueous KF (3 x 25 mL) solution. The mixture was extractedwith DCM (3 x 20 mL). The combined organics were washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered and the solvent was evaporated under reduced pressure. The filtrate w as concentrated in vacuo and the residue w as purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0-5% EtOAc / pet. ether, gradient) to give the title compound. MS (ESI) m / z: 200.1 [M+H]+.Step 4, l-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-l-ol.

[0092] To a solution of l-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-l-one (1.1 g, 5.51 mmol) in MeOH (20 mL) stirred at 0 °C was added NaBH₄ (0.313 g, 8.27 mmol). The reaction was stirred at 25 °C for 1 h. Saturated aqueous ammonium chloride solution (40 mL) was added and the resulting mixture was extracted with EtOAc (3 x 10 mL). Most of water in aqueous phase was removed under vacuum and the leftover mixture was extracted with EtOAc (3 x 25 mL). The combined organics w ere washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum and the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0-60% ethyl acetate / pet. ether gradient) to give the title compound. MS (ESI) m / z: 202.0 [M+H]+.Step 5, 2-chloro-5-(l-chloroethyl)-3-methoxy-4-methylpyridine.

[0093] To a mixture of l-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-l-ol (1.0 g, 4.96 mmol) and triethylamine (2.068 mL, 14.88 mmol) in DCM (15 mL) stirred at -5 °C, was added methanesulfonyl chloride (1.392 mL, 17.98 mmol). The reaction mixture was stirred at 25° C for 16 h. The reaction was quenched by addition of water (25 mL) and layers were separated.Aqueous layer was extracted with EtOAc (10 mL x 3). Combined organic layer was washed with aqueous NaHCO₃ solution (25 mL), followed by water. The solvent was evaporated in vacuo to give the crude title compound. This compound was used in the next step without further modification. MS (ESI) m / z: 220.0 [M+H]+.Step 6, 5-(l-azidoethyl)-2-chloro-3-methoxy-4-methylpyridine.

[0094] To a 100 mL three-mouth flask was added 2-chloro-5-(l-chloroethyl)-3-methoxy-4-methylpyridine (1.091 g, 4.96 mmol), sodium azide (1.050 g, 16.15 mmol), and 20 mL of DMF at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with 5 mL of EtOAc and then added 15 mL of dilute NaOH aqueous solution (pH = 14). After stirred for 5 min, the organic phase was isolated. The aqueous phase was extracted by EtOAc (5 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a solution of the crude title compound in ~5 mL of the leftover solvent. This solution w as used in the next step without further purification. MS (ESI) m / z: 226.8 [M+H]+.Step 7, tert-butyl 1-(1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate.

[0095] The above solution of 5 -(l-azidoethyl)-2-chl oro-3 -methoxy-4-methylpyri dine (1.124 g, 4.96 mmol) was dissolved in / -BuOH (20 mL) and H2O (20 mL). To the stirred solution was added tert-butyl propiolate (0.813 g, 6.45 mmol), sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (1.965 g, 9.92 mmol) and copper(II) sulfate pentahydrate (0.124 g, 0.496 mmol) sequentially at 28 °C. The reaction mixture was stirred at 28 °C for 16 h. It was filtered and the filtrate was concentrated in vacuo. To the residue was added water (30 mL) and the resulting mixture was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residued was purified by flash silica gel chromatography (ISCO; 20 g Agela Silica Flash Column, Eluent of 0-50% EtOAc gradient @ 30 mL / min) to give racemic mixture of the title compound. MS (ESI) m / z: 353.1 [M+H]+.Step 8, tert-butyl l-(l-(5-methoxy-4-methyl-6-(-2-oxo-3-azabicvclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-17T-1.2.3-triazole-4-carboxylate.

[0096] To a stirred solution of tert-butyl 1-(1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (650 mg, 1.842 mmol), (17?,5S)-3-azabicyclo[3.1.0]hexan-2-one (215 mg, 2.211 mmol) in toluene (10 mL) was added cesium carbonate (1201 mg, 3.68 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (213 mg, 0.368 mmol), Pd2(dba)3 (253 mg, 0.276 mmol) under N2. The reaction was stirred at 90 °C for 16 h. It was diluted with water (30 mL), extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO; 12 g Agela Silica Flash Column, Eluent of 0-70% EtOAc / Pet. Ether gradient @ 30 mL / min) to give the title compound. MS (ESI) m / z: 414.3 [M+H]+.Step 9, 1-(1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid.

[0097] Tert-butyl l-(l-(5-methoxy-4-methyl-6-((17?,5 )-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate (133 mg, 0.322 mmol) in DCM / TFA = 1: 2 (4.5 mL) was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo. The residue was dissolved in a mixture of water / MeCN = 1: 2 (~25 mL), added ~ 5 g of resin. After stirring for 1 h at 25 °C. The mixture was filtered and the filter cake was rinsed with MeCN (10 mL). The filtrate was concentrated in vacuo to give the title compound (intermediate E1) as its HCl saltform. Resin information: Bio-RAD AG MP-1M Resin, 500 g, Cat: #141-1841, Macroporous anion exchange resin, 100-200 mesh, chloride form. MS (ESI) m / z: 358.2 [M+H]+.Step 10. l-((«S')-l-(5-methoxy-4-methy’l-6-((17?.5<S)-2-oxo-3-azabicy’clo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-177-1.2.3-triazole-4-carboxylic acid and l-((7?)-l-(5-methoxy-4-methyl-6-(-2-oxo-3-azabicyclo|3. L0|hexan-3-yl)pyridin-3-yl)ethyl)-I77-I.2.3-triazole-4-carboxylic acid.

[0098] The two diastereomers of l-(l-(5-methoxy-4-methyl-6-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid (500 mg, 1.399 mmol) was separated by SFC (DAICEL CHIRALPAK IG (250 mm * 30 mm * 10 pm), Condition CO2 / z-PrOH (0.1%NH₃·H₂O), Begin B 60; End B 60; Gradient Time (min) 1; 100% B Hold Time (min) 1; FlowRate (mL / min) 60; Injections 80) to individually give 1-((S)-1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (intermediate E2, the faster eluting isomer, MS (ESI) m / z: 358.1 [M+H]⁺) and 1-((R)-1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (intermediate E3, the slower eluting isomer, MS (ESI) m / z: 358.1 [M+H]+).Intermediate FSynthesis of 1-(1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acidStep 1. Synthesis of 1-(1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid.

[0099] A mixture of te / 7-butyl l-(l-(5-methoxy-4-methyl-6-((17?,5< S’)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylate (115 mg, 0.278 mmol) and boron tribromide (400 pL, 4.23 mmol) in DCM (1 mL) was stirred at 25 °C for 1 h. The reaction was quenched by slowly adding it into 2 mL of water. The resulting mixture was concentrated under vacuum to remove DCM, the left over material was diluted with MeCN (2 mL), filtered and the filtrate was concentrated under vacuum. The residue was purified by reverse phase HPLC [Column: Boston Green ODS 150 * 30 mm x 5 pm; Condition: water (+ 0.04%HC1)-ACN; 10%-40% B; Gradient Time (min): 10; 100% B HoldTime: 2; Flow Rate (mL I min): 25; Injections: 4] to afford the title compound as its HC1 salt form. MS (ESI) m / z: 344.1 [M+H]+.Intermediate Gl-((S')-l-(4-methyl-2-((l,5< S’)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyrimidin-5-yl)ethyl)-l / / -l,2,3-triazole-4-carboxylic acidStep 1. l-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethan-l-ol.

[0100] To a solution of l-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethan-l-one (300 g, 1.65 mo) in THF (1.5 L) and MeOH (150 mL) stirred at 0 °C was added NaBH₄ (62.3 g, 1.65 mol) in portions over 2 h. The reaction was stirred at 0 °C for 1 h. The reaction was quenched by dropwise addition of saturated aqueous NH4CI solution (500 mL). The resulting mixture was extracted with MTBE (200 mL x 5). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate w as concentrated in vacuo. The residue w as purified by column chromatography (S1O2. Pet. ether / EtOAc = 5 / 1 to 1 / 1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ: 8.56 (s, 1H), 5.18 - 5.00 (m, 1H), 2.63 - 2.45 (m, 6H), 2.13 - 2.02 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H).Step 2, 5-(l-azidoethyl)-4-methyl-2-(methylthio)pyrimidine.

[0101] To a solution of l-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethan-l-ol (230 g, 1.25 mol), DPPA (378 g, 1.37 mol) and DMAP (153 g. 1.25 mol) in EtOAc (1.00 L) stirred at 0 °C, w-as added DBU (209 g, 1.37 mol) drop-wise over 1 h. The reaction mixture was stirred at 20 °C for 23 h. It w as partitioned betw een the reaction solvent and 500 mL of water. The organic phase was isolated, the aqueous phase was extracted with EtOAc (500mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried over anydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure at 35 °C. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ: 8.37 (s, 1H), 4.68 (q, J = 6.8 Hz, 1H), 2.47 (d, J = 18.8 Hz, 6H), 1.51 (d, J = 6.8 Hz, 3H).Step 3, te / 7-butyl l-(l-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-l / / -L2.3-triazole-4-carboxylate.

[0102] To a solution of 5-(l-azidoethyl)-4-methyl-2-(methylthio)pyrimidine (240 g, 1.15 mol), tert-butyl propiolate in MeOH (2.00 L) stirred at 20 °C, was added Sodium ascorbate (114 g, 573 mmol). A solution of CuSO4.5H2O (71.6 g, 287 mmol) in H2O (500 mL) was added drop-wise to the reaction mixture. It was stirred at 20 °C for 2 h. MeOH was removed under reduced pressure. To the leftover content was added H2O (1.0 L), and the resulting mixture was stirred at 20 °C for 1 h. It was filtered, the filter cake was dried under reduced pressure. The crude product was triturated with MTBE (500 mL) at 20 °C for 0.5 h and filtered to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ: 8.83 (s, 1H), 8.62 (s, 1H), 6.20 (q, J = 6.8 Hz, 1H), 2.50 (s, 3H), 2.41 (s, 3H), 1.93 (d, J = 7.2 Hz, 3H), 1.52 (s, 9H).Step 4, te / 7-butyl l-(l-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl )ethyl )-! / / - 1,2.3-triazole-4-carboxylate.

