Plasma kallikrein inhibitors

Abstract

The present invention provides compounds of formula I and pharmaceutical compositions comprising one or more of the compounds, as well as methods of using the compounds for treating or preventing one or more disease states that may benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.

Description

Background Art

[0001] Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma. The gene structure is similar to factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology with factor XI. Proteolytic activation by factor XIIa at the internal I389-R390 bond produces a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with protease inhibitors, including α2 macroglobulin and Cl-inhibitors. Interestingly, in the presence of high molecular weight kininogen (HMWK), heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III. In the blood, most plasma kallikrein circulates in complex with HMWK. Plasma kallikrein cuts HMWK to release bradykinin. Bradykinin release leads to increased vascular permeability and vasodilation (for review, 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 presenting with a genetic defect for the C1 esterase inhibitor suffer from hereditary angioedema (HAE), a lifelong disease resulting in intermittent swelling throughout the body, including the hands, feet, face, throat, genitals, and gastrointestinal tract. Analysis of blisters arising from acute attacks has been shown to contain high levels of plasma kallikrein, and treatment with the protein-based, reversible plasma kallikrein inhibitor, Kalbitor, has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L et al., J. Allergy Clin. Immunol., 120: p. 416 (2007)).

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

[0004] It would be desirable in the art to develop plasma kallikrein inhibitors that would have utility in treating a wide range of disorders, including hereditary angioedema, diabetic macular edema, and diabetic retinopathy. Summary of the invention

[0005] The present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof.

[0006]

[0007] The compounds of formula I are inhibitors of plasma kallikrein, and therefore, can be used to treat, inhibit or improve one or more disease states that can benefit from the inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds of the present invention can be further used in combination with other therapeutically effective agents, including but not limited to other agents that can be used to treat 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 compounds of formula I, and pharmaceutical compositions comprising compounds of formula I and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION

[0008] The present invention relates to a compound of formula I or a pharmaceutically salt thereof:

[0009]

[0010] in Selected from

[0011]

[0012] Selected from

[0013]

[0014] V is CH or N;

[0015] X is CH or N;

[0016] Y is N, NO, NR x Or C=O;

[0017] Z is NR 4 or CR 4 ;

[0018] E is N or CH;

[0019] Q is N or CH;

[0020] G is N or CR 7 ;

[0021] J is N or CR 7 ;

[0022] L is N or CR 7 ;

[0023] M is N or CR 8 ;

[0024] R 1 is selected from hydrogen, halogen, cyano, R x , OR x and SO 2 R x ;

[0025] R 2 is hydrogen or a halogen;

[0026] R 3 is hydrogen or a halogen;

[0027] R 4 is hydrogen, R x , OR x , C 1-3 Alkyl-OR x , C 1-3 Alkyl-OC 3-6 Cycloalkyl or CH=CH 2 ;

[0028] R 5 is hydrogen or C 1-3 Alkyl, which is optionally substituted with 1 to 3 substituents selected from halogen and hydroxy;

[0029] R 6 is hydrogen or C 1-3 alkyl;

[0030] or R 5 and R 6 Together with the carbon atoms between them, they can form C 3-6 Cycloalkyl;

[0031] Each R 7 are independently selected from halogen, R x , OR x , C 1-3 Alkyl-OR x 、NH(C=O)OR x and NH 2 ;

[0032] R 8 Selected from R x ORx ;

[0033] or R 7 and R 8 Together with the carbon atoms between them, they may form a 5-membered cycloalkyl or heterocyclic group, wherein the heterocyclic group is optionally substituted with 1 to 2 substituents independently selected from halogen, methyl or ethyl;

[0034] R 9 is hydrogen or C 1-3 alkyl;

[0035] R 10 is hydrogen, hydroxyl or C 1-3 alkyl;

[0036] R x is hydrogen or C 1-6 Alkyl which is optionally substituted with 1 to 4 substituents selected from halogen and hydroxy.

[0037] In one embodiment of the present invention, yes In another embodiment of the present invention, yes In another embodiment of the present invention, yes In another embodiment of the present invention, yes In another embodiment of the present invention, yes In another embodiment of the present invention, yes In another embodiment of the present invention, yes

[0038] In one embodiment of the present invention, X is CR 2 In another embodiment of the present invention, X is N.

[0039] In one embodiment of the present invention, yes In another embodiment of the present invention, yes

[0040] In one embodiment of the present invention, V is CH. In another embodiment of the present invention, V is N.

[0041] In one embodiment of the present invention, X is CH. In another embodiment of the present invention, X is N.

[0042] 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.

[0043] In one embodiment of the present 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.

[0044] In one embodiment of the present invention, E is N. In another embodiment of the present invention, E is CH.

[0045] In one embodiment of the present invention, Q is N. In another embodiment of the present invention, Q is CH.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In one embodiment of the present invention, R 1 is hydrogen, CH 3 , CHF 2 CF 3 , OCHF 2 or SO 2 CH 3 In one class of embodiments, R 1 In another class of embodiments, R 1 Yes CH 3 In another class of embodiments, R 1 is CHF 2 In another class of embodiments, R 1 It is CF 3 In one class of embodiments, R 1It is OCHF 2 In one class of embodiments, R 1 Yes SO 2 CH 3 .

[0051] In one embodiment of the present invention, R 2 In another embodiment of the present invention, R 2 is halogen. In one class of the invention, R 2 It's fluorine.

[0052] In one embodiment of the present invention, R 3 In another embodiment of the present invention, R 3 is halogen. In one class of the invention, R 3 It's chlorine.

[0053] In one embodiment of the present invention, R 4 is cyano, CH 3 , CHF 2 , CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 O(cyclopropyl), CH(OH)CF 3 , CH 2 C(CH 3 ) 2 OH, CD 2 OH, CH(CH 3 )OH or OCH 3 .

[0054] In one embodiment of the present invention, R 5 is hydrogen, CH 3 or CH 2 OH. In one class of the invention, R 5 In another class of the invention, R 5 Yes CH 3 In another class of the present invention, R 5 Yes CH 2 OH.

[0055] In one embodiment of the present invention, R 6 It's hydrogen.

[0056] In one embodiment of the present invention, R 7 It is hydrogen, chlorine, fluorine, CH 3 、OCH 3 , CHF2 , OCHF 2 , CH 2 OH, NH 2 and NH(C=O)OR x .

[0057] In one embodiment of the present invention, R 7 and R 8 Together with the carbon atoms between them, they may form a 5-membered cycloalkyl or heterocyclic group, wherein the heterocyclic group is optionally substituted by one to two substituents independently selected from the following: halogen, methyl or ethyl. In one class of the present invention, R 7 and R 8 Together with the carbon atoms between them, they may form a heterocyclic group substituted with two fluorine atoms.

[0058] Unless otherwise stated, references to preferred classes and subclasses set forth above are intended to include all combinations of specific and preferred groups.

[0059] Specific embodiments of the present invention include, but are not limited to, compounds identified herein as Examples 1 to 255, or pharmaceutically acceptable salts thereof.

[0060] Also included within the scope of the invention are pharmaceutical compositions consisting of a compound of formula I as described above and a pharmaceutically acceptable carrier. The present invention also contemplates pharmaceutical compositions consisting of a pharmaceutically acceptable carrier and any compound specifically disclosed in the present application. These and other aspects of the invention will be apparent from the teachings contained herein.

[0061] The present invention includes compositions for treating diseases or conditions in which plasma kallikrein activity is involved. Accordingly, the present invention includes compositions for treating: impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, and bleeding from postoperative surgery in mammals, the compositions 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 include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions may be added to blood, blood products, or mammalian organs to achieve the desired inhibition.

[0062] The present invention also includes a composition for preventing or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in mammals, comprising a compound of the present invention in a pharmaceutically acceptable carrier. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0063] The present invention also includes compositions for treating inflammatory conditions of the eye, 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 effusions. These compositions may optionally include anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0064] The present invention also includes compositions for treating posterior ocular diseases, including 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.

[0065] It should be understood that the present invention relates to the compounds of structural formula I described herein, as well as pharmaceutically acceptable salts of the compounds of structural formula I, and salts that are not pharmaceutically acceptable when they are used as precursors of free compounds or pharmaceutically acceptable salts thereof or in other synthetic operations.

[0066] 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 within the term "pharmaceutically acceptable salts" refer to non-toxic salts of compounds of the present invention, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethylacetate, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, ethanesulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate ), hydrazine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinate, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, methylsulfate, methanesulfonate, mucate, naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (spicate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelate, phenylpropionate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, toluenesulfonate, triethiodide, trifluoroacetate, undecanoate, valerate, and the like. In addition, when the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, 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, dicyclohexylamine and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Additionally included are basic nitrogen-containing groups which may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromine and iodine; dialkyl sulfates such as dimethyl, diethyl, dibutyl; and diamyl sulfate, long chain halides such as decanoyl, lauroyl, myristoyl and stearyl chloride, bromine and iodine, aralkyl halides such as benzyl and phenethyl bromide, and others.

[0067] These salts can be obtained by known methods, for example, by mixing an equal amount of the compound of the present invention with a solution containing a desired acid, base, etc., and then collecting the desired salt by filtering the salt or distilling off the solvent. The compound of the present invention and its salt can form a solvate with a solvent such as water, ethanol or glycerol. Depending on the type of the side chain substituent, the compound of the present invention can simultaneously form an acid addition salt and a salt with a base.

[0068] If the compounds of the formula I contain both acidic and basic groups in the molecule, the invention also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned.

[0069] The present invention encompasses all stereoisomeric forms of compounds of formula I. Unless specific stereochemistry is indicated, the present invention is intended to include all such isomeric forms of these compounds. Asymmetric centers present in compounds of formula I can all have (R) configuration or (S) configuration independently of each other. When the bond to a chiral carbon is described as a straight line in the structural formula of the present invention, it is understood that both (R) and (S) configurations of the chiral carbon, and therefore each individual enantiomer and mixture thereof are both included in the formula. When a specific configuration is depicted, the enantiomer ((R) or (S) at the center) is expected. Similarly, when the compound name is narrated without chirality about the chiral carbon, it is understood that both (R) and (S) configurations of the chiral carbon and therefore individual enantiomers and mixtures thereof are included by the name. The production of specific stereoisomers or mixtures thereof can be identified in the embodiments in which such stereoisomers or mixtures are obtained, but this is by no means limited to all stereoisomers and mixtures thereof included within the scope of the present invention.

[0070] Unless a specific enantiomer or diastereomer is indicated, the present invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers in all ratios. Therefore, the subject of the present invention is an enantiomer, which is an enantiomer-pure form, a racemate form, and a mixture of two enantiomers in all ratios as both a left-handed enantiomer and a right-handed enantiomer. In the case of cis / trans isomerism, the present invention includes both cis-form and trans-form and a mixture of these forms in all ratios. When necessary, the preparation of individual stereoisomers can be carried out by separating the mixture via conventional methods, such as by chromatography or crystallization, by using stereochemically consistent raw materials for synthesis or by stereoselective synthesis. Optionally, derivatization can be carried out before the separation of stereoisomers. The separation of a stereoisomer mixture can be carried out at an intermediate step during the synthesis of a compound of formula I, or it can be completed to the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which, if necessary, are derivatized with reagents containing stereogenic centers of known configuration. When the compounds of the invention are capable of tautomerism, 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.

[0071] In the compounds of the invention, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that found predominantly in nature. The invention is intended to include all suitable isotopic variations of the compounds described specifically and generally. For example, different isotopic forms of hydrogen (H) include protium (1 H ) and deuterium (2 H ). Protium is the predominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as characterization standards for biological samples. Isotopically enriched compounds can be prepared without undue experimentation using appropriate isotopically enriched reagents and / or intermediates, by conventional techniques well known to those skilled in the art, or by processes similar to those described in the general process schemes and embodiments herein.

[0072] When any variable (such as R xWhen a (, ...

[0073] It should be understood that one or more silicon (Si) atoms can be incorporated into the compounds of the present invention by those of ordinary skill in the art instead of one or more carbon atoms to provide chemically stable compounds that can be easily synthesized from readily available raw materials by techniques known in the art. When comparing similar C elements and Si element bonds, carbon and silicon differ in their covalent radius, resulting in differences in bond distance and steric arrangement. When compared to carbon, these differences result in subtle changes in the size and shape of silicon-containing compounds. Those of ordinary skill in the art should understand that size and shape differences can result in subtle or significant changes in efficacy, solubility, lack of off-target activity, packaging properties, etc. (Diass, JO et al. Organometallics (2006) 5: 1188-1198; Showell, GA et al. Bioorganic & Medicinal Chemistry Letters (2006) 16: 2555-2558).

[0074] It should be understood that substituents and substitution patterns for compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized from readily available raw materials by techniques known in the art and those described below. If a substituent is itself substituted with more than one group, it should be understood that these multiple groups can be on the same carbon or on different carbons, as long as a stable structure results. The phrase "optionally substituted" (with one or more substituents) should be understood to mean that the group in question is unsubstituted or can be substituted with one or more substituents.

[0075] In addition, the compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and all amorphous and crystalline forms of compounds of formula I and mixtures thereof are contemplated to be included within the scope of the present invention. In addition, some compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates of the compounds of the present invention, particularly pharmaceutically acceptable solvates and hydrates, together with non-solvated and anhydrous forms, are also contemplated within the scope of the present invention.

[0076] In addition, in the case of carboxylic acid (-COOH) or alcohol groups present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl or pivaloyloxymethyl of alcohol, or acyl derivatives, such as O-acetyl, O-pivaloyl, O-benzoyl and O-aminoacyl, may be used. Included are those esters and acyl groups known in the art for use in modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

[0077] Any pharmaceutically acceptable prodrug modification of the compounds of the present invention that results in conversion in vivo to compounds within the scope of the present invention is also within the scope of the present invention. For example, esters can be prepared optionally by esterification of available carboxylic acid groups or by ester formation on available hydroxyl groups in the compound. Similarly, unstable amides can be prepared. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs, which can be hydrolyzed back to the acid (or -COO-, depending on the pH of the fluid or tissue in which the conversion occurs) or hydroxyl form in vivo, and as such are covered within the scope of the present invention. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 Alkyl esters and -C substituted by phenyl esters 1-6 alkyl.

[0078] Accordingly, unless otherwise indicated, the compounds within the general formulae, embodiments, and specific compounds described and claimed herein encompass salts thereof, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvates, and hydrate forms, and any combination of these forms, as well as salts thereof, prodrug forms thereof, and salts of prodrug forms thereof, when such forms are possible.

