Plasma kallikrein inhibitors

Abstract

The present invention provides compounds of formula (I), pharmaceutical compositions comprising one or more of said compounds, and methods of using said compounds to treat or prevent one or more disease states in which inhibition of plasma kallikrein is believed to be beneficial, such as 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

[Background technology]

[0001] Plasma kallikrein is a trypsin-like serine protease zymogen present in plasma. Its gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein shares 58% homology with factor XI. Proteolytic activation by factor XIIa at the internal I389-R390 bond generates a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors such as α2-macroglobulin and Cl- inhibitors. 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 a complex with HMWK. Plasma kallikrein cleaves HMWK, releasing bradykinin. The release of bradykinin leads to increased vascular permeability and vasodilation (for reviews, see Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier AH, "Contact Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)).

[0002] Patients with a genetic deficiency in C1-esterase inhibitor suffer from hereditary angioedema (HAE), a lifelong condition that causes intermittent swelling throughout the body, including the hands, feet, face, throat, genitals, and gastrointestinal tract. Analysis of blisters resulting from acute episodes has shown that they contain high levels of plasma kallikrein, and treatment with ecallantide (Carbitol), a protein-based reversible plasma kallikrein inhibitor, has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L, et al., J. Allergy Clin. Immunol., 120; p. 416 (2007)).

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

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

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

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

[0007] The present invention relates to compounds of formula I: or pharmaceutical salts thereof: [ka] During the ceremony, [ka] teeth, [ka] Selected from TIFF0007776453000005.tif23152; [ka] teeth, [ka] Selected from; V is CH or N; X is CH or N; Y is N, NO, NR x or C=O; Z is NR 4 or CR 4 and; E is N or CH; Q is N or CH; G is N or CR 7 and; J is N or CR 7 and; L is N or CR 7 and; M is N or CR 8 and; R 1 is hydrogen, halo, cyano, R x , OR x and SO2R x R 2 is hydrogen or halo; R 3 is hydrogen or halo; R 4 is hydrogen, R x , OR x , C 1-3 Alkyl-OR x , C 1-3 Alkyl-OC 3-6 cycloalkyl or CH=CH2; R 5 is hydrogen or C 1-3alkyl, which is optionally substituted by 1 to 3 substituents selected from halo and hydroxy; R 6 is hydrogen or C 1-3 is alkyl; or R 5 and R 6 together with the carbon atoms between them, C 3-6 can form a cycloalkyl group; Each R 7 independently halo, R x , OR x , C 1-3 Alkyl-OR x , NH(C=O)OR x and NH2; R 8 is R x OR x selected from the group consisting of: or R 7 and R 8 together with the carbon atoms between them can form a 5-membered cycloalkyl or heterocyclic group, which heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of halo, methyl, or ethyl; R 9 is hydrogen or C 1-3 is alkyl; R 10 is hydrogen, hydroxy or C 1-3 is alkyl; R x is hydrogen or C 1-6 It is alkyl, which is optionally substituted with 1 to 4 substituents selected from halo and hydroxy.

[0008] In one embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] is.

[0009] In one embodiment of the present invention, X is CR2 In another embodiment of the present invention, X is N.

[0010] In one embodiment of the present invention, [ka] teeth, [ka] In another embodiment of the present invention, [ka] teeth, [ka] is.

[0011] In one embodiment of the present invention, V is CH. In another embodiment of the present invention, V is N.

[0012] In one embodiment of the invention, X is CH. In another embodiment of the invention, X is N.

[0013] In one embodiment of the present invention, Y is N. In another embodiment of the present invention, Y is NO. In another embodiment of the present invention, Y is NR x In another embodiment of the present invention, Y is C=O. In one embodiment of the invention, Z is NR 4 In another embodiment of the present invention, Z is CR 4 In one class of the invention, Z is CH.

[0014] In one embodiment of the present invention, E is N. In another embodiment of the present invention, E is CH.

[0015] In one embodiment of the present invention, Q is N. In another embodiment of the present invention, Q is CH.

[0016] In one embodiment of the present invention, G is N. In another embodiment of the present invention, G is CR 7 In one class of the invention, G is CH.

[0017] In one embodiment of the present invention, J is N. In another embodiment of the present invention, J is CR 7 In one class of the invention, J is CH.

[0018] In one embodiment of the present invention, L is N. In another embodiment of the present invention, L is CR 7 In one class of the invention, L is CH.

[0019] In one embodiment of the present invention, M is N. In another embodiment of the present invention, M is CR 8 In one class of the invention, M is CH.

[0020] In one embodiment of the present invention, R 1 is hydrogen, CH3, CHF2, CF3, OCHF2, or SO2CH3. In one class of this embodiment, R 1 is hydrogen. In another class of this embodiment, R 1 In another class of this embodiment, R 1 In another class of this embodiment, R is CHF2. 1 In one class of this embodiment, R is CF3. 1 In one class of this embodiment, R 1 is SO2CH3.

[0021] In one embodiment of the present invention, R 2 is hydrogen. In another embodiment of the present invention, R 2 is halo. In one class of the invention, R 2 is fluoro.

[0022] In one embodiment of the present invention, R3 is hydrogen. In another embodiment of the present invention, R 3 is halo. In one class of the invention, R 3 is chloro.

[0023] In one embodiment of the present invention, R 4 is cyano, CH3, CHF2, CH2OH, CH2OCH3, CH2OC(CH3)3, CH2O(cyclopropyl), CH(OH)CF3, CH2C(CH3)2OH, CD2OH, CH(CH3)OH or OCH3.

[0024] In one embodiment of the present invention, R 5 is hydrogen, CH or CHOH. In one class of the invention, R 5 is hydrogen. In another class of the invention, R 5 is CH3. In another class of the invention, R 5 is CH2OH.

[0025] In one embodiment of the present invention, R 6 is hydrogen.

[0026] In one embodiment of the present invention, R 7 is hydrogen, chloro, fluoro, CH3, OCH3, CHF2, OCHF2, CH2OH, NH2 and NH(C=O)OR x is.

[0027] In one embodiment of the present invention, R 7 and R 8 and together with the carbon atoms between them can form a 5-membered cycloalkyl or heterocyclic group, which is optionally substituted with one or two substituents independently selected from the group consisting of halo, methyl, or ethyl. 7 and R 8 together with the carbon atom between them can form two fluoro-substituted heterocyclic groups.

[0028] Reference to the above preferred classes and subclasses is meant to include all combinations of particular and preferred groups unless otherwise specified.

[0029] Specific embodiments of the present invention include, but are not limited to, the compounds identified herein as Examples 1-255, or pharmaceutically acceptable salts thereof.

[0030] Also included within the scope of the present invention is a pharmaceutical composition comprising a compound of Formula I above and a pharmaceutically acceptable carrier. The present invention is also intended to encompass pharmaceutical compositions containing a pharmaceutically acceptable carrier and any of the compounds specifically disclosed herein. These and other aspects of the present invention will be apparent from the teachings contained herein.

[0031] The present invention includes compositions for treating diseases or conditions in which plasma kallikrein activity is implicated. Accordingly, the present invention includes compositions for treating visual activity disorders, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood clotting during cardiopulmonary bypass surgery, and bleeding from postoperative surgery in mammals, comprising a compound of the present invention in a pharmaceutically acceptable carrier. One class of the present 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 contain anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs to exert the desired inhibition.

[0032] The present invention also includes a composition for preventing or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in a mammal, the composition comprising a compound of the present invention in a pharmaceutically acceptable carrier.

[0033] These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0034] The present invention also includes compositions for treating ocular inflammatory conditions, including, but not limited to, uveitis, posterior uveitis, macular edema, acute macular degeneration, wet age-related macular edema, retinal detachment, retinal vein occlusion, ocular tumors, fungal infections, viral infections, multifocal choroiditis, diabetic uveitis, diabetic macular edema, diabetic retinopathy, proliferative vitreoretinopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, histoplasmosis, and uveal ulcers. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0035] The present invention also includes compositions for treating posterior ocular diseases such as, but 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, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0036] It will be understood that the present invention relates to compounds of structural formula I as described herein, as well as pharmaceutically acceptable salts of compounds of structural formula I, and also to salts that are not pharmaceutically acceptable when used as precursors to the free compounds or pharmaceutically acceptable salts thereof or in other synthetic procedures.

[0037] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compounds of the present invention, prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethylacetate, digluconate, dihydrochloride, dodecylsulfate, and the like. Dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, 2-hydroxybenzoate Ethanesulfonate, hydroxynaphthoate, iodide, isonicotinic acid, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate Acid salts include, but are not limited to, acetate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelate, phenylpropionate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate, and the like.Additionally, when a compound of the present invention contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Also included are 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, dicyclohexylamines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyls such as dimethyl, diethyl, dibutyl sulfates; and diamyl sulfates; long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides such as benzyl and phenethyl bromide; and others.

[0038] These salts can be obtained by known methods, for example, by mixing the compound of the present invention with a solution containing an equivalent amount of the desired acid, base, etc., and then filtering the salt or distilling off the solvent to recover the desired salt. The compound of the present invention and its salt may form a solvate with a solvent such as water, ethanol, or glycerol. The compound of the present invention can simultaneously form an acid addition salt and a salt with a base, depending on the type of substituent on the side chain.

[0039] When the compounds of formula I contain both acidic and basic groups in the molecule, the present invention includes, in addition to the salt forms described above, also inner salts or betaines (zwitterions).

[0040] 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 encompass all such isomers of these compounds. All asymmetric centers present in compounds of Formula I may, independently of one another, have either the (R) or (S) configuration. When a bond to a chiral carbon is depicted as a straight line in a structural formula of the present invention, it is understood that both the (R) and (S) configurations of that chiral carbon, and thus both individual enantiomers and mixtures thereof, are encompassed by the formula. When a specific configuration is depicted, that enantiomer (either (R) or (S) at that center) is intended. Similarly, when a compound name is given without a chiral designation of a chiral carbon, it is understood that both the (R) and (S) configurations of that chiral carbon, and thus individual enantiomers and mixtures thereof, are encompassed by the name. The preparation of a specific stereoisomer or mixture thereof may be specified in the examples in which such stereoisomer or mixture was obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of the present invention.

[0041] Unless a specific enantiomer or diastereomer is indicated, the present invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, e.g., mixtures of enantiomers and / or diastereomers, in all ratios. Accordingly, enantiomers are the subject of the present invention in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of the two enantiomers in all ratios. In the case of cis / trans isomerism, the present invention includes both the cis and trans forms, as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by conventional methods, such as separation of mixtures by chromatography or crystallization, the use of stereochemically uniform starting materials for synthesis, or stereoselective synthesis. Optionally, derivatization can be carried out before the separation of stereoisomers. Separation of stereoisomeric mixtures can be carried out at an intermediate stage during the synthesis of compounds of formula I or on the final racemate. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereocenter of known configuration. Where compounds of the invention can tautomerize, all individual tautomers and mixtures thereof are included within the scope of the invention. The 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.

[0042] In the compounds of the present invention, atoms may exhibit natural isotopic abundance, or one or more atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present invention is intended to include all suitable isotopic variations of the specifically and generically described compounds. For example, different isotopic forms of hydrogen (H) include protium (1 H ) and deuterium (2 H) is the predominant hydrogen isotope found in nature. Enrichment with deuterium may confer certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques known to those of skill in the art, or by processes similar to those described in the general schemes and examples herein using appropriate isotopically enriching reagents and / or intermediates.

[0043] In any component, any variable (e.g., R x When a group (such as aryl, aryl, aryl) occurs more than once, its definition at each occurrence is independent at all other occurrences. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn from substituents into ring systems indicate that the indicated bond may be attached to any of the substitutable ring atoms. When 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.

[0044] It is clear to those skilled in the art that by incorporating one or more silicon (Si) atoms in place of one or more carbon atoms into the compounds of the present invention, it is possible to obtain chemically stable compounds that can be easily synthesized from readily available raw materials using techniques known in the art. Carbon and silicon have different covalent bond radii, which result in differences in bond distances and steric configurations compared to the analogous C-element and Si-element bonds. These differences result in slight variations in the size and shape of silicon-containing compounds compared to carbon. Those skilled in the art will understand that differences in size and shape can lead to minor or significant changes in potency, solubility, lack of targeted activity, packaging characteristics, etc. (Diass, JO et al. Organometallics (2006) 5:1188-1198; Showell, GA et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0045] It will be apparent that one skilled in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by techniques known in the art and the methods described below. It will be apparent that when a substituent is itself substituted with multiple groups, those multiple groups can be on the same carbon or on different carbons, so long as a stable structure results. It will also be understood that the phrase "optionally substituted" (with one or more substituents) means that the group in question may be unsubstituted or substituted with one or more substituents.

[0046] Furthermore, compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and all such amorphous and crystalline forms of the compounds of Formula I, as well as mixtures thereof, are intended to be included within the scope of the present invention. Furthermore, some compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates, particularly pharmaceutically acceptable solvates and hydrates of the compounds of the present invention, are included within the scope of the present invention, as are unsolvated and anhydrous forms.

[0047] Furthermore, when a carboxylic acid (—COOH) or alcohol group is present in a compound of the invention, pharmaceutically acceptable esters of the carboxylic acid derivative, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of the alcohol, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can also be used. These include ester and acyl groups known in the art for altering solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0048] Pharmaceutically acceptable prodrug modifications of the compounds of the invention, which are converted in vivo to compounds within the scope of the invention, are also within the scope of the invention. For example, esters may be formed by esterification of available carboxylic acid groups or by ester formation at available hydroxy groups in the compounds. Similarly, unstable amides may be formed. Pharmaceutically acceptable esters or amides of the compounds of the invention may be hydrolyzed in vivo to give acid (or -COO, depending on the pH of the fluid or tissue where the conversion occurs). - ) or hydroxy form and are therefore within the scope of the present invention. Examples of pharmaceutically acceptable prodrug modifications include -C 1-6 -C substituted with alkyl esters and phenyl esters 1-6 Examples include, but are not limited to, alkyl.

[0049] Thus, compounds within the scope of the general structural formulae, embodiments and specific compounds described and claimed herein include, unless otherwise indicated, salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline), solvates and hydrate forms, and any combination thereof, as well as salts thereof, prodrugs thereof, and salts of the prodrugs thereof, where such forms are possible.

[0050] Except as otherwise 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 this specification, e.g., methyl is represented by conventional abbreviations such as "Me" or CH3, or by symbols that are extended bonds without a defined end group, e.g., [ka] Ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, butyl can be represented by "Bu" or CH2CH2CH2CH3, etc. For example, "C 1-4 "Alkyl" (or "C1-C4 alkyl") means a straight or branched chain alkyl group having the specified number of carbon atoms, including all isomers. For example, the structure: [ka] have equivalent meanings. C 1-4 Alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl, etc. If no number is specified, 1 to 4 carbon atoms are intended for straight or branched chain alkyl groups.

[0051] Unless otherwise noted, the term "cycloalkyl" means a mono- or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0052] Unless otherwise noted, the term "aryl," as used herein, refers to a stable monocyclic or bicyclic ring system of up to 10 carbon atoms in each ring, where at least one ring is aromatic. Bicyclic aryl ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Aryl groups within this definition include, but are not limited to, phenyl, indene, isoindene, naphthalene, and tetralin.

[0053] As used herein, except where otherwise indicated, the term "heteroaryl" refers to a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, in which at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Bicyclic heterocyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Heteroaryl groups within the scope of this definition include azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, and pyrimidinyl. Heteroaryl includes, but is not limited to, phenyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazolooxazinyl, dihydropyrazoliothiazinedioxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetrahydroquinoline, and 3-oxo-3,4-dihydro-2N-benzo[b][1,4]thiazine. If heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxide thereof is also encompassed by this definition.

[0054] The term "heterocycle" or "heterocyclyl," as used herein, unless otherwise specified, is intended to mean a stable non-aromatic monocyclic or bicyclic ring system having up to 10 atoms in each ring, including one to four heteroatoms selected from the group consisting of O, N, S, SO, or SO. Bicyclic heterocyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Thus, "heterocyclyl" includes, but is not limited to, the following: azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxide thereof is also encompassed by this definition.

[0055] Except where otherwise noted, the term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0056] "Celite®" (Fluka) diatomaceous earth is diatomaceous earth and can be referred to as "celite."

[0057] Except as noted herein, structures containing substituent variables such as the variable "R" below: [ka] (which is depicted as not being attached to a specific bicyclic ring carbon atom) represents a structure in which that variable can be optionally attached to any bicyclic ring carbon atom. For example, the variable R shown in the structure above can be attached to any one of the six bicyclic ring carbon atoms i, ii, iii, iv, v, or vi.

[0058] Except as otherwise stated herein, bicyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom.

[0059] The present invention also relates to medicinal products comprising at least one compound of formula I and / or a pharmaceutically acceptable salt of a compound of formula I and / or any stereoisomeric form of a compound of formula I or of a pharmaceutically acceptable salt of a compound of formula I, together with pharmaceutically suitable and pharmaceutically acceptable vehicles, additives and / or other active substances and adjuvants.

[0060] As used herein, the term "patient" is intended to mean mammals such as primates, humans, sheep, horses, cows, pigs, dogs, cats, rats, and mice.

[0061] The pharmaceutical preparations according to the invention can be administered orally, by inhalation, rectally or transdermally, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents and other surfaces in the body that come into contact with blood with the compounds of formula I is possible.

[0062] The present invention also relates to a method for producing a medicament, which comprises bringing at least one compound of formula I into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0063] Suitable solid or galenical preparations include, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations with extended release of active substances, in the preparation of which common excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, propellants and lubricants, flavorings, sweeteners and solubilizers are used. Frequently used adjuvants that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerin.

[0064] The administration regimen using a plasma kallikrein inhibitor is selected depending on a variety of factors, such as the type of patient, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof being used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, eliminate, or arrest the progress of the condition.

[0065] When used for the indicated effects, oral dosages of plasma kallikrein inhibitors range from about 0.01 mg / kg body weight per day (mg / kg / day) to about 30 mg / kg / day, preferably 0.025 to 7.5 mg / kg / day, more preferably 0.1 to 2.5 mg / kg / day, and most preferably 0.1 to 0.5 mg / kg / day (amounts of active ingredient are on a free base basis unless otherwise specified). For example, an 80 kg patient would receive between about 0.8 mg / day and 2.4 g / day, preferably 2 to 600 mg / day, more preferably 8 to 200 mg / day, and most preferably 8 to 40 mg / kg / day. Thus, a pharmaceutical preparation suitable for once-daily administration would contain between 0.8 mg and 2.4 g, preferably 2 mg to 600 mg, more preferably 8 mg to 200 mg, and most preferably 8 mg to 40 mg, e.g., 8 mg, 10 mg, 20 mg, and 40 mg. Advantageously, the plasma kallikrein inhibitor may be administered in divided doses two, three or four times daily. For twice daily administration, a suitable prepared medicament would contain from 0.4 mg to 4 g, preferably from 1 mg to 300 mg, more preferably from 4 mg to 100 mg, most preferably from 4 mg to 20 mg, for example, 4 mg, 5 mg, 10 mg and 20 mg.

[0066] For intravenous administration, a patient will receive an amount of active ingredient sufficient to deliver 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 amounts can be administered in a number of suitable ways, e.g., a single, long-term, or several times daily dose of a low-concentration active ingredient, or a short-term, e.g., once daily, dose of a high-concentration active ingredient. Typically, conventional intravenous formulations containing active ingredient at concentrations of about 0.01-1.0 mg / mL, e.g., 0.1 mg / mL, 0.3 mg / mL, and 0.6 mg / mL, can be prepared and administered at daily doses of 0.01 mL / kg and 10.0 mL / kg patient body weight, e.g., 0.1 mL / kg, 0.2 mL / kg, and 0.5 mL / kg. In one example, an 80 kg patient receiving an 8 mL twice-daily intravenous formulation having an active ingredient concentration of 0.5 mg / mL would receive 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid, or any pharmaceutically acceptable acid / conjugate base with adequate buffering capacity in the pH range acceptable for intravenous administration can be used as a buffer. Selection of an appropriate buffer and formulation pH is within the skill of one in the art, depending on the solubility of the drug being administered.

[0067] The compounds of Formula I can be administered both as monotherapy and in combination with other therapeutic agents, including, but not limited to, anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0068] An "anti-inflammatory agent" is an agent that, when administered at therapeutically effective levels, is effective in reducing inflammation, either directly or indirectly. "Anti-inflammatory agents" include, but are not limited to, steroidal anti-inflammatory agents and glucocorticoids. Suitable anti-inflammatory agents include, but are not limited to, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

[0069] An "anti-VEGF agent" is an agent that is effective directly or indirectly in inhibiting the activity of VEGF (vascular endothelial growth factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, and aflibercept.

[0070] An "immunosuppressant" is a drug that has the effect of directly or indirectly suppressing or reducing the strength of the body's immune system. Suitable immunosuppressants include, but are not limited to, corticosteroids (e.g., prednisone, budesonide, prednisolone), Janus kinase inhibitors (e.g., tofacitinib), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), mTOR inhibitors (e.g., sirolimus, everolimus), IMDH inhibitors (e.g., azathioprine, leflunomide, mycophenolate), biologics (e.g., abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab), and monoclonal antibodies (e.g., basiliximab, daclizumab).

[0071] Suitable anticoagulants include, but are not limited to, factor XIa inhibitors, thrombin inhibitors, thrombin receptor antagonists, factor VIIa inhibitors, factor Xa inhibitors, factor IXa inhibitors, factor XIIa inhibitors, adenosine diphosphate antiplatelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g., for treating or preventing unstable angina or preventing re-occlusion after angioplasty and restenosis), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase for synergistic effects in the treatment of various vascular diseases. Examples of such anticoagulants include apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban, and semuloparin. For example, patients suffering from coronary artery disease and those who have undergone angioplasty may benefit from the co-administration of a fibrinogen receptor antagonist and a thrombin inhibitor.

[0072] In certain embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are used within their conventional dosage ranges and administration regimens as reported in the art, e.g., the dosages set forth in the Physicians' Desk Reference, e.g., 70th Edition (2016) and earlier editions. In other embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are used at doses lower than their conventional dosage ranges.

[0073] Alternatively or additionally, one or more other pharmacologically active agents can be co-administered with the compounds of the invention, by which is meant a pharmaceutically active agent (or agent) that is different from the compounds of the invention and that is active in the body, such as a prodrug, that is converted to a pharmaceutically active form after administration, including free acids, free bases, and pharmaceutically acceptable salts of the other active agents, where such formulations are commercially available or otherwise chemically possible. Generally, any suitable additional active agent (or active agents), such as, but not limited to, an antihypertensive agent, another diuretic agent, an antiatherosclerotic agent, for example, a lipid-modifying agent, an antidiabetic agent, and / or an antiobesity agent, may be used in any combination with a compound of the present invention in a single formulation (fixed-dose combination) or may be administered to the patient in one or more separate formulations that allow for simultaneous or sequential administration of the active agents (co-administration of separate active agents). Examples of other active substances that can be used include 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 can be in free base, free acid, salt, or prodrug form, such as azilsartan, e.g., azilsartan medoxomil potassium (EDA), RBI®), candesartan, e.g. candesartan cilexetil (ATACAND®), eprosartan, e.g. eprosartan mesylate (TEVETAN®), irbesartan (AVAPRO®), losartan, e.g. In combination with thiazide-like diuretics such as losartan potassium (COZAAR®), olmesartan, e.g., olmesartan medoximil (BENICAR®), telmesartan (MICARDIS®), valsartan (DIOVAN®), and hydrochlorothiazide (e.g., HYZAAR®, DIOVAN HCT®, ATACAND HCT®, etc.). Any of these drugs used in combination with HCTZ; Potassium-sparing diuretics such as amiloride HCl, spironolactone, eplerenone, and triamterene; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalclein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamide hemifumarate) SPP600, SPP630, and SPP635; Endothelin receptor antagonists, vasodilators (e.g., nitroprusside); Calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nical dipine); potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam); sympatholytics; beta-adrenergic blocking agents (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha-adrenergic blocking agents (e.g., doxazosin, prazosin, or alpha-methyldopa); central alpha-adrenergic agonists; peripheral vasodilators (e.g., hydralazine);Lipid-lowering drugs, for example, HMG-CoA reductase inhibitors, such as simvastatin and lovastatin (which are sold in lactone prodrug form as ZOCOR® and MEVACOR®, and function as inhibitors after administration), as well as atorvastatin (particularly the calcium salt sold as LIPITOR®), rosuvastatin (particularly the calcium salt sold as CRESTOR®), pravastatin (particularly the sodium salt sold as PRAVACHOL®), and fluvastatin (particularly the sodium salt sold as PRAVACHOL®). Pharmaceutically acceptable salts of dihydroxy open-acid HMG-CoA reductase inhibitors such as vastatin (especially the sodium salt sold under the trademark LESCOL®); cholesterol absorption inhibitors, e.g., ezetimibe (ZETIA®) and any other lipid-lowering agent such as the HMG-CoA reductase inhibitors mentioned above, particularly simvastatin (VYTORIN®) or atorvastatin calcium, in combination with simvastatin (VYTORIN®) or atorvastatin calcium; niacin in immediate or sustained release form, particularly DP antagonists such as laropiprant and / or HMG-Co Niacin in combination with A-reductase inhibitors; niacin receptor agonists, such as acipimox and acifran, and niacin receptor partial agonists; insulin sensitizers 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 known as glitazones (e.g., pioglitazone, rosiglitazone), alginate, niacin receptor agonists ... metabolic modifiers including alphaglucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitagliptin (JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), concomitant 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 their 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 diazoxide; and other agents useful in the prevention or treatment of the above diseases, including, but not limited to, the free acid, free base, and pharmaceutically acceptable salt forms, prodrug forms, e.g., esters, and prodrug salts, of the above pharmaceutical agents where chemically possible. The trade names of the above pharmaceutical agents are provided as examples of the marketed forms of the active agents, and it is contemplated that such pharmaceutical agents may be used in separate formulations for simultaneous or sequential administration with the compounds of this invention, or that the active agents in the formulations may be used in fixed-dose pharmaceutical combinations with the compounds of this invention.

[0074] A typical dose of a plasma kallikrein inhibitor of the present invention in combination with other suitable agents may be the same as the dose of the plasma kallikrein inhibitor administered without co-administration of additional agents, or may be significantly less than the dose of the plasma kallikrein inhibitor administered without co-administration of additional agents, depending on the therapeutic needs of the patient.

[0075] The compound is administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of a compound of the invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e., prevent, inhibit, or ameliorate) a disease state or treat the progression of a disease in the host.

[0076] The compounds of the present invention are preferably administered alone to mammals in a therapeutically effective amount. However, the compounds of the present invention can also be administered to mammals in a therapeutically effective amount in combination with an additional therapeutic agent, as defined below. When administered in combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy occurs when the effect of the compounds when administered in combination (in this case, inhibition of the desired target) is greater than the additive effect of each compound when administered individually as a single agent, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55. Generally, synergy is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect of the combination compared to the individual components, or some other beneficial effect.

[0077] "Combined administration" or "combination therapy" means that a compound of the invention and one or more additional therapeutic agents are administered simultaneously to the mammal being treated. When administered concurrently, each component may be administered simultaneously or sequentially in any order at different times. Thus, each component may be administered separately but sufficiently close in time so as to provide the desired therapeutic effect. Administration of each component need not be by the same route of administration; for example, one component can be administered orally and another component can be administered intravitreally in the eye.

[0078] The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrative of some aspects of the invention, and all embodiments which are functionally equivalent are intended to be within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant arts and are intended to be encompassed within the scope of the appended claims.

[0079] general law The compounds of the invention can be made using conventional techniques or according to the methods outlined in the following general synthetic schemes. Those skilled in the art can vary the procedures and reagents shown to obtain analogous intermediates and / or final compounds.