[0103] To a mixture of mCPBA (241 g, 1.12 mol, 80% purity) in DCM (1.00 L) stirred at 20 °C, was added a solution of tert-butyl l-(l-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-l / 7-l,2,3-triazole-4-carboxylate (125 g, 373 mmol) in DCM (500 mL) drop-wise. The reaction was stirred at 25 °C for 12 h. It was quenched with Na2S20s (200 g in 500 mL H2O) slowly. The organic phase was separated, the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (250 mL), dry over anhydrous Na2SO4, filter and the filtrate was concentrated in vacuo. The residue was triturated with MTBE (500 mL) at 20 °C for 0.5 hr and filter to give the title compound. ’H NMR (400MHz, CDCI3) 5: 8.70 (s, 1H), 8.03 (s, 1H), 6.14 (q, J= 7.2 Hz, 1H), 3.34 (s, 3H). 2.66 (s. 3H), 2.08 (d. J= 7.2 Hz. 3H), 1.59 (s. 8H), 1.64 - 1.54 (m, 1H).Step 5, terLbutyl l-((5)-l-(4-methyl-2-((17?.51S)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyrimidin-5-yl)ethyl)-l / / -1.2.3-triazole-4-carboxylate and tert-buty l l-((7?)-l-(4-methyl-2-((17?.55,)-2-oxo-3-azabicvclo[3. L01hexan-3-yl)pyrimidin-5-yl)ethyl)-1.2.3-triazole-4-carboxylate.

[0104] To a mixture of tert-butyl 1 -(1 -(4-methyl-2-(methylsulfonyl)pyrimi din-5 -yl)ethyl)- 1H-l,2,3-triazole-4-carboxylate (10 g, 27.2 mmol) and (17?,51S)-3-azabicyclo[3.1.0]hexan-2-one (2.64 g, 27.2 mmol) in dry THF (200 mL) was added a solution of 1 M LiHMDS in THF (27.22 mL, 27.2 mmol) drop-wise over 0.5 h at 20 °C. The reaction was stirred at 20 °C for 5 min before it was quenched by adding saturated aqueous NH4CI solution (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 3), washed with brine (500 mL), dried over anhydrous Na2SO4, filter and the filtrate w as concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1 to 0 / 1). The impure productcontaining fractions were combined and concentrated in vacuo. The residue was re-purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD Cl 8, 150*40 mm* 10 pm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%; 8min). The two diastereomers of the product was separated by SFC (Column: CHIRALCEL OJ, 5.0 cm l. D. x 25 cm L, 10 pm; Mobile phase: MeOH 100%; Flow rate: 60 mL / min) to give tert-butyl l-((?)-l-(4-methyl-2-((17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-17 / -l,2,3-triazole-4-carboxylate [the faster eluting isomer; ¹H NMR (400 MHz, CDCl₃) δ: 8.59 (s, 1H), 7.77 (s, 1H), 6.11 - 5.98 (m, 1H), 4.14 (br dd, J = 5.6, 11.6 Hz, 1H), 3.98 (br d, J = 11.6 Hz, 1H), 2.38 (s, 3H), 2.15 (br s, 1H), 2.07 - 1.88 (m, 4H), 1.57 (s, 9H), 1.29 - 1.18 (m, 1H), 0.86 (br d, J = 3.2 Hz, 1H)], and tert-butyl l-((< S)-l-(4-methyl-2-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-17 / -1.2.3-triazole-4-carboxylate [the slower eluting isomer, ¹H NMR (400 MHz, CDCl₃) δ: 8.57 (s, 1H), 7.79 (s, 1H), 6.05 (q, J = 7.2 Hz, 1H), 4.14 (dd, J = 5.6, 11.6 Hz, 1H), 3.97 (d, J = 11.6 Hz, 1H), 2.38 (s, 3H), 2.14 (br d, J = 5.6 Hz, 1H), 2.06 - 1.94 (m, 4H), 1.57 (s, 9H), 1.24 (dt, J = 4.8, 8.0 Hz, 1H), 0.89 - 0.84 (m, 1H)].Step 6, l-((5)-l-(4-methyl-2-(-2-oxo-3-azabicvclo[3.1.01hexan-3-yl)pyrimidin-5-yl)ethyl)-1.2.3-triazole-4-carboxylic acid.

[0105] To a solution of tert-butyl l-((S)-l-(4-methyl-2-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-177-l,2,3-triazole-4-carboxylate (45 g, 117 mmol) in DCM (400 mL) was added TFA (267 g, 2.08 mol) drop-wise at 20 °C. It was stirred at 20 °C for 12 h. The solvent was removed under reduced pressure. The residue was recrystallized from i-Pr₂O (100 mL) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ: 8.85 (s, 1H), 8.61 (s, 1H), 6.18 (q, J = 6.8 Hz, 1H), 4.05 (dd, J = 5.6, 11.2 Hz, 1H), 3.80 (d, J = 11.2 Hz, 1H), 2.37 (s, 3H), 2.06 - 1.96 (m, 2H), 1.90 (d, J = 7.2 Hz, 3H), 1.15 (dt, J = 4.2, 8.0 Hz, 1H), 0.74 (q, J = 4.0 Hz, 1H).Intermediate H(czs)-tert-butyl (3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate

[0106] Intermediate H was prepared according to the procedure described in W02022010828.Intermediate Itert-butyl ((cis)-3-(3-amino-6-methylpyridin-2-yl)cyclobutyl)carbamateStep 1. / e / 7 -butyl ((c7.s)-3-(3-carbamoyl-6-methvhiyridin-2-yl)cvclobutyl (carbamate.

[0107] To a solution of tert-butyl ((cA)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate (0.5 g, 1.740 mmol), hydrogen peroxide (3.96 g, 116 mmol) (30% in water) in DMSO (8 mL) was added potassium carbonate (0.751 g, 5.43 mmol). The mixture was stirred at 60 °C for 0.5 h. The mixture was diluted with water (20 mL) and saturated aqueous solution of Na₂SO₃ (10 mL), extracted with EtOAc (20 mL x 3), washed with brine (80 mL). dried over anhydrous Na₂SO₄. and filtered. The filtrate was concentrated in vacuum to afford the crude title compound. This material was used in the future reactions without further purification. MS (ESI) m / z: 306.1 [M+H]+.Step 2, te / 7-butyl ((cA)-3-(3-amino-6-methylpyridin-2-yl)cvclobutyl)carbamate.

[0108] A mixture of 2-(trimethylsilyl)ethan-l-ol (0.6 mL, 4.16 mmol), pyridine (0.5 mL, 6.21 mmol), tert-butyl ((cA)-3-(3-carbamoyl-6-methylpyridin-2-yl)cyclobutyl)carbamate (0.4 g, 1.310 mmol) and phenyl-13-iodanediyl bis(2,2,2-trifluoroacetate) (1 g, 2.325 mmol) in toluene (5 mL) was stirred at 80 °C for 3 h. The mixture was diluted with EtOAc (30 mL), washed with 0.5 N HC1 (50 mL) solution, brine (80 mL), dried over anhydrous Na2SO4, and filtered. The solvent was removed under vacuum, the residue was dissolved in 10 mL of THF. To this solution was added 1 N TBAF solution in THF (4 mL, 4.00 mmol). The reaction was stirred at 30 °C for 16 h under nitrongen atmosphere. The mixture was diluted with water (30 mL), extracted with EtOAc (10 mL x 3), washed with brine (40 mL). The solvent was removed under vacuum, the residue was purified by flash silica gel chromatography (Biotage; 12 g Agela Silica Flash Column;Eluent of 0-30% EtOAc I Pet. ether, gradient @ 40 mL / min) to give the title compound. MS (ESI) m / z: 278.1 [M+H]+.EXAMPLES EXAMPLE 1 and 2A-((cA)-3-(3-(2-(difluoromethyl)-27 / -tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)-l-((S)-l-(5-fluoro-4-methyl-6-((17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-127-l,2,3-triazole-4-carboxamide andjV-((cA)-3-(3-(2-(difluoromethyl)-27 / -tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)-l-((J?)-l-(5-fluoro-4-methyl-6-((lJ?,51S)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-17T-l,2,3-triazole-4-carboxamideStep 1. tert-butyl ((cA)-3-(6-methyl-3-(22 / -tetrazol-5-yl)pyridin-2-yl)cvclobutvf)carbamate.

[0109] A mixture of tert-butyl ((cz.s,)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate (400 mg, 1.392 mmol), ammonium chloride (149 mg, 2.78 mmol), NaNs (181 mg, 2.78 mmol) in DMA (10 mL) was heated to 120 °C and stirred for 3 days. It was cooled to room temperature, acidified to pH = 2-3 by 1.0 N HC1 aqueous solution, extracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give the crude title compound. This material was used in the next reaction without further purification. MS (ESI) m / z: 331.1 [M+H]+.Step 2, tert-butyl (-3-(3-(2-(difluoromethyl)-277-tetrazol-5-yl)-6-methylpyridin-2-yllcyclobutyllcarbamate and tert-butyl ((cz.,)-3-(3-(l-(difluoromethyl)-177-tetrazol-5-yl)-6-methylpyridin-2-yl)cvclobutyl)carbamate.

[0110] Tert-butyl ((cA)-3-(6-methyl-3-(27 -tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate (460 mg, 1.392 mmol) was dissolved in DCM (8 mL). It was cooled to 0 °C followed by addition of KOH (469 mg, 8.35 mmol), water (2 mL) and (bromodifluoromethyl)trimethylsilane (0.541 mL, 3.48 mmol) sequentially. The mixture was vigorously stirred at 0 °C for 1 h and then warmed to room temperature. It was partitioned between DCM and water. The separated organic phase was dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 0-50% EtOAc / DCM to give / cr / -butyl ((cA)-3-(3-(2-(difluoromethyl)-277-tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)carbamate (faster eluting isomer, MS (ESI) m / z: 381.4 [M+H]+), and tert-butyl ((cA)-3-(3-(l-(difluoromethyl)-17T-tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)carbamate (slower eluting isomer, MS (ESI) m / z: 381.4 [M+H]+).Step 3, (cA)-3-(3-(2-(difluoromethyl)-27 / -tetrazol-5-yl)-6-methylpyridin-2-yl)cvclobutanamine.[OHl] A solution of tert-butyl ((cA)-3-(3-(2-(difluoromethyl)-27 / -tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)carbamate (50 mg, 0.131 mmol) in 2 mL of 4 N HC1 in dioxane was stirred at 40 °C for 15 min. The mixture was concentrated under vacuum to afford the crudetitle compound as its HC1 salt form. This material was used in the next reaction without further purification. ¹H NMR (400 MHz, CD₃OD) δ: 8.75 (d, J = 8.4 Hz, 1H), 8.35 (m, J = 56.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 4.55 - 4.42 (m, 1H), 4.03 - 3.85 (m, 1H), 2.92 (s, 3H), 2.90 - 2.82 (m, 4H).Step 4, A-(( )-3-(3-(2-(difluoromethyl)-27 / -tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)-l-((5)-l-(5-fluoro-4-methyl-6-((17?.5lS)-2-oxo-3-azabicvclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-177-1.2.3 -triazole-4-carboxami de and 7V-((c / .s,)-3-(3-(2-(difluoromethyl)-2F7-tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutyl)-l-((7?)-l-(5-fluoro-4-methyl-6-((17?.5lS)-2-oxo-3-azabicvclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-1.2.3-triazole-4-carboxamide.