[0079] Unless otherwise indicated 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. Common abbreviations for alkyl groups are used throughout the specification, for example, methyl groups may be represented by conventional abbreviations including "Me" or CH 3 or as the symbol for the extended bond of a terminal group such as Indicates that ethyl can be represented by "Et" or CH 2 CH 3 The propyl group can be represented by "Pr" or CH 2 CH 2 CH 3 Indicates that butyl can be represented by "Bu" or CH 2 CH 2 CH 2 CH 3 For example, "C 1-4 Alkyl (or "C 1 -C 4"alkyl" means a straight or branched chain alkyl group having the specified number of carbon atoms, including all isomers. For example, the structure

[0080]

[0081] Have equivalent meanings. 1-4 Alkyl groups include n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, ethyl and methyl. If no number is specified, 1-4 carbon atoms contemplate linear or branched alkyl groups.

[0082] Unless otherwise indicated, the term "cycloalkyl" means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0083] Unless otherwise indicated, as used herein, the term "aryl" means a stable monocyclic or bicyclic ring system having up to 10 carbon atoms in each ring, wherein at least one ring is aromatic. Bicyclic aromatic ring systems include fused ring systems in which the two rings share two atoms, and spiro ring systems in which the two rings share one atom. Aryl groups within the scope of this definition include, but are not limited to, phenyl, indene, isoindene, naphthalene, and tetralin.

[0084] As used herein, unless otherwise indicated, the term "heteroaryl" refers to a stable monocyclic or bicyclic ring system having up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Bicyclic heteroaromatic 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, but are not limited to, azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnozinyl, indanyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphthylpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxaline The term "heteroaryl" refers to a group consisting of 1,2-dihydro-2-nitro- ...

[0085] As used herein, the term "heterocycle" or "heterocyclyl" is intended to mean a stable non-aromatic monocyclic or bicyclic ring system having up to 10 atoms in each ring containing 1 to 4 heteroatoms selected from O, N, S, SO or SO 2 Bicyclic heterocyclic ring systems include fused ring systems in which the two rings share two atoms, and spiro ring systems in which the two rings share one atom. Thus, "heterocyclyl" includes, but is not limited to, the following: azaspironanoyl, azaspirooctanoyl, azetidinyl, dioxanyl, oxadiazaspirodecanyl, oxaspirooctanoyl, oxazolidinone, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothienyl, and the like. If the heterocyclic ring contains nitrogen, it is understood that its corresponding N-oxide is also encompassed by this definition.

[0086] Unless otherwise stated, the term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0087] (Fluka) Diatomite is diatomaceous earth and may be referred to as "celite".

[0088] Unless otherwise indicated herein, structures are depicted containing substituent variables such as the variable "R" below, which are not attached to any particular bicyclic ring carbon atom:

[0089]

[0090] represents a structure in which the variable can be optionally attached to any bicyclic ring carbon atom. For example, the variable R shown in the above structure can be attached to any of the six bicyclic ring carbon atoms i, ii, iii, iv, v or vi.

[0091] Unless otherwise stated herein, bicyclic ring systems include fused ring systems wherein the two rings share two atoms, and spiro ring systems wherein the two rings share one atom.

[0092] The present invention also relates to a medicament containing at least one compound of formula I and / or a pharmaceutically acceptable salt of a compound of formula I and / or an optional stereoisomeric form of a compound of formula I or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of formula I, together with pharmaceutically suitable and pharmaceutically acceptable vehicles, additives and / or other active substances and auxiliaries.

[0093] As used herein, the term "patient" is taken to mean mammals, such as primates, humans, sheep, horses, cows, pigs, dogs, cats, rats, and mice.

[0094] The medicament 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. It is possible to coat stents and other surfaces in contact with blood in vivo with compounds of formula I.

[0095] The invention furthermore relates to a process for producing a medicament, which comprises bringing at least one compound of the formula I into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0096] Suitable solid or galenic forms are, for example, granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations with prolonged release of the active substance, in which conventional excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries that may be mentioned 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 glycols and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol.

[0097] The dosing regimen utilizing a plasma kallikrein inhibitor is selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0098] When used for the indicated effects, oral dosages of plasma kallikrein inhibitors range from about 0.01 mg / kg body weight / day (mg / kg / day) to about 30 mg / kg / day, preferably 0.025-7.5 mg / kg / day, more preferably 0.1-2.5 mg / kg / day, and most preferably 0.1-0.5 mg / kg / day (unless otherwise indicated, the amount of active ingredient is based on the free base). For example, an 80 kg patient would receive about 0.8 mg / day to 2.4 g / day, preferably 2-600 mg / day, more preferably 8-200 mg / day, and most preferably 8-40 mg / kg / day. Thus, a suitably prepared medicament for once daily administration contains 0.8 mg to 2.4 g, preferably 2 mg to 600 mg, more preferably 8 mg to 200 mg, and most preferably 8 mg to 40 mg, such as 8 mg, 10 mg, 20 mg, and 40 mg. Advantageously, the plasma kallikrein inhibitor may be administered in divided doses twice, three or four times daily. For twice daily administration, a suitably prepared medicament will contain 0.4 mg to 4 g, preferably 1 mg to 300 mg, more preferably 4 mg to 100 mg, and most preferably 4 mg to 20 mg, e.g. 4 mg, 5 mg, 10 mg and 20 mg.

[0099] Intravenously, the 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 an amount can be applied in a variety of suitable ways, such as a large volume of low concentration of active ingredient during an extended period of time, or a low volume of high concentration of active ingredient several times a day during a short period of time, such as once a day. Typically, a conventional intravenous preparation can be prepared containing an active ingredient concentration of about 0.01-1.0 mg / mL, such as 0.1 mg / mL, 0.3 mg / mL and 0.6 mg / mL, and applied in an amount of 0.01 mL / kg patient weight to 10.0 mL / kg patient weight, such as 0.1 mL / kg, 0.2 mL / kg, 0.5 mL / kg per day. In one example, an 80 kg patient receiving an intravenous preparation of 8 mL twice a day with an active ingredient concentration of 0.5 mg / mL receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid / conjugate base with reasonable buffering capacity within the acceptable pH range for intravenous administration can be used as a buffer. The selection of an appropriate buffer and pH for the formulation is readily made by one of ordinary skill in the art, depending on the solubility of the drug to be administered.

[0100] The compounds of Formula I can be administered as monotherapy or in combination with other therapeutic agents including, but not limited to, anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

[0101] An "anti-inflammatory agent" is any agent that is effective, directly or indirectly, in reducing inflammation when administered at a therapeutically effective level. "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.

[0102] An "anti-VEGF agent" is any agent that is effective, directly or indirectly, in inhibiting the activity of VEGF (vascular endothelial growth factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, and aflibercept.

[0103] "Immunosuppressants" are any agents that are effective, directly or indirectly, in 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 mofetil), biologics (e.g., abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab) and monoclonal antibodies (e.g., basiliximab, daclizumab).

[0104] 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., to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), other anticoagulants such as aspirin and thrombolytic agents such as plasminogen activators or streptokinase, to achieve a synergistic effect in the treatment of various vascular pathological conditions. Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban and semuloparin. For example, patients with coronary artery disease and patients undergoing angioplasty will benefit from the co-administration of fibrinogen receptor antagonists and thrombin inhibitors.

[0105] In certain embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are employed in their conventional dosage ranges and regimens as reported in the art, including, for example, in Doctor's Desk Reference Test ( Physicians' Desk Reference ) editions, such as the 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.

[0106] Alternatively or in addition, one or more other pharmacologically active agents can be used in combination with the compounds of the present invention. Other active agents (or multiple active agents) are intended to mean active pharmaceutical agents (or multiple active agents) in vivo, including prodrugs converted to pharmaceutically active forms after administration, which are different from the compounds of the present invention, and also include free acids, free alkalis and pharmaceutically acceptable salts of the other active agents, when such forms are sold commercially or are otherwise chemically possible. Generally, any suitable other one or more active agents, including but not limited to antihypertensive agents, other diuretics, antiatherosclerotic agents such as lipid-modified compounds, antidiabetic agents and / or antiobesity agents can be used in single-dose formulations with any combination (fixed-dose drug combination) of the compounds of the present invention, or can be applied to patients in one or more separate dosage formulations, which allow simultaneous or sequential administration of active agents (co-administration of separate active agents). Examples of additional active agents that may be employed include, but are not limited to, angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, mavipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists, also known as angiotensin receptor blockers or ARBs, which may be in free base, free acid, salt, or prodrug form, such as azilsartan, such as mesartan potassium Candesartan such as candesartan cilexetil Eprosartan such as eprosartan mesylate Irbesartan Losartan such as Losartan Potassium Olmesartan such as Olmesartan Medoxomil Telmisartan Valsartan and with thiazide-like diuretics such as hydrochlorothiazide (e.g. DIOVAN ATACAND ) etc.); potassium-sparing diuretics, such as amiloride hydrochloride, spironolactone, eplerenone, triamterene, each containing or not containing HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamide hemifumarate) SPP600, SPP630, and SPP635); endothelin receptor antagonists; vasodilators (e.g., sodium nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine, nicardipine); potassium channel activators (e.g., nicorandil, pinardipine); , serotonin, serotonin, minoxidil, aprilkalim, loprazolam); sympatholitics; beta-adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); alpha-adrenergic blocking drugs (e.g., doxazosin, prazosin, or alpha-methyldopa); central alpha-adrenergic agonists; peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors, such as simvastatin and lovastatin, which are used as lactone prodrugs and are marketed and act as inhibitors upon administration, as well as pharmaceutically acceptable salts of dihydroxy-open-acid HMG-CoA reductase inhibitors, such as atorvastatin (particularly as calcium salts sold), rosuvastatin (especially calcium salts sold), pravastatin (especially sodium salt) and fluvastatin (particularly as Cholesterol absorption inhibitors such as ezetimibe and any other lipid-lowering agent such as the HMG-CoA reductase inhibitors noted above, and in particular simvastatin or atorvastatin calcium; niacin in immediate or controlled release form, and particularly in combination with a DP antagonist such as laropiprant and / or an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifram, and niacin receptor partial agonists; metabolic altering agents, including insulin sensitizers and related compounds used to treat diabetes, such as biguanides (e.g., metformin), glinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also known as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitagliptin alogliptin, vildagliptin, saxagliptin, linagliptin, dulagliptin, gemagliptin), ergot alkaloids (e.g., bromocriptine), combination drugs such as (sitagliptin and metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; glucose uptake inhibitors, 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, togliflozin, LX-4211, canagliflozin, dapagliflozin, erpagliflozin, ipagliptin, repagliflozin and sogliflozin) and SGLT-3; or other drugs that are beneficial for preventing or treating the above-mentioned diseases, including but not limited to diazoxide; and including free acid, free base and pharmaceutically acceptable salt forms, prodrug forms such as esters, and salts of prodrugs of the above-mentioned medicinal agents, if chemically possible. The trade names of the drugs noted above are provided to illustrate the marketed forms of the active agents; such drugs may be used in separate dosage forms for simultaneous or sequential administration with the compounds of the invention, or the active agents therein may be used in fixed dose pharmaceutical combinations including the compounds of the invention.

[0107] Typical dosages of the plasma kallikrein inhibitors of the invention in combination with other suitable agents may be the same as those of the plasma kallikrein inhibitors administered without co-administration of the additional agents, or may be substantially lower than those of the plasma kallikrein inhibitors administered without co-administration of the additional agents, depending on the therapeutic needs of the patient.

[0108] The compound is administered to the mammal in a therapeutically effective amount. "Therapeutically effective amount" means an amount of a compound of the invention that, when administered to a mammal alone or in combination with another therapeutic agent, is effective to treat (ie, prevent, inhibit or ameliorate) a disease condition or treat the progression of a disease in the host.

[0109] The compounds of the present invention are preferably administered to mammals alone in a therapeutically effective amount. However, the compounds of the present invention may also be administered to mammals in a therapeutically effective amount in combination with another therapeutic agent as defined below. When administered in combination, the combination of compounds is preferably but not necessarily a synergistic combination. As described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, when the effect of the compound (in this case, the inhibition of the desired target) is greater than the cumulative effect of each compound when administered individually as a single agent, synergy occurs. In general, synergistic effects are most clearly demonstrated at suboptimal concentrations of the compound. Compared with individual components, synergy can be lower cytotoxicity, increased anticoagulant effect or some other beneficial effects of the combination.

[0110] "Administered in combination" or "combination therapy" means that the compound of the invention and one or more additional therapeutic agents are administered to the mammal to be treated simultaneously. When administered in combination, each component may be administered simultaneously or sequentially in any order at different time points. Thus, each component may be administered separately, but sufficiently close in time to provide the desired therapeutic effect. Administration of each component need not be via the same route of administration; for example, one component may be administered orally, while another component may be delivered into the vitreous of the eye.

[0111] The scope of the present invention is not limited by the specific embodiments disclosed in the examples, which are intended to be illustrations of several aspects of the present invention, and any embodiments that are functionally equivalent are within the scope of the present invention. In fact, various modifications of the present invention, other than those shown and described herein, will become apparent to those skilled in the relevant art, and are intended to fall within the scope of the appended claims.

[0112] General approach

[0113] The compounds of the present invention may be prepared using conventional techniques or according to the methods outlined in the following general synthetic schemes. Those skilled in the art may modify the procedures and reagents shown to obtain similar intermediates and / or final compounds.

[0114] NMR spectra were measured on a VARIAN or NMR Systems (400, 500 or 600 MHz). Chemical shifts are reported in ppm downfield and upfield from tetramethylsilane (TMS) and are referenced to internal TMS or solvent resonances ( 1 H NMR: About CDCl 3 δ7.27, about (CD 3 )(CHD 2 )SO δ 2.50, and 13 C NMR: About CDCl3 δ77.02, about (CD 3 ) 2 SO δ 39.51. Coupling constant (J) is expressed in Hertz (Hz), and spin multiplicity is given as s (singlet), d (doublet), dd (double doublet), t (triplet), m (multiplet) and br (broad peak). Chiral separation is performed on Waters Thar 80SFC or BergerMG II preparative SFC system. LC-MS data are recorded on SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, or Agilent 1100 series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instruments, using C18 columns, using MeCN gradients in water containing 0.02 to 0.1% TFA. UV detection is at 220 and / or 254nm, and ESI ionization is used for MS detection.