[0080] NMR spectra were measured using a VARIAN or Bruker NMR system (400, 500, or 600 MHz). Chemical shifts are reported in ppm downfield and upfield from tetramethylsilane (TMS) and are relative to internal TMS or solvent resonances ( 1 H NMR: δ 7.27 for CDCl3, δ 2.50 for (CD3)(CHD2)SO, and 13 C NMR: δ 77.02 for CDCl3 and δ 39.51 for (CD3)2SO. Coupling constants (J) are expressed in hertz (Hz), and spin multiplicities are indicated as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet), and br (broad). Chiral separations were performed on a Waters Thar 80 SFC or Berger MG II preparative SFC system. LC-MS data were recorded on a SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, Agilent 1100 series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instrument using a C18 column with a MeCN / water gradient containing 0.02 to 0.1% TFA. UV detection was performed at 220 nm and 254 nm, and ESI ionization was used for MS detection.

[0081] When chiral resolution was performed by chromatography using a chiral column, the chiral columns used for the SFC chiral resolution are listed in the table. Some of the chiral columns used were CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK AD-H, and CHIRALPAK AS-H. They will be referred to hereafter by their two- or three-letter abbreviations. By convention, the fast-eluting isomer from a chiral resolution is always listed first in the table, followed immediately by the slower-eluting isomer from the same resolution. When more than two isomers are separated, they are always listed in the order of elution in the table: Peak 1, then Peak 2, Peak 3, etc. Near the chiral center in the structure * The symbol indicates that the chiral center was resolved by chiral resolution without its stereochemical configuration being unambiguously determined.

[0082] Also, TLC is thin layer chromatography; UV is ultraviolet; W is watts; wt. is weight percent; xg is times gravity; α D is the specific rotation of polarized light at 589 nm; °C is degrees Celsius; %w / v is the percentage of the weight of the former drug to the volume of the latter drug; Hz is hertz; cpm is counts per minute; δ H is a chemical shift; d is a doublet; dd is a doublet of a doublet; MHz is megahertz; MS is a mass spectrum; a mass spectrum obtained by ES-MS may be referred to herein as "LC-MS"; m / z is mass / charge ratio; n is normal; N is normality; nm is nanometer; and nM is nanomolar concentration.

[0083] Several catalysts and ligands are used in the following procedures.

[0084] "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-1,1'-biphenyl)]palladium(II) methanesulfonate. "SPhos Pd G4" is also known as "(methanesulfonato-κO)[2'-(methylamino)-2-biphenylyl]palladium-dicyclohexyl(2',6'-dimethoxy-2-biphenylyl)phosphine (1:1)." "BrettPhos" is also known as 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl. "BrettPhos Pd G3" is also known as [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. "[Ir{dFCF3ppy}2(bpy)]PF6" is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridyl]iridium hexafluorophosphate. These catalysts and ligands are available from Millipore Sigma.

[0085] For purposes of this specification, the following abbreviations have the indicated meanings:

[0086] Ac: Acetyl acac: acetylacetone ACN: acetonitrile AcOH or HOAc: acetic acid AIBN: Azobisisobutyronitrile aq.:Aqueous solution Ar: aryl Bn: Benzyl Boc or BOC: tert-butoxycarbonyl Br: Wide :Brettphos:2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl nBu: butyl ℃: Celsius calcd.: Calculated value cBu: cyclobutyl Cbz: benzyloxycarbonyl cHep: Cycloheptyl cHex: cyclohexyl cPen: cyclopentyl cPr: cyclopropyl d:day δ: chemical shift d: double line DABCO: 1,4-diazabicyclo[2.2.2]octane DAST: (Diethylamino) sulfur trifluoride DBA: Dibenzylideneacetone DBAD: Di-tert-butyl azodicarboxylate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DCM: dichloromethane dd: Double line of double lines ddd: double line double line double line DIAD: Diisopropyl azodicarboxylate DIBAL or Dibal-H: diisobutylaluminum hydride DIEA or Hunig's base: N,N-diisopropylethylamine DIPA: Diisopropylamine DMA: 1,2-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMP: Dess-Martin periodinane (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one DMPU: 3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMS: dimethyl sulfide DMSO: dimethyl sulfoxide DPPA: Diphenylphosphoryl azide dppf: 1,1'-bis(diphenylphosphino)ferrocene dt: Triple line double line DTT: dithiothreitol DPy: 2,2′-dipyridine dq: doublet of quad EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTA: Ethylenediaminetetraacetic acid equiv: equivalent amount ESI: electrospray ionization Et: Ethyl EtOH: ethanol EtOAc: ethyl acetate g: grams GST: glutathione S-transferase h: time HATU:N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HMDS: 1,1,1,3,3,3-hexamethyldisilazane HOBt: 1-hydroxybenzotriazole HPLC: High-performance liquid chromatography Hz: Hertz I C 50 : Concentration at which 50% inhibition occurs IPA: Isopropanol iPr: Isopropyl J: Coupling constant L: Liter LAH: Lithium aluminum hydride LC: liquid chromatography LCMS: Liquid Chromatography Mass Spectrometry LDA: lithium diisopropylamide LED: Light-emitting diode M: Mass M: mole m: multiplet mCPBA: m-chloroperbenzoic acid Me: Methyl MeOH: Methanol mg: milligram MHz: Megahertz min:minutes μL: microliter mL: milliliter mmol: millimolar MPLC: Medium pressure liquid chromatography MS: Mass spectrometry Ms: methanesulfonyl (mesyl) MTBE: Methyl tert-butyl ether N: Normality NBS: N-bromosuccinimide NMP: 1-methylpyrrolidinone NMR: nuclear magnetic resonance spectroscopy p:quintet Ph: Phenyl PMB: 4-methoxybenzyl Pr: Propyl psi: pounds per inch 2 q:Quarter qd: doublet quartet rac: racemic RT or rt: room temperature (ambient temperature, approximately 25°C) s: Single line satd.:saturated SEM: 2-(trimethylsilyl)ethoxymethyl sxt: sext SFC: Supercritical Fluid Chromatography S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl t: Triple line T3P: Propylphosphonic anhydride TBAF: tert-butylammonium fluoride TBS or TBDMS: tert-butyldimethylsilyl td:double line triple line TBDPS: tert-butylphenylsilyl TBDPSCl: tert-butyldiphenylsilyl chloride TBSCl: tert-butyldimethylsilyl chloride tBu: tert-butyl tBu X-phos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl TEA: Triethylamine (Et3N) Tf: Triflate TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride THF: tetrahydrofuran TLC: Thin Layer Chromatography TMS: Trimethylsilyl Tris: Tris(hydroxymethyl)aminomethane Ts: toluenesulfonyl (tolyl) tt: Triple line of triple lines X-phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0087] General Starting materials used were obtained from commercial sources, prepared in the examples, or prepared according to methods known in the literature, unless otherwise noted.

[0088] The methods used to prepare the compounds of the present invention are illustrated by the following schemes.

[0089] Schematic AA [ka]

[0090] Scheme AA illustrates a synthetic procedure for preparing bi-heteroaryl derivatives such as AA-6 from arenes AA-1 and alkylpyrazine-2-carboxylates such as AA-4. Deoxofluorination of the aldehyde AA-1 gives AA-2. Treatment of AA-2 with a trialkoxyborane such as AA-7 and a base such as LDA gives the boronate ester AA-3. Palladium-catalyzed cross-coupling of AA-3 with the halide AA-4 gives AA-5. Base-mediated hydrolysis or dealkylation of the ester of AA-5 by treatment with reagents such as LiOH, NaOH, or LiI gives the carboxylic acid AA-6.

[0091] Diagram AB [ka]

[0092] Scheme AB shows a synthetic procedure for preparing bi-heteroaryl derivatives such as AB-6 from alkylpyrazine-2-carboxylates such as AB-1 and arenes AB-3. Palladium-catalyzed displacement of the halide AB-1 with a reagent such as hexamethylditin affords stannane AB-2.

[0093] Iodination of AB-3 by treatment with a base such as LDA, lithium 2,2,6,6-tetramethylpiperidide, or n-butyllithium and iodine affords AB-4. Palladium-catalyzed cross-coupling of AB-2 with the iodo-compound AB-4 then affords AB-5. Base-mediated hydrolysis or dealkylation of the ester of AB-5 by treatment with reagents such as LiOH, NaOH, or LiI affords the carboxylic acid AB-6.

[0094] Schematic AC [ka]

[0095] Scheme AC illustrates a synthetic procedure for preparing bi-heteroaryl derivatives, such as AC-6, from pyrazine AC-1 and arene AC-2. Palladium-catalyzed cross-coupling of bromide AC-1 with boronate AC-2 provides AC-3. Palladium-catalyzed cross-coupling of AC-3 with AC-4, which can be an organometallic, organoboric, or organoboronic acid reagent, provides AC-5. Base-mediated hydrolysis or dealkylation of the ester of AC-5 by treatment with reagents such as LiOH, NaOH, or LiI provides carboxylic acid AC-6.

[0096] Diagram AD [ka]

[0097] Scheme AD illustrates a synthetic procedure for preparing biheteroaryl derivatives, such as AD-10, from arenes AD-1 and pyrazines AD-7. Bromination of AD-1 by treatment with a base such as LDA and a brominating agent AD-2, such as 1,2-dibromo-1,1,2,2-tetrachloroethane, affords AD-3. Copper-catalyzed cross-coupling of AD-2 with potassium thioacetate affords thioester AD-4. Treatment with an aqueous base such as NaOH and an alkylating agent such as methyl iodide converts thioester AD-4 to thioether AD-5, which is then oxidized to sulfoxide AD-6 using an oxidizing agent such as m-CPBA. Palladium-catalyzed cross-coupling of bromide AD-6 with stannane AD-7 affords AD-8. Oxidation of the sulfoxide of AD-8 using an oxidizing agent such as Oxone® affords sulfone AD-9. Base-mediated hydrolysis or dealkylation of the ester of AD-9 by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AD-10.

[0098] Schematic AE [ka]

[0099] Scheme AE illustrates synthetic procedures for preparing bi-heteroaryl derivatives such as AE-5 from AE-1. Esterification of the carobxylic acid of AE-1 gives the t-butyl ester AE-2. Oxidative cleavage of the methylidene group of AE-2 by treatment with reagents such as osmium tetroxide and sodium periodate gives the aldehyde AE-3. Deoxofluorination of AE-3 with a reagent such as bis(2-methoxyethyl)aminosulfur trifluoride gives AE-4. Acid-mediated dealkylation of the ester of AE-4 gives the carboxylic acid AE-5.

[0100] Schematic AF [ka]

[0101] Scheme AF shows a synthetic procedure for preparing bi-heteroaryl derivatives such as AF-4 from AF-1 and alkyl trifluoroborate salts AF-2. Ni salts / ligands such as nickel(II) dichloride ethylene glycol dimethyl ether complex and 4,4′-di-tert-butyl-2,2′-bipyridine, and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N 1 ,N 1′ Cross-coupling of AF-1 and AF-2 by treatment with a mixture of Ir complexes such as bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate affords pyrazine AF-3. Base-mediated hydrolysis of the ester of AF-3 by treatment with reagents such as LiOH or NaOH affords carboxylic acid AF-4.

[0102] Schematic AG [ka]

[0103] Scheme AG shows a synthetic procedure for preparing biheteroaryl derivatives such as AG-5 from pyridine AG-1 and arene AG-2. Palladium-catalyzed cross-coupling of bromide AG-1 with boronic acid AG-2 gives AG-3. Oxidation of AG-3 with an oxidizing agent such as mCPBA gives N-oxide AG-4. Base-mediated hydrolysis of the ester of AG-4 by treatment with a reagent such as LiOH gives carboxylic acid AG-5.

[0104] Diagram AH [ka]

[0105] Scheme AH shows a synthetic procedure for preparing biheteroaryl derivatives such as AH-9 from pyridine AH-1 and arene AH-3. Displacement of chloropyrimidine AH-1 with (4-methoxyphenyl)methanol alcohol affords AH-2. Palladium-catalyzed cross-coupling of AH-2 and boronic acid AH-3 affords AH-4. Oxidation of the thioether AH-4 with an oxidizing agent such as Oxone® affords the sulfone AH-5. Displacement of AH-5 with a cyanide source such as sodium cyanide affords AH-6, which is converted to AH-7 by treatment with methanol under acidic conditions. Alkylation of the pyrimidine of AH-7 with an alkyl electrophile affords AH-8. Base-mediated hydrolysis of the ester of AH-8 by treatment with reagents such as LiOH or NaOH affords the carboxylic acid AH-9.

[0106] Diagram AI [ka]

[0107] Scheme AI illustrates synthetic procedures for preparing bi-heteroaryl derivatives such as AI-3. Amide cross-coupling of AI-1 with 1H-pyrazol-4-amine AI-2 provides amide AI-3.

[0108] Diagram AJ [ka]

[0109] Scheme AJ shows a synthetic procedure for preparing bi-heteroaryl derivatives such as AJ-7 from pyrazine AJ-1 and arene AJ-2. Palladium-catalyzed cross-coupling of bromide AJ-1 with boronic acid AJ-2 affords AJ-3. Treatment of AJ-3 with copper(II) bromide affords AJ-4. Base-mediated hydrolysis of the ester of AJ-4 by treatment with a reagent such as LiOH affords carboxylic acid AJ-5. Nickel-catalyzed reductive cross-coupling of AJ-5 with oxirane AJ-6 affords lactone AJ-7.

[0110] Schematic AK [ka]

[0111] Scheme AK shows a synthetic procedure for the preparation of bi-heteroaryl derivatives such as AK-4 from intermediate AK-1. Bromination of AK-1 by treatment with a reagent such as a mixture of NBS and benzoyl peroxide gives AK-2. Treatment of AK-2 with alcohol AK-3 and a base such as sodium hydride gives ether AK-4.

[0112] Diagram AL [ka]

[0113] Scheme AL shows a synthetic procedure for preparing bi-heteroaryl derivatives such as AL-5 from intermediate AL-1. Palladium-catalyzed carboxylation of AL-1 gives the methyl ester AL-2. Treatment of AL-2 with an organometallic reagent AL-3, such as an alkyl magnesium salt, and a reducing agent such as lithium aluminum hydride or lithium aluminum deuteride gives the alcohol AL-4. Cyclization of AL-4 with a coupling agent such as EDC gives the lactone AL-5.

[0114] Schematic AM [ka]

[0115] Scheme AM shows a synthetic procedure for preparing bi-heteroaryl derivatives such as AM-3 from intermediate AM-1. Trifluoromethylation of aldehyde AM-1 by treatment with a reagent such as (trifluoromethyl)trimethylsilane in the presence of trifluoromethyl N-oxide gives AM-2. Acid-mediated dealkylation of the ester of AM-2 gives carboxylic acid AM-3.

[0116] Diagram AN [ka]

[0117] Scheme AN ​​shows a synthetic procedure for preparing biheteroaryl derivatives such as AN-7 from acetylsuccinic acid AN-1 and arene AN-5. Condensation of AN-1 with hydrazine gives 6-oxo-tetrahydropyrdazine AN-2, which is then oxidized by treatment with a reagent such as bromine to give dihydropyridazine AN-3. Treatment of AN-3 with a reagent such as phosphorus(V) oxybromide gives bromide AN-4. Palladium-catalyzed cross-coupling of bromide AN-4 with boronic acid AN-5 gives AN-6. Base-mediated hydrolysis or dealkylation of the ester of AN-6 by treatment with a reagent such as LiOH, NaOH, or LiI gives carboxylic acid AN-7.

[0118] Schematic BA [ka]

[0119] Scheme BA shows a synthetic procedure for preparing alcohol derivatives such as BA-4 from azaheterocycles BA-1 or BA-2. Treatment of the esters BA-1 or BA-2 with organometallic reagents such as alkylmagnesium salts or DIBAL gives the ketone or aldehyde BA-3, which is then converted to the alcohol BA-4 by treatment with a reducing agent such as sodium borohydride.

[0120] Diagram BB [ka]

[0121] Scheme BB depicts a synthetic procedure for synthesizing alcohol derivatives such as BB-2 from aldehydes such as BB-1 via treatment with organometallic reagents such as alkyl magnesium salts.

[0122] Diagram BC [ka]

[0123] Scheme BC shows a synthetic procedure for the synthesis of alcohols such as BC-2 from aldehydes, ketones, esters, or carboxylic acids such as BC-1 via treatment with a reducing agent such as sodium borohydride, lithium borohydride, or borane (in the case of carboxylic acids).

[0124] Diagram BD [ka]

[0125] Scheme BC depicts a synthetic procedure for the synthesis of cyclopropyl alcohols such as BD-2 from esters such as BD-1 via treatment with titanium(IV) isopropoxide and ethylmagnesium bromide.

[0126] Schematic BE [ka]

[0127] Scheme BE shows a synthetic procedure for synthesizing alcohols such as BE-4 from esters such as BE-1. Ester BE-1 is treated with a reducing agent such as DIBAL to give alcohol BE-2, which is then oxidized with an oxidizing agent such as DMP to aldehyde BE-3. Conversion of the aldehyde of BE-3 with an organometallic reagent such as an alkylmagnesium bromide provides the alcohol BE-4.

[0128] Schematic BF [ka]

[0129] Scheme BF shows a synthetic procedure for synthesizing alcohols such as BF-3 from primary alcohols such as BF-1. Alcohol BF-1 is oxidized to aldehyde BF-2 using an oxidizing agent such as DMP. The aldehyde in BF-2 is converted with an organometallic reagent such as an alkylmagnesium bromide to give alcohol BF-3.

[0130] Diagram BG [ka]

[0131] Scheme BG shows a synthetic procedure for synthesizing alcohols such as BG-5 from arenes or heteroarenes such as BG-1. Conversion of BG-1 with an oxidizing agent such as manganese dioxide provides aldehyde BG-2, which is treated with a deoxyfluorinating agent such as DAST to give BG-3. A two-step procedure involving metal-halogen exchange by addition of an organometallic reagent such as isopropylmagnesium bromide, followed by quenching with the corresponding aldehyde BG-4, gives alcohol BG-5.

[0132] Schematic BH [ka]

[0133] Scheme BH shows a synthetic procedure for synthesizing alcohols such as BH-3 from arenes or heteroarenes such as BH-1. Palladium-catalyzed cross-coupling of BH-1 with potassium vinyltrifluoroborate BH-2 or vinylboronic acid pinacol ester BH-3 provides styrene BH-4. Hydration of BH-2 by treatment with reagents such as cobalt(II) acetylacetonate and phenylsilane provides alcohol BH-3.

[0134] Diagrammatic BI [ka]

[0135] Scheme BI shows a synthetic procedure for synthesizing alcohols such as BI-4 from arenes or heteroarenes such as BI-1. Palladium-catalyzed cross-coupling of BI-1 with tri-n-butylstannane BI-2, followed by treatment with an acid such as aqueous HCl, gives ketone BI-3. Reduction of BI-3 with a reducing agent such as sodium borohydride gives alcohol BI-4.

[0136] Schematic BJ [ka]

[0137] Scheme BJ illustrates a synthetic procedure for synthesizing alcohols such as BJ-5 from chlorides such as BJ-1. Palladium-catalyzed cross-coupling of BJ-1 with potassium vinyltrifluoroborate BJ-2 provides styrene BJ-3. Oxidative cleavage of the vinyl group in BJ-3 using reagents such as osmium tetroxide and sodium periodate provides aldehyde BJ-4. Treatment of BJ-3 with a reducing agent such as sodium borohydride or an organometallic reagent such as an alkylmagnesium bromide provides alcohol BJ-5.

[0138] Diagram BK [ka]

[0139] Scheme BK shows a synthetic procedure for synthesizing alcohols such as BK-3 from arenes or heteroarenes such as BK-1. Metal-halogen exchange of BK-1 with an organometallic reagent such as n-butyllithium, followed by addition of a ketone or aldehyde BK-2, affords BK-3.

[0140] Diagram BL [ka]

[0141] Scheme BL shows a synthetic procedure for synthesizing alcohols such as BL-4 from arenes or heteroarenes such as BL-1. Nucleophilic aromatic substitution of BL-1 with sodium cyanide gives nitrile BL-2. Acid-mediated methanolysis of BL-2 gives ester BL-3.

[0142] BL-3 is reduced with a reducing agent such as sodium borohydride to give alcohol BL-4.

[0143] Schematic BM [ka]

[0144] Scheme BM shows a synthetic procedure for synthesizing alcohols such as BM-3 from esters such as BM-1. Nucleophilic aromatic substitution of BM-1 with sodium methoxide gives the ether BM-2. Reduction of the ester of BM-2 with a reducing agent such as sodium borohydride gives the alcohol BM-3.

[0145] Schematic BN [ka]

[0146] Scheme BM illustrates a synthetic procedure for synthesizing alcohols such as BN-5 from arenes or heteroarenes such as BN-1. Sandmeyer-type halogenation of BN-1 by treatment with reagents such as tert-butyl nitrite, potassium iodide, and cuprate (I) affords the iodide BN-2. Palladium-catalyzed cross-coupling of BN-2 with tri-n-butylstannane BN-3, followed by treatment with an acid such as hydrochloric acid, affords the ketone BN-4. Reduction of BN-4 with a reducing agent such as sodium borohydride affords the alcohol BN-5.

[0147] Diagram BO [ka]

[0148] Scheme BO illustrates a synthetic procedure for synthesizing alcohols such as BO-5 from pyridones such as BO-1. Deoxychlorination of BO-1 with a reagent such as phosphorus(V) oxychloride gives the chloropyridine BO-2. Reduction of the ester of BO-2 by treatment with a reducing agent such as DIBAL gives the alcohol BO-3, which is then oxidized to the aldehyde BO-4 with an oxidizing agent such as DMP. Transformation of the aldehyde of BO-4 with an organometallic reagent such as alkylmagnesium bromide gives the alcohol BO-5.

[0149] Schematic BP [ka]

[0150] Scheme BP illustrates a synthetic procedure for the synthesis of alcohols such as BP-5 from substituted pyridines such as BP-1. Quenching of the ortho-lithiated product with a borate ester followed by oxidative rearrangement affords the phenol BP-2. Demethylation in the presence of a strong acid, preferably boron tribromide, HBr, followed by trapping with dibromomethane in the presence of a suitable mild base, such as cesium carbonate, affords dioxolanes such as BP-3. Lithium-halogen exchange followed by a Vilsmeier condensation quenched with a formyl donor, such as DMF, affords the aldehyde BP-4, which can be reduced under mild conditions as previously described in Scheme BO to afford the alcohol BP-5.

[0151] Diagram BQ [ka]

[0152] Scheme BQ illustrates a synthetic procedure for synthesizing benzyl alcohols such as BQ-6 from substituted pyridines such as BQ-1. Demethylation following methods similar to those described above provides a catechol intermediate, which can be trapped with thiophosgene to afford dioxolothiones such as BQ-2. Activation of the thiocarbonate with a reagent such as the dibromoimidazolodiones described above in the presence of a fluoride source such as HF / pyridine can provide difluorodioxolanes such as BQ-3. Pd-catalyzed cross-coupling with [3.1.0]-lactam (AAA-6), as shown below, can generate heteroaryl amide BQ-4, which can be reacted with a suitable brominating reagent to afford BQ-5. Pd-catalyzed Stille coupling with a vinylstannane reagent such as tributyl(1-ethoxyvinyl)stannane, followed by reduction of the resulting ketone, can provide benzyl alcohol BQ-6, which can be converted to compounds of the invention according to procedures described herein.

[0153] Schematic CA [ka]

[0154] Scheme CA shows a five-step synthetic procedure for synthesizing lactams such as CA-6 or thiolactams such as CA-7 from lactones such as CA-1. Treatment of CA-1 with benzylamine in an acid-mediated transformation affords the imide CA-2. Reduction of the imide in CA-2 by treatment with a reducing agent such as LAH or LiAlD4 affords the amine CA-3. The protecting group in CA-3 is converted to the tert-butyl carbamate by treatment with palladium and tert-butyl carbonate under a hydrogen atmosphere to afford CA-4. Oxidation of CA-4 with a reagent such as ruthenium trichloride and sodium periodate affords the lactam CA-5. Deprotection of CA-5 with an acid such as hydrogen chloride or TFA affords the secondary amide CA-6. CA-6 can be directly treated with, for example, Lawesson's reagent to afford the thiolactam CA-7.

[0155] Schematic AAA [ka]

[0156] Scheme AAA illustrates a five-step synthetic procedure for synthesizing amide derivatives such as AAA-10 from alcohols such as AAA-1 and carboxylic acids such as AAA-9. Alcohol AAA-1 is converted to AAA-2, which is then derivatized with pyrazole AAA-3 to give intermediate AAA-4. Palladium- or copper-catalyzed cross-coupling of AAA-4 with AAA-5 or AAA-6 affords lactam AAA-7. Removal of the Boc protecting group of AAA-7 gives amine AAA-8, which is then coupled with acid AAA-9 to give amide AAA-10.

[0157] Diagram AAB [ka]

[0158] Scheme AAB shows a five-step synthetic procedure for the synthesis of amide derivatives such as AAB-10 from tolyl derivatives such as AAB-1 and carboxylic acids such as AAB-9.

[0159] Bromination of AAB-1 gives AAB-2, which is derivatized with pyrazole AAB-3 to give intermediate AAB-4. Palladium- or copper-catalyzed cross-coupling of AAB-4 and AAB-5 or AAB-6 gives lactam AAB-7. Removal of the Boc protecting group of AAB-7 gives amine AAB-8, which is then coupled with acid AAB-9 to give amide AAB-10.

[0160] Diagram AAC [ka]

[0161] Schematic AAC shows a four-step synthetic procedure for synthesizing amide derivatives such as AAC-7 from alcohols such as AAC-1 and pyrazoles such as AAC-3. Alcohol AAC-1 is converted to bromide AAC-2. Base-mediated nucleophilic substitution of AAC-2 with AAC-3 affords pyrazole AAC-4. Oxidation of the thioether of AAC-4 affords sulfone AAC-5, which is then coupled with amide AAC-6 to afford amide AAC-7.

[0162] Schematic AAD [ka]

[0163] Scheme AAD shows a six-step synthetic procedure for synthesizing amide derivatives such as AAD-10 from alcohols such as AAD-1 and carboxylic acids such as AAD-9. Alcohol AAD-1 is converted to the halide AAD-2. Base-mediated nucleophilic substitution of AAD-2 with AAD-3 gives pyrazole AAD-4. Oxidation of the thioether of AAD-4 gives sulfone AAD-5, which is then displaced with amide AAD-6 to give amide AAD-7. Removal of the Boc protecting group of AAD-7 gives amine AAD-8, which is then coupled with acid AAD-9 to give amide AAD-10.

[0164] Diagram AAE [ka]

[0165] Scheme AAE illustrates a four-step synthetic procedure for synthesizing amide derivatives such as AAE-9 from alcohols such as AAE-1 and carboxylic acids such as AAE-8. Mitsunobu coupling of AAE-1 with pyrazole AAE-2 provides AAE-3. Palladium- or copper-catalyzed cross-coupling of AAE-3 and lactams AAE-4 or AAE-5 provides AAE-6. Reduction of the nitro group of AAE-6 by treatment with reagents such as platinum / H2 or iron / ammonium chloride provides amine AAE-7, which is then coupled with acid AAE-8 to provide amide AAE-9.

[0166] Schematic AAF [ka]

[0167] Scheme AAF shows a seven-step synthetic procedure for synthesizing amide derivatives such as AAF-12 from pyridines such as AAF-1 and carboxylic acids such as AAF-11. Palladium-catalyzed cross-coupling of AAF-1 and lactam AAF-2 gives AAF-3. Bromination of pyridine AAF-3 with a reagent such as N-bromosuccinimide gives AAF-4. Palladium-catalyzed cross-coupling of bromide AAF-4 with tri-n-butylstannane AAF-5, followed by aqueous acidic workup, gives ketone AAF-6. Reduction of AAF-4 with a reducing agent such as sodium borohydride gives alcohol AAF-7. Mitsunobu coupling of AAF-7 with pyrazole AAF-8 gives AAF-9. Reduction of the nitro group of AAF-9 by treatment with a reagent such as platinum / H2 or iron / ammonium chloride gives amine AAF-10, which is then coupled with acid AAF-11 to give amide AAF-12.