[0112] A solution of EDC (100 mg, 0.522 mmol), (cA)-3-(3-(2-(difluoromethyl)-277-tetrazol-5-yl)-6-methylpyridin-2-yl)cyclobutan-l -amine (35 mg, 0.125 mmol) and l-(l-(5-fluoro-4-methyl-6-((17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid (35 mg, 0.101 mmol) in 0.5 mL of pyridine was stirred at 25 °C for 0.5 h. The mixture was purified by reverse phase HPLC [Column: Welch Xtimate C18 150 * 25 mm * 5 pm; Condition: water (+ 0.01% TFA) - ACN; 25%-55% B; Gradient Time (min) 11; 100% B Hold Time 2; Flow Rate (mL / min): 25; Injections: 4] to afford a mixture of the two title compounds. This material was further separated by SFC [Column: DAICEL CHIRALPAK AD (250 mm * 30 mm * 10 pm). Condition: CCh-EtOH; 60% B; Gradient Time(min): 10; 100% B Hold Time: 10; Flow' Rate (mL / min): 80; Injections: 30] to afford the faster-eluting stereoisomer of the title compound (Example 1) and an impure fraction containing mostly the slower-eluting stereoisomer of the title compound. This impure material was further separated by SFC [Column: DAICEL CHIRALPAK OD H, 250 mm * 30 mm * 5 pm; Condition: CCh-EtOH; 40% B; Gradient Time (min): 10; 100% B Hold Time: 10; Flow Rate (mL / min): 80; Injections: 25] to afford the slower-eluting stereoisomer of the title compound (Example 2).Example 1: MS (ESI) m / z: 608.1 [M+Hf.’H NMR (400 MHz, CD3OD) 5: 8.45 - 8.09 (m, 4H), 7.31 (d, J = 8.0 Hz, 1H). 6.25 (q, J = 6.8 Hz, 1H), 4.64 - 4.50 (m, 1H), 4.31 (dd, J = 5.8. 10.3 Hz. 1H). 4.15 - 4.05 (m, 1H), 3.68 (d, J = 10.6 Hz, 1H), 2.82 - 2.71 (m, 2H). 2.68 (s. 3H), 2.59 -2.53 (m, 2H), 2.30 (s, 3H), 2.22 - 2.14 (m, 1H), 2.05 - 1.98 (m, 4H), 1.35 - 1.25 (m, 1H), 0.92 -0.85 (m, 1H).Example 2: MS (ESI) m / z: 608.1 [M+H]+. ’H NMR (400 MHz, CDCh) 5: 8.21 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.77 (br d. J = 8.8 Hz. 1H), 7.76 (t, J = 57.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.02 (q, J = 7.2 Hz, 1H), 4.77 - 4.65 (m, 1H), 4.34 - 4.23 (m, 1H), 4.16 - 4.03 (m, 1H), 3.74-3.35 (m, 1H), 2.92 - 2.78 (m, 2H), 2.72 (s, 3H), 2.51 (q, J = 8.8 Hz, 2H), 2.21 (d, J =2.0 Hz, 3H), 2.10 - 2.06 (m, 2H), 2.04 (d, J= 7.2 Hz, 3H), 1.26 - 1.24 (m, 1H), 0.97 - 0.91 (m,1H).

[0113] The following compounds were prepared using procedures similar to those described for Step 4 of Exampl e 1 using appropriate starting materials.Examples 7 and 8l-((?)-l-(5-hydroxy-4-methyl-6-((U?,5N)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((c / 5)-3-(6-methyl-3-(177-tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-127-l,2,3-triazole-4-carboxamide and l-((N)-l-(5-hydroxy-4-methyl-6-((l.5< S’)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((cz.s’)-3-(6-methyl-3-(177-tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-17T-1,2,3-triazole-4-carboxamideStep 1: tert-butyl (-3-(3-carbamoyl-6-methylpyridin-2-yl)cvclobutyl)carbamate.

[0114] To a solution of tert-butyl ((czs)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate (0.5 g, 1.740 mmol), hydrogen peroxide (3.96 g, 116 mmol) (30% in water) in DMSO (8 mL) was added potassium carbonate (0.751 g, 5.43 mmol). The mixture was stirred at 60 °C for 0.5 h with gas genarating. The mixture was diluted with water (20 mL) and saturated aqueous solution of Na₂SO₃ (10 mL), extracted with EtOAc (20 mL x 3). washed with brine (80 mL), dried over anhydrous Na₂SO₄. and filtered. The filtrate was concentrated in vacuum to afford the crude title compound. This material was used in the future reactions without further purification. MS (ESI) m / z: 306.1 [M+H]+.Step 2: tert-butyl (-3-(3-amino-6-methylpyridin-2-yl)cvclobut\4)carbamate.

[0115] A mixture of 2-(trimethylsilyl)ethan-l-ol (0.6 mL, 4.16 mmol), pyridine (0.5 mL, 6.21 mmol), tert-butyl ((cA)-3-(3-carbamoyl-6-methylpyridin-2-yl)cyclobutyl)carbamate (0.4 g, 1.310 mmol) and phenyl-13-iodanediyl bis(2,2,2-trifluoroacetate) (1 g, 2.325 mmol) in toluene (5 mL) was stirred at 80 °C for 3 h. Solution was black from white and muddy. The mixture was diluted with EtOAc (30 mL), washed with 0.5 N HC1 (50 mL), brine (80 mL), dried over anhydrous Na2SO4, and filtered. The solvent was removed under vacuum, the residue was dissolved in 10 mL of THF. To this solution was added 1 N TBAF solution in THF (4 mL, 4.00 mmol). The reaction was stirred at 30 °C for 16 under nitrongen atmosphere. The mixture w as diluted with water (30 mL). extracted with EtOAc (10 mL x 3), washed with brine (40 mL), concnetrated and purified by flash silica gel chromatography (Biotage; 12 g Agela Silica Flash Column, Eluent of 0-30% EtOAc / Pet. ether gradient @ 40 mL / min) to give the title compound. MS (ESI) m / z: 278.1 [M+H]+.Step 3, tert-butyl ((cA)-3-(6-methyl-3-( IH-tetrazol- 1 -yl )pyridin-2-yl )cvclobutyl )carbamate.

[0116] A solution of trimethyl orthoformate (1 g, 9.42 mmol), azidotrimethylsilane (1 mL, 9.43 mmol) and fert-butyl ((cA)-3-(3-amino-6-methylpyridin-2-yl)cyclobutyl)carbamate (200 mg, 0.721 mmol) in AcOH (8 mL) was stirred at 100 °C for 2 h. The mixture was diluted with 30 mL of saturated NaHCOs solution and then extracted with EtOAc (20 mL x 3). The combined organics was w ashed with brine (80 mL) and concentrated under vacuum. The residue was purified by flash silica gel chromatography (Biotage; 12 g Agela Silica Flash Column, Eluent of 0-45% EtOAc / Pet. ether, gradient @ 40 mL / min) to give crude title compound. This material was further purified by prep-TLC (SiO2. Pet. ether: EtOAc = 1: 2) to afford the title compound. MS (ESI) m / z: 331.1 [M+H]+.Step 4, (uA)-3-(6-methyl-3-( 177-tetrazol-l-yl)pyridin-2-yl)cvclobutanamine.

[0117] A solution of tert-butyl ((cA)-3-(6-methyl-3-(177-tetrazol-l-yl)pyridin-2-yl)cyclobutyl)carbamate (150 mg, 0.454 mmol) in 4 N HC1 in dioxane (4 mL) was stirred at 40 °C for 0.5 h. The solvent as removed under vacuum to afford the title compound as its HC1 salt form. This material was used in the next reaction without further purification.1H NMR (400 MHz, CD3OD) 5: 9.58 (s, 1H), 8.04 (br d, J = 7.2 Hz, 1H), 7.61 (br d, J = 8.0 Hz, 1H), 3.80 -3.71 (m, 1H), 3.54 - 3.43 (m, 1H), 2.81 (s, 3H), 2.71 - 2.45 (m, 4H).Step 5, 1 -(( / ?)- 1 -(5-hvdroxy-4-methyl-6-(( 2-oxo-3-azabicvclo|3. 1,0|hexari-3-yl )pyridiri-3-yl)ethyl)-A-((cA)-3-(6-methyl-3-(17f-tetrazol-l-yl)pyridin-2-yl)cvclobutyl)-l,2.3-triazole-4-carboxamide and l-((> Sf)-l-(5-hvdroxy-4-methyl-6-((17?,55r)-2-oxo-3-azabicvclo[3. L01hexan-3-y Dpyri din-3 -yl )ethyl )-A-((c7.s)-3-(6-methyl-3-( I / / -tetrazol- 1 -yl )pyridin-2-yl jcyclobutyl)-l,2.3-triazole-4-carboxamide.

[0118] A mixture of (cA)-3-(6-methyl-3-(12 / -tetrazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (40 mg, 0.174 mmol), l-(l-(5-hydroxy-4-methyl-6-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-17 / -l,2,3-triazole-4-carboxylic acid (40 mg, 0.117 mmol) and EDC (33.3 mg, 0.174 mmol) in 1 mL of pyridine was stirred at 25 °C for 1 h. The reaction content was purified directly by reverse phase HPLC [Column: Boston Prime C18 150 * 40 mm * 5 pm; Condition: water (10 mM-NH₄HCO₃)-ACN. 25%-55% B; Gradient Time (min): 10; 100% B Hold Time: 2; Flow Rate (mL / min): 60. Injections: 1] to afford the title compound as a mixture of two diastereomers. This material was further separated by SFC [Column: DAICEL CHIRALCEL IG, 250 mm * 30 mm * 10 pm; Condition: Neu-EtOH. 45% EtOH; Gradient Time (min): 10; 100% B Hold Time: 1; Flow Rate (mL / min): 80; Injections: 30] to afford the faster-eluting stereoisomer of the title compound (Example 7) and the slower-eluting stereoisomer of the title compound (Example 8).Example 7: MS (ESI) m / z: 556.2 [M+H]+. 'H NMR (400 MHz, CDCh) 5: 9.90 (s. 1H), 8.73 (s, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7.71 (br d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.06 (q, J = 7.2 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.38 - 4.26 (m, 1H), 4.25 - 4.13 (m, 1H), 3.10 - 2.98 (m, 1H), 2.77 (s, 3H), 2.73 - 2.62 (m, 2H), 2.55 - 2.44 (m, 2H), 2.25 - 2.19 (m, 1H), 2.17 (s, 3H), 2.16 - 2.12 (m, 1H). 1.98 (d, J = 7.2 Hz, 3H), 1.36 - 1.29 (m, 1H), 0.98 - 0.92 (m. 1H);Example 8: MS (ESI) m / z: 556.2 [M+H]+. 'H NMR (400 MHz, CDCh) 5: 9.90 (s, 1H), 8.73 (s, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7.71 (br d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.06 (q, J = 7.2 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.38 - 4.26 (m, 1H), 4.25 - 4.13 (m, 1H), 3.10 - 2.98 (m, 1H), 2.77 (s, 3H). 2.73 - 2.62 (m. 2H), 2.55 - 2.44 (m, 2H), 2.25 - 2.19 (m, 1H), 2.17 (s, 3H), 2.16 - 2.12 (m, 1H), 1.98 (s, J = 7.2 Hz, 3H), 1.36 - 1.29 (m, 1H), 0.98 - 0.92 (m, 1H).Examples 9 and 10l-(( )l-(5-fluoro-4-methyl-6-((l,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((cA)-3-(6-methyl-3-(17 / -tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-lE / -l,2,3-triazole-4-carboxamide and l-((S)l-(5-fluoro-4-methyl-6-((1?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-Ar-((cz4)-3-(6-methyl-3-(127-tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-l / / -1,2,3-triazole-4-carboxamidel-(( / ?)l-(5-fluoro-4-methyl-6-((l / ?,5»S)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-A-((c7.s)-3-(6-rnethyl-3-( I / / -tetrazol- l-yl)pyridin-2-yl)cvclobutyl )- 1.2.3-triazole-4-carboxamide and l-((5f)l-(5-fluoro-4-methyl-6-((lA.55)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridm-3-yl)ethyl)-A-((c7.s)-3-(6-methyl-3-tetrazol-l-yl)pyridin-2-yl)cvclobutyl )-1.2.3-triazole-4-carboxamide.