[0115] When chiral separation is realized by the chromatography using a chiral column, the chiral column for SFC chiral separation is listed in the table. Some chiral columns used are CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK AD-H and CHIRALPAK AS-H. After this, they will be referred to by their two-letter abbreviation or three-letter abbreviation. As a convention, the fast eluting isomer from chiral separation is always listed in the first place in the table, followed by the isomer from the slower eluting of the same separation. If more than two isomers are separated, they will always be listed in the table in the order of their elution, such as peak 1, followed by peak 2, peak 3, and the like. The * symbol near the chiral center in the structure represents that the chiral center is split by chiral separation, and its stereochemical configuration is not clearly determined.

[0116] In addition, TLC is thin layer chromatography; UV is ultraviolet light; W is watt; wt% is percentage by weight; xg is multiple of gravity; α D is the specific rotation of polarized light at 589nm; ℃ is Celsius; %w / v is the weight of the former reagent relative to the volume of the latter reagent; Hz is Hertz; cpm is counts per minute; δ H is chemical shift; d is doublet; dd is doublet of doublets; MHz is megahertz; MS is mass spectrum, and the mass spectrum obtained by ES-MS may be represented herein by “LC-MS”; m / z is mass-to-charge ratio; n is normal; N is normal; nm is nanometer; nM is nanomolar.

[0117] Several catalysts and ligands were used in the following procedures. "XANTPHOS" is also known as 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene. "XANTPHOS Pd G3" is also known as [(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II). "SPhos Pd G4" is also known as "(Methanesulfonato)-κO)[2'-(methylamino)-2-biphenyl]palladium-dicyclohexyl(2',6'-dimethoxy-2-biphenyl)phosphine (1:1)". "BrettPhos" is also known as 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and "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)]methanesulfonate palladium(II). "[Ir{dFCF 3 ppy} 2 (bpy)]PF 6 " is bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridinium][2-2'-bipyridyl]iridium hexafluorophosphate. These catalysts and ligands are available from Millipore Sigma.

[0118] For the purposes of this specification, the following abbreviations have the indicated meanings:

[0119] Ac Acetyl

[0120] acac Acetylacetone

[0121] ACN Acetonitrile

[0122] AcOH or HOAc Acetic acid

[0123] AIBN Azobisisobutyronitrile

[0124] aq. water-based

[0125] Ar Aryl

[0126] Bn Benzyl

[0127] Boc or BOC tert-butyloxycarbonyl

[0128] Br broad peak

[0129] Brettphos 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl

[0130] nBu Butyl

[0131] ℃ Celsius

[0132] calcd. Calculated

[0133] cBu cyclobutyl

[0134] Cbz benzyloxycarbonyl

[0135] cHep Cycloheptyl

[0136] cHex Cyclohexyl

[0137] cPen Cyclopentyl

[0138] cPr Cyclopropyl

[0139] d day

[0140] δ Chemical shift

[0141] d Doublet

[0142] DABCO 1,4-diazabicyclo[2.2.2]octane

[0143] DAST (Diethylamino)sulfur trifluoride

[0144] dba dibenzylideneacetone

[0145] DBAD Di-tert-butyl azodicarboxylate

[0146] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0147] DCE 1,2-Dichloroethane

[0148] DCM Dichloromethane

[0149] dd double doublet

[0150] ddd double doublet

[0151] DIAD Diisopropyl azodicarboxylate

[0152] DIBAL or Dibal-H Diisobutylaluminum hydride

[0153] DIEA or Hünig's base N,N-diisopropylethylamine

[0154] DIPA Diisopropylamine

[0155] DMA 1,2-Dimethylacetamide

[0156] DMAP 4-dimethylaminopyridine

[0157] DMF Dimethylformamide

[0158] DMP Dess-Martin periodinane (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one

[0159] DMPU 3,4,5,6-tetrahydro-2(1H)-pyrimidinone

[0160] DMS Dimethyl sulfide

[0161] DMSO Dimethyl sulfoxide

[0162] DPPA Diphenylphosphorylazide

[0163] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[0164] dt double triplet

[0165] DTT Dithiothreitol

[0166] DPy 2,2'-Bipyridine

[0167] dq double quartet

[0168] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0169] EDTA Ethylenediaminetetraacetic acid

[0170] equiv equivalent

[0171] ESI Electrospray ionization

[0172] Et Ethyl

[0173] EtOH

[0174] EtOAc Ethyl acetate

[0175] g

[0176] GST Glutathione S-transferase

[0177] h hour

[0178] HATU N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate

[0179] HMDS 1,1,1,3,3,3-Hexamethyldisilazane

[0180] HOBt 1-Hydroxybenzotriazole

[0181] HPLC High Performance Liquid Chromatography

[0182] Hz Hertz

[0183] IC 50 The concentration below which there is 50% inhibition

[0184] IPA Isopropyl Alcohol

[0185] iPr Isopropyl

[0186] J coupling constant

[0187] L Liter

[0188] LAH Lithium Aluminum Hydride

[0189] LC Liquid Chromatography

[0190] LCMS Liquid chromatography mass spectrometry

[0191] LDA Lithium diisopropylamide

[0192] LED Light Emitting Diode

[0193] M Mass

[0194] M Moore

[0195] m multiplet

[0196] mCPBA Meta-chloroperbenzoic acid

[0197] Me Methyl

[0198] MeOH Methanol

[0199] mg milligram

[0200] MHz Megahertz

[0201] min

[0202] μL microliter

[0203] mL milliliters

[0204] mmol millimole

[0205] MPLC Medium Pressure Liquid Chromatography

[0206] MS mass spectrometry

[0207] Ms Methylsulfonyl

[0208] MTBE Methyl tert-butyl ether

[0209] N Normal

[0210] NBS N-Bromosuccinimide

[0211] NMP 1-Methylpyrrolidone

[0212] NMR Nuclear Magnetic Resonance Spectroscopy

[0213] p Quintet

[0214] Ph Phenyl

[0215] PMB 4-methoxybenzyl

[0216] Pr Propyl

[0217] psi pounds per square inch

[0218] q quartet

[0219] qd double quartet

[0220] quin quintet

[0221] rac racemic mixture

[0222] RT or rt Room temperature (ambient, about 25°C)

[0223] s Singlet

[0224] satd. saturated

[0225] SEM 2-(Trimethylsilyl)ethoxymethyl

[0226] sxt sextet

[0227] SFC Supercritical Fluid Chromatography

[0228] S-Phos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0229] t Triple Peak

[0230] T3P Propylphosphonic anhydride

[0231] TBAF tert-Butylammonium fluoride

[0232] TBS or TBDMS tert-butyldimethylsilyl

[0233] td double triplet

[0234] TBDPS tert-Butyldiphenylsilyl

[0235] TBDPSCl tert-Butyldiphenylsilyl chloride

[0236] TBSCl tert-Butyldimethylsilyl chloride

[0237] tBu tert-butyl

[0238] tBu X-phos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0239] TEA Triethylamine 3 N)

[0240] Tf triflate

[0241] TFA Trifluoroacetic acid

[0242] TFAA Trifluoroacetic anhydride

[0243] THF Tetrahydrofuran

[0244] TLC Thin Layer Chromatography

[0245] TMS Trimethylsilyl

[0246] Tris(hydroxymethyl)aminomethane

[0247] Ts Tosyl(Toluenesulfonyl)

[0248] tt triple triplet

[0249] X-phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0250] Xantphos 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene

[0251] Overview

[0252] Unless otherwise stated, starting materials used were obtained from commercial sources, prepared in the examples or prepared as known in the literature.

[0253] Methods for preparing the compounds of the present invention are illustrated by the following schemes.

[0254] Plan AA

[0255]

[0256]

[0136] Scheme AA illustrates a synthetic sequence for preparing bisheteroaryl derivatives such as AA-6 from arenes AA-1 and alkylpyrazine-2-carboxylates such as AA-4. Deoxyfluorination of the aldehyde AA-1 provides AA-2. Boration of AA-2 by treatment with a trialkoxyborane such as AA-7 and a base such as LDA provides the boronate ester AA-3. Palladium-catalyzed cross-coupling of AA-3 with the halide AA-4 provides AA-5. Base-mediated hydrolysis or dealkylation of the AA-5 ester by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AA-6.

[0257] Plan AB

[0258]

[0259] Scheme AB illustrates a synthetic sequence for preparing bis-heteroaryl derivatives such as AB-6 from alkylpyrazine-2-carboxylates such as AB-1 and arenes AB-3. Palladium-catalyzed substitution of the halide AB-1 using reagents such as hexamethylditin provides the tin hydride AB-2. Iodination of AB-3 by treatment with a base such as LDA, 2,2,6,6-tetramethylpiperidinium lithium, or n-butyllithium and iodine provides AB-4. Palladium-catalyzed cross-coupling of AB-2 with the iodide AB-4 then provides AB-5. Base-mediated hydrolysis or dealkylation of the AB-5 ester by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AB-6.

[0260] Plan AC

[0261]

[0262] R is preferably Me or Et.

[0263] M' is any suitable metal salt, such as -MgBr or ZnBr.

[0264] Scheme AC illustrates the synthetic sequence for preparing bis-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 affords AC-3. Palladium-catalyzed cross-coupling of AC-3 with AC-4 (which can be an organometallic, organoborate, or organoboronate reagent) affords AC-5. Base-mediated hydrolysis or dealkylation of the AC-5 ester by treatment with reagents such as LiOH, NaOH, or LiI provides carboxylic acid AC-6.

[0265] Plan A-D.

[0266]

[0267] Scheme AD illustrates the synthetic sequence for the preparation of bisheteroaryl derivatives such as AD-10 from arene AD-1 and pyrazine AD-7. Bromination of AD-1 by treatment with a base such as LDA and a brominating agent such as 1,2-dibromo-1,1,2,2-tetrachloroethane AD-2 affords AD-3. Copper-catalyzed cross-coupling of AD-2 with potassium thioacetate affords the thioester AD-4. Treatment with an aqueous base such as NaOH and an alkylating agent such as methyl iodide converts the thioester AD-4 to the thioether AD-5, which is subsequently oxidized to the sulfoxide AD-6 by using an oxidizing agent such as m-CPBA. Palladium-catalyzed cross-coupling of the bromide AD-6 with tin hydride AD-7 affords AD-8. Using an oxidizing agent such as Oxidation of the sulfoxide of AD-8 affords the sulfone AD-9. Base-mediated hydrolysis or dealkylation of the AD-9 ester by treatment with reagents such as LiOH, NaOH, or LiI provides the carboxylic acid AD-10.

[0268] Plan AE.

[0269]

[0270] Scheme AE illustrates a synthetic sequence for preparing bisheteroaryl derivatives such as AE-5 from AE-1. Esterification of the carboxylic acid of AE-1 affords the tert-butyl ester AE-2. Oxidative cleavage of the methylene group of AE-2 by treatment with reagents such as osmium tetroxide and sodium periodate affords the aldehyde AE-3. Deoxyfluorination of AE-3 using reagents such as bis(2-methoxyethyl)aminosulfur trifluoride affords AE-4. Acid-mediated dealkylation of the AE-4 ester affords the carboxylic acid AE-5.

[0271] Plan AF.

[0272]

[0273] Scheme AF illustrates a synthetic sequence for preparing bis-heteroaryl derivatives such as AF-4 from AF-1 and alkyl trifluoroborate AF-2. Cross-coupling of AF-1 and AF-2 affords pyrazine AF-3 by treatment with a mixture of Ni salts / ligands such as nickel(II) chloride glycol dimethyl ether complex and 4,4'-di-tert-butyl-2,2'-bipyridine, and Ir complexes such as [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate. Base-mediated hydrolysis of the AF-3 ester affords carboxylic acid AF-4 by treatment with reagents such as LiOH or NaOH.

[0274] Solution AG.

[0275]

[0276] Scheme AG illustrates a synthetic sequence for preparing bis-heteroaryl derivatives such as AG-5 from pyridine AG-1 and arene AG-2. Palladium-catalyzed cross-coupling of bromide AG-1 with boronate AG-2 affords AG-3. Oxidation of AG-3 with an oxidizing agent such as mCPBA affords the N-oxide AG-4. Base-mediated hydrolysis of the AG-4 ester by treatment with a reagent such as LiOH provides the carboxylic acid AG-5.

[0277] Scheme AH.

[0278]

[0279] Scheme AH illustrates the synthetic sequence for preparing bis-heteroaryl derivatives such as AH-9 from pyridine AH-1 and arene AH-3. Substitution of chloropyrimidine AH-1 with (4-methoxyphenyl)methanol affords AH-2. Palladium-catalyzed cross-coupling of AH-2 and borate AH-3 affords AH-4. Oxidation of the thioether AH-4 affords the sulfone AH-5 by treatment with . Displacement of AH-5 with a cyanide source such as sodium cyanide provides 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 AH-8 ester affords the carboxylic acid AH-9 by treatment with reagents such as LiOH or NaOH.

[0280] Solution AI.

[0281]

[0282] Scheme AI illustrates a synthetic sequence for the preparation of bisheteroaryl derivatives such as AI-3.Amide cross-coupling of AI-1 with 1H-pyrazol-4-amine AI-2 provides amide AI-3.

[0283] Plan AJ.

[0284]

[0285] Scheme AJ illustrates a synthetic sequence for preparing bisheteroaryl derivatives such as AJ-7 from pyrazine AJ-1 and arene AJ-2. Palladium-catalyzed cross-coupling of bromide AJ-1 with borate AJ-2 affords AJ-3. Treatment of AJ-3 with copper(II) bromide affords AJ-4. Base-mediated hydrolysis of the AJ-4 ester by treatment with reagents such as LiOH provides carboxylic acid AJ-5. Nickel-catalyzed reductive cross-coupling of AJ-5 with oxirane AJ-6 provides lactone AJ-7.

[0286] Plan AK

[0287]

[0288] Scheme AK illustrates a synthetic sequence for preparing bis-heteroaryl derivatives such as AK-4 from intermediate AK-1. Bromination of AK-1 affords AK-2 by treatment with a mixture of reagents such as NBS and benzoyl peroxide. Treatment of AK-2 with alcohol AK-3 and a base such as sodium hydride affords ether AK-4.

[0289] Plan AL.