[0168] Schematic AAG [ka]

[0169] Scheme AAG shows a four-step synthetic procedure for synthesizing alcohol derivatives such as AAG-5 from vinyl derivatives such as AAG-1. The amide of AAG-1 is protected, for example with an SEM group, to give AAG-2. The vinyl group of AAG-2 is oxidatively cleaved by treatment with reagents such as osmium tetroxide and sodium periodate to give the aldehyde AAG-3. Reduction of AAG-3 with a reducing agent such as sodium borohydride gives the alcohol AAG-4. Removal of the protecting group of AAG-4 gives AAG-5.

[0170] Diagram AAH [ka]

[0171] Scheme AAH shows an eight-step synthetic procedure for synthesizing alcohol derivatives such as AAG-5 from arenes or heteroarenes such as AAH-1. Palladium-catalyzed cross-coupling of bromide AAH-1 with potassium vinyltrifluoroborate AAH-2 or vinylboronic acid pinacol ester AAH-3 gives styrene AAH-4. Palladium-catalyzed cross-coupling of AAH-4 with lactams AAH-5 or AAH-6 gives AAH-7. Dihydroxylation of the vinyl group of AAH-7 with reagents such as osmium tetroxide and 4-methylmorphine N-oxide gives diol AAH-8. Silylation of AAH-8 with reagents such as tert-butyl(chloro)diphenylsilane gives alcohol AAH-9. Mitsunobu coupling of AAH-9 with pyrazole AAH-10 gives AAH-11. The nitro group of AAH-11 can be reduced by treatment with reagents such as platinum / H2 or iron / ammonium chloride to give the amine AAH-12, which is then coupled with the acid AAH-13 to give the amide AAH-14. Deprotection of the silyl ether of AAH-14 gives the alcohol AAH-15.

[0172] Schematic AAI [ka]

[0173] Scheme AAI shows a seven-step synthetic procedure for synthesizing alcohol derivatives such as AAI-13 from pyrimidines such as AAI-1 and carboxylic acids such as AAI-11. Silver-mediated decarboxylative alkylation of AAI-1 with AAI-2 gives the ether AAI-3. Reduction of the ketone AAI-3 with a reducing agent such as sodium borohydride gives AAI-4. Mitsunobu coupling of AAI-4 with the pyrazole AAI-5 gives AAI-6. Palladium-catalyzed cross-coupling of AAI-6 with the lactam AAI-7 or AAI-8 gives AAI-9. Reduction of the nitro group of AAI-9 with reagents such as platinum / H2 or iron / ammonium chloride gives the amine AAI-10, which is then coupled with the acid AAI-11 to give the amide AAI-12. Deprotection of the tert-butyl ether of AAI-12 gives the alcohol AAI-13.

[0174] Diagram AAJ [ka]

[0175] Scheme AAJ shows a six-step synthetic procedure for synthesizing amide derivatives such as AAJ-11 from pyrimidines such as AAJ-1 and carboxylic acids such as AAJ-10. A two-step procedure involving metal-halogen exchange of AAJ-1 by addition of an organometallic reagent such as isopropylmagnesium chloride, followed by quenching with the corresponding aldehyde AAJ-2, affords alcohol AAJ-3. Mitsunobu coupling of AAJ-3 with pyrazole AAJ-4 affords AAJ-4.

[0176] Nucleophilic displacement of pyrimidine AAJ-5 with an amine or an ammonium salt such as ammonium hydroxide affords AAJ-6. Palladium-catalyzed cross-coupling of AAJ-6 with lactam AAJ-7 affords AAI-8. Reduction of the nitro group of AAJ-8 by treatment with reagents such as platinum / H2 or iron / ammonium chloride affords amine AAJ-9, which is then coupled with acid AAJ-10 to afford amide AAJ-11.

[0177] Schematic AAK [ka]

[0178] Schematic AAK shows an eight-step synthetic procedure for synthesizing amide derivatives such as AAK-13 from an alcohol such as AAK-1 and a carboxylic acid AAK-11 or lactone AAK-12. Conversion of alcohol AAK-1 to halide AAK-2 is followed by base-mediated nucleophilic displacement of AAK-2 with AAK-3 to afford pyrazole AAK-4. Reduction of the nitro group of AAK-4 with reagents such as platinum / H2 or iron / ammonium chloride affords amine AAK-5, which is then protected with tert-butyl carbamate to afford AAK-6. Oxidation of the thioether of AAK-6 affords sulfone AAK-7, which is then displaced with lactam AAK-8 to afford AAK-9. Removal of the Boc protecting group of AAK-10 affords amine AAK-11, which is then coupled with acid AAK-11 or lactone AAK-12 to afford amide AAK-13.

[0179] Schematic AAL [ka]

[0180] Scheme AAL shows a four-step synthetic procedure for synthesizing amide derivatives such as AAL-10 from alcohols such as AAL-1 and carboxylic acids such as AAL-9. Mitsunobu coupling of AAL-1 with triazole AAL-2 gives regioisomers AAL-3, AAL-4, and AAL-5. Palladium-catalyzed cross-coupling of AAL-3 or AAL-4 with lactam AAL-6 gives AAL-7. Reduction of the nitro group of AAL-7 by treatment with reagents such as platinum / H2 or iron / ammonium chloride gives amine AAL-8, which is then coupled with acid AAL-9 to give amide AAL-10.

[0181] Schematic AAM [ka]

[0182] Scheme AAM shows a four-step synthetic procedure for synthesizing amide derivatives such as AAM-8 from alcohols such as AAM-1 and carboxylic acids such as AAM-7. Palladium-catalyzed cross-coupling of AAM-1 with AAM-2 gives the lactam AAM-3. Mitsunobu coupling of AAM-3 with the pyrazole AAM-4 gives AAM-5. Reduction of the nitro group of AAM-5 by treatment with reagents such as platinum / H2 or iron / ammonium chloride gives the amine AAM-6, which is then coupled with the acid AAM-7 to give the amide AAM-8.

[0183] Schematic AAN [ka]

[0184] Scheme AAN shows a one-step synthetic procedure for synthesizing amine derivatives such as AAN-2 from carbamates such as AAN-1. Deprotection of the tert-butyl carbamate of AAN-1 gives AAN-2.

[0185] Diagram AAO [ka]

[0186] Scheme AAO shows a two-step synthetic procedure for the synthesis of alcohol derivatives such as AAO-3 from t-butyl ethers of amines such as AAO-1 and AAO-2. Amide coupling of AAO-1 and AAO-2 gives the amide AAO-3. Deprotection of AAO-3 gives the alcohol AAO-4.

[0187] Schematic AAP [ka]

[0188] Schematic AAP shows a three-step synthetic procedure for synthesizing amide derivatives such as AAP-6 from amines such as AAP-1 and carboxylic acids such as AAP-2. Amide coupling of AAP-1 with AAP-2 gives AAP-3, which is then treated with an oxidizing agent such as Oxone® or mCPBA to give sulfone AAP-4. Nucleophilic aromatic substitution of AAP-4 with amine AAP-5 gives AAP-6.

[0189] Diagram AAQ [ka]

[0190] Scheme AAQ shows a two-step synthetic procedure for the synthesis of alcohol derivatives such as AAQ-4 from amines such as AAQ-1 and carboxylic acids such as AAQ-2. Amide coupling of AAQ-1 with AAQ-2 affords AAQ-3. Transition metal-mediated hydration of the olefin of AAQ-3 by treatment with a reagent such as tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) and phenylsilane under an oxygen atmosphere affords the alcohol AAQ-4 and, optionally, the hydrogenated product AAQ-5. Additionally, AAQ-5 can be generated directly from AAQ-3 by reaction in the presence of a suitable reducing agent such as Raney nickel.

[0191] Schematic AAR [ka]

[0192] Schematic AAR shows a seven-step synthetic procedure for synthesizing amide derivatives such as AAR-12 from pyridines such as AAR-1 and carboxylic acids such as AAR-11. Palladium-catalyzed cross-coupling of AAR-1 with lactam AAR-2 gives AAR-3. Palladium-catalyzed cross-coupling of bromide AAR-3 with potassium vinyltrifluoroborate AAR-4 gives AAR-5. Oxidative cleavage of the vinyl group in AAR-5 by treatment with reagents such as osmium tetroxide and sodium periodate gives aldehyde AAR-6. Reduction of AAR-6 with a reducing agent such as sodium borohydride gives alcohol AAR-7. Mitsunobu coupling of AAR-7 with pyrazole AAR-8 gives AAR-9. Reduction of the nitro group in AAR-9 by treatment with reagents such as platinum / H2 or iron / ammonium chloride gives amine AAR-10, which is then coupled with acid AAR-11 to give amide AAR-12.

[0193] Schematic AAS [ka]

[0194] Scheme AAS shows a synthetic procedure for synthesizing amide derivatives such as AAS-11 from alkyltrifluoroborate salts such as AAS-4 and aryl or heteroaryl halides such as AAS-5. Nucleophilic displacement of iodide AAS-1 with pyrazole AAS-2 gives adduct AAS-3. Treatment of boronate AAS-3 with potassium bifluoride gives alkyltrifluoroborate salt AAS-4. Visible light-promoted iridium photoredox reaction and nickel double-catalyzed cross-coupling of AAS-4 and AAS-5 gives AAS-6. Palladium-catalyzed cross-coupling of AAS-6 with lactam AAS-7 gives AAS-8. Acid-mediated removal of the protecting group of AAS-9 gives amine AAS-7, which is then coupled with acid AAS-10 to give amide AAS-11.

[0195] Schematic AAT [ka]

[0196] Schematic AAT shows a four-step synthetic procedure for synthesizing amide derivatives such as AAT-8 from pyrazoles such as AAT-1 and carboxylic acids such as AAT-7. Base-mediated cyclopropanation of AAT-1 with diphenyl(vinyl)sulfonium salt AAT-2 and DBU affords AAT-3. Palladium-catalyzed cross-coupling of AAT-3 and lactam AAT-4 affords AAT-5. Reduction of the nitro group of AAT-5 by treatment with reagents such as platinum / H2 or iron / ammonium chloride affords amine AAT-6, which is then coupled with acid AAT-7 to afford amide AAT-8.

[0197] Schematic AAU [ka]

[0198] Scheme AAU shows a nine-step synthetic procedure for synthesizing amide derivatives such as AAU-13 from pyridines such as AAU-1 and carboxylic acids such as AAU-12. Nucleophilic aromatic substitution of AAU-1 with sodium methoxide affords the methyl ether AAU-2. Palladium-catalyzed cross-coupling of AAU-2 with tri-n-butylstannane AAU-3, followed by treatment with an acid such as aqueous HCl, affords the ketone AAU-4. Reduction of AAU-4 with a reducing agent such as sodium borohydride affords the alcohol AAU-5. Mitsunobu coupling of AAU-5 with the pyrazole AAU-6 affords AAU-7. Demethylation of ether AAU-7 with a reagent such as boron tribromide affords the alcohol AAU-8. Base-mediated alkylation of AAU-8 with sodium chlorodifluoroacetate affords the difluoromethyl ether AAU-9. Palladium-catalyzed cross-coupling of AAU-9 with the lactam AAU-10 affords AAU-11. The nitro group of AAU-11 is reduced by treatment with reagents such as platinum / H2 or iron / ammonium chloride to give the amine AAU-12, which is then coupled with the acid AAU-13 to give the amide AAU-14.

[0199] Schematic AAV [ka]

[0200] Schematic AAV shows a two-step synthetic procedure for synthesizing amide derivatives such as AAV-4 from amines such as AAV-1 and lactones such as AAV-2. Treatment of AAV-1 and AAV-2 with reagents such as trimethylaluminum yields AAV-3. Tert-butylation of the alcohol AAV-3 yields AAV-4.

[0201] Intermediate AA-6a [ka]

[0202] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (Scheme AA)

[0203] Step 1. 1-Chloro-4-(difluoromethyl)-2-fluorobenzene To a solution of 4-chloro-3-fluorobenzaldehyde (300 g, 1.89 mmol) in DCM (1.5 L) cooled to 0°C under a nitrogen atmosphere, bis(2-methoxyethyl)aminosulfur trifluoride (456 mL, 2.08 mol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was slowly poured into an ice-water solution and then extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide the title compound.

[0204] 1 H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 8.0 Hz, 1H), 7.34 (d, J =9.6 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 6.64 (t, J = 56 Hz, 1H).

[0205] Step 2. 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 1-chloro-4-(difluoromethyl)-2-fluorobenzene (300 g, 1.66 mol) in THF (1.8 L) cooled to −78° C. under a nitrogen atmosphere, LDA (997 mL, 1.99 mol, 2 M solution in THF) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (508 mL, 2.49 mol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then poured into saturated aqueous NH4Cl.

[0206] The resulting mixture was filtered and extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound.

[0207] 1HNMR (400 MHz, CDCl3) δ 7.53 (t, J = 8.0 Hz, 1H), 7.37 (d, J =8.4 Hz, 1H), 7.02 (t, J = 56 Hz, 1H), 1.39 (s , 12H).

[0208] Step 3. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate This reaction was carried out in two parallel vessels at equivalent scales as indicated. To a solution of 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127 g, 415 mmol), methyl 6-bromopyrazine-2-carboxylate (60.0 g, 276 mmol), and potassium fluoride (48.2 g, 829 mmol, 19.4 mL) in a mixture of dioxane (720 mL) and water (120 mL) was added 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (11.3 g, 13.8 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 12 hours. The reaction mixtures from both parallel reactions were cooled to room temperature, combined, and concentrated under reduced pressure. The crude residue was suspended in EtOAc, and the resulting mixture was filtered. The filtrate was washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give the title compound.

[0209] 1 HNMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.96 (d, J = 2.8 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 6.99 (t, J = 56 Hz, 1H), 4.06 (s, 3H).

[0210] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acidTo a solution of methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (350 g, 1.11 mol) in EtOH (1.75 L) at 10-20°C was added aqueous sodium hydroxide (2.10 L, 2.10 mol, 1 M aqueous solution). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure (to remove EtOH). The crude residue was extracted with MTBE. The organic layer was discarded, and the pH of the aqueous layer was adjusted to 2-3 by adding 2N aqueous HCl. The resulting mixture was filtered, and the filter cake was dried to give the title compound.

[0211] 1 H NMR (400 MHz, DMSO-d6) δ 13.9 (br s, 1H), 9.28 (s, 1H), 9.14 (s, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 56 Hz, 1H).

[0212] Intermediate AA-6b [ka]

[0213] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (Scheme AA)

[0214] Step 3. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylateTo a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (25.0 g, 134 mmol) and potassium phosphate (85.6 g, 403 mmol) in THF (500 mL) under a nitrogen atmosphere was added 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8.75 g, 10.7 mmol). The reaction mixture was heated to 70° C., and 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (41.1 g, 134 mmol) was added. The resulting mixture was stirred at 70° C. for 15 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (10:1 petroleum ether / EtOAc) to give the title compound. MS: 331 [M+1] + .

[0215] 1 H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 3.1 Hz, 1H), 7.68 - 7.56 (m, 2H), 7.02 (t, J = 55.3 Hz, 1H), 4.03 (d, J = 3.5 Hz, 3H), 2.96 (s, 3H).

[0216] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. MS: 317 [M+1] + .

[0217] 1 HNMR (400 MHz, CD3OD) δ 8.86 (d, J = 2.6 Hz, 1H), 7.86-7.77 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.04 (t, J = 55.0 Hz, 1H), 2.92 (s, 3H).

[0218] Intermediate AB-6a [ka]

[0219] 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid (Scheme AB)

[0220] Step 1. Methyl 6-(trimethylated)pyrazine-2-carboxylate To a solution of methyl 6-bromopyrazine-2-carboxylate (4.00 g, 18.4 mmol), hexamethyldistannane (9.27 g, 28.3 mmol) in toluene (50.0 mL) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium (1.07 g, 0.922 mmol). The reaction mixture was stirred at 80° C. for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5:1 petroleum ether / EtOAc) to give the title compound. MS=303.0 [M+1] + .

[0221] Step 2. 1-Chloro-2-fluoro-3-iodo-4-(trifluoromethyl)benzene To a solution of 1-chloro-2-fluoro-4-(trifluoromethyl)benzene (250 g, 1.26 mol) in THF (2.25 L) cooled to -78°C under a nitrogen atmosphere, n-butyllithium (757 mL, 1.89 mol, 2.5 M solution in hexane) was added dropwise to the mixture. The reaction mixture was stirred at -78°C for 1 hour, and iodine (481 g, 1.89 mol) in THF (2.25 L) was added dropwise to the mixture (addition period = 2 hours). The reaction mixture was stirred at -78°C for 1 hour and then warmed to -20°C. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc. The organic layers were combined, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure to give the title compound. MS 324 [M+1] + .

[0222] Step 3. Methyl 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylateTo a mixture of methyl 6-(trimethylstannyl)pyrazine-2-carboxylate (1.11 g, 3.70 mmol), 1-chloro-2-fluoro-3-iodo-4-(trifluoromethyl)benzene (800 mg, 2.47 mmol) in toluene (20 mL) under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium (226 mg, 0.247 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene (117 mg, 0.247 mmol) were added. The reaction mixture was stirred at 120° C. for 18 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (1:0 to 5:1 petroleum ether / EtOAc) to give the title compound. MS=335.2 [M+1] + .

[0223] Step 4. 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. MS=321.2 [M+1] + .

[0224] Table 1. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate AB-6a. [Table 1] TIFF0007776453000087.tif67165

[0225] Intermediate AC-6a [ka]

[0226] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid (Scheme AC)

[0227] Step 1. Methyl 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylateTo a solution of methyl 6-bromo-3-chloropyrazine-2-carboxylate (1.00 g, 3.98 mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.22 g, 3.98 mmol), and potassium phosphate (2.53 g, 11.9 mmol) in THF (15 mL) under a nitrogen atmosphere was added 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (518 mg, 0.795 mmol). The reaction mixture was heated to 40° C. for 1.5 h. The reaction mixture was cooled to room temperature and then poured into a mixture of water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (1:0 to 10:1 petroleum ether / EtOAc) to give the title compound. MS: 351.0 [M+1] + .

[0228] Step 2. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylate To a solution of methyl 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (100 mg, 0.285 mmol) in toluene (4 mL) at room temperature under a nitrogen atmosphere were added triethylaluminum (0.854 mL, 0.854 mmol, 1.0 M solution in hexanes) and tetrakis(triphenylphosphine)palladium (32.9 mg, 28.0 μmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, and concentrated under reduced pressure. The crude residue was dissolved in a mixture of water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (5:1 petroleum ether / EtOAc) to give the title compound as a mixture with ethyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylate. MS: 345.1 [M+1] + and 359.0[M+1] + .

[0229] Step 3. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. Na2SO4 aqueous solution MS: 331.0 [M+1] + .

[0230] Table 2. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate AC-6a. [Table 2]

[0231] Intermediate AD-10a [ka]

[0232] 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid (Scheme AD)

[0233] Step 1. 2-Bromo-4-chloro-3-fluoro-1-iodobenzene To a mixture of 1-chloro-2-fluoro-4-iodobenzene (4 g, 15.6 mmol) in THF (50.0 mL) under a nitrogen atmosphere at −70° C., LDA (8.58 mL, 17.2 mmol, 2 M solution in THF) was added dropwise. The reaction mixture was stirred at −70° C. for 30 minutes, and then 1,2-dibromo-1,1,2,2-tetrachloroethane (6.10 g, 18.7 mmol) in THF (10 mL) was added dropwise. The resulting mixture was stirred at −70° C. for 20 minutes, then warmed to 10° C. and stirred for an additional hour. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound.

[0234] 1 H NMR (400 MHz, CDCl3) δ 7.11 (dd, J=8.4, 6.9 Hz, 1H), 7.60 (dd, J=8.6, 1.6 Hz, 1H).

[0235] Step 2. S-(2-bromo-4-chloro-3-fluorophenyl)ethanethioate To a solution of 2-bromo-4-chloro-3-fluoro-1-iodobenzene (5.00 g, 14.9 mmol) in toluene (30.0 mL) under a nitrogen atmosphere was added potassium thioacetate (2.55 g, 22.4 mmol), copper(I) iodide (284 mg, 1.49 mmol), and 1,10-phenanthroline (269 g, 1.49 mmol). The resulting mixture was stirred at 90 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered, and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound.

[0236] 1 H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 8.6, 7.0 Hz, 1H), 7.30 (dd, J = 8.6, 1.6 Hz, 1H), 2.47 (s, 3H).

[0237] Step 3. (2-Bromo-4-chloro-3-fluorophenyl)(methyl)sulfane To a solution of S-(2-bromo-4-chloro-3-fluorophenyl)ethanethioate (2.40 g, 8.46 mmol) in EtOH (10.0 mL) was added NaOH (2.5 mL, 25.4 mmol, 10 M aqueous solution), and iodomethane (4.81 g, 33.9 mmol) was added. The reaction mixture was stirred at 15° C. for 10 minutes. The mixture was concentrated under reduced pressure (to remove EtOH), diluted with water, and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound.

[0238] 1 H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 7.0, 8.6 Hz, 1H), 6.85 (dd, J = 1.4, 8.8 Hz, 1H), 2.48 (s, 3H).

[0239] Step 4. 2-Bromo-4-chloro-3-fluoro-1-(methylsulfinyl)benzene To a solution of (2-bromo-4-chloro-3-fluorophenyl)(methyl)sulfane (1.90 g, 7.44 mmol) in DCM (20 mL) was added mCPBA (2.57 g, 14.9 mmol). The reaction mixture was stirred at room temperature for 1 h and then quenched by the addition of saturated aqueous NaSO (30 mL). The resulting mixture was stirred at room temperature for 30 min, diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to give the title compound.

[0240] 1 H NMR (400 MHz, CDCl3) δ 7.72-7.67 (m, 1H), 7.65-7.59 (m, 1H), 2.84-2.79 (m, 3H).

[0241] Step 5. Methyl 6-(3-chloro-2-fluoro-6-(methylsulfinyl)phenyl)-3-methylpyrazine-2-carboxylate To a solution of methyl 6-(trimethylstannyl)pyrazine-2-carboxylate (332 mg, 1.11 mmol) and 2-bromo-4-chloro-3-fluoro-1-(methylsulfinyl)benzene (200 mg, 0.737 mmol) in dioxane (3.0 mL) was added 1,1′-bis(di-tert-butylphosphino)ferrocene (34.9 mg, 74.0 mol) and tris(dibenzylideneacetone)dipalladium (60 mg, 74 μmol). The reaction mixture was stirred at 90° C. under a nitrogen atmosphere for 15 hours. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 petroleum ether / EtOAc) to give the title compound. MS=328.9 [M+1] + .

[0242] Step 6. Methyl 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylateTo a solution of methyl 6-(3-chloro-2-fluoro-6-(methylsulfinyl)phenyl)pyrazine-2-carboxylate (40.0 mg, 0.122 mmol) in THF (0.5 mL) and water (0.100 mL) was added Oxone® (150 mg, 0.243 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 petroleum ether / EtOAc) to provide the title compound.

[0243] 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.92 (d, J = 2.5 Hz, 1H), 8.01 (dd, J = 1.5, 8.6 Hz, 1H), 7.75 (dd, J = 6.9, 8.6 Hz, 1H), 4.03 (s, 3H), 3.41 (s, 3H).

[0244] Step 7. 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. MS=330.9 [M+1] + .

[0245] Intermediate AE-5 [ka]

[0246] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylic acid (Scheme AE)

[0247] Step 1. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylateTo a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylic acid (700 mg, 2.13 mmol) in THF (15 mL) was added di-tert-butyl dicarbonate (697 mg, 3.19 mmol), triethylamine (0.594 mL, 4.26 mmol), and DMAP (78 mg, 0.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 15% EtOAc / petroleum ether) to give the title compound. MS=385.0 [M+1] + .

[0248] Step 2. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formylpyrazine-2-carboxylate To a solution of tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylate (150 mg, 0.390 mmol) in THF (4.0 mL) and water (0.5 mL) was added osmium tetroxide (20 mg / mL aqueous solution, 0.991 mL, 78.0 μmol) and sodium periodate (334 mg, 1.56 mmol). The mixture was stirred at room temperature for 2 hours and then quenched by the addition of saturated aqueous NaSO. The resulting mixture was stirred at room temperature for 15 minutes and extracted with EtOAc. The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compound. MS=330.9 [M+1-56]. + .

[0249] Step 3. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylate : The title compound was prepared following a procedure similar to that described above in Intermediate AA-6a Step 1. Aqueous MS=409.0 [M+1] + .

[0250] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylic acidTo a solution of tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylate (190 mg, 0.465 mmol) in DCM (6.0 mL) was added TFA (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the title compound. MS=352.9 [M+1] + .

[0251] Intermediate AF-4a [ka]

[0252] 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (Scheme AF)

[0253] Step 1. Methyl 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate A solution of 4,4′-di-tert-butyl-2,2′-bipyridine (38.2 mg, 0.142 mmol) and nickel(II) chloride·ethylene glycol dimethyl ether complex (31.3 mg, 0.142 mmol) in THF (1.0 mL) was stirred at 35 °C for 30 min. The mixture was then concentrated under reduced pressure (to remove THF). In a nitrogen-filled glovebox, potassium hydrogen phosphate (744 mg, 4.27 mmol), methyl 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (500 mg, 1.42 mmol), potassium (tert-butoxymethyl)trifluoroborate (553 mg, 2.85 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N] was added. 1 ,N 1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (Ir(dFCF3ppy)2bpyPF6, 160 mg, 0.142 mmol), 1,4-dioxane (10.0 mL), and DMA (2.0 mL) were added to the mixture. The resulting mixture was stirred in front of one 23 W CFL for 72 hours. The reaction mixture was poured into a mixture of water and EtOAc. The organic layer was separated, and the aqueous solution was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 20% EtOAc / petroleum ether) to give the title compound. MS=403.1 [M+1] + .

[0254] Step 2. 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Intermediate AA-6a Step 4. Aqueous MS=389.1 [M+1] + .

[0255] Table 3. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate AF-4a. [Table 3]

[0256] Intermediate AG-5a [ka]

[0257] 3-Carboxy-5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyridine 1-oxide (Scheme AG)

[0258] Step 1. Methyl 5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)nicotinateTo a solution of methyl 5-bromonicotinate (50.0 mg, 0.231 mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85.0 mg, 0.278 mmol), potassium phosphate (147 mg, 0.694 mmol) in THF (1.00 mL) and water (0.500 mL) was added 1,1′-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (15.1 mg, 23.0 μmol). The reaction mixture was heated in a microwave reactor at 80° C. for 30 minutes and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 50% EtOAc / petroleum ether) to give the title compound. MS=315.9 [M+1] + .

[0259] Step 2. 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-5-(methoxycarbonyl)pyridine-1-oxide To a solution of methyl 5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)nicotinate (50.0 mg, 0.158 mmol) in DCM (1.00 mL) was added mCPBA (42.6 mg, 0.190 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. Water and DCM were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 27%, ending B 57%) to give the title compound. MS=332.0 [M+1] + .

[0260] Step 3. 3-Carboxy-5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyridine 1-oxide : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. MS=318.0 [M+1] + .

[0261] Intermediate AH-8 [ka]

[0262] 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid (Scheme AH)

[0263] Step 1. 4-Chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine To a solution of 4,6-dichloro-2-(methylthio)pyrimidine (10.0 g, 51.3 mmol) and (4-methoxyphenyl)methanol (7.08 g, 51.3 mmol) in DMF (150 mL) was added sodium hydride (60% dispersion in mineral oil, 2.05 g, 51.3 mmol) in small portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h and at room temperature for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were combined, washed with water and brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 5% EtOAc / petroleum ether) to give the title compound. MS=297.0 [M+1] + .