[0119] To a solution of l-(l-(5-fluoro-4-methyl-6-((l / ?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-17 / -l,2,3-triazole-4-carboxylic acid (40 mg, 0.116 mmol) and (c / s)-3-(6-methyl-3-(17f-tetrazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (29.3 mg, 0.127 mmol) in pyridine was added EDC (66.6 mg, 0.347 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate w as concentrated in vacuo. The residue w as purified by reverse phase HPLC (Boston Prime Cl 8, 150 * 30 mm * 5 pm; Condition: water (0.04% NH3 H2O+IO mM NHiHCOsj / ACN Begin B, 45%; End B, 75%; Gradient Time (min) 10; 100% B Hold Time 2; Flow Rate (mL / min) 25; Injections 1) to give a mixture of the two title compounds along with some impurity. The two stereoisomers were separated by SFC (DAICEL CHIRALPAK OJ (250mm * 30 mm, 10 pm); Condition: CO2-EtOH (0.1% NH3H2O); Begin B 50%, End B 50%; Gradient Time (min) 10; 100% B Hold Time 1; Flow’ Rate (mL / min) 80; Injections 40). The faster eluting isomer was re-purified by reversed prep-HPLC (Boston Green ODS 150 * 30 mm * 5 pm Condition water (+ 0.1% TFA)-ACN; Begin B, 32; End B 52;Gradient Time (min) 11; 100% B Hold Time, 2; Flow- Rate (mL / min) 25; Injections 1) to give 1-(l(J?)-(5-fluoro-4-methyl-6-((lJ?,5S)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-A-i(c7.s)-3-(6-methyl-3-( l / 7-tetrazol-l-yl)pyri din-2 -yljcyclobutyl)- 1 / 7-1, 2, 3-triazole-4-carboxamide as its TFA salt form (Example 9). The slower eluting isomer was re-purified by reversed prep-HPLC (Boston Green ODS 150 * 30 mm * 5 pm; Condition: waler (+ 0.1% TFA)- ACN; Begin B, 32; End B, 52; Gradient Time (min) 11; 100% B Hold Time 2; Flow Rate (mL / min), 25; Injections: 1) to give l-(l(S)-(5-fluoro-4-methyl-6-((lA,5S)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((ciA)-3-(6-methyl-3-(l / / -tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-17 / -L2,3-triazole-4-carboxamide as its TFA salt form (Example 10).Example 9: MS (ESI) m / z: 558.2 [M+H]+. 'H NMR (400 MHz, CDCh) 8: 8.75 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.09 - 6.00 (m, 1H), 4.62 - 4.50 (m, 1H), 4.36 (dd, J = 4.7, 9.8 Hz, 1H), 3.66 (d, J = 10.4 Hz, 1H), 3.10 -3.05 (m, 1H), 2.78 (s. 3H), 2.72 - 2.64 (m, 2H), 2.54 - 2.42 (m, 2H). 2.22 (d, J = 1.7 Hz. 3H), 2.13 - 2.07 (m, 2H), 2.02 (d, J = 7.0 Hz. 3H), 1.32 - 1.22 (m, 1H), 0.97 - 0.91 (m, 1H).Example 10: MS (ESI) m / z: 558.2 [M+H]+. 'H NMR (400 MHz, CDCl3) 5: 8.75 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.88 (d, J - 8.7 Hz, 1H), 7.52 (d, J - 8.1 Hz, 1H), 7.24 (d, J - 8.2 Hz, 1H), 6.09 - 6.00 (m, 1H), 4.62 - 4.50 (m, 1H), 4.36 (dd, J = 4.7, 9.8 Hz, 1H), 3.66 (d, J = 10.4 Hz, 1H), 3.10 -3.05 (m, 1H). 2.78 (s. 3H), 2.72 - 2.64 (m, 2H), 2.54 - 2.42 (m, 2H). 2.22 (d, J = 1.7 Hz, 3H), 2.13 - 2.07 (m, 2H), 2.02 (d, J = 7.0 Hz, 3H), 1.32 - 1.22 (m, 1H), 0.97 - 0.91 (m, 1H).Example 11 and 12l-((< S)l-(5-hydroxy-4-methyl-6-((17?,55)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)- V-((cz.s')-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)-177-l,2,3-triazole-4-carboxamide andl-((7?)l-(5-hydroxy-4-methyl-6-((17?,55)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)- / V-((cA)-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)pyri din-2 -yl)cyclobulyl)- 177-1, 2, 3-triazole-4-carboxamideStep 1. zc / 7-butyl ((cA)-3-(6-methyl-3-( 177- 1.2.3-triazol-l-yl)pyri din-2 -vDcvclobutvDcarbamate.

[0120] To a solution of 4-methylbenzenesulfonohydrazide (67.1 mg, 0.361 mmol) in THF (0.82 rnL) was added 2,2-dimethoxyacetaldehyde (103 mg, 0.595 mmol) (60% wt. in H2O). It was stirred at RT for 2 h. A solution of / er / -butyl ((c7s)-3-(3-arruno-6-methylpyridin-2-yl)cyclobutyl)carbamate (50 mg, 0.180 mmol) and acetic acid (32.5 mg, 0.541 mmol)) in THF (0.41 mL) was then added. The reaction was stirred at 75 °C for 5 h. It was concentrated in vacuum, the residue was purified by prep-MPLC (SiCh, EtOAc / Pet. Ether = 1 / 1) to give the title compound. MS (ESI) m / z: 330.2 [M+H]+.Step 2, (cz\s)-3-(6-methyl-3-( 177-1.2.3-triazol-l-yl)pyridin-2-yl)cvclobutan-l-amine.

[0121] A solution of tert-butyl ((czs)-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)carbamate (55 mg, 0.167 mmol) in 1 mL of 4 M HC1 in dioxane was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo, the residue was purified by prep-HPLC[Boston Green ODS 150 * 30 mm * 5 pm; water (0.04% HC1)-ACN; Begin B 0; End B: 20 Gradient Time (min) 1; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 1] to give the title compound. MS (ESI) m / z: 230.1 [M+H]+.Step 3, l-((A)l-(5-methoxy-4-methyl-6-((1?.5A)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-A-((cA)-3-(6-methyl-3-( 177-1.2.3-triazol-l-yl)pyridin-2-yl)cyclobutyll- 177-1,2.3-triazole-4-carboxamide.

[0122] To a solution of (c / .s)-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (19 mg, 0.083 mmol) and l-((< S)l-(5-methoxy-4-methyl-6-((17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid (33 mg. 0.092 mmol) in DMF (0.75 mL) was added HOBt (25.4 mg, 0.166 mmol), EDC (23.83 mg, 0.124 mmol) and DIEA (0.058 mL, 0.331 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was purified by pre-HPLC [Boston Green ODS 150 * 30 mm * 5 pm, water (0.1% TFA)-ACN. Begin B: 26, End B: 46, Gradient Time (min): 11, 100% B Hold Time: 2, Flow Rate (mL / min): 25, Injections: 1] to give the title compound. MS (ESI) m / z: 569.3 [M+H]+.Step 4, l-(l-(5-hvdroxy-4-methyl-6-((17?.5M-2-oxo-3-azabicvclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-iV-((cA)-3-(6-methyl-3-(177-1.2.3-triazol-l-yl)pyridin-2-yl)cvclobutyl)-177-1.2.3-triazole-4-carboxamide.

[0123] To a solution of l-(l-(5-methoxy-4-methyl-6-((l,5S’)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyri din-3-yl)ethyl)-A^-((c / v)-3-(6-methyl-3-(l 77-1, 2,3-triazol-l -yljpyri din-2 -yljcyclobutyl)-177-l,2,3-triazole-4-carboxamide (30 mg, 0.053 mmol) in DMSO (0.5 mL) at 25 °C was added lithium chloride (44.7 mg, 1.055 mmol). The resulting solution was stirred at 120 °C for 16 h. The reaction mixture was purified by prep-HPLC [Boston Green ODS 150 * 30 mm *5 pm; water (0.1%TFA)-ACN; Begin B 30; End B 50; Gradient Time (min) 11; 100% B Hold Time(min) 2; FlowRate (mL / min) 25; Injections 1] to give the title compound as its TFA salt (Example 11). MS (ESI) m / z: 555.2 [M+H]+.JH NMR (400 MHz, CD3OD) 5: 8.34 (s, 1H), 8.26 (d, J = 0.8 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz. 1H), 6.22 (q, J = 7.1 Hz. 1H). 4.48 - 4.38 (m. 1H), 4.33 - 4.26 (m, 1H). 4.02 - 3.95 (m.1H), 3.28 - 3.20 (m, 1H), 2.73 (s, 3H), 2.58 - 2.46 (m, 4H), 2.23 (s, 3H), 2.21 - 2.13 (m, 2H), 1.99 (d, J - 7.2 Hz, 3H), 1.36 - 1.28 (m, 1H), 0.95 - 0.88 (m, 1H).Step 5, l-((7?)l-(5-methoxy-4-methyl-6-((17?.5<S)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-A-((cA)-3-(6-methyl-3-(177-1.2.3-triazol-l-yl)pyridin-2-yl)cyclobutyl)-L77-L2.3-triazole-4-carboxamide.

[0124] To a solution of (cz.s)-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (13 mg, 0.057 mmol) and l-((7?)l-(5-methoxy-4-methyl-6-((17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid (22. mg, 0.062 mmol) in DMF (0.5 mL) was added HOBt (17.37 mg, 0.113 mmol), EDC (16.30 mg, 0.085 mmol) and DIEA (0.040 mL, 0.227 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was purified by pre-HPLC (Boston Green ODS 150 * 30 mm * 5 pm; water (0.1% TFA)_ACN; Begin B: 26; End B: 46; GradientTime (min): 11; 100% B Hold Time: 2; Flow Rate (mL / min): 25; Injections: 1) to give the title compound. MS (ESI) m / z: 569.3 [M+H]+.Step 6, 1-((R)1-(5-hydroxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(6-methyl-3-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)cyclobutyl)-1H-1,2,3-triazole-4-carboxamide.