[0290]

[0291] Scheme AL illustrates a synthetic sequence for preparing bis-heteroaryl derivatives such as AL-5 from intermediate AL-1. Palladium-catalyzed carboxylation of AL-1 affords the methyl ester AL-2. Treatment of AL-2 with an organometallic reagent AL-3 such as an alkyl magnesium salt or a reducing agent such as lithium aluminum hydride or lithium aluminum deuteride affords the alcohol AL-4. Cyclization of AL-4 affords the lactone AL-5 by treatment with a coupling agent such as EDC.

[0292] Solution AM.

[0293]

[0294] Scheme AM illustrates a synthetic sequence for preparing bis-heteroaryl derivatives such as AM-3 from intermediate AM-1. Aldehyde AM-1 is trifluoromethylated to give AM-2 by treatment with a reagent such as (trifluoromethyl)trimethylsilane in the presence of trimethyl N-oxide. Acid-mediated dealkylation of the AM-2 ester provides the carboxylic acid AM-3.

[0295] Solution AN.

[0296]

[0297] Scheme AN ​​illustrates a synthetic sequence for preparing bisheteroaryl derivatives such as AN-7 from acetyl succinate AN-1 and arene AN-5. Condensation of AN-1 with hydrazine affords 6-oxo-tetrahydropyridazine AN-2, which is subsequently oxidized by treatment with a reagent such as bromine to afford dihydropyridazine AN-3. Treatment of AN-3 with a reagent such as phosphorus(V) oxybromide provides bromide AN-4. Palladium-catalyzed cross-coupling of bromide AN-4 with borate AN-5 affords AN-6. Base-mediated hydrolysis or dealkylation of the AN-6 ester by treatment with a reagent such as LiOH, NaOH, or LiI provides carboxylic acid AN-7.

[0298] Scheme BA

[0299]

[0300] Scheme BA illustrates a synthetic sequence for preparing alcohol derivatives such as BA-4 from azaheterocycles BA-1 or BA-2. Treatment of esters BA-1 or BA-2 with organometallic reagents such as alkyl magnesium salts or DIBAL affords ketones or aldehydes BA-3, which are subsequently converted to alcohols BA-4 by treatment with reducing agents such as sodium borohydride.

[0301] Plan BB.

[0302]

[0303] R' means Or you can convert it to Suitable groups

[0304] Scheme BB illustrates a synthetic sequence for the synthesis of alcohol derivatives such as BB-2 from aldehydes such as BB-1 via treatment with organometallic reagents such as alkyl magnesium salts.

[0305] Plan BC.

[0306]

[0307] R' means Or you can convert it to Suitable groups

[0308] Scheme BC illustrates a synthetic sequence 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 (for carboxylic acids).

[0309] Plan BD.

[0310]

[0311] Scheme BC illustrates the synthetic sequence for the synthesis of cyclopropanols such as BD-2 from esters such as BD-1 via treatment with titanium(IV) isopropoxide and ethylmagnesium bromide.

[0312] Plan BE.

[0313]

[0314] R' means Or you can convert it to Suitable groups

[0315] Scheme BE illustrates a synthetic sequence 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 provide alcohol BE-2, which is subsequently oxidized to aldehyde BE-3 with an oxidizing agent such as DMP. Conversion of the aldehyde of BE-3 with an organometallic reagent such as an alkylmagnesium bromide affords alcohol BE-4.

[0316] Plan BF.

[0317]

[0318] Scheme BF illustrates a synthetic sequence for synthesizing an alcohol such as BF-3 from a primary alcohol such as BF-1. Alcohol BF-1 is oxidized to aldehyde BF-2 using an oxidizing agent such as DMP. Aldehyde conversion of BF-2 with an organometallic reagent such as an alkylmagnesium bromide affords alcohol BF-3.

[0319] Scheme BG.

[0320]

[0321] Scheme BG illustrates a synthetic sequence for the synthesis of alcohols such as BG-5 from arenes or heteroarenes such as BG-1. Conversion of BG-1 using an oxidizing agent such as manganese dioxide provides aldehyde BG-2, which is treated with a deoxyfluorinating agent such as DAST to provide BG-3. A two-step sequence involving metal-halogen exchange affords alcohol BG-5 by addition of an organometallic reagent such as isopropylmagnesium bromide followed by quenching with the corresponding aldehyde BG-4.

[0322] Scheme BH

[0323]

[0324] Scheme BH illustrates a synthetic sequence for the synthesis of alcohols such as BH-3 from arenes or heteroarenes such as BH-1. Palladium-catalyzed cross-coupling of BH-1 with potassium vinyl trifluoroborate BH-2 or vinyl boronic acid pinacol ester BH-3 provides styrene BH-4. Hydration of BH-2 affords alcohol BH-3 by treatment with reagents such as cobalt(II) acetylacetonate and phenylsilane.

[0325] Solution BI.

[0326]

[0327] Scheme BI illustrates a synthetic sequence for the synthesis of alcohols such as BI-4 from aromatic or heteroaromatic hydrocarbons such as BI-1. Palladium-catalyzed cross-coupling of BI-1 with tri-n-butyltin hydride BI-2, followed by treatment with an acid such as aqueous HCl, provides ketone BI-3. Reduction of BI-3 using a reducing agent such as sodium borohydride provides alcohol BI-4.

[0328] Scheme BJ

[0329]

[0330] Scheme BJ illustrates a synthetic sequence for the synthesis of alcohols such as BJ-5 from chlorides such as BJ-1. Palladium-catalyzed cross-coupling of BJ-1 with potassium vinyl trifluoroborate BJ-2 provides styrene BJ-3. Oxidative cleavage of the vinyl group of 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.

[0331] Scheme BK.

[0332]

[0333] Scheme BK illustrates a synthetic sequence for the synthesis of 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, provides BK-3.

[0334] Scheme BL.

[0335]

[0336] Scheme BL illustrates a synthetic sequence for the synthesis of alcohols such as BL-4 from aromatic or heteroaromatic hydrocarbons such as BL-1. Nucleophilic aromatic substitution of BL-1 with sodium cyanide provides nitrile BL-2. Acid-mediated methanolysis of BL-2 provides ester BL-3. Reduction of BL-3 using a reducing agent such as sodium borohydride provides alcohol BL-4.

[0337] Plan BM.

[0338]

[0339] Scheme BM illustrates a synthetic sequence for synthesizing alcohols such as BM-3 from esters such as BM-1. Nucleophilic aromatic substitution of BM-1 with sodium methoxide provides the ether BM-2. Ester reduction of BM-2 using a reducing agent such as sodium borohydride provides the alcohol BM-3.

[0340] Scheme BN.

[0341]

[0342] Scheme BM illustrates a synthetic sequence for the synthesis of alcohols such as BN-5 from aromatic or heteroaromatic hydrocarbons such as BN-1. Sandmeyer-type halogenation of BN-1 by treatment with reagents such as tert-butyl nitrite, potassium iodide, and cuprous (I) iodide acid provides the iodide BN-2. Palladium-catalyzed cross-coupling of BN-2 with tri-n-butyltin hydride BN-3, followed by treatment with an acid such as aqueous HCl, provides the ketone BN-4. Reduction of BN-4 using a reducing agent such as sodium borohydride provides the alcohol BN-5.

[0343] Plan BO.

[0344]

[0345] Scheme BO illustrates a synthetic sequence for the synthesis of alcohols such as BO-5 from pyridones such as BO-1. Deoxychlorination of BO-1 using a reagent such as phosphorus oxychloride (V) affords the chloropyridine BO-2. Ester reduction of BO-2 by treatment with a reducing agent such as DIBAL provides the alcohol BO-3, which is subsequently oxidized to the aldehyde BO-4 with an oxidizing agent such as DMP. Aldehyde conversion of BO-4 with an organometallic reagent such as an alkylmagnesium bromide affords the alcohol BO-5.

[0346] Plan BP.

[0347]

[0348] Scheme BP illustrates a synthetic sequence for the synthesis of alcohols such as BP-5 from substituted pyridines such as BP-1. Ortholithiation quenched with a borate ester followed by an oxidative rearrangement affords phenol BP-2. Demethylation in the presence of a strong acid, preferably boron tribromide, HBr, etc., followed by capture with dibromomethane in the presence of a suitable weak base such as cesium carbonate, etc., yields a dioxolane such as BP-3. Wherein a lithium-halogen exchange followed by a quenched Villsmeyer condensation with a formyl donor such as DMF, etc., yields aldehyde BP-4, which can be reduced under mild conditions as described above in Scheme BO to afford alcohol BP-5.

[0349] Solution BQ.

[0350]

[0351] Scheme BQ illustrates a synthetic sequence for the synthesis of benzyl alcohols such as BQ-6 from substituted pyridines such as BQ-1. Demethylation following methods similar to those described above produces a catechol intermediate, which can be trapped with thiophosgene to provide a dioxolothione such as BQ-2. Activation with the above reagents such as dibromoimidazolodione thiocarbonate in the presence of a fluoride source such as HF / pyridine can provide a difluorodioxolane such as BQ-3. As shown below, Pd-catalyzed cross-coupling with [3.1.0]-lactam (AAA-6) can generate heteroaryl amide BQ-4, which can be reacted with a suitable brominating agent to provide BQ-5. Stille coupling with a vinyl tin hydride reagent such as tributyl(1-ethoxyvinyl)tin hydride under Pd catalysis, followed by reduction of the resulting ketone, can provide benzyl alcohol BQ-6, which can be converted to compounds of the present invention following the procedures described herein.

[0352] Scheme CA

[0353]

[0354] Scheme CA illustrates a five-step synthetic sequence for the synthesis of lactams such as CA-6 or thiolactams such as CA-7 from lactones such as CA-1. Acid-mediated transformation of CA-1 by treatment with benzylamine affords the imide CA-2. 4 The imide of CA-2 is reduced by treatment with t-butyl carbonate to provide the amine CA-3. The protecting group of CA-3 is converted to t-butyl carbamate by treatment with palladium and t-butyl carbonate under a hydrogen atmosphere to give CA-4. Oxidation of CA-4 with reagents such as ruthenium trichloride and sodium periodate gives the lactam CA-5. Deprotection of CA-5, for example, using an acid such as hydrogen chloride or TFA, gives the secondary amide CA-6. CA-6 can be directly carried forward to the thiolactam CA-7 by treatment with Lawes' reagent or the like.

[0355] Plan AAA.

[0356]

[0357] Scheme AAA illustrates a 5-step synthetic sequence for the synthesis of 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 provide intermediate AAA-4. Palladium or copper catalyzed cross-coupling of AAA-4 with AAA-5 or AAA-6 produces 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 provide amide AAA-10.

[0358] Scheme AAB.

[0359]

[0360] Scheme AAB illustrates a 5-step synthetic sequence for the synthesis of amide derivatives such as AAB-10 from tolyl derivatives such as AAB-1 and carboxylic acids such as AAB-9. Bromination of AAB-1 provides AAB-2, which is then 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 produces 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 provide amide AAB-10.

[0361] Scheme AAC.

[0362]

[0363] Scheme AAC illustrates a 4-step synthetic sequence for the synthesis of amide derivatives such as AAC-7 from alcohols such as AAC-1 and pyrazoles such as AAC-3. Alcohol AAC-1 is converted to the bromide AAC-2. Base-mediated nucleophilic substitution of AAC-2 by AAC-3 produces the pyrazole AAC-4. Thioether oxidation of AAC-4 gives the sulfone AAC-5, which is then coupled with the amide AAC-6 to provide the amide AAC-7.

[0364] Scheme AAD.

[0365]

[0366] Scheme AAD illustrates a 6-step synthetic sequence for the synthesis of 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 halide AAD-2. Base-mediated nucleophilic displacement of AAD-2 by AAD-3 produces pyrazole AAD-4. Thioether oxidation of AAD-4 gives sulfone AAD-5, which is then displaced with amide AAD-6 to provide 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 provide amide AAD-10.

[0367] Scheme AAE.

[0368]

[0369] Scheme AAE illustrates a 4-step synthetic sequence for the synthesis of 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 yields AAE-3. Palladium or copper catalyzed cross-coupling of AAE-3 and lactams AAE-4 or AAE-5 provides AAE-6. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAE-6 affords the amine AAE-7, which is then coupled with the acid AAE-8 to provide the amide AAE-9.

[0370] Scheme AAF.

[0371]

[0372] Scheme AAF illustrates a seven-step synthetic sequence for the synthesis of 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 produces AAF-3. Bromination of the pyridine AAF-3 using a reagent such as N-bromosuccinimide gives AAF-4. Palladium-catalyzed cross-coupling of the bromide AAF-4 with tri-n-butyltin hydride AAF-5 followed by aqueous acidic workup gives the ketone AAF-6. Reduction of AAF-4 with a reducing agent such as sodium borohydride gives the alcohol AAF-7. Mitsunobu coupling of AAF-7 with pyrazole AAF-8 gives AAF-9. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAF-9 afforded the amine AAF-10, which was then coupled with the acid AAF-11 to provide the amide AAF-12.

[0373] Scheme AAG.

[0374]

[0375] Scheme AAG illustrates a 4-step synthetic sequence 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 a SEM group, to give AAG-2. Oxidative cleavage of the vinyl group of AAG-2 by treatment with reagents such as osmium tetroxide and sodium periodate yields the aldehyde AAG-3. Reduction of AAF-3 with a reducing agent such as sodium borohydride yields the alcohol AAG-4. Removal of the protecting group of AAG-4 provides AAG-5.

[0376] Scheme AAH.

[0377]

[0378] Scheme AAH illustrates an 8-step synthetic sequence for the synthesis of alcohol derivatives such as AAG-5 from arenes or heteroarenes such as AAH-1. Palladium-catalyzed cross-coupling of the bromide AAH-1 with potassium vinyl trifluoroborate AAH-2 or vinyl boronic acid pinacol ester AAH-3 provides the styrene AAH-4. Palladium-catalyzed cross-coupling of AAH-4 with lactams AAH-5 or AAH-6 provides AAH-7. Vinyl dihydroxylation of AAH-7 using reagents such as osmium tetroxide and 4-methylmorphine N-oxide provides the diol AAH-8. Silylation of AAH-8 with reagents such as tert-butyl(chloro)diphenylsilane provides the alcohol AAH-9. Mitsunobu coupling of AAH-9 with the pyrazole AAH-10 produces AAH-11. The styrene AAH-11 can be obtained by reacting the styrene with, for example, platinum / H 2 Reduction of the nitro group of AAH-11 by treatment with ferric or ammonium chloride affords the amine AAH-12, which is then coupled with the acid AAH-13 to provide the amide AAH-14. Deprotection of the silyl ether of AAH-14 yields the alcohol AAH-15.