[0264] Step 2. 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine To a solution of 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.36 g, 11.0 mmol), 4-chloro-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (2.50 g, 8.42 mmol), and potassium phosphate (5.36 g, 25.3 mmol) in toluene (40.0 mL) and water (8.00 mL) was added methanesulfonato(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) dichloromethane adduct (SPhos Pd G4, 0.657 g, 0.842 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 14 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the reaction mixture, which was then extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 100% EtOAc / petroleum ether) to give the title compound. MS=441.1 [M+1] + .

[0265] Step 3. 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine To a solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine (2.60 g, 5.90 mmol) in a mixture of THF (100 mL) and water (25 mL) was added Oxone® (36.3 g, 59.0 mmol). The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (25% to 100% EtOAc / petroleum ether) to give the title compound. MS=473.1 [M+1] + .

[0266] Step 4. 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)pyrimidine-2-carbonitrile To a solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine (1.90 g, 4.02 mmol) in a mixture of ACN (20.0 mL) and DMSO (1.00 mL) was added sodium cyanide (0.985 g, 20.1 mmol). The reaction mixture was stirred at room temperature for 14 hours and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 15% EtOAc / petroleum ether) to give the title compound. MS=420.1 [M+1] + .

[0267] Step 5. Methyl 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-hydroxypyrimidine-2-carboxylate A solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)pyrimidine-2-carbonitrile (900 mg, 2.14 mmol) in 4 M methanolic HCl solution (15 mL) was stirred at room temperature for 20 hours. Triethylamine was added to the reaction mixture to quench the acid, and it was concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 41%, ending B 62%) to give the title compound. MS=333.0 [M+1] + .

[0268] Step 6. Methyl 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylate To a solution of methyl 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-2-carboxylate (25.0 mg, 75.0 μmol) in a mixture of DCM (1.0 mL) and MeOH (0.1 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 0.400 mL, 0.800 mmol) at room temperature. After the addition was complete, the reaction mixture was stirred for 1 h, then quenched with acetic acid (a few drops) and concentrated under reduced pressure. The residue was purified by preparative TLC (3:1 petroleum ether / EtOAc) to give the title compound. MS=347.0 [M+1] + .

[0269] Step 7. 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. MS=332.9 [M+1] + .

[0270] Intermediate AI-3a [ka]

[0271] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AI) To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (1.50 g, 4.96 mmol) and 1H-pyrazol-4-amine (0.618 g, 7.43 mmol) in DCM (20.0 mL) at 0° C. was added 1-propanephosphonic anhydride (5.90 mL, 9.91 mmol) followed by DIEA (3.46 mL, 19.8 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate and extracted with DCM. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 100% EtOAc / hexanes) to give the title compound. MS 382.0 [M+1] + .

[0272] Table 4. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate AI-3a. [Table 4]

[0273] Intermediate AJ-7a [ka]

[0274] 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one (Scheme AJ)

[0275] Step 1. Methyl 3-amino-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate : The title compound was prepared following a procedure similar to that described above in Intermediate AA-6b Step 1. MS=332.1 [M+1] + .

[0276] Step 2. Methyl 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate To a solution of copper(II) bromide (1.62 g, 7.24 mmol) and tert-butyl nitrite (0.746 g, 7.24 mmol) in ACN (20.0 mL) heated at 70° C., methyl 3-amino-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (1.20 g, 3.62 mmol) was added. The reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to room temperature, and then water was added. The resulting mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-15% EtOAc / petroleum ether) to give the title compound. MS=396.9 [M+1] + .

[0277] Step 3. 3-Bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a.

[0278] 1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 2.4 Hz, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 6.95 (t, J = 54.8 Hz, 1H). MS = 380.8, 382.8 [M+1] + .

[0279] Step 4. 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one A solution of 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (30 mg, 0.079 mmol), 2,2-dimethyloxirane (11 mg, 0.16 mmol), zinc (10 mg, 0.16 mmol), sodium iodide (2.4 mg, 0.016 mmol), 4,4′-bipyridine (1.2 mg, 7.9 μmol), triethylamine hydrochloride (11 mg, 0.079 mmol), nickel(II) iodide (2.5 mg, 7.9 μmol), and pyridine (1.3 μL, 0.016 mmol) in DMPU (1.0 mL) was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting 33%, ending 63%) to give the title compound. MS=357.0[M+1] + .

[0280] Intermediate AK-4a [ka]

[0281] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropoxymethyl)pyrazine-2-carboxylic acid (Scheme AK)

[0282] Step 1. Methyl 3-(bromomethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylateTo a solution of methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylate (20 mg, 0.060 mmol), NBS (12 mg, 0.067 mmol) in CCl4 (1.0 mL) was added benzoyl peroxide (2.9 mg, 0.012 mmol). The mixture was stirred at 80°C for 8 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. MS=410.9 [M+1] + .

[0283] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropoxymethyl)pyrazine-2-carboxylic acid To a solution of cyclopropanol (14 mg, 0.24 mmol) in THF (0.5 mL) cooled to 0°C, sodium hydride (60% dispersion in oil, 5.3 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 30 min. Next, a solution of methyl 3-(bromomethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate (30 mg, 0.073 mmol) in THF (0.8 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 12 h. Saturated aqueous NH₄Cl was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 42% ending B 72%) to give the title compound. MS=372.9[M+1] + .

[0284] Intermediate AL-5a [ka]

[0285] 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethylfuro[3,4-b]pyrazin-5(7H)-one (Scheme AL)

[0286] Step 1. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxycarbonyl)pyrazine-2-carboxylic acidTo a solution of 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (300 mg, 0.786 mmol) and DIEA (0.28 mL, 1.6 mmol) in MeOH (10.0 mL) under a nitrogen atmosphere was added 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (57.5 mg, 79.0 μmol). The reaction mixture was stirred at 50° C. under a CO atmosphere (50 psi) for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was purified by preparative TLC (SiO, 20% methanol / DCM) to give the title compound. MS=360.9 [M+1] + .

[0287] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxycarbonyl)pyrazine-2-carboxylic acid (60 mg, 0.17 mmol) in THF (1.0 mL) cooled to 0 °C was added methylmagnesium chloride (0.055 mL, 0.17 mmol). The mixture was stirred at 0 °C for 5 min and then quenched by the addition of saturated aqueous NH4Cl. The resulting mixture was diluted with ACN (3 mL), filtered, and the filtrate was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN, starting B 45%, ending B 65%) to give the title compound. MS = 360.9 [M+1] + .

[0288] Step 3. 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethylfuro[3,4-b]pyrazin-5(7H)-one To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid (40 mg, 0.11 mmol) in DMF (0.50 mL) was added EDC (21 mg, 0.11 mmol) and pyridine (0.050 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted by adding EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO2, 1:1 EtOAc / petroleum ether) to give the title compound. MS=343.1 [M+1]+ .

[0289] Table 5. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate AL-5a. [Table 5]

[0290] Intermediate AM-3a [ka]

[0291] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylic acid (Scheme AM) Step 1: tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylate To a solution of tert-butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formylpyrazine-2-carboxylate (130 mg, 0.336 mmol) in 1,2-dimethoxyethane (6.000 mL) was added trimethylamine N-oxide (25.2 mg, 0.336 mmol) and (trifluoromethyl)trimethylsilane (143 mg, 1.01 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 12% EtOAc / petroleum ether) to give the title compound. MS=457.0 [M+1] + .

[0292] Step 2: 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. MS=400.8 [M+1] + .

[0293] Intermediate AN-7 [ka]

[0294] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylic acid (Scheme AN)

[0295] Step 1. Ethyl 3-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-4-carboxylate To a solution of diethyl 2-acetylsuccinate (1.00 g, 4.62 mmol) in EtOH (5.0 mL) was added hydrazine hydrate (0.272 g, 4.62 mmol). The reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 60% EtOAc / petroleum ether) to give the title compound. MS=185.1 [M+1] + .

[0296] Step 2. Ethyl 3-methyl-6-oxo-1,6-dihydropyridazine-4-carboxylate To a solution of ethyl 3-methyl-6-oxo-1,4,5,6-tetrahydropyridazine-4-carboxylate (100 mg, 0.543 mmol) in AcOH (5.0 mL) was added bromine (174 mg, 1.09 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and concentrated under reduced pressure to give the title compound. MS=183.0 [M+1] + .

[0297] Step 3. Ethyl 6-bromo-3-methylpyridazine-4-carboxylate A mixture of ethyl 3-methyl-6-oxo-1,6-dihydropyridazine-4-carboxylate (99.0 mg, 0.543 mmol) and phosphorus(V) oxybromide (1.00 g, 3.49 mmol) was stirred at 80° C. under a nitrogen atmosphere for 15 hours. The reaction mixture was cooled to room temperature and poured into ice-cold water. The resulting mixture was stirred for 1 hour, and saturated aqueous NaHCO was added (to adjust the pH of the mixture to approximately 7). The mixture was extracted with EtOAc. The organic layers were combined, washed with saturated brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.2% TFA)-ACN gradient) to give the title compound. MS=245.0, 247.0 [M+1] + .

[0298] Step 4. Ethyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylateTo a solution of ethyl 6-bromo-3-methylpyridazine-4-carboxylate (35 mg, 0.14 mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.430 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.029 mmol) in toluene (1.5 mL) and water (0.3 mL) under a nitrogen atmosphere was added cesium carbonate (140 mg, 0.430 mmol). The reaction vessel was sealed and heated in a microwave at 100° C. for 1 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO, 1:4 EtOAc / petroleum ether) to provide the title compound. MS=345.3[M+1] + .

[0299] Step 5. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylic acid : The title compound was prepared following a procedure similar to that described above in Step 4 of Intermediate AA-6a. MS=316.9 [M+1] + .

[0300] Intermediate BA-1a [ka]

[0301] 1-(5-Bromopyrimidin-2-yl)ethan-1-ol (Scheme BA)

[0302] Step 1. 1-(5-Bromopyrimidin-2-yl)ethan-1-one To a solution of methyl 5-bromo-4-methylpyrimidine-2-carboxylate (1.00 g, 4.33 mmol) in THF (43 mL) cooled to −78° C. was added methylmagnesium bromide (4.33 mL, 4.33 mmol) in one portion and the mixture was stirred at −78° C. for 30 minutes. The reaction mixture was quenched by adding saturated aqueous NH4Cl, and then the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound. MS=215.0, 217.0 [M+1] + .

[0303] Step 2. 1-(5-Bromopyrimidin-2-yl)ethan-1-ol To a solution of 1-(5-bromo-4-methylpyrimidin-2-yl)ethan-1-one (550 mg, 2.56 mmol) in 2-propanol (35.0 mL) cooled to 0° C., sodium borohydride (97.0 mg, 2.56 mmol) was added, and the mixture was stirred at 0° C. for 1 hour. Saturated aqueous NH4Cl was added to the mixture, and the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound. MS=217.0, 219.0 [M+H] + .

[0304] Table 6. Using the appropriate starting materials, the following compounds were prepared using a procedure similar to that described for intermediate BA-1a. [Table 6]

[0305] Intermediate BA-1c [ka]

[0306] 1-(5-Bromo-3-fluoropyridin-2-yl)ethanol (Scheme BA) Step 1. 1-(5-Bromo-3-fluoropyridin-2-yl)ethanone : To a solution of 5-bromo-3-fluoropicolinonitrile (2.0 g, 10 mmol) in toluene (30 mL) at 0 °C was added methylmagnesium bromide (6.6 mL, 20 mmol, 3 M solution in THF). The reaction mixture was stirred at 0 °C for 1 h, then quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compound. MS = 217.9, 219.9 [M+1] + .

[0307] Step 2. 1-(5-Bromo-3-fluoropyridin-2-yl)ethanol : The title compound was prepared in a similar manner as described for intermediate BA-1a. MS=219.9, 221.9 [M+1] + .

[0308] Intermediate BB-2a [ka]

[0309] 1-(5,6-Dichloropyridin-3-yl)ethan-1-ol (Scheme BB) : To a solution of 5,6-dichloronicotinaldehyde (300 mg, 1.71 mmol) in THF (3.0 mL) cooled to 0 °C under a nitrogen atmosphere was added methylmagnesium bromide (0.852 mL, 2.56 mmol, 3.0 M in diethyl ether) dropwise over 2 h. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 60% EtOAc / hexanes) to give the title compound. MS=191.9 [M+1] + .

[0310] Table 7. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate BB-2a. [Table 7]

[0311] Intermediate BC-2a [ka]

[0312] (5-chloro-6-methylpyrazin-2-yl)methanol (Scheme BC) : To a solution of 5-chloro-6-methylpyrazine-2-carbaldehyde (2.00 g, 12.8 mmol) in THF (10.0 mL) was added sodium borohydride (0.580 g, 15.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched by adding acetone, then water was added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 50% EtOAc / petroleum ether) to give the title compound. MS=158.9 [M+1] + .

[0313] Table 8. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate BC-2a. [Table 8]

[0314] Intermediate BD-2a [ka]

[0315] 1-(2-chloro-4-methylpyrimidin-5-yl)cyclopropan-1-ol (Scheme BD) : To a solution of methyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5.4 mmol) in diethyl ether (27 mL) cooled to -78 °C under a nitrogen atmosphere was added titanium(IV) isopropoxide (1.6 mL, 5.4 mmol), followed by the dropwise addition of ethylmagnesium bromide (3 M solution in diethyl ether, 5.7 mL, 17 mmol) over 15 min. The reaction mixture was warmed to 0 °C and stirred for 2 h, then quenched by the addition of water. The resulting mixture was extracted with EtOAc, and the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 10% MeOH / DCM). MS=185.0 [M+1] + .

[0316] Intermediate BE-4a [ka]

[0317] 1-(5-Bromo-6-methylpyridin-2-yl)ethan-1-ol (Scheme BE) Step 1. (5-Bromo-6-methylpyridin-2-yl)methanol A solution of methyl 5-bromo-6-methylpinacolinate (1.00 g, 4.40 mmol) in THF (22 mL) was cooled to -78 °C, followed by the dropwise addition of DIBAL (10.9 mL, 10.9 mmol, 1 M solution in THF). The reaction mixture was stirred at -78 °C for 15 minutes, then slowly warmed to room temperature and allowed to stir for 1 hour. The reaction mixture was cooled to 0 °C and quenched by the addition of EtOAc and 40% aqueous Rochelle's salt (potassium sodium tartrate hydrate, 60 mL) and stirred vigorously at room temperature overnight. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification. MS=203.0 [M+1] + .

[0318] Step 2. 5-Bromo-6-methylpicolinaldehydeA solution of (5-bromo-6-methylpyridin-2-yl)methanol (523 mg, 2.60 mmol) in DCM (8.6 mL) was cooled to 0° C. and DMP (1.60 g, 3.90 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 (10 mL) and saturated aqueous sodium thiosulfate and stirred vigorously for 1 hour. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound, which was used without further purification. MS=201.0[M+1] + .

[0319] Step 3. 1-(5-Bromo-6-methylpyridin-2-yl)ethan-1-ol A solution of 5-bromo-6-methylpicolinaldehyde (517 mg, 2.60 mmol) was dissolved in THF (13 mL), cooled to -78 °C, and a solution of methylmagnesium bromide (3.90 mL, 3.90 mmol, 1 M solution in THF) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and stirred for 20 min. The resulting mixture was filtered, and the filtrate was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification. MS=217.0 [M+1] + .

[0320] Table 9. Using appropriate starting materials, the following compounds were prepared using a procedure similar to that described in Intermediate BE-4a. [Table 9]

[0321] Intermediate BF-3a [ka]

[0322] 1-(6-bromo-5-methylpyridin-3-yl)ethan-1-ol Step 1. 6-Bromo-5-methylnicotinaldehyde The title compound was prepared in a manner similar to that described for 5-bromo-6-methylpicolinaldehyde (in the preparation of intermediate BE-4a). MS=210.9 [M+1] + .

[0323] Step 2. 1-(6-bromo-5-methylpyridin-3-yl)ethan-1-ol The title compound was prepared in a similar manner as described for 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol (Intermediate BE-4a). MS=217.9 [M+1] + .

[0324] Table 10. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate BF-3a. [Table 10]

[0325] Intermediate BG-5a [ka]

[0326] 1-(6-chloro-5-(difluoromethyl)pyridin-3-yl)ethan-1-ol (Scheme BG) Step 1. 5-Bromo-2-chloronicotinaldehyde To a solution of (5-bromo-2-chloropyridin-3-yl)methanol (4.00 g, 18.0 mmol) in DCM (10 mL) was added manganese(IV) oxide (7.82 g, 90.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% EtOAc / petroleum ether) to give the title compound.

[0327] 1 H NMR (400 MHz, CDCl3) δ 10.34 (s, 1 H), 8.63 (d, J = 2.7 Hz, 1 H), 8.29 (d, J = 2.7 Hz, 1 H).

[0328] Step 2. 5-Bromo-2-chloro-3-(difluoromethyl)pyridine: To a solution of 5-bromo-2-chloronicotinaldehyde (3.70 g, 16.8 mmol) in DCM (30 mL) cooled to 0° C. was added DAST (11.1 mL, 84.0 mmol) dropwise. The reaction mixture was stirred at 15° C. for 1 h. The reaction mixture was quenched by adding saturated aqueous sodium carbonate and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% EtOAc / petroleum ether) to provide the title compound.

[0329] 1 H NMR (400 MHz, CD3OD) δ 8.68-8.54 (m, 1 H), 8.29-8.14 (m, 1 H), 7.19-6.76 (m, 1 H).

[0330] Step 3. 1-(6-chloro-5-(difluoromethyl)pyridin-3-yl)ethanol To a solution of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (2.60 g, 10.7 mmol) in THF (25 mL) cooled to 0 °C was added isopropylmagnesium bromide (16.5 mL, 21.5 mmol) dropwise. Upon complete addition, the resulting mixture was stirred at 0 °C for 30 minutes, and acetaldehyde (6.4 mL, 32 mmol) was added. The reaction mixture was stirred for 16 hours while warming to room temperature. The reaction mixture was quenched by the addition of water and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (5% EtOAc / petroleum ether) to provide the title compound. MS=208.0[M+1] + .

[0331] Intermediate BH-5a [ka]

[0332] 1-(2-chloro-4-methylpyrimidin-5-yl)ethan-1-ol (Scheme BH)

[0333] Step 1. 2-Chloro-4-methyl-5-vinylpyrimidine The title compound was prepared following a procedure similar to that described above in Intermediate AG-5a Step 1. MS=154.6 [M+1] + .

[0334] Step 2. 1-(2-chloro-4-methylpyrimidin-5-yl)ethanol A mixture of 2-chloro-4-methyl-5-vinylpyrimidine (1.50 g, 9.70 mmol), cobalt(II) acetylacetonate (0.250 g, 0.970 mmol), and phenylsilane (2.10 g, 19.4 mmol) in THF (30 mL) was stirred at room temperature under an O atmosphere (15 psi) for 14 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0% to 50% EtOAc / petroleum ether) to give the title compound. MS=172.6 [M+1] + .

[0335] Intermediate BI-4a [ka]

[0336] 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethan-1-ol (Scheme BI)

[0337] Step 1. 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanoneTo a suspension of bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.313 mmol) in toluene (6.0 mL) was added tributyl(1-ethoxyvinyl)stannane (1.47 mL, 4.35 mmol) and 2-chloro-3-fluoro-5-iodo-4-methylpyridine (850 mg, 3.13 mmol). The resulting mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and 6 M aqueous HCl (ca. 1 mL) was added. The resulting mixture was stirred at room temperature for 1 h, then saturated aqueous NaHCO was added, and the mixture was washed with saturated aqueous potassium fluoride. The mixture was extracted with DCM. The combined organic fractions were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-12% EtOAc / petroleum ether) to give the title compound. MS=188.0 [M+1] + .

[0338] Step 2. 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanol : The title compound was prepared following a procedure similar to that described above in Step 1 of Intermediate BC-2a. Na2SO4 aqueous solution MS=190.0 [M+1] + .

[0339] Table 11. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate BI-4a. [Table 11]

[0340] Intermediates BJ-5a and BJ-5b [ka]

[0341] (6-chloro-5-methylpyridazin-3-yl)methanol and (6-chloro-4-methylpyridazin-3-yl)methanol (Scheme BJ) Step 1. 3-Chloro-4-methyl-6-vinylpyridazine and 6-chloro-4-methyl-3-vinylpyridazineTo a solution of 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol) in dioxane (80 mL) and water (40 mL) was added potassium vinyltrifluoroborate (4.11 g, 30.7 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (1.12 g, 1.53 mmol), and potassium phosphate (13.0 g, 61.3 mmol). The reaction mixture was stirred at 90° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, and water was added. The mixture was filtered, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compounds as a mixture. MS=155.0 [M+1] + .

[0342] Step 2. 6-Chloro-4-methylpyridazine-3-carbaldehyde and 6-chloro-5-methylpyridazine-3-carbaldehyde To a solution of a mixture of 3-chloro-4-methyl-6-vinylpyridazine and 6-chloro-4-methyl-3-vinylpyridazine (1.80 g, 5.82 mmol) in dioxane (80 mL) and water (20 mL) was added osmium tetroxide (25 mL, 1.97 mmol, 2% aqueous solution) and sodium periodate (2.49 g, 11.6 mmol). The mixture was stirred at room temperature for 2 hours. Saturated aqueous NaSO was added to the mixture, and the resulting mixture was stirred for 10 minutes. The mixture was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compounds as a mixture. MS=157.0 [M+1] + .

[0343] Step 3. (6-chloro-4-methylpyridazin-3-yl)methanol and (6-chloro-5-methylpyridazin-3-yl)methanolTo a solution of a mixture of 6-chloro-4-methylpyridazine-3-carbaldehyde and 6-chloro-5-methylpyridazine-3-carbaldehyde (1.10 g, 3.51 mmol) in methanol (10 mL) cooled to 0° C. was added sodium borohydride (0.199 g, 5.27 mmol). The mixture was stirred at 0° C. for 30 minutes, and acetone was added to the mixture. The resulting mixture was stirred at room temperature for 30 minutes, and the mixture was concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 petroleum ether / EtOAc) to give the title compounds as a mixture. MS=158.6 [M+1] + .

[0344] Table 12. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediates BJ-5a and BJ-5b. [Table 12]

[0345] Intermediate BK3a [ka]

[0346] 1-(2-chloro-4-methylpyrimidin-5-yl)cyclobutanol (Scheme BK) To a solution of 5-bromo-2-chloro-4-methylpyrimidine (1.00 g, 4.82 mmol) in THF (10 mL) cooled to −100° C. was added n-butyllithium (2.12 mL, 5.30 mmol, 2.5 M solution in hexane). The reaction mixture was stirred at −100° C. for 30 minutes. Next, cerium(III) chloride (1.98 g, 5.30 mmol) as a solution in THF (10 mL) was added at −100° C., and the resulting mixture was stirred at −100° C. for 30 minutes. At this point, cyclobutanone (0.507 g, 7.23 mmol) was added at −100° C. The reaction mixture was stirred at −100° C. for 2 hours, and then the mixture was stirred at room temperature for 12 hours. The mixture was quenched by the addition of saturated aqueous NH4Cl and then extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-15% EtOAc / petroleum ether) to give the title compound. MS=199.0 [M+1] + .

[0347] Table 13. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate BK-3a. [Table 13]

[0348] Intermediate BL-4a [ka]

[0349] (5-Bromo-4-methylpyrimidin-2-yl)methanol (Scheme BL)

[0350] Step 1. 5-Bromo-4-methylpyrimidine-2-carbonitrile A mixture of 5-bromo-2-chloro-4-methylpyrimidine (2.00 g, 9.64 mmol), NaCN (0.510 g, 10.4 mmol), and DABCO (0.389 g, 3.47 mmol) in DMSO (10 mL) and water (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0351] 1 H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 2.69 (s, 3H).

[0352] Step 2. Methyl 5-bromo-4-methylpyrimidine-2-carboxylate To a solution of 5-bromo-4-methylpyrimidine-2-carbonitrile (750 mg, 3.79 mmol) in methanol (10.0 mL) was added aqueous HCl (10 mL, 122 mmol). After the addition, the mixture was stirred at 80° C. for 1.5 hours. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound.

[0353] 1 H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 3.97 (s, 3H), 2.70 (s, 3H).

[0354] Step 3. (5-Bromo-4-methylpyrimidin-2-yl)methanol The title compound was prepared following a procedure similar to that described above in Step 3 of Intermediate BJ-5a. 1 H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 4.66 (s, 2H), 2.62 (s, 3H).

[0355] Intermediate BN-5 [ka]

[0356] 1-(5-Bromo-4-methyl-3-nitropyridin-2-yl)ethan-1-ol (Scheme BN)

[0357] Step 1. 5-Bromo-2-iodo-4-methyl-3-nitropyridine To a cooled solution of 5-bromo-4-methyl-3-nitropyridin-2-amine (10.0 g, 43.1 mmol) in a mixture of 1,2-dimethoxyethane and toluene (2.5:1, 150 mL) cooled to 0° C. was added copper(I) iodide (2.50 g, 13.1 mmol) and potassium iodide (15.0 g, 90.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, and then tert-butyl nitrite (12.0 g, 116 mmol) was added. The reaction mixture was stirred at 60° C. for 14 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (20% EtOAc / petroleum ether) to give the title compound. MS=342.8, 344.8 [M+1] + .

[0358] Step 2. 1-(5-Bromo-4-methyl-3-nitropyridin-2-yl)ethanone : The title compound was prepared following a procedure similar to that described above in Intermediate BI-4a Step 1. MS=258.9, 260.9[M+1] + .

[0359] Step 3. 1-(5-bromo-4-methyl-3-nitropyridin-2-yl)ethanol : The title compound was prepared following a procedure similar to that described above in Step 3 of Intermediate BJ-5a. MS=260.9, 262.9 [M+1] + .

[0360] Intermediate BO-5 [ka]

[0361] 1-(1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)ethan-1-ol (Scheme BO)

[0362] Step 1. Methyl 1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylate A solution of methyl 1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[c]pyridine-4-carboxylate (2.00 g, 10.4 mmol) in phosphorus(V) oxychloride (9.65 mL, 104 mmol) was stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature and then quenched by the addition of saturated aqueous NaHCO3. Additional saturated aqueous NaHCO3 was added to adjust the pH to approximately 7. The resulting mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 20% EtOAc / petroleum ether) to give the title compound. MS = 212.1 [M+1] + .

[0363] Step 2. (1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methanol To a solution of methyl 1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylate (2.00 g, 9.45 mmol) in THF (50 mL) at 0 °C was added DIBAL (18.9 mL, 18.9 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched by adding water and then extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS=184.1 [M+1] + .

[0364] Step 3. 1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehydeThe title compound was prepared in a manner similar to that described for 5-bromo-6-methylpicolinaldehyde (in the preparation of intermediate BE-4a). MS=182.1 [M+1] + .

[0365] Step 4. 1-(1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)ethanol The title compound was prepared in a similar manner as described for 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol (Intermediate BE-4a). MS=198.1 [M+1] + .

[0366] Intermediate BP-5 [ka]

[0367] (4-chloro-[1,3]dioxolo[4,5-c]pyridin-7-yl)methanol (Scheme BP)

[0368] Step 1: 5-Bromo-2-chloro-4-methoxypyridin-3-ol A solution of 5-bromo-2-chloro-4-methoxypyridine (5.60 g, 25.2 mmol) in THF (80 mL) was cooled to −78°C. To this solution was added a solution of LDA (13.8 mL, 27.7 mmol, 2 M in hexanes) dropwise, and the resulting solution was stirred at −78°C for 30 minutes. Trimethyl borate (6.54 g, 62.9 mmol) was added, and the reaction was continued to stir at −78°C for 2 hours, at which point hydrogen peroxide (6.61 mL, 76 mmol) was added. The mixture was allowed to warm to 0°C with stirring for 2 hours, and sodium dithionite (20 g in 20 mL of water) was added dropwise. The mixture was adjusted to pH 3 by the addition of 2N HCl and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified by silica gel chromatography (0% to 20% EtOAc / petroleum ether) to provide the title compound.