[0125] To a solution of l-((7?)l-(5-methoxy-4-methyl-6-((17?,5< S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((czs')-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)py ri din-2 -yljcyclobutyl)- 177-1, 2, 3-triazole-4-carboxami de (20 mg, 0.035 mmol) in DMSO (0.5 mL) at 25 °C was slowly added lithium chloride (29.8 mg, 0.703 mmol). The resulting mixture was stirred at 120 °C for 16 h. The reaction mixture was purified by prep-HPLC [Boston Green ODS 150 * 30 mm * 5 pm; water (0.1% TFA)-ACN; Begin B 30; End B 50 Gradient Time (min) 11; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 1] to give the title compound (Example 12). MS (ESI) m / z: 555.2 [M+H]+.1H NMR (400 MHz, CD3OD) 5: 8.30 (s, 1H), 8.21 (s, 1H). 7.95 (s. 1H), 7.89 (s. 1H), 7.76 (d. J = 8.1 Hz. 1H), 7.39 (d. J = 8.1 Hz, 1H), 6.20 (q,.7 = 7.1 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.31 - 4.27 (m, 1H), 4.0 - 4.00 (m, 1H), 3.28 -3.18 (m, 1H), 2.74 (s, 3H), 2.61 - 2.45 (m, 4H), 2.23 (s, 3H), 2.21 - 2.13 (m, 2H), 2.00 (d, J = 7.0 Hz, 3H), 1.31 - 1.36 (m, 1H), 0.95 - 0.91 (m, 1H).Example 13 and 14l-((7?)l-(5-amino-4-fluoro-6-((lR,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)- V-((czs)-3-(6-methyl-3-(177-tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-177-l,2,3-triazole-4-carboxamide and l-((S)l-(5-amino-4-fluoro-6-((lA.5< S1)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((cA)-3-(6-methyl-3-(l / 7-tetrazol-l-yl)pyridin-2-yl)cyclobutyl)-177-1,2,3-triazole-4-carboxamideStep 1. tert-butyl (2-chloro-4-fluoropyridin-3-yl)carbamate.

[0126] To a solution of / e / 7-butyl (2-chloropyridin-3-yl)carbamate (10 g, 43.7 mmol) in THF (100 mL) and TEMED (15 mL, 100 mmol) was added a solution of 2.5 M n-BuLi in hexanes (38 mL, 95 mmol) at -65 °C. It was stirred at -40 °C for 1 h and then cooled to -65 °C. To this mixture was added a solution of w-fluorobenzenesulfonimide (16 g, 50.7 mmol) in THF (80 mL) at -65 °C. The resulting mixture was stirred at -65 °C for 10 min, at 0 °C for 1 h and then at 25 °C for 16 h. The mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 2), washed with brine (150 mL), concentrated in vacuo. The residue was purified by flash silica gel chromatography (Biotage; 120 g, Agela Silica Flash Column, Eluent of 0-11% EtOAc / Pet. ether gradient @ 40 mL / min) to give the title compound. 'H NMR (400 MHz, CDCh) 5: 8.25 - 8.18 (m, 1H), 7.07 (dd, J = 5.6, 8.8 Hz, 1H), 6.23 (br s, 1H), 1.49 (s, 9H).Step 2, te / 7-butyl (2-chloro-4-fluoro-5-(l -hydroxy ethyl)pyridin-3-yl)carbamate.

[0127] To a solution of tert-butyl (2-chloro-4-fluoropyridin-3-yl)carbamate (8.5 g, 34.5 mmol) in THF (80 mL) was added a solution of 2 N LDA in THF (40 mL, 80 mmol) at -65 °C over 0.5 h. It was stirred at -65 °C for 20 min. To this solution was added solution of acetaldehyde (4 mL, 71.6 mmol) in THF (2 mL) and the reaction was stirred at -65 °C for 0.5 h. The mixture was warmed to 0 °C and stirred at 0 °C for 1 h. It was diluted with water (150 mL). extracted with EtOAc (80 mL x 3), washed with brine (200 mL), and the organic layer was concentrated under vacuum. The residue was purified by flash silica gel chromatography (Biotage; 80 g Agela Silica Flash Column, Eluent of 0-50% EtOAc / Pet. ether gradient @ 40 mL / min) to give the title compound. MS (ESI) m / z: 291.1 [M+H]+. 'H NMR (400 MHz, CDCh) 5: 8.39 (d, J = 8.8 Hz, 1H), 6.12 (br s, 1H), 5.19 (q, J = 6.4 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H), 1.51 (s, 9H).Step 3, l-(5-((terLbutoxycarbonyl)amino)-6-chloro-4-fluoropyridin-3-yl)ethyl methanesulfonate.

[0128] To a solution of / T-butyl (2-chloro-4-fluoro-5-(l -hydroxy ethyl)pyridin-3-yl)carbamate (6.2 g, 21.33 mmol) and EtsN (9 mL, 64.6 mmol) in DCM (100 mL) was added MsCl (4.33 mL, 55.6 mmol) at 0 °C over 5 min. The mixture was stirred at 0 °C for 1.5 h and then at 25 °C for 3days. The mixture was diluted with water (100 mL), extracted with DCM (50 mL x 3). washed with brine (150 mL), dried over anhydrous Na2SO4. The solvent was removed under vacuum to afford the title compound. This material was used the next reaction without further purification. MS (ESI) m / z: 369.1 [M+H]+.Step 4, tert-butyl (5-(l-azidoethyl)-2-chloro-4-fluoropyndin-3-yl)carbamate.

[0129] A mixture of l-(5-((terf-butoxycarbonyl)amino)-6-chloro-4-fluoropyridin-3-yl)ethyl methanesulfonate (7.87 g, 21.34 mmol) and NaNs (5.79 g, 89 mmol) in DMF (80 mL) was stirred at 25 °C for 3 h. To this mixture was added 300 mL of water slowly. It was stirred for 5 min. The resulting mixture was extracted by EtOAc (150 mL x 4). The combined organics was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo at 30 °C to give the title compound in ~15 mL of the leftover solvent. This material was used in the next reaction without further purification. MS (ESI) m / z: 316.1 [M+H]+.Step 5, tert-butyl l-(l-(5-((terLbutoxycarbonyl)amino)-6-chloro-4-fluoropyridin-3-yl)ethyl)-l / / -1.2.3-triazole-4-carboxylate.

[0130] To a solution of tert-butyl (5-(l-azidoethyl)-2-chloro-4-fluoropyridin-3-yl)carbamate (6.74 g, 21.35 mmol) and tert-butyl propiolate (3.77 g, 29.9 mmol) in t-BuOH (20 mL) and H2O (20 mL) was added sodium (7?)-2-((S)-l,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (8.46 g. 42.7 mmol) and copper(II) sulfate pentahydrate (0.533 g. 2.135 mmol). The mixture was stirred at 12 °C for 1 h. It was diluted with water (30 mL), extracted with EtOAc (30 mL x 3). washed with brine (90 mL). The organic layer was concentrated under vacuum and purified by flash silica gel chromatography (Biotage; 12 g Agela Silica Flash Column, Eluent of 0-36% EtOAc / Pet.ether, gradient @ 40 mL / min). The product containing fractions were combined and concentrated under vacuum. The residue was further purified by reverse phase HPLC [Column: Waters Xbridge BEH C18 100 * 40 * 10 pm; Condition: w ater (10 mM-NH4HCO3)-ACN. 37%-67% B. Gradient Time (mm): 11. 100% B Hold Time: 3. Flow Rate (mL / min): 50. Injections: 14] to afford the title compound. 'H NMR (400 MHz. CDCh) 5: 8.19 (d, J = 8.8 Hz, 1H). 8.05 (s, 1H). 6.13 (s. 1H), 6.06 (q. J = 7.2 Hz, 1H). 2.07 (d. J = 7.2 Hz, 3H), 1.59 (s, 9H), 1.49 (s, 9H).Step 6, tert-butyl 1-(1-(5-((tert-butoxycarbonyl)amino)-4-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylate.

[0131] A mixture of tert-butyl l-(l-(5-((tert-butoxycarbonyl)amino)-6-chloro-4-fluoropyridin-3-yl)ethyl)-l / 7-l,2,3-triazole-4-carboxylate (1 g, 2.263 mmol), (17?,5< S)-3-azabicyclo[3.1.0]hexan-2-one (0.2 g, 2.059 mmol), CS2CO3 (2 g, 6.14 mmol), tris(dibenzvlideneacetone)dipalladium(0) (0.2 g, 0.218 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.2 g, 0.346 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (Biotage; 20 g Agela Silica Flash Column, Eluent of 0-70% EtOAc / Pet. ether, gradient @ 40 mL / min) to give the title compound. MS (ESI) m / z: 503.3 [M+H]+.Step 7, l-(l-(5-amino-4-fluoro-6-((17?.5M-2-oxo-3-azabicyclo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-lH-1.2.3-triazole-4-carboxylic acid.

[0132] A solution of tert-butyl l-(l-(5-((tert-butoxycarbonyl)amino)-4-fluoro-6-((lA,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-17 / -l,2,3-triazole-4-carboxylate (1 g. 1.990 mmol) in DCM / TFA = 1: 1 (20 mL) was stirred at 25 °C for 1 h. The mixture was dried with N2gas flow and the residue was purified by reverse phase HPLC [Column: Boston Uni C18 150 * 40 mm * 5 pm. Condition: water (0.1% TFA)-ACN; 0-30% B; Gradient Time (min): 10; 100%B Hold Time: 2; Flow Rate (mL / min): 60; Injections: 1] to afford the title compound. MS (ESI) m / z: 347.1 [M+H]+.Step 8, l-(l-(5-amino-4-fluoro-6-((17?.5< S)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-A-((cA)-3-(6-methyl-3-(177-tetrazol-l-yl)pyridin-2-yl)cvclobutyl)-L2.3-triazole-4-carboxamide.