[0379] Scheme AAI.

[0380]

[0381] Scheme AAI illustrates a 7-step synthetic sequence for the synthesis of alcohol derivatives such as AAI-13 from pyrimidines such as AAI-1 and carboxylic acids AAI-11. Silver-mediated decarboxylative alkylation of AAI-1 with AAI-2 affords the ether AAI-3. Reduction of the ketone AAI-3 using a reducing agent such as sodium borohydride affords AAI-4. Mitsunobu coupling of AAI-4 with the pyrazole AAI-5 produces AAI-6. Palladium-catalyzed cross-coupling of AAI-6 with lactams AAI-7 or AAI-8 provides AAI-9. 2 Reduction of the nitro group of AAI-9 by treatment with ferric or iron / ammonium chloride affords the amine AAI-10, which is then coupled with the acid AAI-11 to provide the amide AAI-12. Deprotection of the tert-butyl ether of AAI-12 yields the alcohol AAI-13.

[0382] Scheme AAJ.

[0383]

[0384] R f This is why -N(R f ) 2 By R 7 Limited Group

[0385] Scheme AAJ illustrates a six-step synthetic sequence for the synthesis of amide derivatives such as AAJ-11 from pyrimidines such as AAJ-1 and carboxylic acids AAJ-10. A two-step sequence 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 produces AAJ-4. Nucleophilic substitution of pyrimidine AAJ-5 by amines or ammonium salts such as ammonium hydroxide produces AAJ-6. Palladium-catalyzed cross-coupling of AAJ-6 with lactam AAJ-7 provides AAI-8. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAJ-8 affords the amine AAJ-9, which is then coupled with the acid AAJ-10 to provide the amide AAJ-11.

[0386] Scheme AAK.

[0387]

[0388] p is a group such that -ppO- can be formed by R 4 Represent or convert to R 4

[0389] Scheme AAK illustrates an 8-step synthetic sequence for the synthesis of amide derivatives such as AAK-13 from alcohol AAK-1 and carboxylic acid AAK-11 or lactone AAK-12. Alcohol AAK-1 is converted to halide AAK-2. Base-mediated nucleophilic substitution of AAK-2 by AAK-3 produces pyrazole AAK-4. 2 Treatment with ferric or ammonium chloride reduces the nitro group of AAK-4 to give the amine AAK-5, which is then protected as the tert-butyl carbamate to provide AAK-6. Oxidation of the thioether of AAK-6 gives the sulfone AAK-7, which is then substituted with the lactam AAK-8 to provide AAK-9. Removal of the Boc protecting group of AAK-10 gives the amine AAK-11, which is then coupled with the acid AAK-11 or the lactone AAK-12 to provide the amide AAK-13.

[0390] Solution AAL.

[0391]

[0392] Scheme AAL illustrates a 4-step synthetic sequence for the synthesis of amide derivatives such as AAL-10 from alcohols such as AAL-1 and carboxylic acid AAL-9. Mitsunobu coupling of AAL-1 with triazole AAL-2 produces regioisomers AAL-3, AAL-4, and AAL-5. Palladium-catalyzed cross-coupling of AAL-3 or AAL-4 with lactam AAL-6 provides AAL-7. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAL-7 afforded the amine AAL-8, which was then coupled with the acid AAL-9 to provide the amide AAL-10.

[0393] Scheme AAM.

[0394]

[0395] Scheme AAM illustrates a 4-step synthetic sequence for the synthesis of 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 provides lactam AAM-3. Mitsunobu coupling of AAM-3 with pyrazole AAM-4 produces AAM-5. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAM-5 afforded the amine AAM-6, which was then coupled with the acid AAM-7 to provide the amide AAM-8.

[0396] Scheme AAN.

[0397]

[0398] Scheme AAN illustrates a 1-step synthetic sequence for the synthesis of amine derivatives such as AAN-2 from carbamates such as AAN-1. Tert-butyl carbamate deprotection of AAN-1 yields AAN-2.

[0399] Scheme AAO.

[0400]

[0401] Scheme AAO illustrates a 2-step synthetic sequence for synthesizing alcohol derivatives such as AAO-3 from amines AAO-1- and tert-butyl ethers such as AAO-2. Amide coupling of AAO-1- and AAO-2 provides amide AAO-3. Deprotection of AAO-3 provides alcohol AAO-4.

[0402] Program AAP.

[0403]

[0404] R d and R eAAP-5 is allowed Group

[0405] Scheme AAP illustrates a 3-step synthetic sequence for the synthesis of amide derivatives such as AAP-6 from amines such as AAP-1 and carboxylic acids such as AAP-2. AAP-1 is coupled with the amide of AAP-2 to give AAP-3, which is then treated with an oxidizing agent such as Treatment with mCPBA or mCPBA afforded the sulfone AAP-4. Nucleophilic aromatic substitution of AAP-4 with the amine AAP-5 gave AAP-6.

[0406] Scheme AAQ.

[0407]

[0408] Scheme AAQ illustrates a 2-step synthetic sequence 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 provides AAQ-3. Transition metal-mediated hydration of the AAQ-3 olefin by treatment with reagents 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 in some cases the hydrogenated product AAQ-5. Alternatively, AAQ-5 can be generated directly from AAQ-3 by reaction in the presence of a suitable reducing agent such as Raney nickel.

[0409] Scheme AAR.

[0410]

[0411] Scheme AAR illustrates a seven-step synthetic sequence for the synthesis of 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 and lactam AAR-2 produces AAR-3. Palladium-catalyzed cross-coupling of the bromide AAR-3 with potassium vinyl trifluoroborate AAR-4 gives AAR-5. Oxidative cleavage of the vinyl group of AAR-5 by treatment with reagents such as osmium tetroxide and sodium periodate gives the aldehyde AAR-6. Reduction of AAR-6 with a reducing agent such as sodium borohydride gives the alcohol AAR-7. Mitsunobu coupling of AAR-7 with pyrazole AAR-8 gives AAR-9. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAR-9 afforded the amine AAR-10, which was then coupled with the acid AAR-11 to provide the amide AAR-12.

[0412] Scheme AAS

[0413]

[0414] Scheme AAS illustrates the synthetic sequence for the synthesis of amide derivatives such as AAS-11 from alkyl trifluoroborate such as AAS-4 and aryl or heteroaryl halides such as AAS-5. Nucleophilic substitution of the iodide AAS-1 by the pyrazole AAS-2 affords the adduct AAS-3. Treatment of the borate AAS-3 with potassium bifluoride affords the alkyl trifluoroborate AAS-4. Visible light-promoted iridium photoredox and nickel-catalyzed cross-coupling of AAS-4 and AAS-5 dually produces AAS-6. Palladium-catalyzed cross-coupling of AAS-6 with the lactam AAS-7 affords AAS-8. Acid-mediated removal of the protecting group of AAS-9 affords the amine AAS-7, which is then coupled with the acid AAS-10 to provide the amide AAS-11.

[0415] Scheme AAT.

[0416]

[0417] Scheme AAT illustrates a 4-step synthetic sequence for the synthesis of 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 by treatment with diphenyl(vinyl)sulfonium salt AAT-2 and DBU affords the cyclopropane AAT-3. Palladium-catalyzed cross-coupling of AAT-3 and lactam AAT-4 produces AAT-5. 2 Or treatment with iron / ammonium chloride, reduction of the nitro group of AAT-5 afforded the amine AAT-6, which was then coupled with the acid AAT-7 to provide the amide AAT-8.

[0418] Scheme AAU.

[0419]

[0420] Scheme AAU illustrates a nine-step synthetic sequence for the synthesis of 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 by treatment with sodium methoxide affords the methyl ether AAU-2. Palladium-catalyzed cross-coupling of AAU-2 with tri-n-butyltin hydride AAU-3, followed by treatment with an acid such as aqueous HCl, provides 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 produces AAU-7. Demethylation of the ether AAU-7 with a reagent such as boron tribromide affords the alcohol AAU-8. Base-mediated alkylation of AAU-8 by treatment with sodium chlorodifluoroacetate affords the difluoromethyl ether AAU-9. Palladium-catalyzed cross-coupling of AAU-9 and the lactam AAU-10 affords AAU-11. 2Or treatment with iron / ammonium chloride, reduction of the nitro group of AAU-11 afforded the amine AAU-12, which was then coupled with the acid AAU-13 to provide the amide AAU-14.

[0421] Protocol AAV.

[0422]

[0423] Scheme AAV illustrates a 2-step synthetic sequence for the synthesis of amide derivatives such as AAV-4 from amines such as AAV-1 and lactones AAV-2. Treatment of AAV-1 and AAV-2 with reagents such as trimethylaluminum yields AAV-3. Tert-butylation of the alcohol AAV-3 provides AAV-4.

[0424] Intermediate AA-6a

[0425]

[0426] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (Scheme AA)

[0427] Step 1. 1-Chloro-4-(difluoromethyl)-2-fluorobenzene: Under nitrogen atmosphere, to a solution of 4-chloro-3-fluorobenzaldehyde (300 g, 1.89 mmol) in DCM (1.5 L) cooled to 0°C, bis(2-methoxyethyl)aminosulfur trifluoride (456 mL, 2.08 mol) was added dropwise to the mixture. The reaction mixture was stirred at rt for 12 hours. The resulting mixture was slowly poured into an ice-water solution and then extracted with DCM. The organic layers were combined and washed with brine, and then heated to 40 ℃ for 12 hours. The mixture was stirred for 12 hours at rt. The mixture was stirred for 12 hours at 40 ℃ for 12 hours. The mixture was stirred for 12 hours at 40 ℃ for 12 hours. The organic layers were combined and washed with brine, and then heated to 40 ℃ for 20 minutes. The mixture was stirred for 20 minutes. The mixture was stirred for 20 minutes. The mixture was stirred for 20 minutes. 2 SO 4 The resulting mixture was dried over medium and concentrated under reduced pressure to provide the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ7.53 (t, J=8.0Hz, 1H), 7.34 (d, J=9.6Hz, 1H), 7.27 (d, J=9.2Hz, 1H), 6.64 (t, J=56Hz, 1H).

[0428] Step 2. 2-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane Borane (dioxaborolane): Under nitrogen atmosphere, LDA (997 mL, 1.99 mol, 2M THF solution) was added dropwise to a solution of 1-chloro-4-(difluoromethyl)-2-fluorobenzene (300 g, 1.66 mol) in THF (1.8 L) cooled to -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes, and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (508 mL, 2.49 mol) was added dropwise to the mixture. The reaction mixture was stirred at -78 ° C for 30 minutes, and then saturated NH 4 Cl aqueous solution.

[0429] The resulting mixture was filtered and then extracted with EtOAc. The organic layers were combined and washed with brine and concentrated in Na 2 SO 4 The resulting mixture was dried over medium and concentrated under reduced pressure to provide the title compound. 1 HNMR (400 MHz, CDCl 3 ) δ7.53 (t, J=8.0Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.02 (t, J=56Hz, 1H), 1.39 (s, 12H).

[0430] Step 3. Methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: The reaction was carried out in two parallel containers on an equivalent scale as specified. Under a nitrogen atmosphere, 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (11.3g, 13.8mmol) was added to a solution of 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127g, 415mmol), 6-bromopyrazine-2-carboxylic acid methyl ester (60.0g, 276mmol) and potassium fluoride (48.2g, 829mmol, 19.4mL) in a mixture of dioxane (720mL) and water (120mL). The reaction mixture was stirred at 120°C for 12 hours. The reaction mixtures from the two reactions carried out in parallel were cooled to rt, combined, and then concentrated under reduced pressure. The crude residue was suspended in EtOAc, and the resulting mixture was filtered. The filtrate was washed with water, brine, and concentrated in Na 2 SO 4 The resulting mixture was dried over medium and concentrated under reduced pressure to provide the title compound. 1 HNMR (400 MHz, CDCl 3 ) δ9.36 (s, 1H), 8.96 (d, J = 2.8Hz, 1H), 7.65 (t, J = 8.4Hz, 1H), 8.56 (d, J = 8.4Hz, 1H), 6.99 (t, J = 56Hz, 1H), 4.06 (s, 3H).

[0431] Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid:At 10-20 ℃, to 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester (350g, 1.11mol) in EtOH (1.75L), sodium hydroxide aqueous solution (2.10L, 2.10mol, 1M aqueous solution) was added. The reaction mixture was stirred at rt for 30 minutes, then concentrated under reduced vacuum (to remove EtOH). The crude residue was extracted with MTBE. The organic layer was discarded, and the pH of the water layer was adjusted to 2-3 by adding 2N HCl aqueous solution. The resulting mixture was filtered, and the filter cake was dried to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ13.9 (br s, 1H), 9.28 (s, 1H), 9.14 (s, 1H), 7.98 (t, J = 8.0Hz, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.02 (t, J = 56Hz, 1H).

[0432] Intermediate AA-6b

[0433]

[0434] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid (Scheme AA)

[0435] Step 3. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid methyl ester: Under nitrogen atmosphere, to 6-chloro-3-methylpyrazine-2-methylformate (25.0g, 134mmol) and potassium phosphate (85.6g, 403mmol) in THF (500mL) solution, add 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride (8.75g, 10.7mmol). The reaction mixture is heated to 70 ° C, and 2- (3-chloro-6- (difluoromethyl) -2-fluorophenyl) -4,4,5,5-tetramethyl -1,3,2-dioxaborolane (41.1g, 134mmol) is added. The resulting mixture is stirred at 70 ° C for 15 hours. The reaction mixture is cooled to rt, filtered and concentrated under reduced pressure. The crude residue is purified by silica gel chromatography (10: 1 petroleum ether / EtOAc) to provide the title compound. MS: 331 [M + 1] + . 1 H NMR (400 MHz, CDCl 3 )δ8.84 (d, J=3.1Hz, 1H), 7.68–7.56 (m, 2H), 7.02 (t, J=55.3Hz, 1H), 4.03 (d, J=3.5Hz, 3H), 2.96 (s, 3H).

[0436] Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylic acid:The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. MS: 317 [M+1] + . 1 HNMR (400 MHz, CD 3 OD) δ8.86 (d, J=2.6Hz, 1H), 7.86-7.77 (m, 1H), 7.65 (d, J=8.5Hz, 1H), 7.04 (t, J=55.0Hz, 1H), 2.92 (s, 3H).