[0369] 1 H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 4.08 (s, 3H). MS = 239.9 (M+1).

[0370] Step 2: 5-Bromo-2-chloropyridine-3,4-diolTo a solution of 5-bromo-2-chloro-4-methoxypyridin-3-ol (2.00 g, 8.39 mmol) in DCM (30 mL) was added BBr3 (1.59 mL, 16.8 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h, at which time the mixture was cooled to 0 °C, quenched with MeOH, concentrated, and purified by silica gel chromatography (0% to 30% MeOH / DCM) to give the title compound. MS = 225.8 (M+1).

[0371] Step 3: 7-Bromo-4-chloro-[1,3]dioxolo[4,5-c]pyridine To a solution of 5-bromo-2-chloropyridine-3,4-diol (0.90 g, 4.0 mmol) in DMF (15 mL) was added CsCO (2.61 g, 8.02 mmol) and dibromomethane (0.836 g, 4.81 mmol), and the resulting mixture was heated to 60 °C for 16 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was washed with water, dried (NaSO), and concentrated to give the crude residue, which was purified by silica gel chromatography (0% to 20% EtOAc / petroleum ether) to give the title compound. MS=237.8 (M+1).

[0372] Step 4: 4-Chloro-[1,3]dioxolo[4,5-c]pyridine-7-carbaldehyde To a solution of 7-bromo-4-chloro-[1,3]dioxolo[4,5-c]pyridine (300 mg, 1.27 mmol) in THF (4 mL) was added n-butyllithium (0.558 mL, 1.396 mmol, 2.5 M solution in hexane) at −78° C. After the mixture was stirred at −78° C. for 0.5 h, DMF (0.49 mL, 6.3 mmol) (dissolved in 0.5 mL of THF) was added dropwise and the reaction mixture was continued stirring at −78° C. for 1 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give the crude residue, which was purified by preparative TLC eluting with EtOAc to give the title compound.

[0373] 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.39 (s, 1H), 6.31 (s, 2H). MS = 186.0 (M+1).

[0374] Step 5: (4-chloro-[1,3]dioxolo[4,5-c]pyridin-7-yl)methanol To a solution of 4-chloro-[1,3]dioxolo[4,5-c]pyridine-7-carbaldehyde (190 mg, 1.02 mmol) in THF (2 mL) and MeOH (0.2 mL) was added sodium borohydride (39 mg, 1.02 mmol) at 0 °C. After stirring the mixture at 0 °C for 5 minutes, acetone was added to the mixture, which was then warmed to room temperature and allowed to sit for 1 hour. The reaction was concentrated to give the crude residue, which was purified by preparative TLC eluting with EtOAc to give the title compound. MS=188.0 (M+1).

[0375] Intermediate BQ-6 [ka]

[0376] (1R,5S)-3-(2,2-difluoro-7-(1-hydroxyethyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (Scheme BQ)

[0377] Step 1: 2-chloropyridine-3,4-diol To a solution of 2-chloro-4-methoxypyridin-3-ol (9.00 g, 56.4 mmol) in DCM (200 mL) was added BBr3 (5.33 mL, 56.4 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. The mixture was quenched with MeOH and concentrated to give a crude residue, which was purified by silica gel chromatography (10% to 20% MeOH / DCM) to give the title compound. MS = 146.1 (M+1).

[0378] Step 2: 4-chloro-[1,3]dioxolo[4,5-c]pyridine-2-thione2-Chloropyridine-3,4-diol (8.00 g, 55.0 mmol) and DMAP (26.9 g, 220 mmol) were suspended in DCM (200 mL), and the resulting mixture was cooled to 0 °C. Thiophosgene (12.0 mL, 165 mmol) was added dropwise, and after 10 min, the reaction was warmed to room temperature. After 1 h, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (10% to 30% EtOAc / petroleum ether) to give the title compound. MS=188.0 (M+1).

[0379] Step 3: 4-Chloro-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridine 4-Chloro-[1,3]dioxolo[4,5-c]pyridine-2-thione (2.00 g, 10.7 mmol) was dissolved in DCM (20 mL) and cooled to -78 °C. Pyridine hydrofluoride (20.0 mL, 155 mmol) was added dropwise, followed by the addition of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (9.14 g, 32.0 mmol) in several portions. After 20 min, the reaction was warmed to -20 °C. After an additional 40 min, the reaction was adjusted to pH 7 by careful addition of 5 M NaOH. Sodium thiosulfate was added, and the resulting mixture was diluted with water and extracted with DCM. The organic layer was concentrated to give the crude residue, which was purified by silica gel chromatography (10% to 30% EtOAc / petroleum ether) to give the title compound. MS=194.0 (M+1).

[0380] 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 5.5 Hz, 1H), 7.07 (d, J = 5.1 Hz, 1H).

[0381] Step 4: (1R,5S)-3-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (750 mg, 7.72 mmol), 4-chloro-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridine (1.50 g, 7.75 mmol), CsCO (7.58 g, 23.3 mmol), and XANTPHOS (224 mg, 0.388 mmol) in 1,4-dioxane (20 mL) was added Pd(dba) (355 mg, 0.388 mmol). The mixture was degassed and backfilled with N, and the resulting mixture was heated to 90 °C for 14 h. The reaction was cooled to room temperature and concentrated to give the crude residue, which was purified by silica gel chromatography (30% to 40% EtOAc / petroleum ether) to give the title compound. MS=255.1 (M+1).

[0382] 1 H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 5.3 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 4.34 (dd, J=5.1, 10.6 Hz, 1H), 3.76-3.79 (m, 1H), 2.08-2.11 (m, 1H), 1.28 (br dd, J = 3.1, 8.1 Hz, 1H), 0.95 (q, J = 4.3 Hz, 1H), 0.84-0.88 (m, 1H).

[0383] Step 5: (1R,5S)-3-(7-bromo-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (500 mg, 1.97 mmol) in AcOH (10 mL) and TFA (1.0 mL, 13 mmol) was added 2-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (619 mg, 2.36 mmol), and the resulting mixture was heated to 100 °C. After 16 h, the reaction was concentrated to give a crude residue, which was purified by reverse-phase preparative HPLC (C18 stationary phase, ACN / water with 0.1% TFA) to give the title compound. MS = 332.9, 334.9 (M+1).

[0384] 1 H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 4.31 (dd, J = 4.9, 10.8 Hz, 1H), 3.76 (d, J = 11.0 Hz, 1H), 2.04-2.18 (m, 2H), 1.30 (dt, J = 5.1, 8.0 Hz, 1H), 0.88-1.01 (m, 1H).

[0385] Step 6: (1R,5S)-3-(7-acetyl-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(7-bromo-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (300 mg, 0.901 mmol) and tributyl(1-ethoxyvinyl)stannane (395 μL, 1.17 mmol) in toluene (5 mL) was added Pd(PPh3)2Cl2 (63 mg, 0.090 mmol), and the resulting mixture was heated to 90 °C. After 14 h, the reaction was cooled to room temperature, 6 M HCl (2 mL) was added, and the mixture was stirred for 30 min. The reaction was quenched with saturated aqueous KF solution, stirred for 1 h, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude residue, which was purified by silica gel chromatography (30% to 50% EtOAc / petroleum ether) to give the title compound. MS=297.1(M+1).

[0386] Step 7: (1R,5S)-3-(2,2-difluoro-7-(1-hydroxyethyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(7-acetyl-2,2-difluoro-[1,3]dioxolo[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (250 mg, 0.844 mmol) in THF (3 mL) and MeOH (0.3 mL) at 0 °C was added NaBH (31.9 mg, 0.844 mmol). The resulting mixture was stirred at 0 °C for 1 h, at which point excess acetone was added and the resulting mixture was allowed to warm to room temperature. After 1 h, the reaction was concentrated to give a crude residue that was purified by silica gel chromatography (40% to 50% EtOAc / petroleum ether) to give the title compound. MS=299.1 (M+1).

[0387] Intermediates CA-6a and CA-6b [ka]

[0388] (1S,5R)-3-azabicyclo[3.1.0]hexan-2-one and (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (Scheme CA)

[0389] Step 1. 3-Benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione The following procedure was carried out in two parallel batches at equivalent scales. These batches were combined for subsequent reaction workup. Benzylamine (574 g, 5.35 mol) was added to a solution of 3-oxabicyclo[3.1.0]hexane-2,4-dione (400 g, 3.57 mol) in acetic acid (2.00 L) at 15°C. The reaction mixture was stirred at 120°C for 12 hours. The reaction mixture was cooled to room temperature and poured into water. The resulting mixture was stirred for 30 minutes and filtered. The filtered solid was washed with water and dissolved by adding EtOAc. The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS=202.1 [M+1] + .

[0390] Step 2. 3-Benzyl-3-azabicyclo[3.1.0]hexane The following procedure was carried out in three batches in parallel on an equivalent scale. To a suspension of LAH (87.9 g, 2.32 mol) in THF (700 mL) was added dropwise a solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (333 g, 1.65 mol) in THF (1.40 L) at 10 °C. The resulting mixture was stirred at 40 °C for 12 hours and then cooled to 0 °C. Water (87 mL), aqueous sodium hydroxide (87 mL, 15% by volume), and then water (261 mL) were added dropwise to the mixture, successively. Na2SO4 was added to the mixture, and the resulting mixture was stirred for 30 minutes and filtered. The filtered solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure to give the title compound. MS = 174.2 [M+1] + .

[0391] Step 3. tert-Butyl 3-azabicyclo[3.1.0]hexane-3-carboxylateThe following procedure was carried out in eight batches in parallel at equivalent scales. To a solution of 3-benzyl-3-azabicyclo[3.1.0]hexane (110 g, 635 mmol) and di-tert-butyl dicarbonate (208 g, 952 mmol) in MeOH (770 mL) was added palladium on carbon (11.0 g, 10.4 mmol, 10 wt%). The reaction mixture was stirred at 40° C. under a H atmosphere (45 psi) for 2 hours. Reactions run in parallel were filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% to 20% EtOAc / petroleum ether) to give the title compound.

[0392] 1 HNMR (400 MHz, CDCl3) δ 3.47-3.59 (m, 2H), 3.30-3.34 (m, 2H), 1.44-1.46 (m, 11H), 0.63-0.68 (m, 1H), 0.15-0.18 (m, 1H).

[0393] Step 4. Butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate The following procedure was carried out in two batches in parallel on an equivalent scale. To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (330 g, 1.80 mol) and ruthenium trichloride (11.2 g, 54.0 mmol) in EtOAc (1.6 L) and water (1.60 L) at room temperature was added sodium periodate (770 g, 3.60 mol) in small portions. The resulting mixture was stirred for 12 hours. The parallel reactions were combined and filtered. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with saturated aqueous sodium dithionite, dried over Na2SO4, filtered, and then concentrated under reduced pressure to provide the title compound as a racemate. 1 HNMR (400 MHz, CDCl3) δ 3.82-3.78 (m, 1H), 3.72-3.69 (m, 1H), 2.05-2.00 (m, 1H), 1.90-1.89 (m, 1H), 1.52 (s, 9H), 1.26-1.18 (m, 1H), 0.80-0.78 (m, 1H). The enantiomers of the title compound were analyzed by chiral chromosome analysis. Separation by HPLC (SFC, DAICEL CHIRALPAK IC: 0.1% NH3H2O-EtOH start B 25% end B 25%) afforded the individual isomeric compounds in pure form. Faster-eluting enantiomer of the title compound (Intermediate CA-5a). Slower-eluting enantiomer of the title compound (Intermediate CA-5a): 1 H NMR (400 MHz, CDCl3) δ: 3.81-3.77 (m, 1H), 3.72-3.68 (m, 1H), 2.00-1.99 (m, 1H), 1.99-1.87 (m, 1H), 1.48 (s, 9H), 1.25-1.17 (m, 1H), 0.78-0.77 (m, 1H).

[0394] Step 5. (1S,5R)-3-azabicyclo[3.1.0]hexan-2-one and (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one A mixture of tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (650 g, 3.30 mol) in HCl / EtOAc (4 M, 3.25 L) was stirred at 15° C. for 1 hour. The reaction mixture was filtered, and the solid was washed with EtOAc (2.0 L, 1.0 L) and dried to give the title compound as a mixture of enantiomers. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (br s, 1H), 7.09 (br s, 1H), 3.35-3.31 (m, 1H), 3.14-3.12 (m, 1H), 1.92-1.88 (m, 1H), 1.61-1.60 (m, 1H), 1.02-0.97 (m, 1H), 0.45-0.42 (m, 1H).

[0395] Step 5. (1R,5S)-3-Azabicyclo[3.1.0]hexan-2-one A mixture of tert-butyl (1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (the later-eluting enantiomer from the previous step, 370 g, 1.88 mol) in HCl / EtOAc (4 M, 1.4 L) was stirred at 0-10° C. for 1 h. The reaction mixture was filtered, and the filtered solid was washed with EtOAc (500 mL) and dried to give the title compound.

[0396] 1 H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H), 7.07 (s, 1H), 3.34-3.30 (m, 1H), 3.13 (d, J = 10.4 Hz, 1H), 1.90-1.87 (m, 1H), 1.60-1.59 (m, 1H), 1.01-0.96 (m, 1H), 0.44-0.41 (m, 1H). MS = 98.1 [M+1] +

[0397] Table 14. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for intermediate CA-6. [Table 14]

[0398] Intermediate CA-7 [ka]

[0399] (1R,5S)-3-azabicyclo[3.1.0]hexane-2-thione (scheme CA To a vial containing (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 1.03 mmol) was added DCM (5.2 mL). In a separate vial, DCM (5.2 mL) was added to Lawesson's reagent (208 mg, 0.520 mmol). The lactam solution was slowly added to the Lawesson's reagent solution and stirred at room temperature for 15 hours. The reaction was concentrated and purified by silica gel chromatography (EtOAc / hexanes). The fractions were combined and concentrated under reduced pressure to give the title compound. MS=114.0 [M+1] + .

[0400] Examples 1 and 2 [ka]

[0401] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAA).

[0402] Step 1. 5-Bromo-2-(1-bromoethyl)-4-methylpyrimidine To a mixture of 1-(5-bromo-4-methylpyrimidin-2-yl)ethan-1-ol (550 mg, 2.53 mmol) and triphenylphosphine (997 mg, 3.80 mmol) in THF (8.5 mL) cooled to 0°C, carbon tetrabromide (1.26 g, 3.80 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound. MS=280.9 [M+1] + .

[0403] Step 2. tert-Butyl (1-(1-(5-bromo-4-methylpyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate To a solution of 5-bromo-2-(1-bromoethyl)-4-methylpyrimidine (210 mg, 0.750 mmol) in DMF (10 mL) was added tert-butyl (1H-pyrazol-4-yl)carbamate (210 mg, 0.750 mmol) and CsCO (733 mg, 2.25 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound. MS=284.1 [M+1] + .

[0404] Step 3. tert-Butyl (1-(1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate A mixture of (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (15 mg, 0.16 mmol), tert-butyl (1-(1-(5-bromo-4-methylpyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate (30 mg, 0.078 mmol), Xantphos-Pd-G3 (7.4 mg, 7.9 μmol), and cesium carbonate (77 mg, 0.24 mmol) in 1,4-dioxane (0.79 mL) was stirred at 100° C. for 3 hours. After cooling to room temperature, the mixture was filtered (eluting with additional EtOAc). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (MeOH / DCM) to give the title compound. MS=399.3 [M+1] + .

[0405] Step 4. (1R,5S)-3-(2-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-5-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. MS=299.1 [M+1] + .

[0406] Step 5. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide To a mixture of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (127 mg, 0.402 mmol), (1R,5S)-3-(2-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-5-yl)-3-azabicyclo[3.1.0]hexan-2-one (80.0 mg, 0.268 mmol) in pyridine (2.68 mL) cooled to 0 °C was added EDC (103 mg, 0.536 mmol). The reaction mixture was stirred overnight at room temperature, then saturated aqueous NaHCO was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, ACN / water + 0.1% TFA) to give a diastereomeric mixture of the title compound. The isomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD-H: neutral EtOH start B 40% end B 40%) to give the individual isomers in pure form. Faster-eluting diastereomer of the title compound (Example 1): 1H NMR (600 MHz, CD3OD) δ 8.85 (d, J = 2.4 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.90-7.74 (m, 1H), 7.75-7.59 (m, 2H), 6.94 (t, J = 54.6 Hz, 1H), 5.70 (q, J = 7.1 Hz, 1H), 4.05 (dd, J = 10.2, 5.9 Hz, 1H), 3.75-3.54 (m, 1H), 2.99 (s, 3H), 2.36 (s, 3H), 2.21-2.13 (m, 1H), 2.09-1.97 (m, 1H), 1.93 (d, J = 7.1 Hz, 3H), 1.36-1.24 (m, 2H), 0.93 (d, J = 3.4 Hz, 1H). MS = 597.1 [M+1] + .The final dissolution of the title compound (Example 2): 1 H NMR (600 MHz, CD3OD) δ 8.85 (d, J = 2.4 Hz, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.84-7.78 (m, 1H), 7.69-7.64 (m, 2H), 6.94 (t, J = 54.6 Hz, 1H), 5.70 (q, J = 7.1 Hz, 1H), 4.05 (dd, J = 10.2, 5.9 Hz, 1H), 3.67 (d, J = 10.2 Hz, 1H), 2.99 (s, 3H), 2.36 (s, 3H), 2.21-2.14 (m, 1H), 2.08-2.01 (m, 1H), 1.93 (d, J = 7.1 Hz, 3H), 1.36-1.25 (m, 1H), 0.96-0.87 (m, 1H). MS = 597.1 [M+1] + .

[0407] Table 15. The following compounds were prepared using procedures similar to those described in Examples 1 and 2, using appropriate starting materials. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. For pairs or sets of isomers, the isomers are listed in order of elution (i.e., the earlier-eluting isomer is listed first). This convention for listing isomers from chiral SFC or HPLC separations is used in all tables below. [Table 15] TIFF0007776453000134.tif212158TIFF0007776453000135.tif198160TIFF0007776453000136.t if209159TIFF0007776453000137.tif177158TIFF0007776453000138.tif209159TIFF00077764530 00139.tif178159TIFF0007776453000140.tif209158TIFF0007776453000141.tif178159TIFF000 7776453000142.tif210159TIFF0007776453000143.tif177158TIFF0007776453000144.tif122158

[0408] Example 21 [ka]

[0409] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAB)

[0410] Step 1. 3-(Bromomethyl)-6-chloropyridazineA mixture of 3-chloro-6-methylpyridazine (1 g, 7.78 mmol), NBS (1.384 g, 7.78 mmol), and AIBN (0.128 g, 0.778 mmol) in CCl4 (26 mL) was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound. MS = 208.9 [M+1] + .

[0411] Step 2. tert-Butyl (1-((6-chloropyridazin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate To a solution of 3-(bromomethyl)-6-chloropyridazine (530 mg, 2.55 mmol) in DMF (10 mL) at room temperature was added tert-butyl (1H-pyrazol-4-yl)carbamate (702 mg, 3.83 mmol) and cesium carbonate (2.50 g, 7.66 mmol). The mixture was stirred at room temperature for 16 hours, diluted with EtOAc, and washed with water and then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound. MS=310.0 [M+1] + .

[0412] Step 3. tert-Butyl (1-((6-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate To a suspension of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (500 mg, 0.936 mmol) in DCM (20 mL) was added mCPBA (441 mg, 2.0 mmol) at room temperature. The mixture was stirred at room temperature for 1 h, diluted with DCM, and washed with 1N aqueous Na2CO3. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane to give 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylsulfonyl)-pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide. A mixture of tert-butyl (1-((6-chloropyridazin-3-yl)methyl)-1H-pyrazol-4-yl)carbamate (250 mg, 0.807 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (118 mg, 1.21 mmol), ethylenediamine (5.5 μL, 0.081 mmol), and CuI (15.4 mg, 0.081 mmol) in 1,4-dioxane (4.0 mL) was stirred at 100° C. for 2 h. The mixture was cooled to room temperature and filtered through Celite® (washed with DCM). The filtrate was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (MeOH / DCM) to give the title compound. MS=371.1 [M+1] + .

[0413] Step 4. (1R,5S)-3-(6-((4-amino-1H-pyrazol-1-yl)methyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. MS=271.1[M+1] + .

[0414] Step 5. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : The title compound was prepared following a procedure similar to that described above in Example 1, Step 5. 1 H NMR (600 MHz, CD3OD) δ 8.88 (d, J = 1.9 Hz, 1H), 8.55 (d, J = 9.3 Hz, 1H), 8.30 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 9.4 Hz, 1H), 6.96 (s, 1H), 5.61 (s, 2H), 4.26 (dd, J = 11.5, 5.6 Hz, 1H), 4.20 (d, J = 11.6 Hz, 1H), 3.01 (s, 3H), 2.22 (p, J = 6.0 MS = 555.3 [M+1]+

[0415] Examples 22 and 23 [ka]

[0416] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAC).

[0417] Step 1. 5-(1-Bromoethyl)-4-methyl-2-(methylthio)pyrimidine The title compound was prepared following a procedure similar to that described above in Example AAA-10a, Step 1. MS=248.9 [M+1] + .

[0418] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylthio)-pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide To a solution of 5-(1-bromoethyl)-4-methyl-2-(methylthio)pyrimidine (310 mg, 1.25 mmol) in DMF (3.4 mL) was added 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1H-pyrazol-4-yl)pyrazine-2-carboxamide (461 mg, 1.25 mmol) and cesium carbonate (1.23 g, 3.76 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EtOAc / hexanes) to give the title compound. MS=533.9 [M+1] + .

[0419] Step 3. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylsulfonyl)-pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideTo a suspension of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (500 mg, 0.936 mmol) in DCM (20 mL) was added mCPBA (441 mg, 2.00 mmol). The mixture was stirred at room temperature for 1 h, diluted with DCM, and washed with 1N aqueous sodium carbonate. The layers were dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / hexane to give the title compound. MS=565.9 [M+1] + .

[0420] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide A mixture of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-methyl-2-(methylsulfonyl)-pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (200 mg, 0.353 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (137 mg, 1.40 mmol), and cesium carbonate (461 mg, 1.40 mmol) in 1,4-dioxane (3.5 mL) was stirred at 90° C. for 30 minutes. The mixture was cooled to room temperature and purified by reverse-phase preparative HPLC (C18 stationary phase, ACN / water with 0.1% TFA) to give the diastereomeric title compounds as a mixture. The isomeric title compounds were separated by chiral chromatography (SFC, DAICELCHIRALELIA, 0.1% DEA-EtOH start B 35% end B 35%) to give the individual isomers in pure form. Fast-eluting isomer of the title compound (Example 22): 1H NMR (600 MHz, CD3OD) δ 9.38 (s, 1H), 9.01 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 54.7 Hz, 1H), 5.80 (q, J = 7.0 Hz, 1H), 4.18 (dd, J = 11.5, 5.0 Hz, 1H), 3.99 (d, J = 11.5 Hz, 1H), 2.43 (s, 3H), 2.10 (dt, J = 8.2, 4.5 Hz, 2H), 1.89 (d, J = 7.0 Hz, 3H), 1.27 (td, J = 7.7, 4.1 Hz, 1H), 0.82 (q, J = 3.7 Hz, 1H). MS = 583.0 [M+1] + Title Combination The heterosexual substance that is dissolved after the substance is dissolved (Example 23): 1 H NMR (600 MHz, CD3OD) δ 9.39 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 3.7 Hz, 1H), 8.26 (s, 1H), 7.87 - 7.81 (m, 1H), 7.78 (d, J = 3.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 54.7 Hz, 1H), 5.85 (q, J = 7.0 Hz, 1H), 4.18 (dq, J = 11.3, 4.5, 4.0 Hz, 1H), 4.05 (d, J = 11.5 Hz, 1H), 2.51 (s, 3H), 2.17 (dt, J = 8.2, 4.7 Hz, 2H), 1.90 (d, J = 6.9 Hz, 3H), 1.37-1.30 (m, 1H), 0.89 (q, J = 4.1 Hz, 1H). MS = 583.0 [M+1] + .

[0421] Table 16. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 22 and 23. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 16] TIFF0007776453000148.tif179157TIFF0007776453000149.tif209158TIFF00077764530 00150.tif178159TIFF0007776453000151.tif208158TIFF0007776453000152.tif180159

[0422] Examples 33 and 34 [ka]

[0423] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAD).

[0424] Step 1. 5-(Bromomethyl)-4-methyl-2-(methylthio)pyrimidine To a solution of (4-methyl-2-(methylthio)pyrimidin-5-yl)methanol (500 mg, 2.94 mmol) in DCM (5.0 mL) cooled to 0° C. was added carbon tetrabromide (1.267 mg, 3.82 mmol) and triphenylphosphine (1.00 g, 3.82 mmol). The mixture was stirred at 0° C. for 2 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 20% EtOAc / hexanes) to give the title compound. MS=234.9.0 [M+1] + .

[0425] Step 2. tert-Butyl (1-((4-methyl-2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamateTo a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (754 mg, 4.12 mmol) in DMF (10.0 mL) was added 5-(bromomethyl)-4-methyl-2-(methylthio)pyrimidine (640 mg, 2.75 mmol) and cesium carbonate (3.58 g, 11.0 mmol). The mixture was stirred at room temperature for 16 min, then diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% to 60% EtOAc / hexanes) to give the title compound. MS=336.0 [M+1] + .

[0426] Step 3. tert-Butyl (1-((4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate The title compound was prepared following a procedure similar to that described above in Example 22, Step 3. Aqueous MS=368.0 [M+1] + .

[0427] Step 4. tert-Butyl (1-((4-methyl-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate A mixture of (1-((4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate (660 mg, 1.80 mmol), 3-azabicyclo[3.1.0]hexan-2-one (523 mg, 5.39 mmol), and cesium carbonate (1.76 g, 5.39 mmol) in 1,4-dioxane (18.0 mL) was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (MeOH / DCM) to give the title compound. MS=385.1 [M+1] + .

[0428] Step 5. 3-(5-((4-amino-1H-pyrazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]-hexan-2-one : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. MS=285.1 [M+1] + .

[0429] Step 6. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideThe title compound was prepared following a procedure similar to that described above in Example 1, Step 5. The isomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRACEL AS-H:MeOH start B 25% end B 25%) to provide the individual isomers in pure form. Fast-eluting isomer of the title compound (Example 33): 1 H NMR (600 MHz, CD3OD) δ 8.85 (d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.84-7.78 (m, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 54.6 Hz, 1H), 5.37 (s, 2H), 4.19 (dd, J = 11.5, 5.1 Hz, 1H), 4.00 (d, J = 11.1 Hz, 1H), 2.98 (s, 3H), 2.46 (s, 3H), 2.14-2.08 (m, 2H), 1.27 (dt, J = 12.6, 4.4 Hz, 1H), 0.83 (q, J = 4.2 Hz, 1H). MS = 583.0 [M+1] + Isomer eluting after the title compound (Example 34): 1 H NMR (600 MHz, CD3OD) δ 8.85 (d, J = 2.4 Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.84-7.78 (m, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.93 (t, J = 54.6 Hz, 1H), 5.37 (s, 2H), 4.19 (dd, J = 11.5, 5.1 Hz, 1H), 4.00 (d, J = 11.1 Hz, 1H), 2.98 (s, 3H), 2.46 (s, 3H), 2.14-2.08 (m, 2H), 1.31-1.24 (m, 1H), 0.92-0.80 (m, 1H). MS = 583.0 [M+1] + .

[0430] Table 17. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 33 and 34. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 17] TIFF0007776453000155.tif123159

[0431] Examples 37 and 38 [ka]

[0432] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE).