[0133] A mixture of EDC (120 mg, 0.626 mmol), l-(l-(5-amino-4-fluoro-6-((l,5< S')-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-l / 7-l,2,3-triazole-4-carboxylic acid (90 mg, 0.260 mmol) and (c / .s)-3-(6-methyl-3-(17 / -tetrazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (30 mg, 0.130 mmol) in pyridine (1.5 mL) was stirred at 25 °C for 16 h. The reaction content was purified by reverse phase HPLC [Column: Boston Prime C18 150 * 40 mm * 5 pm; Condition: water (10 mM-NH4HCO3)-ACN; 26% - 56% B. Gradient Time (mm): 10; 100%B Hold Time: 2; Flow Rate (mL / min): 60; Injections: 1], The product containing fractions were combined and concentrated under vacuum. The residue was further separated by SFC [Column: DAICEL CHIRALPAK OJ (250 mm * 30 mm, 10 pm); Condition: CO2-MeOH. 40% B. Gradient Time (min): 10; 100% B Hold Time: 1; Flow Rate (mL / min): 80; Injections: 40. Whole time: 40 min] to afford the faster-eluting stereoisomer of the title compound (Example 13) and the slower-eluting stereoisomer of the title compound (Example 14).Example 13: MS (ESI) m / z: 559.1 [M+H]+. ’H NMR (400 MHz, CDCl3) 5: 8.72 (s, 1H), 8.09 (s, 1H), 7.75 (d. J= 8.8 Hz. 1H), 7.73 - 7.65 (m, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 6.01 (q, J=7.2Hz, 1H), 4.67 - 4.53 (m, 1H), 4.40 (dd, J=5.2, 11.2 Hz, 1H), 4.35 - 4.28 (m, 2H), 3.83 (d, J= 11.2 Hz, 1H), 3.11 - 2.97(m, 1H), 2.76 (s, 3H), 2.70 - 2.62 (m, 2H), 2.51 -2.42 (m, 2H), 2.13 - 2.07 (m, 2H), 2.03 (d, J= 7.2 Hz, 3H), 1.29 - 1.25 (m, 1H), 0.97 - 0.90 (m, 1H).Example 14: MS (ESI) m / z: 559.1 [M+H]+. ’H NMR (400 MHz, CDCl3) 5: 8.72 (s, 1H), 8.09 (s, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.73 - 7.65 (m, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 6.01 (q, J = 7.2 Hz. 1H), 4.67 - 4.53 (m, 1H), 4.40 (dd, J = 5.2, 11.2 Hz. 1H), 4.35 - 4.28 (m, 2H), 3.83 (d, J= 11.2 Hz, 1H), 3.11 - 2.97(m, 1H), 2.76 (s, 3H), 2.70 - 2.62 (m, 2H), 2.51 -2.42 (m, 2H), 2.13 - 2.07 (m, 2H), 2.03 (d, J = 7.2 Hz, 3H), 1.29 - 1.25 (m, 1H), 0.97 - 0.90 (m, 1H).Example 15 and 16l-(l-(5-hydroxy-4-methyl-6-((U?,5<S’)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)- A-((czs)-3-(6-methyl-3-(4-(trifluoromethyl)-l / -l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)-17 -1,2,3 -triazole-4-carboxamide and 1 -( 1 -(5 -hy droxy-4-methy l-6-(( 1 A,5S)-2-oxo-3 -azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-A-((cz\s')-3-(6-methyl-3-(4-(trifluoromethyl)-l / f-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)-17 / -l,2,3-triazole-4-carboxamideStep 1. te / 7-butyl ((cA)-3-(3-azido-6-methylpyridin-2-yl)cvclobutyl)carbamate.

[0134] To a solution of tert-butyl ((czs)-3-(3-amino-6-methylpyridin-2-yl)cyclobutyl)carbamate (300 mg, 1.082 mmol) in HC1 (7% wt in H2O) (9 mL) was slowly added sodium nitrite (97 mg, 1.406 mmol) at 0 °C. It was stirred at 0 °C for 1 h before azidotrimethylsilane (0.142 mL, 1.082 mmol) was added. The reaction was stirred at 25 °C for 3.5 h. The pH of the reaction mixture was adjusted to pH = 9 by saturated NaOH solution, the resulting mixture was extracted by EtOAc (3 x 20 mL). The combined organics was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (6 mL). Triethylamine (0.453 mL, 3.25 mmol) and di- / c / 7-butvl dicarbonate (0.383 mL.1.624 mmol) was then added sequentially. The reaction was stirred at 25 °C for 12 h. The solvent was removed in vacuo, the residue was purified by prep-TLC (SiO2, Pet. ether: EtOAc=3:1) to give the title compound. MS (ESI) m / z: 304.1 [M+H]+.Step 2, tert-butyl ((cte)-3-(6-methyl-3-(4-(trifluoromethyl)- 177-1.2.3-triazol-l -yl)pyridin-2-yl)cyclobutyl)carbamate.

[0135] A mixture of tetrabutylammonium iodide (53.6 mg, 0.145 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) in DME (4.5 mL) was stirred at 25 °C for 30 min. To this was added sequentially a solution of tert-butyl ((czs)-3-(3-azido-6-methylpyridin-2-yl)cyclobutyl)carbamate (220 mg, 0.725 mmol), a solution of lithium hydroxide (52.1 mg, 2.176 mmol) in water (1.5 mL) and ethyl 4,4,4-trifluorobut-2-ynoate (181 mg, 1.088 mmol). The resulting mixture was stirred at 70 °C for 3 h. It was diluted with water (20 mL), extracted with EtOAc (15 mL x 3). washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by prep. TLC (SiO2, Pet.ether: EtOAc = 1:1) to give the title compound. MS (ESI) m / z: 398.2 [M+H]+.Step 3: (c7.s)-3-(6-metbyl-3-(4-(trifluoromethyl)-l / / - 1.2,3-triazol-l -yl)pyridin-2-yl)cvclobutan- 1-amine

[0136] A solution of tert-butyl I(c7.s)-3-(6-methyl-3-(4-(trilluoromethyl)-1 / -1.2.3-triazol-l-yl)pyridin-2-yl)cyclobutyl)carbamate (100 mg, 0.252 mmol) in a solution of 4 N HC1 in dioxane (3 mL) was stirred at 25 °C for 0.5 h. The solvent was removed under vacuum to afford the crude title compound as its HC1 salt form. This material was used in the future reactions without further purification. MS (ESI) m / z: 298.0 [M+H]+.Step 4, 1 -(l-(5-methoxy-4-methyl-6-((17?.5M-2-oxo-3-azabicvclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-A-((crt)-3-(6-methyl-3-(4-(trifluoromethyl)- 177-1, 2.3-triazol-l-yl)pyri din-2-yl)cyclobutyl)-177-1.2,3-triazole-4-carboxamide.

[0137] To a solution of l-(l-(5-methoxy-4-methyl-6-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid (108 mg, 0.303 mmol) and (cis)-3-(6-methyl-3-(4-(trifluoromethyl)-177-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (75 mg, 0.252 mmol) in pyridine (3 mL) was added EDC (169 mg, 0.883 mmol), the mixture was stirred at 25 °C for 12 h. The solvent was removed under reduced pressure, the residue was purified by reverse phase HPLC (YMC-Actus Triart C18 150 * 30 mm * 5 pm, Condition: water (0.1% TFA)-ACN; Begin B 36, End B 56; Gradient Time (min) 11.5; 100% B Hold Time (min) 2; FlowRate (mL / min) 40; Injections 3) to give the title compound. MS (ESI) m / z: 637.3 [M+H]+.Step 5, l-(l-(5-hydroxy-4-methyl-6-((17?.5<S)-2-oxo-3-azabicvclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-A-((czM-3-(6-methyl-3-(4-(trifluoromethyl)- 177-1,2,3-tri azol- l-yl)pyri din-2-yl)cyclobutyl)-177-L2,3-triazole-4-carboxamide and l-(l-(5-hydroxy-4-methyl-6-((17?,5S)-2-oxo-3-azabicyclo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-V-((cz.s,)-3-(6-methyl-3-(4-(trifluoromethyl)-17 / -1.2.3-triazol-l-yl)pyridin-2-yl)cvclobutyl)-lE7-l,2,3-triazole-4-carboxamide.

[0138] A solution of l-(l-(5-methoxy-4-methyl-6-((U?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-A-(( )-3-(6-methyl-3-(4-(trifluoromethyl)-17f-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)-H / -l,2,3-triazole-4-carboxamide (60 mg, 0.094 mmol) and magnesium bromide (52.1 mg, 0.283 mmol) in MeCN (1.5 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep. TLC (SiCh, DCM / MeOH = 10:1). The product containing fractions were combined and concentrated under vacuum, the residue was further separated by SFC (REGIS (R. R) WHELK-01, 250 mm * 25 mm, 10 pm; Condition: CO2-EtOH (0.1% NH3H2O); Begin B 60, End B 60; Gradient Time (min) 10; 100% B Hold Time (min) 10; FlowRate (mL / min) 80; Injections 45) to give the faster-eluting stereoisomer of the title compound (Example 15) and the slower-eluting stereoisomer of the title compound (Example 16)Example 15: MS (ESI) m / z: 623.3 [M+H]+. 'H NMR (400 MHz, CDCh) 5: 9.91 (s, 1H), 7.99 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.78 - 7.70 (m, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.22 (d, J= 8.0 Hz, 1H), 6.07 (q, J= 7.2 Hz, 1H), 4.66 - 4.54 (m, 1H), 4.35 - 4.26 (m, 1H), 4.17 (d, J= 10.4 Hz, 1H), 3.15-3.05 (m, 1H), 2.77 (s. 3H), 2.72 - 2.63 (m, 2H), 2.53-2.44 (m, 2H), 2.26-2.20 (m, 1H), 2.18 (s, 3H), 2.17-2.14 (m, 1H),1.99 (d, J = 7.2 Hz, 3H). 1.37 - 1.32 (m. 1H), 0.97 - 0.93 (m, 1H). Example 16: MS (ESI) m / z: 623.3 [M+H]+. T1 NMR (400MHz, CD3OD) 5: 8.87 (s, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.35 (d, J= 8.1 Hz, 1H), 6.21 (q, J= 7.4 Hz, 1H), 4.51-4.40 (m, 1H), 4.34-4.28 (m, 1H), 3.98 (d, J= 11.4 Hz, 1H), 3.26-3.14 (m, 1H), 2.70 (s, 3H), 2.57 - 2.43 (m.4H), 2.22 (s, 3H), 2.21-2.14 (m, 2H), 1.99 (d, J= 7.2 Hz, 3H), 1.36-1.30 (m, 1H), 0.95-0.90 (m, 1H).Example 17l-((S)-l-(5-fluoro-4-methyl-6-((17?,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)- A-((cA)-3-(6-methyl-3-(177-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)-17 / -l,2,3-triazole-4-carboxamidel-((6>l-(5-fluoro-4-methyl-6-((17?.55>2-oxo-3-azabicvclor3.1.0]hexan-3-yl)Dyridin-3-yl)ethyl)- A-((c / v)-3-(6-methyl-3-(17T-1.2.3-triazol-l-yl)pyridin-2-yl)cvclobutyl)-17T-1.2.3-triazole-4-carboxamide.