[0437] Intermediate AB-6a

[0438]

[0439] 6-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid (Scheme AB)

[0440] Step 1. 6-(Trimethylated)pyrazine-2-carboxylic acid methyl ester: In a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (1.07 g, 0.922 mmol) was added to a solution of methyl 6-bromopyrazine-2-carboxylate (4.00 g, 18.4 mmol) and hexamethyltin dihydride (9.27 g, 28.3 mmol) in toluene (50.0 mL). The reaction mixture was stirred at 80 ° C for 12 hours. The mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5: 1 petroleum ether / EtOAc) to provide the title compound. MS = 303.0 [M + 1] + .

[0441] Step 2. 1-Chloro-2-fluoro-3-iodo-4-(trifluoromethyl)benzene: Under nitrogen atmosphere, 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, n-butyl lithium (757 mL, 1.89 mol, 2.5 M in hexane) was added dropwise to the mixture. The reaction mixture was stirred at -78°C for 1 hour, and then a solution of iodine (481 g, 1.89 mol) in THF (2.25 L) was added dropwise to the mixture (duration of addition = 2 hours). The reaction mixture was stirred at -78°C for 1 hour, and then allowed to warm to -20°C. The reaction mixture was stirred by adding saturated NH 4 The mixture was quenched with aqueous Cl solution. The resulting mixture was extracted with EtOAc. The organic layers were combined and washed with water and brine. 2 SO 4 Dry over medium and concentrate under reduced pressure to provide the title compound. MS 324 [M+1] + .

[0442] Step 3. 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid methyl ester:Under nitrogen atmosphere, to a mixture of 6-(trimethylstannyl)pyrazine-2-carboxylic acid methyl ester (1.11 g, 3.70 mmol), 1-chloro-2-fluoro-3-iodo-4-(trifluoromethyl)benzene (800 mg, 2.47 mmol) in toluene (20 mL), 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 rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (1: 0 to 5: 1 petroleum ether / EtOAc) to provide the title compound. MS=335.2[M+1] + .

[0443] Step 4. 6-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrazine-2-carboxylic acid: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. MS = 321.2 [M+1] + .

[0444] Table 1. The following compounds were prepared using procedures similar to those described for intermediate AB-6a using appropriate starting materials.

[0445]

[0446] Intermediate product AC-6a

[0447]

[0448] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid (Scheme AC)

[0449] Step 1. 3-Chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester: To a solution of 6-bromo-3-chloropyrazine-2-carboxylic acid methyl ester (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) was added 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (518 mg, 0.795 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 40 °C for 1.5 hours. The reaction mixture was cooled to rt 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 and washed with brine and heated to 40 °C for 1.5 hours. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (1:0 to 10:1 petroleum ether / EtOAc) to provide the title compound. MS: 351.0 [M+1] + .

[0450] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid methyl ester: Under nitrogen atmosphere, at rt, to a solution of 3-chloro-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester (100 mg, 0.285 mmol) in toluene (4 mL), triethylaluminum (0.854 mL, 0.854 mmol, 1.0 M hexane solution) and tetrakis(triphenylphosphine)palladium (32.9 mg, 28.0 μmol) were added. The reaction mixture was stirred at 80 ° C for 16 hours, then cooled to rt and concentrated under reduced vacuum. 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 and washed with brine (20 mL) and concentrated in Na 2 SO 4 The mixture was dried over medium, 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] + .

[0451] Step 3. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethylpyrazine-2-carboxylic acid: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. 2 SO 4 Aqueous solution MS: 331.0 [M+1] + .

[0452] Table 2. The following compounds were prepared using procedures similar to those described for intermediate AC-6a using appropriate starting materials.

[0453]

[0454] Intermediate product AD-10a

[0455]

[0456] 6-(3-Chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid (Scheme AD)

[0457] Step 12-Bromo-4-chloro-3-fluoro-1-iodobenzene: Under nitrogen atmosphere, at -70 ° C, to a mixture of 1-chloro-2-fluoro-4-iodobenzene (4g, 15.6mmol) in THF (50.0mL), LDA (8.58mL, 17.2mmol, 2M THF solution) was added dropwise. The reaction mixture was stirred at -70 ° C for 30 minutes, and then a THF (10mL) solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (6.10g, 18.7mmol) was added dropwise. The resulting mixture was stirred at -70 ° C for 20 minutes, then allowed to warm to 10 ° C and stirred for another 1 hour. The reaction mixture was heated to 40 ° C by adding saturated NH 4 The solution was quenched with aqueous Cl and water, and then extracted with EtOAc. The combined organic layers were stirred for 2 h at 4 °C for 1 h. 2 SO 4 Dry over 400 °C, filter and concentrate under reduced pressure.The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ7.11 (dd, J=8.4, 6.9Hz, 1H), 7.60 (dd, J=8.6, 1.6Hz, 1H).

[0458] Step 2 S-(2-bromo-4-chloro-3-fluorophenyl)thioacetate: Under nitrogen atmosphere, to a solution of 2-bromo-4-chloro-3-fluoro-1-iodobenzene (5.00 g, 14.9 mmol) in toluene (30.0 mL), potassium thioacetate (2.55 g, 22.4 mmol), cuprous iodide (I) (284 mg, 1.49 mmol) and 1,10-phenanthroline (269 g, 1.49 mmol) were added. The resulting mixture was stirred at 90 ° C for 16 hours. The reaction mixture was cooled to rt, filtered and then diluted with water and extracted with EtOAc. The organic layers were combined and washed with brine, then heated to 40 ° C for 16 hours. 2 SO 4 Dry over 400 °C, filter and concentrate under reduced pressure.The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ7.41 (dd, J=8.6, 7.0Hz, 1H), 7.30 (dd, J=8.6, 1.6Hz, 1H), 2.47 (s, 3H).

[0459] Step 3. (2-Bromo-4-chloro-3-fluorophenyl)(methyl)sulfane:To a solution of S-(2-bromo-4-chloro-3-fluorophenyl)thioacetate (2.40 g, 8.46 mmol) in EtOH (10.0 mL) was added NaOH (2.5 mL, 25.4 mmol, 10 M aqueous solution) followed by iodomethane (4.81 g, 33.9 mmol). 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 and concentrated in Na 2 SO 4 Dry over 400 °C, filter and concentrate under reduced pressure.The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ7.33 (dd, J=7.0, 8.6Hz, 1H), 6.85 (dd, J=1.4, 8.8Hz, 1H), 2.48 (s, 3H).

[0460] 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 rt for 1 hour and then concentrated by the addition of saturated Na 2 SO 3 The resulting mixture was stirred at rt for 30 minutes, then diluted with water and extracted with EtOAc. The organic layers were combined and washed with brine and then heated to 40 ℃ for 10 minutes. 2 SO 4 The crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to provide the title compound. 1 H NMR (400 MHz, CDCl 3 )δ7.72–7.67(m, 1H), 7.65–7.59(m, 1H), 2.84–2.79(m, 3H).

[0461] Step 5. Methyl 6-(3-chloro-2-fluoro-6-(methylsulfinyl)phenyl)-3-methylpyrazine-2-carboxylate:To a solution of 6-(trimethylstannyl)pyrazine-2-carboxylic acid methyl ester (332mg, 1.11mmol) and 2-bromo-4-chloro-3-fluoro-1-(methylsulfinyl)benzene (200mg, 0.737mmol) in dioxane (3.0mL), 1,1'-bis(di-tert-butylphosphino)ferrocene (34.9mg, 74.0μmol) and tris(dibenzylideneacetone)dipalladium (60mg, 74μmol) were added. The reaction mixture was stirred at 90 °C for 15 hours under a nitrogen atmosphere. The mixture was cooled to rt, filtered and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:1 petroleum ether / EtOAc) to provide the title compound. MS=328.9[M+1] + .

[0462] Step 6. 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid methyl ester: To 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 (150mg, 0.243mmol). The resulting mixture was stirred at rt for 16 hours. The mixture was diluted by adding 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. 1 H NMR (400 MHz, CDCl 3 ) δ9.35 (s, 1H), 8.92 (d, J=2.5Hz, 1H), 8.01 (dd, J=1.5, 8.6Hz, 1H), 7.75 (dd, J=6.9, 8.6Hz, 1H), 4.03 (s, 3H), 3.41 (s, 3H).

[0463] Step 7. 6-(3-Chloro-2-fluoro-6-(methylsulfonyl)phenyl)-3-methylpyrazine-2-carboxylic acid: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. MS = 330.9 [M+1] + .

[0464] Intermediate product AE-5

[0465]

[0466] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylic acid (Scheme AE)

[0467] Step 1. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-vinylpyrazine-2-carboxylate:To 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 rt for 2 hours. The reaction mixture was heated to 40 ℃ by adding saturated NaHCO 3 The aqueous solution was quenched and extracted with EtOAc. The organic layers were combined and 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0-15% EtOAc / petroleum ether) to provide the title compound. MS = 385.0 [M+1] + .

[0468] 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 in water, 0.991 mL, 78.0 μmol) and sodium periodate (334 mg, 1.56 mmol). The mixture was stirred at rt for 2 hours and then heated to room temperature by adding saturated Na 2 S 2 O 3 The resulting mixture was stirred at rt for 15 minutes and then extracted with EtOAc. The organic layers were combined and stirred at RT for 15 minutes. 2 SO 4 Dry over medium and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to provide the title compound. MS = 330.9 [M+1-56] + .

[0469] Step 3. tert-Butyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylate: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 1. MS = 409.0 [M+1] + .

[0470] Step 4. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)pyrazine-2-carboxylic acid: To 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 rt for 2 hours and then concentrated under reduced pressure to provide the title compound. MS=352.9[M+1] + .

[0471] Intermediate product AF-4a

[0472]

[0473] 3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid (Scheme AF)

[0474] 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 minutes. The mixture was then concentrated under reduced pressure (to remove THF). In a nitrogen-filled glove box, potassium dihydrogen 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'-bipyridyl-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C] iridium (III) hexafluorophosphate (Ir(dFCF 3 ppy) 2 PF 6 , 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 for 72 hours in front of a single 23WCFL. The reaction mixture was poured into a mixture of water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine and heated to 40 ℃ for 10 minutes. 2 SO 4 Dry over medium and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound. MS=403.1[M+1] + .

[0475] Step 2. 3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. Aqueous MS = 389.1 [M+1] + .

[0476] Table 3. The following compounds were prepared using procedures similar to those described for intermediate AF-4a using appropriate starting materials.

[0477]

[0478] Intermediate product AG-5a

[0479]

[0480] 3-Carboxy-5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyridine 1-oxide (Scheme AG)

[0481] Step 1. 5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)nicotinate: To a solution of 5-bromonicotinoic acid methyl ester (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), 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (15.1 mg, 23.0 μmol) was added. The reaction mixture was then heated at 80 ° C for 30 minutes in a microwave reactor and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound. MS=315.9[M+1] + .

[0482] 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) at rt was added mCPBA (42.6 mg, 0.190 mmol). The reaction mixture was stirred at rt 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 and washed with brine and concentrated in Na 2 SO 4 Dry over medium and concentrate under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 27%, end B 57%) to provide the title compound. MS = 332.0 [M+1] + .

[0483] Step 3. 3-Carboxy-5-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyridine 1-oxide: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. MS = 318.0 [M+1] + .

[0484] Intermediate product AH-8

[0485]

[0486] 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid (Scheme AH)

[0487] 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 portionwise sodium hydride (60% dispersion in mineral oil, 2.05 g, 51.3 mmol) under nitrogen at 0°C. The resulting mixture was stirred at 0°C for 1 hour and at rt for 2 hours. The reaction mixture was stirred by adding saturated NH 4 The solution was quenched with aqueous Cl solution and then extracted with EtOAc. The organic layers were combined and washed with water and brine, then with Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0-5% EtOAc / petroleum ether) to provide the title compound. MS = 297.0 [M+1] + .

[0488] 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 methanesulfonic acid (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 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 and extracted with EtOAc. The organic layers were combined and 2 SO 4 Dry over medium and concentrate under reduced vacuum. The crude residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to provide the title compound. MS=441.1 [M+1] + .

[0489] Step 3. 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)- Acyl) 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 (36.3 g, 59.0 mmol). The reaction mixture was stirred at rt for 14 hours. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine, then heated to 40 °C for 2 h. 2 SO 4 Dry over medium, filter and concentrate under reduced vacuum. The crude residue was purified by silica gel chromatography (25-100% EtOAc / petroleum ether) to provide the title compound. MS = 473.1 [M+1] + .

[0490] Step 4. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)pyrimidine-2-carboxylate Nitrile: 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 rt for 14 hours and then diluted with EtOAc. The organic layer was washed with water and brine and then washed with Na 2 SO 4 Dry over medium, filter and concentrate under reduced vacuum. The crude residue was purified by silica gel chromatography (0-15% EtOAc / petroleum ether) to provide the title compound. MS = 420.1 [M+1] + .

[0491] Step 5. 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-hydroxypyrimidine-2-carboxylic acid methyl ester: A solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-((4-methoxybenzyl)oxy)pyrimidine-2-carbonitrile (900 mg, 2.14 mmol) in 4M methanolic HCl (15 mL) was stirred at rt for 20 hours. Triethylamine was added to the reaction mixture to quench the acid, which was then concentrated under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 41%, end B 62%) to provide the title compound. MS=333.0[M+1] + .

[0492] Step 6. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylate Methyl ester:At rt, to a solution of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-2-carboxylic acid methyl ester (25.0 mg, 75.0 μmol) in a mixture of DCM (1.0 mL) and MeOH (0.1 mL), (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 0.400 mL, 0.800 mmol) was added. After the addition was complete, the reaction mixture was stirred for 1 hour, 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 provide the title compound. MS=347.0[M+1] + .

[0493] Step 7. 4-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-2-carboxylate acid : The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. MS = 332.9 [M+1] + .

[0494] Intermediate AI-3a

[0495]

[0496] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl- N -(1 H -pyrazol-4-yl)pyrazine-2-carboxamide (Solution AI)

[0497] At 0 ° C, to 6- (3-chloro-6- (difluoromethyl) -2-fluorophenyl) pyrazine-2-carboxylic acid (1.50g, 4.96mmol) and 1H-pyrazole-4-amine (0.618g, 7.43mmol) in DCM (20.0mL) solution, add 1-propanephosphonic anhydride (5.90mL, 9.91mmol), followed by DIEA (3.46mL, 19.8mmol). Allow the reaction mixture to warm up to rt and stir for 2 hours. The reaction mixture is diluted with saturated aqueous sodium carbonate and extracted with DCM. The organic layers are combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by silica gel chromatography (0 to 100% EtOAc / hexane) to provide the title compound. MS 382.0 [M + 1] + .