[0433] Step 1. 3-Chloro-4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine To a solution of a mixture of 1-(6-chloro-4-methylpyridazin-3-yl)ethanol and 1-(6-chloro-5-methylpyridazin-3-yl)ethanol (480 mg, 1.39 mmol), 4-nitro-1H-pyrazole (377 mg, 3.34 mmol), and triphenylphosphine (875 mg, 3.34 mmol) in THF (10 mL) was added di-tert-butyl azodicarboxylate (960 mg, 4.17 mmol) at 0° C. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 4% EtOAc / petroleum ether) to afford the title compound as a mixture with 6-chloro-4-methyl-3-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine. MS=267.9 [M+1] + .

[0434] Step 2. (1R,5S)-3-(4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of a mixture of 3-chloro-4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine and 6-chloro-4-methyl-3-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine (600 mg, 1.12 mmol) in dioxane (10.0 mL) was added (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (218 mg, 2.24 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (130 mg, 0.224 mmol), tris(dibenzylideneacetone)dipalladium (205 mg, 0.224 mmol), and cesium carbonate (730 mg, 2.24 mmol). The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (30% EtOAc / petroleum ether) and then preparative TLC (50% EtOAc / petroleum ether) to give the title compound. MS=329.2 [M+1] + .

[0435] Step 3. (1R,5S)-3-(6-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (80.0 mg, 0.244 mmol) in a mixture of 0.6 mL of EtOAc and 0.2 mL of MeOH was added platinum(IV) oxide (5.5 mg, 0.024 mmol). The reaction mixture was stirred at room temperature under a H atmosphere (15 psi) for 2 hours. The reaction mixture was filtered and then concentrated under reduced pressure to give the title compound. MS=299 [M+1] + .

[0436] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideA solution of (1R,5S)-3-(6-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (16.0 mg, 54 μmol), 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (16.2 mg, 54 μmol), pyridine (22 μL, 0.268 mmol), and EDC (21 mg, 0.11 mmol) in DCM (2.0 mL) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 45% ending B 75%) to give a diastereomeric mixture of the title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD: neutral IPA start B 55% end B 55%) to give the individual isomeric compounds in pure form. Faster eluting diastereomer of the title compound (Example 37): 1 H NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.27 (s, 1H), 7.03-6.79 (m, 1H), 5.76 (d, J = 7.2 Hz, 1H), 4.37 (dd, J = 5.8, 10.4 Hz, 1H), 3.71 (d, J = 10.1 Hz, 1H), 2.15-2.11 (m, 1H), 2.08 (s, 3H), 1.96 (br s, 1H), 1.90 (d, J = 7.2 Hz, 3H), 1.23 (dt, J = 4.7, 8.0 Hz, 1H), 0.90-0.86 (m, 1H). MS = 583.2 [M+1] + Diastereomer eluting after the title compound (Example 38): 1H NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.26 (s, 1H), 7.04-6.78 (m, 1H), 5.77 (d, J = 7.2 Hz, 1H), 4.37 (dd, J = 5.9, 10.5 Hz, 1H), 3.71 (d, J = 9.9 Hz, 1H), 2.16-2.10 (m, 1H), 2.08 (s, 3H), 1.97 (br s, 1H), 1.90 (d, J = 7.0 Hz, 3H), 1.27-1.22 (m, 1H), 0.91-0.86 (m, 1H). MS = 583.2 [M+1] + .

[0437] Examples 39 and 40

change

[0438] 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE).

[0439] Step 5. 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideTo a solution of 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (140 mg, 0.421 mmol) and (1R,5S)-3-(6-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (151 mg, 0.505 mmol) in pyridine (2.0 mL) was added EDC (161 mg, 0.842 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 37% ending B 67%) to afford a diastereomeric mixture of the title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD: 0.1% NH3H2O-IPA start B 50% end B 50%) to give the individual isomeric compounds in pure form. Faster-eluting diastereomer of the title compound (Example 39): 1 H NMR (400 MHz, CD3OD) δ 8.79 (s, 1 H), 8.32 (s, 1 H), 7.77 (s, 1 H), 7.74-7.68 (m, 1 H), 7.36 (d, J = 0.8 Hz, 1 H), 7.25 (d, J = 9.0 Hz, 1 H), 6.93 (t, J = 72.8 Hz, 1 H), 5.85 (q, J = 7.3 Hz, 1 H), 4.47 (dd, J = 10.6, 5.9 Hz, 1 H), 3.82 (d, J = 9.4 Hz, 1 H), 2.98 (s, 3 H), 2.27-2.20 (m, 1 H), 2.18 (d, J = 0.8 MS = 613.2 [M+1] + Diastereomer eluting after the title compound (Example 40): 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1 H), 8.31 (s, 1 H), 7.77 (s, 1 H), 7.71 (t, J = 8.6 Hz, 1 H), 7.35 (s, 1 H), 7.25 (d, J = 9.0 Hz, 1 H), 6.93 (t, J = 72.8 Hz, 1 H), 5.86 (q, J = 7.0 Hz, 1 H), 4.47 (dd, J = 10.6, 5.9 Hz, 1 H), 3.81 (d, J = 9.4 Hz, 1 H), 2.98 (s, 3 H), 2.27-2.20 (m, 1 H), 2.18 (s, 3 H), 2.10-2.04 (m, 1 H), 2.00 (d, J = 7.0 Hz, 3 H), 1.37-1.33 (m, 1 H), 1.01-0.96 (m, 1 H). MS = 613.2 [M+1] + .

[0440] Example 41 [ka]

[0441] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

[0442] Step 1. 2-Bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridine To a solution of (6-bromo-5-methylpyridin-3-yl)methanol (10.0 g, 49.5 mmol), 4-nitro-1H-pyrazole (8.39 g, 74.2 mmol), and triphenylphosphine (19.5 g, 74.2 mmol) in THF (200 mL) cooled to 0° C. was added di-isopropyl azodicarboxylate (14.4 mL, 74.2 mmol). After the addition was complete, the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 100% EtOAc / hexanes) to provide the title compound. MS=297.0, 299.0 [M+1] + .

[0443] Step 2. (1R,5S)-3-(3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a vessel containing [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 4.69 g, 4.95 mmol), cesium carbonate (48.4 g, 148 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (7.21 g, 74.2 mmol), and 2-bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridine (14.7 g, 49.5 mmol) was added 1,4-dioxane (200 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 6% MeOH / DCM) to give the title compound. MS=314.1 [M+1] + .

[0444] Step 3. (1R,5S)-3-(5-((4-amino-1H-pyrazol-1-yl)methyl)-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a vessel containing (1R,5S)-3-(3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16.1 g, 17.5 mmol), iron (7.80 g, 140 mmol), and NH4Cl (9.34 g, 175 mmol) at room temperature was added EtOH (70 mL) and water (18 mL). The resulting mixture was stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite® (eluting with additional DCM). The filtrate was concentrated under reduced pressure, and the resulting residue was suspended in EtOH and filtered to give the title compound. MS=284.1 [M+1] + .

[0445] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideTo a solution of (1R,5S)-3-(5-((4-amino-1H-pyrazol-1-yl)methyl)-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16.5 g, 17.5 mmol) in ACN (87 mL) cooled to 0° C. was added 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (6.92 g, 21.8 mmol) and HATU (8.30 g, 21.8 mmol), followed by DIEA (9.15 mL, 52.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 10% MeOH / DCM) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 8.95 (d, J = 3.4 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 7.75-7.66 (m, 2H), 7.60 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 6.60 (t, J = 54.0 Hz, 1H), 5.27 (s, 2H), 4.42-4.33 (m, 1H), 3.68 (d, J = 10.0 Hz, 1H), 3.15 (s, 3H), 2.17 (s, 3H), 2.09-2.00 (m, 2H), 1.27-1.23 (m, 1H), 0.91 (q, J = 3.8 Hz, 1H). MS = 582.0 [M+1] + .

[0446] Examples 42 and 43 [ka]

[0447] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE).

[0448] Step 1. 2-Chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidineTo a solution of 4-nitro-1H-pyrazole (197 mg, 1.74 mmol), 1-(2-chloro-4-methylpyrimidin-5-yl)ethanol (150 mg, 0.869 mmol), and triphenylphosphine (456 mg, 1.738 mmol) in THF (5.0 mL) under a nitrogen atmosphere was added di-tert-butyl azodicarboxylate (400 mg, 1.74 mmol). The reaction mixture was stirred at 15° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0% to 40% EtOAc / hexanes) to give the title compound. MS=268.0 [M+1] + .

[0449] Step 2. (1R,5S)-3-(4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a mixture of 2-chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (185 mg, 0.691 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (87.0 mg, 0.898 mmol), and cesium carbonate (450 mg, 1.38 mmol) in dioxane (5.0 mL) under a nitrogen atmosphere was added tris(dibenzylideneacetone)dipalladium (63 mg, 69 μmol) and Xantphos (40 mg, 69 μmol). The reaction mixture was stirred at 90° C. for 16 hours, cooled to room temperature, and concentrated under reduced pressure. Water was added to the resulting mixture, which was then extracted with EtOAc. The organic layers were combined, washed with brine, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 EtOAc / petroleum ether) to provide the title compound. MS=329.1[M+1] + .

[0450] Step 3. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of (1R,5S)-3-(4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (80 mg, 0.24 mmol) in 3.0 mL of EtOAc and 1.0 mL of MeOH was added 5.5 mg of platinum(IV) oxide (0.024 mmol). The resulting mixture was stirred at 15° C. under a hydrogen atmosphere (pressure: 15 psi) for 1 hour. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS=299.0 [M+1] + .

[0451] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : Following a procedure similar to that described above in Step 3 of Intermediate AL-5a, the title compound was prepared as an initial mixture of diastereomers. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD: neutral EtOH start B 50% end B 50%) to give the individual isomeric compounds in pure form. Faster-eluting diastereomer of the title compound (Example 42): 1 H NMR (400 MHz, CD3OD ) δ 8.83 (d, J = 2.5 Hz, 1H), 8.47-8.26 (m, 1H), 8.25-8.07 (m, 1H), 7.83-7.74 (m, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.05-6.77 (m, 1H), 5.77 (q, J = 6.9 Hz, 1H), 4.22-4.09 (m, 1H), 4.03-3.91 (m, 1H), 2.95 (s, 3H), 2.41 (s, 3H), 2.12-2.03 (m, 2H), 1.86 (d, J = 7.1 Hz, 3H), 1.25 (dt, J = 4.7, 8.0 Hz, 1H), 0.84-0.77 (m, 1H). MS = 597.2 [M+1] + .mark Diastereomer eluting after the title compound (Example 43): 1H NMR (400 MHz, CD3OD) δ 8.83 (d, J = 2.5 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 7.82-7.75 (m, 1H), 7.68 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.17-6.68 (m, 1H), 5.77 (q, J = 7.10 Hz, 1H), 4.24-4.11 (m, 1H), 3.96 (d, J = 11.3 Hz, 1H), 2.95 (s, 3H), 2.41 (s, 3H), 2.14-2.02 (m, 2H), 1.86 (d, J = 7.1 MS = 597.2 [M+1] + .

[0452] Examples 44 and 45 [ka]

[0453] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE).

[0454] Step 1. (1R,5S)-3-(3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Example 1, Step 3. MS=207.1 [M+1] + .

[0455] Step 2. (1R,5S)-3-(4-bromo-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneN-Bromosuccinimide (4.00 g, 22.5 mmol) was added to a stirring solution of (1R,5S)-3-(3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (3.09 g, 15.0 mmol) and TFA (1.73 mL, 22.5 mmol) in ACN (50 mL), and the resulting mixture was heated to 50 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated to give the crude residue, which was purified by silica gel chromatography (0% to 80% EtOAc / hexanes) to give the title compound. MS = 284.9, 286.9 [M+1, M+3] + .

[0456] Step 3. (1R,5S)-3-(5-acetyl-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1R,5S)-3-(4-bromo-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.50 g, 5.26 mmol) was added to a vial containing tetrakis(triphenylphosphine)palladium(0) (608 mg, 0.526 mmol), and the resulting solid mixture was degassed and replaced with N2. Tributyl(1-ethoxyvinyl)tin (2.49 mL, 7.37 mmol) and toluene (26 mL) were added, and the resulting mixture was heated to 100 °C overnight. The reaction was cooled to room temperature, quenched with concentrated HCl, and stirred at room temperature for 1 hour. The mixture was then added to saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were concentrated to give the crude residue, which was purified by silica gel chromatography (0% to 10% MeOH / DCM) to give the title compound. MS=249.0[M+1] + .

[0457] Step 4. (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a stirred solution of (1R,5S)-3-(5-acetyl-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.11 g, 4.47 mmol) in a mixture of THF (17 mL) and MeOH (5.5 mL) was added sodium borohydride (220 mg, 5.81 mmol). The resulting mixture was stirred at room temperature for 30 minutes, at which point the reaction was concentrated to give a crude mixture which was added to saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to give the crude residue to give the title compound. MS=251.0 [M+1] + .

[0458] Step 5. (1R,5S)-3-(3-fluoro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To a stirring solution of 4-nitro-1H-pyrazole (529 mg, 4.67 mmol) and triphenylphosphine (1.23 g, 4.67 mmol) in THF (18 mL) was added (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (900 mg, 3.60 mmol). DIAD (910 μL, 4.7 mmol) was added, and the resulting mixture was heated to 50° C. for 1 h. The reaction was cooled to room temperature and concentrated to give the crude residue, which was purified by silica gel chromatography (0% to 10% MeOH / DCM) to give the title compound. MS=346.0 [M+1] + .

[0459] Step 6. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideTo a stirred suspension of iron powder (1.68 g, 30.0 mmol) and ammonium chloride (1.93 g, 36.0 mmol) in a mixture of EtOH (11 mL) and water (3.8 mL) was added (1R,5S)-3-(3-fluoro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.04 g, 3.00 mmol). The resulting mixture was heated to 50° C. for 2 h, at which point the reaction was cooled to room temperature and filtered. The filtrate was concentrated, added to saturated aqueous NaHCO3, and extracted with DCM. The combined organic layers were dried (MgSO), filtered, and concentrated to give the title compound, which was carried forward directly, combining with HATU (1.37 g, 3.60 mmol) and dissolving in DMF (15 mL). 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (1.09 g, 3.60 mmol) and TEA (1.25 mL, 9.00 mmol) were added, and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc, and the organic layer was washed with water and brine and concentrated to give the crude residue, which was purified by silica gel chromatography (0% to 10% MeOH / DCM) to give the title compound. MS=600.0 [M+1] + . The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK OD-H: neutral EtOH start B 20% end B 20%) to give the individual isomeric compounds in pure form. Faster eluting diastereomer of the title compound (Example 44): 1 H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.23 ​​(s, 1H), 8.03 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 6.86 - 7.17 (m, 1H), 5.85 (q, J = 7.3 Hz, 1H), 4.29 (dd, J = 10.2, 5.9 Hz, 1H), 3.68 (d, J = 10.6 Hz, 1H), 2.28 (d, J = 2.0 Hz, 3H), 2.14 - 2.21 (m, 1H), 2.03 (br s, 1H), 1.92 (d, J = 7.0 Hz, 3H), 1.29 - 1.31 (m, 1H), 0.86 - 0.91 (m, 1H). MS = 600.1 [M+1] + .The title compound's subsequent dissolution process Example 45): 1 H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.81 - 7.88 (m, 1H), 7.79 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 6.86 - 7.17 (m, 1H), 5.85 (q, J = 6.9 Hz, 1H), 4.27 (dd, J = 10.6, 5.9 Hz, 1H), 3.70 (d, J = 11.0 Hz, 1H), 2.28 (d, J = 2.0 Hz, 3H), 2.13 - 2.20 (m, 1H), 2.03 (br s, 1H), 1.92 (d, J = 7.0 Hz, 3H), 1.32 (br d, J = 3.5 Hz, 1H), 0.89 (br d, J = 3.1 Hz, 1H). MS = 600.1 [M+1] + .

[0460] Table 18. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 37-45. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 18] TIFF0007776453000162.tif208159TIFF0007776453000163.tif208158TIFF0007776453000164.tif209157TIFF0007776453000165.tif210158TIFF0007776453000166.tif209157TIFF0007776453000167.tif210159TIFF0007776453000168.tif210159TIFF0007776453000169.tif208158TIFF0007776453000170.tif210159TIFF0007776453000171.tif166158TIFF0007776453000172.tif210159TIFF0007776453000173.tif209158TIFF0007776453000174.tif200158TIFF0007776453000175.tif210158TIFF0007776453000176.tif208158TIFF0007776453000177.tif211158TIFF0007776453000178.tif209158TIFF0007776453000179.tif208158TIFF0007776453000180.tif209158TIFF0007776453000181.tif209158TIFF0007776453000182.tif209159TIFF0007776453000183.tif102158TIFF0007776453000184.tif211158TIFF0007776453000185.tif123158TIFF0007776453000186.tif209158TIFF0007776453000187.tif208158TIFF0007776453000188.tif212159TIFF0007776453000189.tif208159TIFF0007776453000190.tif199159TIFF0007776453000191.tif210160TIFF0007776453000192.tif209161TIFF0007776453000193.tif211161TIFF0007776453000194.tif208158TIFF0007776453000195.tif210159TIFF0007776453000196.tif210159TIFF0007776453000197.tif209159TIFF0007776453000198.tif209158TIFF0007776453000199.tif175157TIFF0007776453000200.tif211158TIFF0007776453000201.tif208159TIFF0007776453000202.tif211159TIFF0007776453000203.tif210159TIFF0007776453000204.tif212159TIFF0007776453000205.tif166158TIFF0007776453000206.tif209159TIFF0007776453000207.tif210159TIFF0007776453000208.tif211158TIFF0007776453000209.tif210158TIFF0007776453000210.tif210158TIFF0007776453000211.tif209162TIFF0007776453000212.tif211159TIFF0007776453000213.tif210159TIFF0007776453000214.tif209159TIFF0007776453000215.tif210159TIFF0007776453000216.tif210161TIFF0007776453000217.tif210158TIFF0007776453000218.tif209158TIFF0007776453000219.tif100158TIFF0007776453000220.tif210159TIFF0007776453000221.tif209159TIFF0007776453000222.tif208158TIFF0007776453000223.tif177158TIFF0007776453000224.tif211160TIFF0007776453000225.tif209158TIFF0007776453000226.tif211157TIFF0007776453000227.tif210160TIFF0007776453000228.tif103160TIFF0007776453000229.tif21 0158TIFF0007776453000230.tif209157TIFF0007776453000231.tif210159T IFF0007776453000232.tif176160TIFF0007776453000233.tif177158TIFF00 07776453000234.tif210158TIFF0007776453000235.tif208158TIFF0007776 453000236.tif209160TIFF0007776453000237.tif208158TIFF000777645300 0238.tif210159TIFF0007776453000239.tif209158TIFF0007776453000240. tif200159TIFF0007776453000241.tif211159TIFF0007776453000242.tif20 8159TIFF0007776453000243.tif210158TIFF0007776453000244.tif101159.

[0461] Examples 150 and 151 [ka]

[0462] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-fluoro-2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-fluoro-2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAF).

[0463] Step 1. (1R,5S)-3-(3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of 2-chloro-3-fluoro-6-methylpyridine (1.00 g, 6.87 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (0.667 g, 6.87 mmol), and cesium carbonate (4.48 g, 13.7 mmol) in dioxane (10 mL) was added Xantphos (0.398 g, 0.687 mmol) and tris(dibenzylideneacetone)dipalladium (556 mg, 0.687 mmol). The reaction mixture was stirred at 100 °C for 12 h. The mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to give the title compound. MS=207.1 [M+1] + .

[0464] Step 2. (1R,5S)-3-(5-bromo-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (700 mg, 3.39 mmol) in ACN (10 mL) was added NBS (665 mg, 3.73 mmol). The resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compound. MS=284.9, 286.9 [M+1] + .

[0465] Step 3. (1R,5S)-3-(5-acetyl-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Intermediate BI-4a Step 1. MS=249.2 [M+1] + .

[0466] Step 4. (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Step 3 of Intermediate BJ-5a. MS=251.1 [M+1] + .

[0467] Step 5: (1R,5S)-3-(3-fluoro-6-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (600 mg, 2.40 mmol), 4-nitro-1H-pyrazole (325 mg, 2.88 mmol), and triphenylphosphine (943 mg, 3.60 mmol) in THF (10 mL) was added di-isopropyl azodicarboxylate (0.699 mL, 3.60 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compound. MS=346.2 [M+1] + .

[0468] Step 6. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. MS=316.2 [M+1] + .

[0469] Step 7. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(5-fluoro-2-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : Following a procedure similar to that described above in Example 1, Step 5, the title compound was prepared as an initial mixture of diastereomers. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD: 0.1% NH3H2O·EtOH start B 35% end B 35%) to give the individual isomeric compounds in pure form. Faster-eluting diastereomer of the title compound (Example 150): 1H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 7.86-7.84 (m, 1H), 7.78 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 10.6 Hz, 1H), 7.18-6.84 (m, 1H), 5.81 (d, J = 7.0 Hz, 1H), 4.29 (dd, J = 10.6, 5.9 Hz, 1H), 3.67 (d, J = 10.2 Hz, 1H), 2.48 (d, J = 0.8 Hz, 3H), 2.15 MS = 600.1 [M+1] + .The final dissolution of the title compound (Example 151): 1 H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.88-7.81 (m, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 10.6 Hz, 1H), 7.18-6.83 (m, 1H), 5.81 (d, J = 7.0 Hz, 1H), 4.28 (dd, J = 10.6, 5.9 Hz, 1H), 3.70 (d, J = 9.4 Hz, 1H), 2.48 (s, 3H), 2.20-2.13 (m, 1H), 2.02 (br d, J = 7.0 Hz, 1H), 1.86 (d, J = 7.0 Hz, 3H), 1.32-1.26 (m, 1H), 0.92-0.85 (m, 1H). MS = 600.2 [M+1] + .

[0470] Table 19. Using appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 150 and 151. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 19] TIFF0007776453000247.tif211159TIFF0007776453000248.tif209158TIFF0007776453000249.tif101159

[0471] Example 156 [ka]

[0472] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAG)

[0473] Step 1. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)-3-vinylpyrazine-2-carboxamide To a mixture of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide (120 mg, 0.202 mmol) in DMF (2.0 mL) was added sodium hydride (16 mg, 0.40 mmol, 60% oil dispersion). The resulting mixture was stirred at 0° C. for 5 minutes, then 2-(trimethylsilyl)ethoxymethyl chloride (71.5 mL, 0.403 mmol) was added. The mixture was stirred at 0° C. for 2 hours, then quenched by the addition of saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound. MS=752.2 [M+1] + .

[0474] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrazine-2-carboxamide : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 2. MS=745.1 [M+H2O+1] + .

[0475] Step 3. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)pyrazine-2-carboxamide : The title compound was prepared following a procedure similar to that described above in Step 2 of Intermediate BA-1a. MS=731.2 [M+1] + .

[0476] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. 1 H NMR (600 MHz, CD3OD) δ 8.98 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 6.95 (t, J = 54.6 Hz, 1H), 5.37 (s, 2H), 5.23 (s, 2H), 4.19 (dd, J = 11.5, 5.0 Hz, 1H), 4.00 (d, J = 11.5 Hz, 1H), 2.45 (s, 3H), 2.10 (dt, J = MS = 599.4 [M+1] + .

[0477] Examples 157 to 160 [ka]

[0478] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, 3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAH).

[0479] Step 1. 2-Chloro-4-methyl-5-vinylpyrimidineA solution of 5-bromo-2-chloro-4-methylpyrimidine (7.00 g, 33.7 mmol), TEA (7.05 mL, 50.6 mmol), potassium vinyltrifluoroborate (4.97 g, 37.1 mmol), and bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.741 g, 1.01 mmol) in ethanol (100 mL) was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 20% EtOAc / petroleum ether) to provide the title compound. 1 H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 6.93-6.83 (m, 1H), 5.90-5.85 (m, 1H), 5.58-5.52 (m, 1H), 2.52 (d, J = 1.2 Hz, 3H).

[0480] Step 2. 3-(4-methyl-5-vinylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one A mixture of 2-chloro-4-methyl-5-vinylpyrimidine (1.10 g, 7.12 mmol), 3-azabicyclo[3.1.0]hexan-2-one (898 mg, 9.25 mmol), cesium carbonate (4.64 g, 14.2 mmol), tris(dibenzylideneacetone)dipalladium (652 mg, 0.712 mmol), and Xantphos (412 mg, 0.712 mmol) in dioxane (20 mL) was stirred at 100 °C under a nitrogen atmosphere for 14 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 95% EtOAc / petroleum ether) to give the title compound. MS=216.0 [M+1] + .

[0481] Step 3. 3-(5-(1,2-dihydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of 3-(4-methyl-5-vinylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (815 mg, 3.79 mmol) in a mixture of ACN (15 mL) and water (5.0 mL) was added aqueous osmium tetroxide (9.63 mL, 0.379 mmol, 10 mg / mL) and 4-methylmorpholine N-oxide (444 mg, 3.79 mmol). The resulting mixture was stirred at room temperature for 12 hours. The mixture was cooled to 0°C, and then saturated aqueous NaSO was added to the reaction mixture. The resulting mixture was stirred for 30 minutes. The mixture was then filtered through a pad of diatomaceous earth (eluting with ACN), and the filtrate was concentrated under reduced pressure to give the title compound. MS=250.3 [M+1] + .

[0482] Step 4. 3-(5-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of 3-(5-(1,2-dihydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.25 g, 5.01 mmol) in DMF (30 mL) was added 1H-imidazole (750 mg, 11.0 mmol) and TBDPSCl (1.65 g, 6.01 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to room temperature. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-95% EtOAc / petroleum ether, then 0-10% MeOH / DCM) to give the title compound. MS=488.2 [M+1] + .

[0483] Step 5: 3-(5-(2-((tert-butyldiphenylsilyl)oxy)-1-(4-nitro-1H-pyrazol-1-yl)ethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of 3-(5-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (1.46 g, 2.99 mmol), di-tert-butyl azodicarboxylate (1.38 g, 5.99 mmol), and triphenylphosphine (1.57 g, 5.99 mmol) in THF (20 mL) was added 4-nitro-1H-pyrazole (0.677 g, 5.99 mmol). The reaction mixture was stirred at 50° C. for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 100% EtOAc / petroleum ether) to give the title compound. MS=583.6 [M+1] + .

[0484] Step 6: 3-(5-(1-(4-amino-1H-pyrazol-1-yl)-2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. MS=553.3 [M+1] + .

[0485] Step 7. N-(1-(2-((tert-butyldiphenylsilyl)oxy)-1-(4-methyl-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide The title compound was prepared following a procedure similar to that described above in Example 41, Step 4. MS=837.3 [M+1] + .