[0139] (cA)-3-(6-methyl-3-(17T-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutan-l-amine (23 mg, 0.10 mmol) and!-((< S')-l-(5-fluoro-4-methyl-6-((l,51S’)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-I7T-I,2,3-triazole-4-carboxylic acid (35 mg, 0.10 mmol) were dissolved in pyridine (1.0 mL). EDC (58 mg, 0.30 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Water and the mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₃, filtered and concentrated in vacuo. The residue was purified on a Waters Sunfire Cl 8, 30 x 150 mm column, eluting at 20 mL / min using a 10 minute 20-70% Acetonitrile / Water (0.05% TFA) gradient. The product containing fractions were frozen and lyophilized to obtain the title compound as its TFA salt form. MS (ESI) m / z: 557.5 [M+H]+. 'HNMR (500 MHz, MeOD) 5: 8.44 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H). 7.97 (s.1H), 7.73 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.26 (d, J = 6.8 Hz, 1H), 4.45 (d, J = 8.5 Hz, 1H), 4.32 (dd, J= 10.3, 5.7 Hz, 1H), 3.70 (d, J= 10.4 Hz, 1H), 3.23-3.17 (m, 1H), 2.73 (s, 3H), 2.58-2.51 (m, 2H), 2.51-2.45 (m, 2H), 2.31 (s, 3H), 2.23-2.16 (m, 1H), 2.07-2.01 (m, 1H), 2.04 (d,.7= 7.1 Hz, 3H), 1.36-1.28 (m, 1H), 0.92-0.88 (m, 1H).Example ISA-((czM-3-(3-(4-chloro-lE7-L2.3-triazol-l-yl)-6-methylpyridin-2-yl)cyclobutyl)-l-(6S,)-l-(4.5- dimethyl-6-((lA.5S')-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-17 / -1.2.3-triazole- 4-carboxamideStep 1. tert-butyl ((czs)-3-(6-methyl-3-(4-(trimethylsilyl)-177-1.2.3-triazol-l-yl)pyridin-2-vDcyclobutvDcarbamate.

[0140] Tert-butyl ((cA)-3-(3-azido-6-methylpyridin-2-yl)cyclobutyl)carbamate (119 mg, 392 prnol) was dissolved in THF (1.57 mL) and degassed with an Nz sparge for 10 minutes. Ethynyl-trimethyl-silane (385 mg, 548 pL. 3.92 mmol), DIEA (253 mg, 1.96 mmol) and Cui (112 mg, 588 pmol) were added sequentially, and the reaction was stirred at 80 °C overnight. The reactionwas then cooled to room temperature. Water was added and the solution was extracted with EtOAc. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound. This material was used in the next reaction without further purification. MS (ESI) m / z: 402.4 [M+H]+.Step 2, tert-butyl ((cA)-3-(3-(4-chloro-1.2.3-triazol-l-yl)-6-methylpyridin-2-vDcvclobutyllcarbamate.

[0141] To a vial containing tert-butyl ((czs)-3-(6-methyl-3-(4-(trimethylsilyl)-17T-l,2,3-triazol-l-yl)pyridin-2-yl)cyclobutyl)carbamate (40 mg, 0.10 mmol) in MeCN (1.00 mL) was added potassium fluoride (58 mg, 1.0 mmol) followed by NCS (0.13 g, 1.0 mmol). The solution was stirred at 90 °C overnight. It was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 0-100% (3:1 EtOAc / EtOH) / hexanes to afford the title compound. MS (ESI) m / z: 364.3 [M+H]+.Step 3, (cA)-3-(3-(4-chloro- 1, 2.3-triazol-l-yl)-6-methylpyridin-2-yl)cvclobutan-l-amine.

[0142] Tert-butyl ((cA)-3-(3-(4-chloro-177-l,2,3-triazol-l-yl)-6-methylpyridin-2-yl)cyclobutyl)carbamate (11.0 mg, 30.2 pmol) was dissolved in MeOH (302 pL). 4 N HC1 in dioxane (378 pL, 1.51 mmol) was added and the solution was stirred at room temperature for 4 h. The reaction content was concentrated in vacuo to afford the title compound. This material was used in the next reaction without further purification. MS (ESI) m / z: 264.3 [M+H]+.Step 4, A-((c / .v)-3-(3-(4-chl oro-1, 2.3-triazol-l-yl)-6-methylpyridin-2-yl)cvclobutyl)-l-((M-l-(4.5-dimethyl-6-((17?.5lS)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)pyridin-3-yl)ethyl)-177-1.2.3-triazole-4-carboxamide.

[0143] (cA)-3-(3-(4-chloro-177-l,2,3-triazol-l-yl)-6-methylpyridin-2-yl)cyclobutan-l -amine (14.0 mg, 53.1 pmol) and l-((S)-l-(4,5-dimethyl-6-((17?,5S)-2-oxo-3-azabicyclo[3. L0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid (18.1 mg, 53.1 pmol) were dissolved in DMF (1.06 mL). EDC (20.4 mg, 106 pmol), HOBt (24.4 mg, 159 pmol) and DIEA (27.4 mg, 212 pmol) were added sequentially and the reaction was stirred at room temperature for 5 h before being filtered through a frit. The crude reaction mixture was purified on a Waters Sunfire C18, 30 x 150 mm column, eluting at 20 mL / min using a 10 minute 25-60% Acetonitrile / Water (0.05% TFA) gradient. The product containing fractions were frozen and lyophilized to obtain the title compound as its TFA salt form. MS (ESI) m / z: 587.4 [M+H]+. 'H NMR (500 MHz, MeOD) 5: 8.40 (d, J= 6.0 Hz, 2H), 8.24 (s. 1H), 7.77 (d. J= 8.1 Hz. 1H), 7.39 (d. J= 8.1 Hz, 1H), 6.33 (d, J= 7.0 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.25 (dd, J= 10.3, 6.0 Hz, 1H), 3.71 (d, J = 10.4 Hz, 1H), 3.30-3.23 (m, 1H), 2.73 (s, 3H), 2.58 (d, J= 8.1 Hz, 2H), 2.54-2.45 (m, 2H),2.33 (s, 3H), 2.20 (s, 1H), 2.11 (s, 3H), 2.08-2.00 (m, 1H), 2.03 (d, J= 7.0 Hz, 3H), 1.35-1.29 (m, 1H), 1.01-0.96 (m, 1H).Example 19A-((cA)-3-(3-(4-chl pro- 17 / - 1.2.3-triazol-l-yl)-6-methylpyri din-2 -yl)cvclobiilyl)-l-((. S')-l-(5- fluoro-4-methyl-6-((17?.5A)-2-oxo-3-azabicvclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-1.2.3- triazole-4-carboxamideA-((cA)-3-(3-(4-chloro-l / / -E2.3-triazol-l-yl)-6-methylpyridin-2-yl')cvclobutyl')-l-((.y)-l-(5-fluoro-4-methyl-6-((17?.5lS)-2-oxo-3-azabicvclor3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-17 -1.2.3-triazole-4-carboxamide.

[0144] (cA)-3-(3-(4-chloro- 177-1, 2, 3-triazol-l-yl)-6-methylpyridin-2-yl)cyclobutan-l -amine (8.00 mg, 30.3 pmol) and l-((< S’)-l-(5-fluoro-4-methyl-6-((17?,5< S’)-2-oxo-3-azabicyclo[3.1,0]hexan-3-yl)pyridin-3-yl)ethyl)-l 7 / -1,2,3-triazole-4-carboxylic acid (10.5 mg, 30.3 pmol) were dissolved in DMF (607 pL). EDC (11.6 mg, 60.7 pmol), HOBt (13.9 mg, 91.0 pmol) and DIEA (15.7 mg, 121 pmol) were then added sequentially and the reaction was stirred at room temperature for 5 h. The crude reaction mixture was filtered through a frit and purified on a Waters Sunfire C18, 30 x 150 mm column, eluting at 20 mL / min with a 10 minute 20-60% Acetonitrile / Water (0.05% TFA) gradient. The product containing fractions were frozen and lyophilized to obtain the title compound as its TFA salt form. MS (ESI) m / z: 591.5 [M+H]+.JH NMR (500 MHz, MeOD) 5: 8.46 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.79 (d, J= 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H). 6.27 (q, J = 7.0 Hz, 1H). 4.55 - 4.44 (m. 1H), 4.33 (dd, J = 10.4, 5.8 Hz, 1H), 3.72 (d, J= 9.8 Hz, 1H), 3.29 (dd, J= 17.2, 9.0 Hz, 1H), 2.75 (s, 3H), 2.64 - 2.56 (m, 2H), 2.56 - 2.47 (m, 2H), 2.33 (d, J= 1.9 Hz, 3H), 2.27 - 2.17 (m, 1H), 2.09-2.10 (m, 1H) 2. O6 (d, J = 7.0 Hz, 3H), 1.34 (td, J= 8.0, 4.7 Hz, 1H), 0.96 - 0.88 (m, 1H).Example 20I -( OS)- 1 -14.5-dimethyl-6-(( I / ?.5 )-2-oxo-3-a / abicvclo|3. l ()|hexan-3-yl )pyndin-3-yl )ethyl )- jV((cA)-3-(6-methyl-3-(2-methyl-27 -tetrazol-5-y’l)pyridin-2-yl)cvclobutyrl)-17f-L2.3-triazole-4- carboxamideStep 1. / -butyl ((c / M-3-(6-methyl-3-( I / / -tetrazol-5-yl )pyridin-2-yl Icvclobutyl (carbamate, trifluroacetic acid salt.

[0145] A mixture of tert-butyl ((cz\’)-3-(3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate (500 mg, 1.7 mmol), triethylamine hydrochloride (1.2 g, 8.7 mmol), sodium azide (566 mg, 8.7 mmol) in DMF (7 mL) was reacted at 130 °C in a microwave vial under microwave radiation for 2 h. The reaction crude was diluted in water and purified by C18 reverse phase chromatography eluting with 0-80% MeCN / H2O (0.05%TFA). The desired fractions was lyophilized overnight to provide the title compound as its TFA salt form. MS (ESI) m / z: 331.1 [M+H]+.Step 2, / crt-butyl ((c.s )-3-(6-methyl-3-(2-metliyl-2H-tetrazol-5-yl )pyridin-2yl ) cyclobutyl) carbamate and tert-butyl (-3-(6-methyl-3-(l-methyl-177-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate.

[0146] To a mixture of tert-butyl ((c7.s )-3-(6-methyl-3-(lrt-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate, trifluroacetic acid salt (100 mg, 0.23 mmol), potasium carbonate (155 mg, 1.1 mmol) in DMF (5 mL) was added iodomethane via syringe drop- wise. The reaction was stirred at room temperature overnight. It was diluted with water and extracted by EtOAc. The organic phase was dried by anhydrous MgSCh, filtered and concentrated under vacuum. The residue w as purified by silica gel chromatography eluting with 0-100% EtOAc / hexanes to provide the title compounds individually. MS (ESI) m / z: 345.1[M+H]+.Step 3, (cte)-3-(6-methyl-3-(2-methyl-2 / -tetrazol-5-yl)pyridin-2-yl)cy cl obutan-1 -amine, hydrochloride salt.