[0498] Table 4. The following compounds were prepared using procedures similar to those described for intermediate AI-3a using appropriate starting materials.

[0499]

[0500] Intermediate product AJ-7a

[0501]

[0502] 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5-(4-(2-fluorophenyl)-1-yl)-1-nitropropene H -pyrano[3,4-b] ... Oxazine-5-one (Scheme AJ)

[0503] Step 1. 3-amino-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester: The title compound was prepared following a similar procedure as described above in Intermediate AA-6b, Step 1. MS = 332.1 [M+1] + .

[0504] Step 2. 3-bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester: 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, 3-amino-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester (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 rt, and then water was added. The resulting mixture was extracted with EtOAc. The organic layers were combined and heated to 40 ° C for 16 hours. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 15% EtOAc / petroleum ether) to provide the title compound. MS = 396.9 [M+1] + .

[0505] Step 3. 3-Bromo-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. 1 H NMR (400 MHz, CD 3 OD) δ8.74 (d, J=2.4Hz, 1H), 7.80 (t, J=7.8Hz, 1H), 7.62 (d, J=8.6Hz, 1H), 6.95 (t, J=54.8Hz, 1H). MS=380.8, 382.8[M+1] + .

[0506] Step 4. 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5-(4-(2-fluorophenyl)-1-yl)-1-nitropropene H -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 rt for 12 hours. The mixture was concentrated under reduced pressure and purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 33%, end B 63%) to provide the title compound. MS=357.0[M+1] + .

[0507] Intermediate AK-4a

[0508]

[0509] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropyloxymethyl)pyrazine-2-carboxylic acid (Scheme AK)

[0510] Step 1. Methyl 3-(bromomethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylate: To methyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxylate (20 mg, 0.060 mmol), NBS (12 mg, 0.067 mmol) in CCl 4 To the (1.0 mL) solution, benzoyl peroxide (2.9 mg, 0.012 mmol) was added. The mixture was stirred at 80°C for 8 hours. The reaction mixture was concentrated under reduced pressure to provide the title compound. MS = 410.9 [M+1] + .

[0511] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropyloxymethyl)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% in dispersed oil, 5.3 mg, 0.22 mmol) was added, and the mixture was stirred at rt for 30 minutes. Then, a solution of 3-(bromomethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxylic acid methyl ester (30 mg, 0.073 mmol) in THF (0.8 mL) was added to the reaction mixture. The resulting mixture was stirred at rt for 12 hours. Saturated NH 4 Cl aqueous solution, and the mixture was extracted with EtOAc. The organic layers were combined and washed with brine, 2 SO 4Dry over medium, filter and concentrate 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 provide the title compound. MS = 372.9 [M+1] + .

[0512] Intermediate AL-5a

[0513]

[0514] 3-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethylfuran[3,4-b]pyrazin-5(7H)-one (square Case AL)

[0515] Step 1. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxycarbonyl)pyrazine-2-carboxylic acid: To 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 nitrogen atmosphere, 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (57.5 mg, 79.0 μmol) was added. The reaction mixture was stirred at 50 °C under CO (50 psi) atmosphere for 4 hours. The mixture was cooled to rt and filtered, then analyzed by preparative TLC (SiO 2 , 20% methanol / DCM) to provide the title compound. MS=360.9[M+1] + .

[0516] 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., methylmagnesium chloride (0.055 mL, 0.17 mmol) was added. The mixture was stirred at 0° C. for 5 minutes and then heated to room temperature by adding saturated NH 4 The resulting mixture was diluted by adding ACN (3 mL) and 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 provide the title compound. MS = 360.9 [M+1] + .

[0517] Step 3. 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethylfuro[3,4-b]pyrazine-5(7H)- ketone:To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxypropyl-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 rt for 16 hours. The mixture was diluted by adding EtOAc and then washed with water and brine. The organic layer was concentrated to Na 2 SO 4 Dry over 400 °C, filter and concentrate under reduced pressure. The crude residue was purified by preparative TLC (SiO2, 1:1 EtOAc / petroleum ether) to provide the title compound. MS = 343.1 [M+1] + .

[0518] Table 5. The following compounds were prepared using procedures similar to those described for intermediate AL-5a using appropriate starting materials.

[0519]

[0520] Intermediate AM-3a

[0521]

[0522] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylic acid (square (AM)

[0523] Step 1: 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylate Tert-butyl acid ester: To a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-formylpyrazine-2-carboxylic acid tert-butyl ester (130 mg, 0.336 mmol) in 1,2-dimethoxyethane (6.000 mL), trimethylamine N-oxide (25.2 mg, 0.336 mmol) and (trifluoromethyl)trimethylsilane (143 mg, 1.01 mmol) were added. The reaction mixture was stirred at rt for 14 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was then extracted with EtOAc. The organic layers were combined and heated to 40 ℃ for 14 hours under a nitrogen atmosphere. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 12% EtOAc / petroleum ether) to provide the title compound. MS = 457.0 [M+1] + .

[0524] Step 2: 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxylate acid: The title compound was prepared following a similar procedure as described above in Intermediate AE-5, Step 4. MS = 400.8 [M+1] + .

[0525] Intermediate product AN-7

[0526]

[0527] 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylic acid (Scheme AN)

[0528] Step 1. 3-Methyl-6-oxo-1,4,5,6-tetrahydropyridazine-4-carboxylic acid ethyl ester: To a solution of diethyl 2-acetyl succinate (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 rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 60% EtOAc / petroleum ether) to provide the title compound. MS = 185.1 [M + 1] + .

[0529] 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 rt for 15 hours. The reaction mixture was diluted with water and concentrated under reduced pressure to provide the title compound. MS = 183.0 [M + 1] + .

[0530] 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 for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to rt and then poured into ice-cold water. The resulting mixture was stirred for 1 hour and then saturated NaHCO 3 Aqueous solution (to adjust the pH of the mixture to ~7). The mixture was extracted with EtOAc. The organic layers were combined and washed with saturated brine, and then heated to 40 ℃ for 2 h. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.2% TFA)-ACN gradient) to provide the title compound. MS = 245.0, 247.0 [M+1] + .

[0531] Step 4. Ethyl 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylate:Under nitrogen atmosphere, to 6-bromo-3-methylpyridazine-4-ethyl formate (35mg, 0.14mmol), 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130mg, 0.430mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium (II) (19mg, 0.029mmol) in toluene (1.5mL) and water (0.3mL) solution, cesium carbonate (140mg, 0.430mmol) was added. The reaction vessel was sealed and heated in a microwave at 100°C for 1 hour. The reaction mixture was cooled to rt, then filtered and concentrated under reduced pressure. By preparative TLC (SiO 2 The crude residue was purified by evaporation with 1:4 EtOAc / petroleum ether to provide the title compound. MS = 345.3 [M+1] + .

[0532] Step 5. 6-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyridazine-4-carboxylic acid: The title compound was prepared following a similar procedure as described above in Intermediate AA-6a, Step 4. MS = 316.9 [M+1] + .

[0533] Intermediate BA-1a

[0534]

[0535] 1-(5-Bromopyrimidin-2-yl)ethan-1-ol (Scheme BA)

[0536] 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, methylmagnesium bromide (4.33 mL, 4.33 mmol) was added in one portion and the mixture was stirred at -78 °C for 30 min. The reaction mixture was heated by adding saturated NH 4 The mixture was quenched with aqueous Cl solution and then extracted with EtOAc. The organic layers were combined and washed with brine and then heated to 40 ℃ for 2 h. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue is purified by silica gel column chromatography (EtOAc / hexanes) to provide the title compound. MS=215.0, 217.0 [M+1] +

[0537] 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 NH 4 Cl aqueous solution, and the mixture was extracted with DCM. The organic layers were combined and washed with brine, 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to provide the title compound. MS = 217.0, 219.0 [M+H] +

[0538] Table 6. The following compounds were prepared using procedures similar to those described for Intermediate BA-1a using appropriate starting materials.

[0539]

[0540] Intermediate BA-1c

[0541]

[0542] 1-(5-Bromo-3-fluoropyridin-2-yl)ethanol (Scheme BA)

[0543] 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 in THF). The reaction mixture was stirred at 0°C for 1 hour, then quenched by the addition of water and extracted with EtOAc. The organic layers were combined and washed with brine, and then heated to 40 °C for 1 hour. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc / petroleum ether) to provide the title compound. MS = 217.9, 219.9 [M+1] + .

[0544] Step 2. 1-(5-bromo-3-fluoropyridin-2-yl)ethanol: The title compound was prepared following a similar procedure as described for intermediate BA-1a. MS = 219.9, 221.9 [M+1] + .

[0545] Intermediate product BB-2a

[0546]

[0547] 1-(5,6-Dichloropyridin-3-yl)ethan-1-ol (Scheme BB)

[0548] Under nitrogen atmosphere, to a solution of 5,6-dichloronicotinaldehyde (300 mg, 1.71 mmol) in THF (3.0 mL) cooled to 0°C, methylmagnesium bromide (0.852 mL, 2.56 mmol, 3.0 M diethyl ether solution) was added dropwise over 2 hours. The mixture was stirred at 0°C for 30 minutes. The reaction mixture was heated to 40°C by adding saturated NH 4 The solution was quenched with aqueous Cl and extracted with EtOAc. The organic layers were combined and washed with brine and then heated to 40 ℃ for 2 h. 2 SO 4 Dry over medium and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0-60% EtOAc / hexanes) to provide the title compound. MS = 191.9 [M+1] + .

[0549] Table 7. The following compounds were prepared using procedures similar to those described for intermediate BB-2a using appropriate starting materials.

[0550]

[0551] Intermediate BC-2a

[0552]

[0553] (5-Chloro-6-methylpyrazin-2-yl)methanol (Scheme BC)

[0554] To a solution of 5-chloro-6-methylpyrazine-2-carboxaldehyde (2.00 g, 12.8 mmol) in THF (10.0 mL), sodium borohydride (0.580 g, 15.3 mmol) was added. The reaction mixture was stirred at rt 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 and washed with brine, and the mixture was concentrated to 4% by volume. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0-50% EtOAc / petroleum ether) to provide the title compound. MS = 158.9 [M+1] + .

[0555] Table 8. The following compounds were prepared using procedures similar to those described for intermediate BC-2a using appropriate starting materials.

[0556]

[0557] Intermediate product BD-2a

[0558]

[0559] 1-(2-Chloro-4-methylpyrimidin-5-yl)cyclopropan-1-ol (Scheme BD)

[0560] Under a nitrogen atmosphere, titanium (IV) isopropoxide (1.6 mL, 5.4 mmol) was added 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, and then ethyl magnesium bromide (3M in diethyl ether, 5.7 mL, 17 mmol) was added dropwise over 15 minutes. The reaction mixture was warmed to 0 ° C and stirred for 2 hours, and then quenched by adding 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] + .

[0561] Intermediate BE-4a

[0562]

[0563] 1-(5-Bromo-6-methylpyridin-2-yl)ethan-1-ol (Scheme BE)

[0564] Step 1. (5-Bromo-6-methylpyridin-2-yl)methanol: A solution of 5-bromo-6-methylpicolinate (1.00 g, 4.40 mmol) in THF (22 mL) was cooled to -78 °C, and DIBAL (10.9 mL, 10.9 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at -78 °C for 15 minutes, then allowed to slowly warm to rt and stirred for 1 hour. The reaction mixture was cooled to 0 °C and quenched by adding EtOAc and 40% Rochelle salt aqueous solution (sodium potassium tartrate tetrahydrate, 60 mL), and stirred vigorously overnight at rt. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were combined and the Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound, which was used without further purification. MS = 203.0 [M+1] + .

[0565] Step 2. 5-Bromo-6-methylpyridinecarboxaldehyde: A 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 warmed to rt and stirred at this temperature for 2 hours. The reaction was quenched by the addition of saturated NaHCO 3 The mixture was quenched with saturated sodium thiosulfate aqueous solution (10 mL) and stirred vigorously for 1 hour. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined and washed with water under reduced pressure.2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound, which was used without further purification. MS = 201.0 [M+1] + .

[0566] Step 3. 1-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol: A solution of 5-bromo-6-methylpyridinecarboxaldehyde (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 in THF) was added dropwise. The reaction mixture was allowed to slowly warm to rt and stirred at this temperature for 1 hour. The reaction was stirred by adding saturated NH 4 The Cl aqueous solution was quenched and stirred for 20 minutes. 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 and the Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound, which was used without further purification. MS = 217.0 [M+1] + .

[0567] Table 9. The following compounds were prepared using procedures similar to those described for intermediate BE-4a using appropriate starting materials.

[0568]

[0569] Intermediate product BF-3a

[0570]

[0571] 1-(6-Bromo-5-methylpyridin-3-yl)ethan-1-ol

[0572] Step 1. 6-Bromo-5-methylnicotinaldehyde: The title compound was prepared in a similar manner as described for 5-bromo-6-methylpicolinaldehyde (via intermediate BE-4a). MS=210.9 [M+1] + .

[0573] 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] + .

[0574] Table 10. The following compounds were prepared using procedures similar to those described for intermediate BF-3a using appropriate starting materials.

[0575]

[0576] Intermediate product BG-5a

[0577]

[0578] 1-(6-Chloro-5-(difluoromethyl)pyridin-3-yl)ethan-1-ol (Scheme BG)

[0579] Step 1.5-Bromo-2-chloronicotinaldehyde: To (5-bromo-2-chloropyridin-3-yl)methanol (4.00g, 18.0mmol) in DCM (10mL) solution, add manganese dioxide (IV) (7.82g, 90.0mmol). The mixture was stirred at rt 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 provide the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ10.34 (s, 1H), 8.63 (d, J = 2.7Hz, 1H), 8.29 (d, J = 2.7Hz, 1H).