[0486] Step 8. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1S,5R)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide The title compound was prepared as an initial mixture of diastereomers following a procedure similar to that described above for Intermediate AE-5, Step 4. The diastereomeric title compounds were separated by chiral chromatography (SFC, REGIS(S,S)WHELK-O1: 0.1% NH3H2O·EtOH start B 40% end B 40%) to afford the individual isomeric compounds in pure form. Faster-eluting diastereomer of the title compound (Example 157): 11H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.03 - 6.80 - (m, 1H), 5.61 - 5.56 (m, 1H), 4.21 (dd, J = 11.8, 7.2 Hz, 1H), 4.09 (dd, J = 11.6, 5.2 Hz, 2H), 3.89 (d, J = 11.3 Hz, 1H), 2.40 (s, 3H), 2.05 - 1.96 (m, 2H), 1.18 (dd, J = 8.1, 4.4 Hz, 1H), 0.72 (q, J = 4.1 Hz, 1H). MS = 599.1 [M+] + . The second eluted diastereomer (Example 158): 1 1H NMR (400 MHz, CD3OD) δ 9.41 (s, 1H), 9.07 - 9.03 (m, 1H), 8.54 (s, 1H), 8.37 - 8.31 (m, 1H),7.89 - 7.82 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.16 - 6.92 (m, 1H), 5.73 (br t, J = 5.8 Hz, 1H), 4.33 (dd, J = 11.9, 7.0 Hz, 1H), 4.27 - 4.17 (m, 2H), 4.05 (br d, J = 11.6 Hz, 1H), 2.55 (s, 3H), 2.16 (br d, J = 4.3 Hz, 2H), 1.38 - 1.29 (m, 1H), 0.89 (br d, J = 3.7 Hz, 1H). MS = 599.1 [M+] + . The third eluted diastereomer of the title compound (Example 159): 1H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.92 (d, J = 2.1 Hz, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.04-6.80 (m, 1H), 5.60-5.56 (m, 1H), 4.21 (dd, J = 11.8, 7.2 Hz, 1H), 4.09 (dd, J = 11.6, 5.2 Hz, 2H), 3.89 (d, J = 11.3 Hz, 1H), 2.40 (s, 3H), 2.00 (dd, J = 7.5, 4.1 Hz, 2H), 1.18 (dt, J = 7.9, 4.0 Hz, 1H), 0.72 (q, J = 4.0 Hz, 1H). MS = 599.2 [M+1] + .The fourth dissolution test of the title compound (Example 160): 1 H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.92 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.74 (br t, J = 7.5 Hz, 1H), 7.72-7.70 (m, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.03-6.80 (m, 1H), 5.57 (t, J = 6.3 Hz, 1H), 4.21 (dd, J = 11.4, 7.2 Hz, 1H), 4.09 (dd, J = 11.6, 5.2 Hz, 2H), 3.89 (d, J = 11.6 Hz, 1H), 2.39 (s, 3H), 2.00 (br d, J = 4.6 Hz, 2H), 1.18 (br d, J = 9.2 Hz, 1H), 0.72 (br d, J = 4.0 Hz, 1H). MS = 599.1 [M+1] + .

[0487] Table 20. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 157-160. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 20] TIFF0007776453000253.tif177158TIFF0007776453000254.tif177160TIFF0007776453000255.tif176158TIFF0007776453 000256.tif176159TIFF0007776453000257.tif210160TIFF0007776453000258.tif210160TIFF0007776453000259.tif80159

[0488] Example 169 [ka]

[0489] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-(hydroxymethyl)-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide

[0490] Step 1. 1-(4-Butoxymethyl)-2-chloropyrimidin-5-yl)ethanone To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (400 mg, 2.55 mmol) in ACN (9.0 mL) and water (9.0 mL) at room temperature was added 2-(tert-butoxy)acetic acid (675 mg, 5.11 mmol), silver nitrate (1.2 g, 7.06 mmol), and ammonium persulfate (2.10 g, 9.20 mmol). After the addition was complete, the mixture was stirred at 6 °C for 1 h. The mixture was poured into water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 8% EtOAc / petroleum ether) to give the title compound. MS=243.3 [M+1] + .

[0491] Step 2. 1-(4-(tert-butoxymethyl)-2-chloropyrimidin-5-yl)ethanol: The title compound was prepared following a procedure similar to that described above in Step 3 of Intermediate BJ-5a. Aqueous MS=245.1 [M+1] + .

[0492] Step 3. 4-(tert-butoxymethyl)-2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine To a solution of 1-(4-(tert-butoxymethyl)-2-chloropyrimidin-5-yl)ethanol (150 mg, 0.613 mmol), 4-nitro-1H-pyrazole (90 mg, 0.80 mmol), and triphenylphosphine (241 mg, 0.919 mmol) in toluene (5.0 mL) cooled to 0° C. under a nitrogen atmosphere was added di-isopropyl azodicarboxylate (186 mg, 0.919 mmol). After the addition was complete, the reaction was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 18% EtOAc / petroleum ether) to give the title compound. MS=339.9 [M+1] + .

[0493] Step 4. (1S,5R)-3-(4-(tert-butoxymethyl)-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of 4-(tert-butoxymethyl)-2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (90.0 mg, 0.265 mmol), (1S,5R)-3-azabicyclo[3.1.0]hexan-2-one (36.0 mg, 0.371 mmol), Xantphos (16.0 mg, 28.0 μmol), and cesium carbonate (173 mg, 0.530 mmol) in dioxane (2.0 mL) was added tris(dibenzylideneacetone)dipalladium (25 mg, 27 μmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (1:1 EtOAc / petroleum ether) to give the title compound. MS=401.1[M+1] + .

[0494] Step 5. 3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-4-(tert-butoxymethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneThe title compound was prepared following a procedure similar to that described above in Example 41, Step 3. MS=371.5 [M+1] + .

[0495] Step 6. N-(1-(1-(4-(tert-butoxymethyl)-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide The title compound was prepared following a procedure similar to that described above in Example 1, Step 5. MS=655.2 [M+1] + .

[0496] Step 7. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-(hydroxymethyl)-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. 1 H NMR (500 MHz, CDCl3) δ 9.51-9.48 (m, 1H), 9.06 (d, J = 2.9 Hz, 1H), 8.55 (br d, J = 7.6 Hz, 1H), 8.14 (s, 1H), 7.70-7.76 (m, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.61 (br s, 1H), 6.73-6.46 (m, 1H), 5.57 (br d, J = 7.2 Hz, 1H), 4.82-4.69 (m, 1H), 4.60 (br s, 1H), 4.18 (br d, J = 3.5 Hz, 1H), 4.07 (br d, J MS = 599.2 (br d, J = 7.0 Hz, 3H), 1.27 (br d, J = 6.1 Hz, 1H), 0.90 (br s, 1H). [M+1] + .

[0497] Examples 170 and 171 [ka]

[0498] N-(1-((S)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide and N-(1-((R)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide (Scheme AAJ).

[0499] Step 1. 1-(2,4-Dichloropyrimidin-5-yl)ethanolTo a solution of 2,4-dichloro-5-iodopyrimidine (8.00 g, 29.1 mmol) in THF (100 mL) cooled to −78°C under a nitrogen atmosphere was added isopropylmagnesium chloride (17.5 mL, 34.9 mmol, 2M solution in THF) dropwise. The resulting mixture was stirred at −78°C for 20 minutes, then acetaldehyde (11.6 mL, 58.2 mmol, 5M solution in THF) was added dropwise, and the resulting mixture was stirred at −78°C for 2 hours and at room temperature for an additional hour. The reaction mixture was quenched by the addition of saturated aqueous NH₄Cl, and the resulting mixture was extracted with EtOAc. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 25% EtOAc / petroleum ether) to give the title compound. MS=192.6 [M+1] + .

[0500] Step 2. 2,4-Dichloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine A mixture of 1-(2,4-dichloropyrimidin-5-yl)ethanol (3.70 g, 19.2 mmol), 4-nitro-1H-pyrazole (3.25 g, 28.8 mmol), triphenylphosphine (10.1 g, 38.3 mmol), and di-tert-butyl azodicarboxylate (8.83 g, 38.3 mmol) in THF (50 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (0% to 15% EtOAc / petroleum ether) followed by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 40%, ending B 70%) to give the title compound. 1 H NMR (400 MHz, CDCl3, ppm) δ 8.55 (d, J = 3.2 Hz, 1H), 8.31 (d, J = 3.2 Hz, 1H), 8.11 (d, J = 3.2 Hz, 1H), 5.81 (m, 1H), 1.98 (dd, J = 3.3, 7.0 Hz, 3H).

[0501] Step 3. 2-Chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-4-amineA mixture of 2,4-dichloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (800 mg, 2.78 mmol) in THF (15 mL) and ammonium hydroxide (10 mL) was stirred at room temperature for 14 hours. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 24%, ending B 44%) to give the title compound. MS=268.6 [M+1] + .

[0502] Step 4. (1R,5S)-3-(4-amino-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one A mixture of 2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-4-amine (320 mg, 1.19 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (174 mg, 1.79 mmol), cesium carbonate (1.16 g, 3.57 mmol), and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 113 mg, 0.119 mmol) in dioxane (6.0 mL) was stirred at 100° C. under a nitrogen atmosphere for 14 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by reverse-phase MPLC (C18 stationary phase, 0% to 18% ACN / water (0.5% TFA)) to give the title compound. MS=329.6 [M+1] + .

[0503] Step 5. (1R,5S)-3-(4-amino-5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 42, Step 3. MS=300.0 [M+1] + .

[0504] Step 6. N-(1-((R)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide and N-(1-((S)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamideThe title compound was prepared as an initial mixture of diastereomers following a procedure similar to that described above in Step 4 of Example 41. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD: 0.1% NH3H2O·IPA start B 60% end B 60%) to afford the individual isomeric compounds in pure form. The first-eluting diastereomer of the title compound (Example 170): 1 H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.71-7.78 (m, 1H), 7.69 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.05-6.64 (m, 2H), 5.44 (m, 1H), 4.00 (m, 1H), 3.82 (d, J = 11.0 Hz, 1H), 1.97-1.94 (m, 2H), 1.76 (d, J = 7.1 Hz, 3H), 1.14 (m, 1H), 0.83-0.81 (m, 1H). MS = 584.2 [M+1] + .Title Later eluting diastereomer of compound (Example 171): 1 H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 8.92 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.77-7.71 (m, 1H), 7.69 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.06-6.78 (m, 2H), 5.49-5.39 (m, 1H), 4.01 (m, 1H), 3.82 (d, J = 11.5 Hz, 1H), 1.95-1.97 (m, 2H), 1.75 (m, 3H), 1.14 (m, 1H), 0.83-0.81 (m, 1H). MS = 584.2 [M+1] + .

[0505] Example 172 [ka]

[0506] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAK)

[0507] Step 1. 5-(1-chloroethyl)-2-(methylthio)pyrimidine To a solution of 1-(2-(methylthio)pyrimidin-5-yl)ethan-1-ol (370 g, 2.17 mol) in DCM (1.11 L) cooled to 0° C. was added thionyl chloride (388 g, 3.26 mmol, 237 mL). Upon complete addition, the resulting mixture was stirred at 0° C. for 10 minutes, and then the reaction mixture was concentrated under reduced pressure. To the crude residue was added DCM, and the mixture was stirred, then filtered and concentrated under reduced pressure to give the title compound. TLC (R f =0.7, 1:4 EtOAc / petroleum ether).

[0508] Step 2. 2-(Methylthio)-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine To a solution of 5-(1-chloroethyl)-2-(methylthio)pyrimidine (336 g, 1.78 mol), 4-nitro-1H-pyrazole (201 g, 1.78 mol) in DMF (1.69 L) cooled to 0°C was added cesium carbonate (1.74 kg, 5.34 mol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with water and then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 100% EtOAc / petroleum ether) to give the title compound. TLC (R f =0.15, 1:5 EtOAc / petroleum ether).

[0509] Step 3. 1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-amine The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. MS=236.2 [M+1] + .

[0510] Step 4. tert-Butyl (1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 1. MS=336.1 [M+1] + .

[0511] Step 5. tert-Butyl (1-(1-(2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate The following procedure was carried out in two parallel batches at equivalent scales. These batches were combined for subsequent workup. To a solution of tert-butyl (1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate (200 g, 596 mmol) in DCM (1.40 L) cooled to −10° C. under a nitrogen atmosphere was added mCPBA (326 g, 1.49 mol, 80% purity) in portions. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixtures were combined, quenched by the addition of saturated aqueous sodium carbonate, and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. 1 HNMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.95 (s, 2H), 7.91 (s, 1H), 7.28 (s, 1H), 5.83-5.78 (m, 1H), 3.40 (s, 3H), 1.88 (d, J = 7.2 Hz, 3H), 1.45 (s, 9H).

[0512] Step 6. tert-Butyl (1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamateTo a solution of tert-butyl (1-(1-(2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate (250 g, 680 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (99.1 g, 1.02 mol) in dioxane (1.75 L) was added cesium carbonate (333 g, 1.02 mol). The reaction mixture was stirred at 50 °C for 2.5 h. The reaction mixture was cooled to room temperature and then quenched by the addition of brine and extracted with MTBE. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. The crude residue was purified by silica gel chromatography (0:0:1 to 1:10:0 MeOH / EtOAc / petroleum ether) to provide the title compound as a mixture of diastereomers. The diastereomeric compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AY: 0.1% NH₃H₂O·EtOH starting 45% ending 45%) to give the individual isomeric compounds in pure form. The title compound was the slower-eluting diastereomer, which was purified by reverse-phase preparative HPLC (C₁₈ stationary phase, water (0.05% HCl)-ACN starting 5% ending 45%) to give the title compound.

[0513] 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.56 (s, 2H), 7.81 (s, 1H), 7.31 (s, 1H), 5.55-5.60 (m, 1H), 4.08-4.04 (m, 1H), 3.81 (d, J = 12 Hz, 1H), 2.06-1.99 (m, 2H), 1.78 (d, J = 7.2 Hz, 3H), 1.43 (s, 9H), 1.17-1.15 (m, 1H), 0.78-0.76 (m, 1H).

[0514] Step 7. (1R,5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of tert-butyl (1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate (26.0 g, 67.6 mmol) in DCM (210 mL) cooled to 0° C. was added HCl (4 M in EtOAc, 169 mL). The reaction mixture was stirred at 25° C. for 12 hours and then concentrated under reduced pressure to provide the title compound as the hydrochloride salt. MS=285.2 [M+1] + .

[0515] Step 8. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide The following procedure was carried out in three parallel batches at equivalent scales. These batches were combined for subsequent workup. To a solution of (1R,5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (5.00 g, 17.6 mmol) in DCM (35 mL) cooled to 0 °C, 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (4.43 g, 14.7 mmol), 1-propanephosphonic anhydride solution (T3P, 22.4 g, 35.2 mmol, 20.9 mL, 50% purity), and DIEA (9.09 g, 70.3 mmol, 12.3 mL) were added in that order. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixtures were combined, quenched by the addition of saturated aqueous NaHCO3, and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 100% EtOAc / petroleum ether) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.8 (s, 1H), 9.34 (s, 1H), 9.16 (s, 1H), 8.61 (s, 2H), 8.30 (s, 1H), 7.99 (t, J = 7.2 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 54 Hz, 1H), 5.72-5.67 (m, 1H), 4.09-4.02 (m, 1H), 3.83-3.80 (m, 1H), 2.05-1.99 (m, 2H), 1.83 (d, J = 6.8 Hz, 3H), 1.19-1.15 (m, 1H), 0.78-0.76 (m, 1H). MS = 569.1 [M+1] + .

[0516] Table 21. Using appropriate starting materials, the following compounds were prepared using procedures similar to those described in Example 172. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 21] TIFF0007776453000264.tif212158TIFF0007776453000265.tif188159TIFF0007776453000266.tif209159

[0517] Example 180 [ka]

[0518] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAK)

[0519] To a solution of (1R,5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16 mg, 0.056 mmol) in toluene (0.5 mL) was added trimethylaluminum (0.084 mL, 0.17 mmol). The reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one (20 mg, 0.056 mmol) in toluene (0.5 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 37%, ending B 67%) to provide the title compound. 1 H NMR (400 MHz, CD3OD) δ 8.93 (d, J = 2.4 Hz, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.83-7.75 (m, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 6.92 (t, J = 54.4 Hz, 1H), 5.64 (q, J = 6.8 Hz, 1H), 4.15 (dd, J = 10.9, 4.8 Hz, 1H), 3.98 (d, J = 11.7 Hz, 1H), 3.57 (s, 2H), 2.09 (br dd, J = 7.8, 3.2 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.32-1.21 (m, 7H), 0.82 (br d, J = 4.2 Hz, 1H). MS = 641.2 [M+1] + .

[0520] Table 22. Using appropriate starting materials and procedures similar to those described in Example 180, the following compounds were prepared. [Table 22]

[0521] Example 183 [ka]

[0522] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide (Scheme AAL)

[0523] Step 1. 2-Chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine and 2-chloro-4-methyl-5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)pyrimidine To a solution of (2-chloro-4-methylpyrimidin-5-yl)methanol (500 mg, 3.15 mmol), 4-nitro-1,2,3-triazole (396 mg, 3.47 mmol), and triphenylphosphine (1.24 g, 4.73 mmol) in toluene (0.6 mL) cooled to 0° C., di-isopropyl azodicarboxylate (0.92 mL, 4.7 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The crude residue was purified by reverse-phase MPLC (C18 stationary phase, 10% to 20% ACN / water (0.5% TFA)) to afford the regioisomeric title compounds in individual forms. The faster-eluting regioisomer is 2-chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine: 1 H NMR ((500 MHz, CDCl3) δ 8.45 (s, 1H), 8.43 (s, 1H), 6.00 (s, 2H), 2.68 ppm (s, 3H). MS = 254.9 [M+1] + The second eluting isomer is 2 -chloro-4-methyl-5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)pyrimidine: 1 H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 8.21 (s, 1H), 5.68 (s, 2H), 2.66 ppm (s, 3H). MS = 254.9 [M+1] + The third eluting isomer is 2-chloro-4-methyl-5-((4-nitro-3H-1,2,3-triazol-2-yl)methyl)pyrimidine: 1H NMR (500 MHz, CDCl3,) δ 8.53 (s, 1H), 8.27 (s, 1H), 5.66 (s, 2H), 2.61 ppm (s, 3H). MS = 254.9 [M+1] + .

[0524] Step 2. (1R,5S)-3-(4-methyl-5-((4-nitro-1H-2,3-triazol-1-yl)methyl)pyrimidin-2-yl)-3- 1 Azabicyclo[3.1.0]hexan-2-one To a solution of 2-chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine (120 mg, 0.471 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (46 mg, 0.47 mmol), and cesium carbonate (307 mg, 0.943 mmol) in dioxane (2.0 mL) was added [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 45 mg, 0.047 mmol). The reaction mixture was stirred at 100° C. for 12 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (40% to 60% EtOAc / petroleum ether) to give the title compound. MS=316.0 [M+1] + .

[0525] Step 3. (1R,5S)-3-(5-((4-amino-1H-1,2,3-triazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. Aqueous MS=286.0 [M+1] + .

[0526] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxamideTo a solution of (1R,5S)-3-(5-((4-amino-1H-1,2,3-triazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (11 mg, 0.038 mmol), 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (12 mg, 0.038 mmol), and 1-methyl-1H-imidazole (3.1 mg, 0.038 mmol) in ACN (0.5 mL) was added chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (11 mg, 0.038 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.2 mM HFBA + 0.1% TFA)-ACN start B 40% finish B 70%) to provide the title compound. 1 H NMR (400 MHz, CD3OD) δ 8.92 (d, J = 2.7 Hz, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 7.87-7.77 (m, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.11-6.76 (m, 1H), 5.70 (s, 2H), 4.20 (dd, J = 11.3, 5.1 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 2.99 (s, 3H), 2.53 (s, 3H), 2.18-2.07 (m, 2H), 1.36-1.22 (br m, 1H), 0.87 ppm (br d, J = 3.9 Hz, 1H). MS = 584.2 [M+1] + .

[0527] Table 23. Using appropriate starting materials and procedures similar to those described in Example 183, the following compounds were prepared. [Table 23] TIFF0007776453000271.tif176162TIFF0007776453000272.tif175164TIFF0007776453000273.tif154169

[0528] Example 188 [ka]

[0529] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)cyclobutyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAM)

[0530] Step 1. (1R,5S)-3-(5-(1-hydroxycyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of 1-(2-chloro-4-methylpyrimidin-5-yl)cyclobutanol (200 mg, 1.01 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (196 mg, 2.01 mmol), and cesium carbonate (984 mg, 3.02 mmol) in dioxane (1.0 mL) was added Xantphos (58 mg, 0.10 mmol) and tris(dibenzylideneacetone)dipalladium (81 mg, 0.10 mmol). The reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:0 EtOAc / petroleum ether) to give the title compound. MS=260.0 [M+1] + .

[0531] Step 2. (1R,5S)-3-(4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclobutyl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one To a solution of (1R,5S)-3-(5-(1-hydroxycyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (180 mg, 0.694 mmol), 4-nitro-1H-pyrazole (94 mg, 0.83 mmol), and triphenylphosphine (273 mg, 1.04 mmol) in toluene (3.0 mL) was added di-tert-butyl azodicarboxylate (240 mg, 1.04 mmol). The reaction mixture was stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:0 EtOAc / petroleum ether) to give the title compound. MS=355.0 [M+1] + .

[0532] Step 3. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)cyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. Aqueous MS=325.0 [M+1]+ .

[0533] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)cyclobutyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : Following a procedure similar to that described above in Example 1, Step 5, the title compound was prepared. 1 H NMR (500 MHz, CD3OD) δ 8.88 (d, J = 2.4 Hz, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.08-6.81 (m, 1H), 4.30-4.17 (m, 1H), 4.07 (d, J = 11.6 Hz, 1H), 3.18-3.06 (m, 2H), 3.00 (s, 3H), 2.95 (br d, J = 8.9 Hz, 2H), 2.31-2.23 (m, 4H), 2.21-2.15 (m, 2H), 2.05-1.96 (m, 1H), 1.35 (td, J = 8.1, 4.9 Hz, 1H), 0.91 (br d, J = 4.0 Hz, 1H). MS = 623.2 [M+1] + .

[0534] Examples 189 and 190 [ka]

[0535] N-(1-((S)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide and N-(1-((R)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide (Scheme AAN).

[0536] Following a procedure similar to that described above in Step 4 of Intermediate AE-5, the title compound was prepared as an initial mixture of diastereomers. The diastereomeric title compounds were separated by chiral chromatography (SFC, REGIS (S,S) WHELK-O1: 0.1% NH3H2O·EtOH start B 55% end B 55%) to afford the individual isomeric compounds in pure form. The faster-eluting diastereomer of the title compound (Example 189): 1H NMR (500 MHz, CD3OD) δ 8.88 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 6.96 (s, 1H), 5.60 (br d, J = 7.0 Hz, 1H), 4.22 (dd, J = 10.5, 6.0 Hz, 1H), 3.69 (d, J = 10.7 Hz, 1H), 3.01 (s, 3H), 2.13-2.23 (m, 1H), 2.08-1.99 (m, 1H), 1.91 (d, J = 7.3 Hz, 3H), 1.30 (br dd, J = 8.2, 4.6 Hz, 1H), 1.04-0.97 (m, 1H). MS = 597.0 [M+1] + .The final dissolution of the title compound (Example 190): 1 H NMR (500 MHz, CD3OD) δ 8.88 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.76-7.74 (m, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 7.11-6.81 (m, 1H), 5.60 (q, J = 7.0 Hz, 1H), 4.22 (dd, J = 10.7, 5.8 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.01 (s, MS = 597.0 [M+1] + .

[0537] Table 24. Using appropriate starting materials and procedures similar to those described in Examples 189 and 190, the following compounds were prepared. [Table 24]

[0538] Example 192 [ka]

[0539] 3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAO)

[0540] Following a procedure similar to that described above in Example 41, Step 4, the title compound was prepared. 1 H NMR (400 MHz, CD3OD) δ 8.90 (d, J = 2.5 Hz, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.09-6.78 (m, 1H), 5.64 (d, J = 7.1 Hz, 1H), 5.06 (s, 2H), 4.15 (dd, J = 4.3, 11.6 Hz, 1H), 3.97 (d, J = 11.5 Hz, 1H), 2.09 (dd, J = 3.4, 8.1 Hz, 2H), 1.90 (d, J = 7.1 Hz, 3H), 1.26 (br s, 1H), 1.24 (s, 9H), 0.85-0.76 (m, 1H). MS = 655.1 [M+1] + .

[0541] Example 193 [ka]

[0542] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAO)

[0543] Following a procedure similar to that described above in Intermediate AE-5 Step 4, the title compound was prepared. 1 H NMR (400 MHz, CDCl3) δ 9.82 (br s, 1H), 8.99 (d, J = 2.5 Hz, 1H), 8.51 (s, 2H), 8.20 (s, 1H), 7.74-7.68 (m, 1H), 7.67-7.62 (m, 1H), 7.60 (s, 1H), 6.81-6.34 (m, 1H), 5.52 (q, J = 7.0 Hz, 1H), 5.28 (s, 2H), 4.14 (dd, J = 5.7, 11.37 Hz, 1H), 3.98 (br s, 1H), 2.15 (br s, 1H), 2.07-1.99 (m, 1H), 1.93 (br d, J = 6.8 Hz, 3H), 1.28-1.17 (m, 1H), 0.86 (br d, J = 3.4 Hz, 1H). MS = 599.2 [M+1] + .

[0544] Table 25. Using appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 192 and 193. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 25] TIFF0007776453000280.tif187165TIFF0007776453000281.tif183169TIFF0007776453000282.tif187169 TIFF0007776453000283.tif188168TIFF0007776453000284.tif187167TIFF0007776453000285.tif187165 TIFF0007776453000286.tif198166TIFF0007776453000287.tif198170TIFF0007776453000288.tif186162 TIFF0007776453000289.tif187165TIFF0007776453000290.tif198165TIFF0007776453000291.tif199163

[0545] Example 207 [ka]

[0546] (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(3-methyl-2-oxoimidazolidin-1-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAP)

[0547] Step 1. ()-6-(3-S-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : The title compound was prepared following a procedure similar to that described above in Example AAA-10a, step 5. MS=548.1[M+1] + .

[0548] Step 2. (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideTo a solution of (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (70 mg, 0.130 mmol) in MeOH (3.0 mL) and water (0.5 mL) was added Oxone® (240 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 EtOAc / petroleum ether) to give the title compound. MS=580.1 [M+1] + .

[0549] Step 3. (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(3-methyl-2-oxoimidazolidin-1-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide To a solution of (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (50 mg, 0.086 mmol) in ACN (1.0 mL) was added 1-methylimidazolidin-2-one (26 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol). The resulting mixture was stirred at 80° C. for 12 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by preparative HPLC (C18 stationary phase water (0.1% TFA)-ACN starting B 33%, ending B 63%) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 8.86 (d, J=2.3 Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.86-7.77 (m, 1H), 7.73 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.08-6.75 (m, 1H), 5.87 (d, J=6.7 Hz, 1H), 4.10 (br d, J=8.2 Hz, 2H), 3.66-3.56 (m, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.56 (s, 3H), 1.90 (d, J=7.0 Hz, 3H). MS = 600.2 [M+1] + .

[0550] Examples 208 and 209 [ka]

[0551] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((R)-1-hydroxyethyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((S)-1-hydroxyethyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAQ).

[0552] Step 1. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylic acid (127 mg, 0.387 mmol), EDC (202 mg, 1.06 mmol), and pyridine (57 μL, 0.70 mmol) in DCM (10 mL) was added (1R,5S)-3-(6-((4-amino-1H-pyrazol-1-yl)methyl)-4-methylpyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 0.352 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 45% ending B 65%) to give the title compound. MS=595.1 [M+1] + .

[0553] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(1-hydroxyethyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideTo a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide (60 mg, 0.10 mmol) in 2-propanol (5.0 mL) was added phenylsilane (27 mg, 0.25 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (12 mg, 0.020 mmol) at room temperature under an oxygen atmosphere. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 35% finish B 55%) to afford a diastereomeric mixture of the title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALCEL OJ-H: 0.1% NH3H2OMeOH start B 25% end B 25%) to give the individual isomeric compounds in pure form. Faster-eluting diastereomer of the title compound (Example 208): 1H NMR (400 MHz, CD3OD) δ 8.98 (d, J = 2.5 Hz, 1H), 8.31 (s, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 6.93 (t, J = 54.4 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 5.60 (s, 2H), 4.45 (dd, J = 5.7, 10.39 Hz, 1H), 3.80 (d, J = 9.5 Hz, 1H), 2.25-2.18 (m, 1H), 2.17 (s, 3H), 2.09-2.01 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.35-1.31 (m, 1H), 1.00-0.93 (m, 1H). MS = 613.2 [M+1] + .The title compound's subsequent dissolution process - (Example 209): 1 H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 2.5 Hz, 1H), 8.30 (s, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.36 (s, 1H), 6.95 (t, J = 54.8 Hz, 1H), 5.80 (q, J = 6.6 Hz, 1H), 5.60 (s, 2H), 4.45 (dd, J = 5.7, 10.39 Hz, 1H), 3.80 (d, J = 10.5 Hz, 1H), 2.26-2.15 (m, 4H), 2.05 (br t, J = 5.6 Hz, 1H), 1.60 (d, J = 6.4 Hz, 3H), 1.36-1.31 (m, 1H), 1.01-0.93 (m, 1H). MS = 613.2 [M+1] + .