[0147] A solution of tert-butyl ((c7.s )-3-(6-methyl-3-(2-methyl-2rt-tetrazol-5-yl)pyndin-2-yl)cyclobutyl)carbamate (79.5 mg, 0.23 mmol) in DCM((1.2 mL) and trifluroacetic acid (1.2 mL) was stirred at room temperature for 30 min. The reaction was concentrated under vacuum, the residue was dissolved in water, and loaded onto Bio-RAD AG MP-1M Resin: Macroporousanion exchange resin (Cl), Cat#141-1841. Load: 100 mg / 2 g resin. It was rinsed with 2 colomn volume of water (with drops of MeCN). The solution was lyophilized to provide the title compound as its HC1 salt form. MS (ESI) m / z: 245.1 [M+H]+.Step 4, l-((N)-l-(4.5-dimethyl-6-((l. R.5)Sf)-2-oxo-3-azabicvclo[3.1.01hexan-3-yl)pyridin-3-yl)ethyl)-M(c4s)-3-(6-methyl-3-(2-methyl-277-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)-lJ / - 1.2,3-triazole-4-carboxamide, trifluroacetate acid salt.

[0148] A mixture of l-((N)-l-(4,5-dimethyl-6-((17?,5N)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-177-l,2,3-triazole-4-carboxylic acid, trifluroacetic acid (40 mg, 0.088 mmol). (cA)-3-(6-methyl-3-(2-methyl-2 / / -tetrazol-5-yl)pyri din-2 -yl)cyclobutan- 1 -amine, hydrochloride salt (29.6 mg, 0.11 mmol) and A-ethyl- / V'-(3-dimethylaminopropyl)carbodiirnide hydrochloride, (50.5 mg, 0.26 mmol) in pyridine (1.8 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and purified by C 18 reverse phase chromatography eluting with 10-60% MeCN / ELO (0.05% TFA). The desired fractions were combined and lyophilized to provide the title compound as its TFA salt form. MS (ESI) m / z: 568.2 [M+H]+. ‘HNMR (500 MHz, DMSO- e) 5: 8.67 (d, J= 6.7 Hz, 2H), 8.20 (s, 1H), 8.10 (d, J= 7.9 Hz, 1H), 7.32 (d, J= 7.9 Hz, 1H), 6.28 (q, J= 6.8 Hz, 1H), 4.47 (s, 4H), 4.38 (dd, J = 16.2, 8.2 Hz, 3H), 3.96 - 3.86 (m, 2H), 3.57 (d, J= 10.3 Hz, 1H). 2.60 (s, 3H), 2.44 (q, J= 9.6 Hz. 2H), 2.23 (s, 3H), 2.15 - 2.06 (m, 1H), 1.95 (s, 4H), 1.92 (d, J= 6.9 Hz, 3H), 1.20 (q, J= 7.8 Hz, 1H), 0.82 - 0.76 (m, 1H).

[0149] The following compounds were prepared using procedures similar to those described for Step 4 of Example 20, using appropriate starting materials.Example 28N-((cis)-3-(5-chloro-6-methyl-3-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxamideStep 1. tert-butyl ((cis)-3-(5-chloro-3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate.

[0150] A mixture of tert-butyl (3-iodocyclobutyl)carbamate (1.5 g, 5.1 mmol), 5-chloro-2-iodo-6-methylnicotinonitrile (1.7 g, 6.1 mmol), tetrabutylammonia iode (1.9 g, 5.1 mmol), [4.4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride (211 mg, 0.51 mmol) and zinc (495 mg, 7.6 mmol) was flushed with nitrogen for 2 min. Dimethylacetamide (30 mL) was then added and the resulting mixture w as stirred under nitrogen at room temperature for 20 h. It was diluted with EtOAc and water, filtered through a celite pad. The organic phase was separated and washed with brine, dried over anhydrous MgSO4. filtered and then concentrated in vacuo. The residue w as purified by silica gel chromatography eluting with 0-40% EtOAc / hexanes to provide the title compound. MS (ESI) m / z: 322.0 [M+H]+.Step 2. tert-butyl ((cis)-3-(5-chloro-6-methyl-3-(1H-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate. trifluroacetic acid salt.

[0151] A mixture of tert-butyl ((cte)-3-(5-chloro-3-cyano-6-methylpyridin-2-yl)cyclobutyl)carbamate (70 mg, 0.22 mmol), sodium azide (42.4 mg, 0.66 mmol) and triethylamine hydrochloride (89.8 mg, 0.66 mmol) in DMF (2.2 mL), was heated at 100 °C for 20 h. The reaction mixture was cooled to room temperature, diluted with water and purified by C18 reverse phase chromatography eluting with 0-100% MeCN / H2O (+ 0.05%TFA). The desired fractions were lyophilized to provide the title compound as its TFA salt form. MS (ESI) m / z: 365.1 [M+H]+.Step 3. tert-butyl ((cis)-3-(5-chloro-6-methyl-3-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate.

[0152] To a mixture of tert-butyl ((cis)-3-(5-chloro-6-methyl-3-(2H-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate, trifluoroacetic acid (60 mg, 0.13 mmol), potassium carbonate (87 mg, 0.63 mmol) in DMF (2 mL) was added Mel (26.7 mg, 11.8 pL. 0.19 mmol) drop-wise via a syringe. It was stirred at room temperature for 40 minutes. The reaction content was diluted with ethylacetate and water, dried over anhydrous MgSO4. filtered and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc / hexanes to provide the title compound. MS (ESI) m / z: 379.1 [M+H]+.Step 4. (cis)-3-(5-chloro-6-methyl-3-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)cyclobutan-1-amine. hydrochloride salt.

[0153] A solution of tert-butyl ((cis)-3-(5-chloro-6-methyl-3-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)cyclobutyl)carbamate (37.4 mg, 99 mmol) in 2 mL of 4 N HC1 in was stirred at room temperature for 30 minutes. It was diluted with acetonitrile and concentrated under vacuum without heating to provide the title compound. This material was used in the next reaction without further purification. MS (ESI) m / z: 279.1 [M+H]+.Step 5, A-((c / y)-3-(5-chloro-6-methyl-3-(2-methyl-2E7-tetrazol-5-yl)pyridin-2-yl)cvclobutyd)-l-((5')-l-(4,5-dimethyl-6-((U?,5A)-2-oxo-3-azabicyclo[3. L01hexan-3-yl)py’ridin-3-yl)ethyl)-177-L2.3-triazole-4-carboxamide.

[0154] A mixture of 1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazole-4-carboxylic acid, TFA (44.8 mg, 95 mmol), (cis)-3-(5-chloro-6-methyl-3-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl)cyclobutan-1-amine, hydrochloride salt (31 mg, 98 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride. (57 mg, 0.3 mmol) in pyridine (2 mL) was stirred at room temperature for 30 minutes. The reaction was diluted with EtOAc, and washed with water and brine, dried over anhydrous MgSO4. filtered and the filtrate w as concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc / hexanes to provide the title compound. MS (ESI)m / z: 602.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6) 5: 8.69 (d, J= 7.8 Hz, 1H), 8.67 (s, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 6.28 (d, J= 6.9 Hz, 1H), 4.48 (s, 3H), 4.38 (d, J= 7.9 Hz, 1H), 4.21 (s, 1H), 3.89 (d, J= 7.5 Hz, 1H), 3.58 (s, 1H), 3.17 (d, J= 5.2 Hz, 1H), 2.66 (s, 3H), 2.44 (d, J= 9.9 Hz. 3H), 2.23 (s, 3H), 2.13-2.08 (m, 1H), 1.95 (s, 4H), 1.92 (d, J = 7.1 Hz, 3H), 1.23-1.16 (m, 1H), 0.78 (s, 1H).Kallikrein assay

[0155] The effectiveness of a compound of the present invention as an inhibitor of Kallikrein can be determined using a relevant purified serine protease, and an appropriate synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of compounds of the present invention. Assays were conducted at room temperature or at 37°C. Hydrolysis of the substrate resulted in release of amino trifluoromethylcoumarin (AFC), which was monitored spectrofluorometrically by measuring the increase in emission at 510 nm with excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of inhibitor is indicative of enzyme inhibition. Such methods are known to one skilled in the art. The results of this assay are expressed as the half-maximal inhibitory concentrations (IC50), or the inhibitory constant, Ki.

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

[0157] Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration < 0.2 Km into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. The reactions were performed under linear progress curve conditions and fluorescence increase measured at 405 Ex / 510 Em nm. Values were converted to percent inhibition of the control reaction (after subtracting 100% Inhibition value). IC50 was determined by inflection point from a four parameter logistic curve fit. Ki was calculated using the Cheng Prusoff equation. Ki = IC5o / (l+([S] / Km)).

[0158] The activities shown by this assay indicate that the compounds of the invention may be therapeutically useful for treating or preventing various ophthalmic, cardiovascular and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndrome, refractory angina, myocardial infarction, transient ischemic attacks, atrialfibrillation, stroke such as thrombotic stroke or embolic stroke, venous thrombosis, coronary and cerebral arterial 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 edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.

Claims

WHAT IS CLAIMED IS:

1. The compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein:A is C or N, provided that when A is N, R1does not exist;R1is F, Cl, NR5R6, C1-C6 alkyl, C3-C6 cycloalkyl, or O-R4;R2is F, C1-C3 alkyl, or C3-C6 cycloalkyl;R3is H, F or Cl;( B Jis a heterocycle having up to 4 heteroatoms selected from N, S or O and optionally substituted with CH3, CHF2, CF3, or Cl; or a heteroaryl having up to 4 heteroatoms selected from N, S or O and optionally substituted with CH3, CHF2, CF3, or Cl;R4is H, C1-C6alkly, or C3-C6cycloalkyl;R5is H or C1-C4alkyl; andR6is H or C1-C4alkyl.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is F or Cl.

3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C6alkyl.

4. The compound of Claim 1. or a pharmaceutically acceptable salt thereof, wherein R1is NR5R6.

5. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is C3-C6 cycloalkyl.

6. The compound of Claim 1. or a pharmaceutically acceptable salt thereof, wherein R1is O-R4.

7. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is F.

8. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C3 alkyl.

9. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is C3-C6 cycloalkyl.

10. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R4is H.

11. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R4is C1-C6alkyl.

12. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R4is C3-C6 cycloalkyl.

13. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein B is a heterocycle having up to 4 heteroatoms.

14. The compound of Claim 13. or a pharmaceutically acceptable salt thereof, wherein said heteroatoms are N.

15. The compound of Claim 13, or a pharmaceutically acceptable salt thereof, wherein said heterocycle is substituted with CH3, CHF2, or Cl.

16. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein B is a heteroaryl having up to 4 heteroatoms.

17. The compound of Claim 16, or a pharmaceutically acceptable salt thereof, wherein said heteroatoms are N.

18. The compound of Claim 16. or a pharmaceutically acceptable salt thereof, wherein said heteroaryl is substituted with CTC. CHF2, or Cl.

19. The compound of Claim 1 selected from any one of compounds numbered 1-28, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

21. A pharmaceutical composition comprising a compound of claim 1 to 20 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22. A method for treating impaired visual activity, 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 coagulation during cardiopulmonary bypass surgery, or bleeding from postoperative surgery in a mammal, comprising administering a composition of Claim 21 to a mammal in need of thereof.

23. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion in a mammal in need thereof.

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