[0554] Table 26. Using appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 208 and 209. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 26] TIFF0007776453000295.tif210168TIFF0007776453000296.tif209164TIFF0007776453000297.tif209162

[0555] Example 215 [ka]

[0556] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide (Scheme AAR)

[0557] Step 1. (1R,5S)-3-(6-chloro-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one In a nitrogen-filled glovebox, a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (300 mg, 1.11 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (150 mg, 1.55 mmol), and cesium carbonate (1.08 g, 3.32 mmol) in toluene (5.0 mL) was added with [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (Xantphos-Pd-G3, 60 mg, 58 mol) at room temperature. After the addition, the reaction vessel was sealed and stirred at 80°C for 15 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO2, 2:1 EtOAc / petroleum ether) to give the title compound. MS=241.0 [M+1] + .

[0558] Step 2. (1R,5S)-3-(5-fluoro-4-methyl-6-vinylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a mixture of (1R,5S)-3-(6-chloro-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 0.416 mmol), potassium vinyltrifluoroborate (111 mg, 0.831 mmol), and TEA (126 mg, 1.25 mmol) in ethanol (5.0 mL) was added bis(di-tert-butylphosphino)ferrocenepalladium dichloride (30 mg, 41 μmol). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 15 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by preparative TLC (SiO, 3:2 EtOAc / petroleum ether) to give the title compound. MS=233.1 [M+1] + .

[0559] Step 3. 3-Fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)picolinaldehyde : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 2. MS=235.1 [M+1] + .

[0560] Step 4. (1R,5S)-3-(5-fluoro-6-(hydroxymethyl)-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Step 3 of Intermediate BJ-5a. MS=237.1 [M+1] + .

[0561] Step 5. (1R,5S)-3-(5-fluoro-4-methyl-6-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 150, Step 5. MS=332.1 [M+1] + .

[0562] Step 6. (1R,5S)-3-(6-((4-amino-1H-pyrazol-1-yl)methyl)-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 42, Step 3. MS=302.1 [M+1] + .

[0563] Step 7. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide : Following a procedure similar to that described above in Example 1, Step 5, the title compound was prepared. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 8.94 (d, J = 3.1 Hz, 1H), 8.24 (br d, J = 15.7 Hz, 2H), 7.78-7.60 (m, 3H), 6.76-6.39 (m, 1H), 5.57-5.44 (m, 2H), 4.03 (dd, J = 10.0, 5.3 Hz, 1H), 3.64 (br d, J = 10.2 Hz, 1H), 3.15 (s, 3H), 2.19-2.08 (m, 5H), 1.34 (td, J = 8.0, 5.5 Hz, 1H), 0.90 (q, J = 4.2 (Hz, 1H). MS = 600.2 [M+1] + .

[0564] Examples 216 and 217

change

[0565] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide (Scheme AAS).

[0566] Step 1. tert-Butyl (1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-1H-pyrazol-4-yl)carbamateThe following procedure was carried out in three parallel batches at equivalent scales. These batches were combined for subsequent workup. To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (65.0 g, 355 mmol) in DMF (1.30 L) at 0 °C was added sodium hydride (17.0 g, 426 mmol, 60% dispersion in mineral oil). The resulting mixture was stirred at 0 °C for 1 hour, and then 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 g, 461 mmol) was added dropwise. Upon complete addition, the reaction mixture was stirred at room temperature for 11 hours. The reaction mixture was combined, quenched by the addition of saturated aqueous NH4Cl, and extracted with a 10:1 EtOAc / MeOH mixture. The organic layers were combined, washed with water and then brine, dried over NaSO, filtered, and concentrated under reduced pressure to give (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)boronic acid. The following procedure was carried out in two parallel batches on an equivalent scale. These batches were combined and used in subsequent workup. To a solution of (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)boronic acid (165 g, 401 mmol) in THF (1.20 L) was added 2,3-dimethylbutane-2,3-diol (47.4 g, 401 mmol), and the resulting mixture was stirred at 35° C. under a nitrogen atmosphere for 6 hours. The reaction mixtures were combined and concentrated under reduced pressure to give the title compound.

[0567] Step 2. Potassium (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)trifluoroborate : The following procedure was carried out in three parallel batches on an equivalent scale. These batches were combined and used in subsequent workup. To a solution of tert-butyl (1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-1H-pyrazol-4-yl)carbamate (135 g, 400 mmol) in MeOH (1.35 L) was added potassium bifluoride (125 g, 1.60 mol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixtures were combined and concentrated under reduced pressure. The crude residue was suspended in EtOAc and filtered. The solid was washed with acetone and the combined filtrates were concentrated under reduced pressure to give the title compound: 1H NMR: (400 MHz, DMSO-d6) δ8.85 (s, 1H), 7.56 (s, 1H), 7.09 (s, 1H), 3.13 (br d, J = 3.2 Hz, 1H), 1.44 (s, 9H), 1.10 (d, J = 7.2 Hz, 3H).

[0568] Step 3. tert-Butyl (1-(1-(6-chloro-5-((4-methoxybenzyl)oxy)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)carbamate In a nitrogen-filled glovebox, to a solution of 5-bromo-2-chloro-3-((4-methoxybenzyl)oxy)pyridine (500 mg, 1.52 mmol) and potassium (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)trifluoroborate (483 mg, 1.52 mmol) in 1,3-dimethyl-2-imidazolidinone (5.0 mL) was added lithium hydroxide (109 mg, 4.56 mmol), 4,4′-di-tert-butyl-2,2′-bipyridine (49 mg, 0.18 mmol), and [Ir{dFCF3ppy}2(bpy)]PF6 (33 mg, 38 μmol). The reaction mixture was stirred at room temperature in front of a blue LED (450 nm) for 6 h. The mixture was quenched by adding water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compound. MS=459.2 [M+1] + .

[0569] Step 4. tert-Butyl (1-(1-(5-((4-methoxybenzyl)oxy)-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)carbamateA mixture of tert-butyl (1-(1-(6-chloro-5-((4-methoxybenzyl)oxy)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)carbamate (150 mg, 0.327 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (48 mg, 0.49 mmol), cesium carbonate (319 mg, 0.981 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19 mg, 33 μmol), and tris(dibenzylideneacetone)dipalladium (40 mg, 49 μmol) in 1,4-dioxane (2.0 mL) was stirred at 100° C. under a nitrogen atmosphere for 14 hours. The mixture was cooled to room temperature, quenched by the addition of water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 10% MeOH / DCM) to give the title compound. MS=520.3 [M+1] + .

[0570] Step 5. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-hydroxypyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one : The title compound was prepared following a procedure similar to that described above in Intermediate AE-5 Step 4. MS=300.1 [M+1] + .

[0571] Step 6. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide : The title compound was prepared as an initial mixture of diastereomers following a procedure similar to that described above in Example 1, Step 5. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICELCHIRALCELAD: 0.1% NH3H2O·IPA start B 40% end B 40%) to afford the individual isomeric compounds in pure form. The fast-eluting diastereomer of the title compound (Example 216): 1H NMR (500 MHz, CD3OD) δ 8.88 (d, J = 2.4 Hz, 1H), 8.26 (s, 1H), 7.85 (dd, J = 15.3, 7.2 Hz, 2H), 7.78-7.64 (m, 2H), 7.18 (s, 1H), 7.12-6.73 (t, J = 54.4 Hz, 1H), 5.63 (q, J = 7.0 Hz, 1H), 4.24 (br dd, J = 10.9, 6.0 Hz, 1H), 3.86 (br d, J = 11.0 Hz, 1H), 3.01 (s, 3H), 2.24-2.04 (m, 2H), 1.92 (d, J = 7.2 Hz, 3H), 1.39-1.31 (m, 1H), 0.95 (br d, J = 3.4 Hz, 1H). MS = 598.2 [M+1] + The diastereomer that eluted after the title compound (Example 217): 1 H NMR (400 MHz, CD3OD): δ 8.84 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 7.90-7.75 (m, 2H), 7.71 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.13 (s, 1H), 7.07-6.77 (t, J = 54.4 Hz, 1H), 5.65-5.53 (m, 1H), 4.20 (br dd, J = 11.1, 6.0 Hz, 1H), 3.81 (br d, J = 11.0 Hz, 1H), 2.97 (s, 3H), 2.17-2.02 (m, 2H), 1.87 (d, J = 7.1 Hz, 3H), 1.30-1.25 (m, 1H), 0.91 (br d, J = 3.4 Hz, 1H). MS = 598.2 [M+1] + .

[0572] Table 27. Using appropriate starting materials, the following compounds were prepared using procedures similar to those described in Examples 216 and 217. In some examples, the racemic products or diastereomeric mixtures were separated using the chiral column (SFC or HPLC) indicated in the table. [Table 27] TIFF0007776453000301.tif143165

[0573] Example 220 [ka]

[0574] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)cyclopropyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (scheme AAT) Step 1. 2-Bromo-3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazine To a solution of 2-bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyrazine (200 mg, 0.671 mmol) in DMF (8.0 mL) was added diphenyl(vinyl)sulfonium triflate (486 mg, 1.34 mmol) and DBU (0.30 mL, 2.0 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. EtOAc was added to the mixture, and the resulting mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 25% EtOAc / petroleum ether) to give the title compound. MS = 324.0, 326.0 [M+1] + .

[0575] Step 2. (1R,5S)-3-(3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a mixture of (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (81.0 mg, 0.833 mmol), 2-bromo-3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazine (180 mg, 0.555 mmol), and cesium carbonate (543 mg, 1.67 mmol) under a nitrogen atmosphere was added tris(dibenzylideneacetone)dipalladium (51 mg, 56 μmol) and Xantphos (32 mg, 56 μmol). The reaction mixture was stirred at 100° C. for 14 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was extracted with DCM. The organic layers were combined, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 50% EtOAc / petroleum ether) to provide the title compound. MS=341.1[M+1] + .

[0576] Step 3. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)cyclopropyl)-3-methylpyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one A mixture of (1R,5S)-3-(3-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (50 mg, 0.15 mmol) and platinum(IV) oxide (3.3 mg, 0.015 mmol) in EtOAc (3.0 mL) and MeOH (1.0 mL) was stirred under a hydrogen atmosphere (pressure: 15 psi) at room temperature for 2 hours. The crude mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS=311.1[M+1] + .

[0577] Step 4. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)cyclopropyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide : Following a procedure similar to that described above in Example 41, Step 4, the title compound was prepared. 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 7.87 (s, 1H),7.84-7.80 (m, 1H), 7.68-7.66 (m, 1H), 7.27 (s, 1H), 6.95 (t, J = 54.8 Hz, 1H), 4.29-4.25 (m, 1H), 3.68-3.65 (m, 1H), 3.00 (s, 3H), 2.35 (s, 3H), 2.16-2.01 (m, 1H), 1.93-1.90 (m, 1H), 1.87-1.84 (m, 1H) 1.79-1.78 (m, 1H), 1.32-1.30 (m, 2H), 1.29-1.27 (m, 1H), 0.92-0.91 (m, 1H). MS = 609.1 [M+1] + .

[0578] Table 28. Using appropriate starting materials and procedures similar to those described in Example 220, the following compounds were prepared. [Table 28] TIFF0007776453000304.tif210167TIFF0007776453000305.tif121162

[0579] Examples 224 and 225 [ka]

[0580] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-(difluoromethoxy)-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-(difluoromethoxy)-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide (Scheme AAU).

[0581] Step 1. 2-Chloro-5-iodo-3-methoxy-4-methylpyridineTo a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (2.3 g, 8.5 mmol) in MeOH (40 mL) was added sodium methoxide (0.69 g, 13 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 48 hours. The reaction mixture was cooled to room temperature, and water was added to the mixture. The resulting mixture was extracted with EtOAc, and the organic layers were then combined, washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 7% EtOAc / petroleum ether) and then reverse-phase preparative HPLC (C18 stationary phase, 30% ACN / H2O+0.5% TFA) to give the title compound. MS=283.9 [M+1] + .

[0582] Step 2. 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-1-one : The title compound was prepared following a procedure similar to that described above in Intermediate BI-4a Step 1. Aqueous MS=200.1 [M+1] + .

[0583] Step 3. 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-1-ol To a solution of 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethan-1-one (1.4 g, 7.0 mmol) in THF (20 mL) and MeOH (2.0 mL) at 0 °C was added sodium borohydride (0.32 g, 8.4 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0% to 50% EtOAc / petroleum ether) to give the title compound. MS=202.1 [M+1] + .

[0584] Step 4. 2-Chloro-3-methoxy-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine The title compound was prepared following a procedure similar to that described above in Step 1 of Example 183. MS=297.0 [M+1] + .

[0585] Step 5. 2-Chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-3-olTo a stirring solution of 2-chloro-3-methoxy-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine (1.1 g, 1.9 mmol) in DCM (15 mL) was added boron tribromide (1.0 mL, 11 mmol) dropwise at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (10 mL), cooled to 0° C., and then quenched by the addition of MeOH (5 mL). The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give the title compound. MS=283.0 [M+1] + .

[0586] Step 6. 2-Chloro-3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine To a stirred solution of 2-chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-3-ol (420 mg, 1.49 mmol) in DMF (8.0 mL) was added sodium 2-chloro-2,2-difluoroacetate (340 mg, 2.23 mmol) and cesium carbonate (968 mg, 2.97 mmol) at room temperature, and the reaction mixture was stirred at 70° C. for 12 hours. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0% to 30% EtOAc / petroleum ether) to give the title compound. MS=333.0 [M+1] + .

[0587] Step 7. (1R,5S)-3-(3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-oneTo a solution of 2-chloro-3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine (360 mg, 1.08 mmol) in toluene (8.0 mL) was added (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (137 mg, 1.41 mmol), Xantphos (63 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (99 mg, 0.11 mmol), and cesium carbonate (705 mg, 2.16 mmol). The resulting mixture was stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography (0% to 75% EtOAc / petroleum ether) to provide the title compound. MS=394.1[M+1] + .

[0588] Step 8. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-(difluoromethoxy)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. MS=364.1 [M+1] + .

[0589] Step 9. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(5-(difluoromethoxy)-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide The title compound was prepared as an initial mixture of diastereomers following a procedure similar to that described above in Example 1, Step 5. The diastereomeric title compounds were separated by chiral chromatography (SFC, Phenomenex-Cellulose-2: 0.1% NH3H2O·EtOH start B 55% end B 55%) to afford the individual isomeric compounds in pure form. The first-eluting diastereomer of the title compound (Example 224): 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.78-7.85 (m, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.10-6.78 (t, J = 54.8 Hz, 1H), 6.76-6.36 (t, J = 72.8 Hz, 1H), 5.86 (q, J = 7.0 Hz, 1H), 4.26 (dd, J = 10.3, 5.9 Hz, 1H), 3.67 (d, J = 10.3 Hz, 1H), 2.98 (s, MS = 662.2 [M+1] + .Dissolution of the title compound afterward (Example 225) : 1 H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 2.4 Hz, 1H), 8.23 ​​(s, 1H), 8.14 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.09-6.77 (t, J = 54.8 Hz, 1H), 6.73-6.33 (t, J = 73.2 Hz, 1H), 5.86 (q, J = 7.1 Hz, 1H), 4.28 (dd, J = 10.3, 5.9 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 2.98 (s, 3H), 2.33 (s, 3H), 2.23-2.13 (m, 1H), 2.06-1.97 (m, 1H), 1.92 (d, J = 7.1 Hz, 3H), 1.25 (dt, J = 8.0, 3.9 Hz, 1H), 1.00-0.93 (m, 1H). MS = 662.2 [M+1] + .

[0590] Examples 226 and 227 [ka]

[0591] 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAV). To a solution of (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (11 mg, 36 μmol) in toluene (2.0 mL) was added trimethylaluminum (0.018 mL, 36 μmol, 2 M solution in toluene). The reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of 3-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)furo[3,4-b]pyrazin-5(7H)-one (10 mg, 30 μmol) in DCM (1.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched by the addition of water (0.5 mL), then concentrated under reduced pressure and purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 33%, ending B 63%) to give a diastereomeric mixture of the title compounds. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICELCHIRALCELAD: 0.1% NH3HO·EtOH starting B 45% ending B 45%) to give the individual isomeric compounds in pure form. The faster-eluting diastereomer of the title compound (Example 226): 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.77-7.67 (m, 2H), 7.61 (d, J = 1.7 Hz, 1H), 7.24 (d, J = 9.1 Hz, 1H), 7.13-6.72 (m, 1H), 5.62 (d, J = 7.1 Hz, 1H), 5.21 (s, 2H), 4.22 (dd, J = 5.9, 10.5 Hz, 1H), 3.65 (d, J = 10.3 Hz, 1H), 2.13 (s, 4H), 2.03-1.96 (m, 1H), 1.89 (d, J = 7.1 Hz, 3H), 1.26 (br s, 1H), 0.94-0.87 (m, 1H). MS = 628.2 [M+1] + Title Dissolution of the compound afterward (Example 227): 1 H NMR (400 MHz, CD3OD) δ 8.82 (br s, 1H), 8.18 (s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.66 (s, 1H), 7.62 (t, J = 8.7 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.16 (d, J = 9.1 Hz, 1H), 7.04-6.65 (m, 1H), 5.54 (q, J = 7.1 Hz, 1H), 5.13 (s, 2H), 4.14 (dd, J = 6.0, 10.4 Hz, 1H), 3.57 (d, J = 10.3 Hz, 1H), 2.10-2.02 (m, 4H), 1.96-1.88 (m, 1H), 1.81 (d, J = 7.1 Hz, 3H), 1.21-1.19 (m, 1H), 0.85-0.80 (m, 1H). MS = 628.2 [M+1] + .

[0592] Example 228

change

[0593] 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((R and S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAV)

[0594] To a solution of 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-(1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (60 mg, 0.096 mmol) in DCM (1.0 mL) was added tert-butyl acetate (110 mg, 0.960 mmol) and sulfuric acid (0.5 μL, 10 μmol). The reaction was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure, and the crude material was purified by reverse-phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 45% ending B 75%) to afford a diastereomeric mixture of the title compounds. 1 H NMR (500 MHz, CD3OD) δ 8.87 (s, 1H), 8.28 (s, 1H), 8.21 (br d, J = 5.3 Hz, 1H), 7.72-7.76 (m, 2H), 7.64 (br s, 1H), 7.27 (br d, J = 9.3 Hz, 1H), 7.10-6.77 (m, 1H), 5.73-5.64 (m, 1H), 5.09 (s, 2H), 4.26 (dd, J = 5.9, 10.3 Hz, 1H), 3.70 (d, J = 11.4 Hz, 1H), 2.18 (s, 4H), 2.04 (br d, J = 5.2 Hz, MS = 684.0 [M+1] + .

[0595] Table 29. Using appropriate starting materials and a procedure similar to one of those described above, the following compounds were prepared. [Table 29] TIFF0007776453000310.tif187158TIFF0007776453000311.tif187161TIFF0007776453000312.tif187160TIFF0007776453000313.tif184160TIFF0007776453000314.tif211159TIFF0007776453000315.tif208161TIFF0007776453000316.tif210162TIFF0007776453000317.tif210159TIFF0007776453000318.tif210162TIFF0007776453000319.tif210158TIFF0007776453000320.tif210158TIFF0007776453000321.tif218166TIFF0007776453000322.tif216164TIFF0007776453000323.tif211165TIFF0007776453000324.tif214167TIFF0007776453000325.tif211165TIFF0007776453000326.tif215166TIFF0007776453000327.tif213165TIFF0007776453000328.tif213168TIFF0007776453000329.tif212158TIFF0007776453000330.tif209162TIFF0007776453000331.tif204167TIFF0007776453000332.tif204169TIFF0007776453000333.tif71158

[0596] Factor XIa assay The efficacy of the compounds of the present invention as inhibitors of coagulation factor XIa can be determined using the relevant purified serine protease and an appropriate synthetic substrate. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of the compounds of the present invention. Assays were performed at room temperature or 37°C. Hydrolysis of the substrate resulted in the release of aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorimetrically by measuring the increase in emission at 510 nm upon excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of an inhibitor indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of this assay are reported as the half-maximal inhibitory concentration (IC 50 ), or the inhibition constant Ki.

[0597] Compounds were preincubated with human factor XIa (0.04 nM) in 50 mM HEPES buffer containing 150 mM sodium chloride, 5 mM calcium chloride, 0.1% PEG 8000, pH 7.4, for 30 minutes at 25°C. Factor XIa enzymatic activity was determined by adding the substrate glycine-proline-arginine-7-amido-4-trifluoromethylcoumarin (GPR-AFC) and measuring fluorescence at 400 / 505 nm after 60 minutes of incubation at 25°C. The percent inhibition of each data point was calculated from the data and analyzed using a four-parameter equation of log(inhibitor) versus response to determine the half-maximal inhibitory concentration (IC). 50 ) was calculated. IC 50 was converted to an equilibrium inhibition constant (Ki) using the Cheng-Prusoff equation.

[0598] Activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful in the treatment or prevention of a variety of cardiovascular and / or cerebrovascular thromboembolic conditions in patients with unstable angina, acute coronary syndromes, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, stroke such as thrombotic or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, arteriosclerosis, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.

[0599] Kallikrein assay The efficacy of the compounds of the present invention as inhibitors of kallikrein can be determined using the relevant purified serine protease and an appropriate synthetic substrate. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of the compounds of the present invention. Assays were performed at room temperature or 37°C. Hydrolysis of the substrate resulted in the release of aminotrifluoromethylcoumarin (AFC), which was monitored spectrofluorimetrically by measuring the increase in emission at 510 nm upon excitation at 405 nm. A decrease in the rate of fluorescence change in the presence of an inhibitor indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of this assay are expressed as the half-maximal inhibitory concentration (IC 50 ), or the inhibition constant Ki.

[0600] Kallikrein measurements were performed in 50 mM HEPES buffer, pH 7.4, containing 150 mM NaCl, 5 mM CaCl, and 0.1% PEG 8000 (polyethylene glycol; Fisher Scientific). Measurements were performed using purified human plasma kallikrein (Enzyme Research Laboratories) at a final concentration of 0.5 nM and the synthetic substrate, acetyl-KPR-AFC (Sigma #C6608), at a concentration of 100 mM.

[0601] Activity measurements were performed by diluting the substrate stock solution at least 10-fold to a final concentration ≤0.2 Km and injecting it into a solution containing enzyme or enzyme equilibrated with inhibitor. The time required for equilibration between enzyme and inhibitor was determined in control experiments. Reactions were run under linear progress curve conditions, and the increase in fluorescence was measured at 405Ex / 510Em nm. Values ​​were converted to percent inhibition of the control reaction (after subtracting the 100% inhibition value). IC 50 was determined by the inflection point from a four-parameter logistic curve fit. Ki was calculated using the Cheng-Prusoff equation: Ki=IC 50 Calculated using / (1+([S] / Km)).

[0602] Activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful for the treatment or prevention of a variety of ophthalmic, cardiovascular and / or cerebrovascular thromboembolic conditions in patients with unstable angina, acute coronary syndromes, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, stroke such as thrombotic or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, arteriosclerosis, deep vein thrombosis, disseminated intravascular coagulation, and 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.

[0603] Plasma kallikrein (PKal) and factor XIa (FXIa) IC for selected compounds 50 (nM) is as follows: [Table 30] TIFF0007776453000335.tif209152TIFF0007776453000336.tif210162TIFF0007776453000337.tif209144TIFF0007776453000338.t if208153TIFF0007776453000339.tif209157TIFF0007776453000340.tif209161TIFF0007776453000341.tif209152TIFF00077764530 00342.tif209148TIFF0007776453000343.tif208151TIFF0007776453000344.tif210159TIFF0007776453000345.tif209162TIFF000 7776453000346.tif210157TIFF0007776453000347.tif210150TIFF0007776453000348.tif209158TIFF0007776453000349.tif208154

Claims

1. A compound of the formula: or a pharmaceutically acceptable salt of said compound: 【Chemistry 1】 [In the formula, 【Chemistry 2】 teeth, 【Transformation 3】 Selected from: 【Chemistry 4】 teeth, 【Transformation 5】 Selected from: V is CH or N; X is CH or N; Y is N, NO, NR ｘ or C=O; Z is NR ４ or CR ４ and E is N or CH; Q is N or CH; G is N or CR ７ and J is N or CR ７ and L is N or CR ７ and M is N or CR ８ and R １ is hydrogen, halo, cyano, R ｘ , OR ｘ and SO ２ R ｘ selected from the group consisting of: R ２ is hydrogen or halo; R ３ is hydrogen or halo; R ４ is cyano, hydrogen, R ｘ , OR ｘ , C １－３ Alkyl-OR ｘ , C １－３ Alkyl-O-C ３－６ Cycloalkyl or CH=CH ２ and R ５ is hydrogen or C １－３ alkyl, which is optionally substituted by 1 to 3 substituents selected from halo and hydroxy; R ６ is hydrogen or C １－３ is alkyl; or R ５ and R ６ together with the carbon atoms between them, C ３－６ can form a cycloalkyl group; Each R ７ are independently halo, R ｘ , OR ｘ , C １－３ Alkyl-OR ｘ , NH(C=O)OR ｘ and N.H. ２ selected from the group consisting of: R ８ is R ｘ OR ｘ selected from the group consisting of: or R ７ and R ８ together with the carbon atoms between them can form a 5-membered cycloalkyl or heterocyclic group, which heterocyclic group is optionally substituted with one or two substituents independently selected from the group consisting of halo, methyl, and ethyl; R ９ is hydrogen or C １－３ is alkyl; R １０ is hydrogen, hydroxy or C １－３ is alkyl; R ｘ is hydrogen or C １－６ alkyl, which is optionally substituted with 1 to 4 substituents selected from halo and hydroxy.

2. 2. The compound of claim 1, wherein E is CH and Z is CH, or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 6】 but 【Transformation 7】 3. The compound of claim 1 or 2, wherein:

4. R １ is hydrogen, CH ３ , CHF ２ , C.F. ３ , OCHF ２ and SO ２ CH ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

5. R ４ Cyano, CH ３ , CHF ２ , C.H. ２ OH, CH ２ OCH ３ , C.H. ２ OC (CH ３ ) ３ , C.H. ２ O(cyclopropyl), CH(OH)CF ３ , C.H. ２ C(CH ３ ) ２ OH, CD ２ OH, CH(CH ３ ) OH and OCH ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. R ５ is hydrogen, CH ３ or CH ２ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is 0 or 1;

7. 7. The compound of any one of claims 1 to 6, wherein X is N; Y is N; and V is CH; or a pharmaceutically acceptable salt thereof.

8. Each R ７ are independently hydrogen, chloro, fluoro, CH ３ , OCH ３ , CHF ２ , OCHF ２ , C.H. ２ OH, NH ２ and NH(C=O)OR ｘ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

9. The following table: The compound according to claim 1, selected from any one of compounds 1 to 255 identified by compound numbers 1 to 255 defined above, or a pharmaceutically acceptable salt of said compound.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier.

11. 11. The pharmaceutical composition of claim 10 for the treatment of visual activity disorders, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood clotting during cardiopulmonary bypass surgery, or bleeding from post-operative surgery in mammals.

12. 11. The pharmaceutical composition of claim 10 for the treatment of uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal.

13. 11. The pharmaceutical composition of claim 10 for the treatment of diabetic retinopathy or diabetic macular edema in a mammal.

14. 11. The pharmaceutical composition of claim 10 for the treatment of retinal vein occlusion in a mammal.

15. 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal in need thereof.

16. 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in therapy.

17. 11. The composition of claim 10, further comprising another agent selected from the group consisting of an anti-inflammatory agent, an anti-VEGF agent, an immunosuppressant, an anticoagulant, an antiplatelet agent, and a thrombolytic agent.

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

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