[0580] 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, DAST (11.1 mL, 84.0 mmol) was added dropwise. The reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was quenched by adding saturated aqueous sodium carbonate solution and extracted with DCM. The organic layer was stirred at room temperature for 2 hours. 2 SO 4 Dry over , filter and concentrate under reduced pressure.The crude residue was purified by silica gel chromatography (5% EtOAc / petroleum ether) to provide the title compound. 1 H NMR (400 MHz, CD 3 OD) δ 8.68–8.54 (m, 1H), 8.29–8.14 (m, 1H), 7.19–6.76 (m, 1H).

[0581] Step 3. 1-(6-chloro-5-(difluoromethyl)pyridin-3-yl)ethanol: To a THF (25 mL) solution of 5-bromo-2-chloro-3-(difluoromethyl)pyridine (2.60 g, 10.7 mmol) cooled to 0°C, isopropylmagnesium bromide (16.5 mL, 21.5 mmol) was added dropwise. After the addition was complete, the resulting mixture was stirred at 0°C for 30 minutes, and then acetaldehyde (6.4 mL, 32 mmol) was added. The reaction mixture was stirred for 16 hours while warming to rt. The reaction mixture was quenched by adding water and then extracted with EtOAc. The organic layers were combined and washed with brine, and then heated to room temperature in Na 2 SO 4Dry over medium, filter and concentrate 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] + .

[0582] Intermediate product BH-5a

[0583]

[0584] 1-(2-Chloro-4-methylpyrimidin-5-yl)ethan-1-ol (Scheme BH)

[0585] Step 1. 2-Chloro-4-methyl-5-vinylpyrimidine: The title compound was prepared following a similar procedure as described above in Intermediate AG-5a, Step 1. MS = 154.6 [M+1] + .

[0586] 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 0.5 °C for 1 h. 2 Stir at rt for 14 hours under atmosphere (15 psi). 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 provide the title compound. MS = 172.6 [M+1] + .

[0587] Intermediate BI-4a

[0588]

[0589] 1-(6-Chloro-5-fluoro-4-methylpyridin-3-yl)ethan-1-ol (Scheme BI)

[0590] Step 1. 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanone: To a suspension of bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.313 mmol) in toluene (6.0 mL) was added tributyl(1-ethoxyvinyl)tin hydride (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. under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to rt and a 6M HCl (~1 mL) aqueous solution was added. The resulting mixture was stirred at rt for 1 hour and then saturated NaHCO 3 The mixture was extracted with DCM. The combined organic fractions were washed with brine and concentrated in Na 2 SO 4Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 12% EtOAc / petroleum ether) to provide the title compound. MS = 188.0 [M+1] + .

[0591] Step 2. 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethanol: The title compound was prepared following a similar procedure as described above in Intermediate BC-2a, Step 1. Aqueous Na2SO4 MS = 190.0 [M+1] + .

[0592] Table 11. The following compounds were prepared using procedures similar to those described for intermediate BI-4a using appropriate starting materials.

[0593]

[0594] Intermediate products BJ-5a and BJ-5b

[0595]

[0596] (6-Chloro-5-methylpyridazin-3-yl)methanol and (6-chloro-4-methylpyridazin-3-yl)methanol (Scheme BJ)

[0597] Step 1. 3-Chloro-4-methyl-6-vinylpyridazine and 6-chloro-4-methyl-3-vinylpyridazine: To a solution of 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol) in dioxane (80 mL) and water (40 mL), potassium vinyl trifluoroborate (4.11 g, 30.7 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.12 g, 1.53 mmol) and potassium phosphate (13.0 g, 61.3 mmol) were added. The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to rt and water was added. The mixture was filtered and the filtrate was extracted with EtOAc. The organic layer was washed with brine and heated to 40 ° C for 16 hours under Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc / petroleum ether) to provide the title compounds as a mixture. MS = 155.0 [M+1] + .

[0598] Step 2. 6-Chloro-4-methylpyridazine-3-carbaldehyde and 6-chloro-5-methylpyridazine-3-carbaldehyde: To a solution of 3-chloro-4-methyl-6-vinylpyridazine and 6-chloro-4-methyl-3-vinylpyridazine (1.80 g, 5.82 mmol) in dioxane (80.0 mL) and water (20 mL) was added osmium tetroxide (25.0 mL, 1.97 mmol, 2% aqueous solution) and sodium periodate (2.49 g, 11.6 mmol). The mixture was stirred at rt for 2 hours. Saturated Na 2 SO 3The aqueous solution was added and the resulting mixture was stirred for 10 minutes. The mixture was extracted with EtOAc and the organic layers were combined and washed with brine. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound as a mixture. MS = 157.0 [M + 1] + .

[0599] Step 3. (6-Chloro-4-methylpyridazin-3-yl)methanol and (6-chloro-5-methylpyridazin-3-yl)methanol: To a methanol (10 mL) solution of 6-chloro-4-methylpyridazine-3-carboxaldehyde and 6-chloro-5-methylpyridazine-3-carboxaldehyde (1.10 g, 3.51 mmol) cooled to 0°C, sodium borohydride (0.199 g, 5.27 mmol) was added. The mixture was stirred at 0°C for 30 minutes, and acetone was then added to the mixture. The resulting mixture was stirred at rt 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 provide the title compound as a mixture. MS=158.6[M+1] + .

[0600] Table 12. The following compounds were prepared using procedures similar to those described for intermediates BJ-5a and BJ-5b using appropriate starting materials.

[0601]

[0602] Intermediate BK3a

[0603]

[0604] 1-(2-Chloro-4-methylpyrimidin-5-yl)cyclobutanol (Scheme BK)

[0605] To a solution of 5-bromo-2-chloro-4-methylpyrimidine (1.00 g, 4.82 mmol) in THF (10 mL) cooled to -100 ° C, n-butyl lithium (2.12 mL, 5.30 mmol, 2.5 M in hexane) was added. The reaction mixture was stirred at -100 ° C for 30 minutes. Then, cerium (III) chloride (1.98 g, 5.30 mmol) was added as a THF (10 mL) solution at -100 ° C, and the resulting mixture was stirred at -100 ° C for 30 minutes. At this time, 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 rt for 12 hours. The mixture was stirred by adding saturated NH 4 The quenching was carried out with aqueous Cl solution, and then extracted with EtOAc. The organic layers were combined and 2 SO 4Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 15% EtOAc / petroleum ether) to provide the title compound. MS = 199.0 [M+1] + .

[0606] Table 13. The following compounds were prepared using procedures similar to those described for intermediate BK-3a using appropriate starting materials.

[0607]

[0608] Intermediate BL-4a

[0609]

[0610] (5-Bromo-4-methylpyrimidin-2-yl)methanol (Scheme BL)

[0611] 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 rt for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined and washed with brine and heated to 40 ℃ for 10 min. The residue was purified by column chromatography on a column chromatography elution. The column chromatography was repeated 10 min. The column chromatography was repeated 20 ℃ for 30 min. The column chromatography was repeated 10 ℃ for 30 ℃. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound. 1 H NMR (400 MHz, CD 3 OD) δ8.93 (s, 1H), 2.69 (s, 3H).

[0612] Step 2. 5-bromo-4-methylpyrimidine-2-carboxylic acid methyl ester: To a solution of 5-bromo-4-methylpyrimidine-2-carbonitrile (750 mg, 3.79 mmol) in methanol (10.0 mL) was added an aqueous solution of HCl (10 mL, 122 mmol). After addition, the mixture was stirred at 80 °C for 1.5 hours. The mixture was then cooled to rt, then diluted with water and extracted with EtOAc. The organic layers were combined and heated to 40 °C for 1 h. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound. 1 H NMR (400 MHz, CD 3 OD) δ8.93 (s, 1H), 3.97 (s, 3H), 2.70 (s, 3H).

[0613] Step 3. (5-Bromo-4-methylpyrimidin-2-yl)methanol: The title compound was prepared following a similar procedure as described above in Intermediate BJ-5a, Step 3. 2SO 4 1 H NMR (400 MHz, CD 3 OD) δ8.74 (s, 1H), 4.66 (s, 2H), 2.62 (s, 3H).

[0614] Intermediate product BN-5

[0615]

[0616] 1-(5-Bromo-4-methyl-3-nitropyridin-2-yl)ethan-1-ol (Scheme BN)

[0617] Step 1. 5-Bromo-2-iodo-4-methyl-3-nitropyridine: To a solution of 5-bromo-4-methyl-3-nitropyridine-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, copper (I) iodide (2.50 g, 13.1 mmol) and potassium iodide (15.0 g, 90.0 mmol) were added. 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 rt, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (20% EtOAc / petroleum ether) to provide the title compound. MS = 342.8, 344.8 [M + 1] + .

[0618] Step 2. 1-(5-bromo-4-methyl-3-nitropyridin-2-yl)ethanone: The title compound was prepared following a similar procedure as described above in Intermediate BI-4a, Step 1. MS = 258.9, 260.9 [M+1] + .

[0619] Step 3. 1-(5-bromo-4-methyl-3-nitropyridin-2-yl)ethanol: The title compound was prepared following a similar procedure as described above in Intermediate BJ-5a, Step 3. MS = 260.9, 262.9 [M+1] + .

[0620] Intermediate product BO-5

[0621]

[0622] 1-(1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)ethan-1-ol (Scheme BO)

[0623] Step 1. 1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylic acid methyl ester: 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 hours. The reaction mixture was cooled to rt and then heated to room temperature by adding saturated NaHCO3 The aqueous solution was quenched. Additional saturated NaHCO 3 The aqueous solution was added to adjust the pH to 7. The resulting mixture was extracted with EtOAc. The organic layers were combined and 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 20% EtOAc / petroleum ether) to provide the title compound. MS = 212.1 [M+1] + .

[0624] Step 2. (1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)methanol: To a solution of 1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxylic acid methyl ester (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 rt for 2 hours. The mixture was quenched by the addition of water and then extracted with EtOAc. The organic layers were combined and washed with water and then with 4% paraffin. The resulting mixture was stirred for 2 hours at rt. The resulting mixture was quenched by the addition of water and then extracted with EtOAc. The organic layers were combined and washed with water and 4% paraffin. The resulting mixture was quenched ... 4% paraffin. The resulting mixture was quenched with water and 4% para 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound. MS = 184.1 [M+1] + .

[0625] Step 3. 1-Chloro-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde: The title compound was prepared in a similar manner as described for 5-bromo-6-methylpicolinaldehyde (via intermediate BE-4a). MS=182.1[M+1] + .

[0626] 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] + .

[0627] Intermediate product BP-5

[0628]

[0629] (4-Chloro-[1,3]dioxolano[4,5-c]pyridin-7-yl)methanol (Scheme BP)

[0630] 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, 2M in hexanes) dropwise, and the resulting solution was allowed to stir at -78°C for 30 minutes. Trimethyl borate (6.54 g, 62.9 mmol) was added, and the reaction continued to stir at -78°C for 2 hours, at which time hydrogen peroxide (6.61 mL, 76 mmol) was added. The mixture was allowed to warm to 0°C with stirring for 2 hours, and then sodium dithionite (20 g in 20 mL of water) was added dropwise. The mixture was adjusted to pH = 3 by adding 2N.HCl, and extracted with ethyl acetate. The organic layer was dried, concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc / petroleum ether) to provide the title compound. 1 H NMR (400 MHz, CDCl 3 )δ8.04(s, 1H), 4.08(s, 3H). MS=239.9(M+1).

[0631] Step 2: 5-Bromo-2-chloropyridine-3,4-diol: To a solution of 5-bromo-2-chloro-4-methoxypyridin-3-ol (2.00 g, 8.39 mmol) in DCM (30 mL) was added BBr at 0 °C. 3 (1.59 mL, 16.8 mmol). The mixture was stirred at rt for 16 h, at which time the mixture was cooled to 0 °C and quenched with MeOH, concentrated, and purified by silica gel chromatography (0-30% MeOH / DCM) to give the title compound. MS=225.8 (M+1).

[0632] Step 3: 7-Bromo-4-chloro-[1,3]dioxolano[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 Cs 2 CO 3 (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 hours. The reaction mixture was cooled to rt, poured into water and extracted with EtOAc. The organic layer was washed with water, dried (Na 2 SO 4 ) and concentrated to provide a crude residue which was purified by silica gel chromatography (0-20% EtOAc / petroleum ether) to give the title compound. MS=237.8 (M+1).

[0633] Step 4: 4-Chloro-[1,3]dioxolane[4,5-c]pyridine-7-carbaldehyde:To a solution of 7-bromo-4-chloro-[1,3]dioxolane[4,5-c]pyridine (300 mg, 1.27 mmol) in THF (4 mL) at -78°C was added n-butyl lithium (0.558 mL, 1.396 mmol, 2.5 M in hexane). After the mixture was stirred at -78°C for 0.5 h, DMF (0.49 mL, 6.3 mmol) (dissolved in 0.5 mL THF) was added dropwise, and the reaction mixture was stirred at -78°C for 1 h. The mixture was poured into saturated NH 4 The organic layer was washed with brine and dried (Na2O3) 2 SO 4 ) and concentrated to give a crude residue which was purified by preparative TLC eluting with EtOAc to give the title compound. 1 HNMR (400 MHz, CDCl 3 )δ10.11(s, 1H), 8.39(s, 1H), 6.31(s, 2H). MS=186.0(M+1).

[0634] Step 5: (4-chloro-[1,3]dioxolano[4,5-c]pyridin-7-yl)methanol: To a solution of 4-chloro-[1,3]dioxolane and [4,5-c]pyridine-7-carbaldehyde (190 mg, 1.02 mmol) in THF (2 mL) and MeOH (0.2 mL) at 0°C, sodium borohydride (39 mg, 1.02 mmol) was added. After the mixture was stirred at 0°C for 5 minutes, acetone was added to the mixture and warmed to rt for 1 hour. The reaction was concentrated to give a crude residue, which was purified by preparative TLC eluting with EtOAc to give the title compound. MS=188.0 (M+1).

[0635] Intermediate product BQ-6

[0636]

[0637] (1R,5S)-3-(2,2-difluoro-7-(1-hydroxyethyl)-[1,3]dioxolano[4,5-c]pyridin-4-yl)-3- Azabicyclo[3.1.0]hexan-2-one (Scheme BQ)

[0638] 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 BBr at 0°C. 3 (5.33 mL, 56.4 mmol). The mixture was stirred at rt for 12 h. The mixture was quenched with MeOH and concentrated to give a crude residue which was purified by silica gel chromatography (10-20% MeOH / DCM) to provide the title compound. MS=146.1 (M+1).

[0639] Step 2: 4-Chloro-[1,3]dioxolano[4,5-c]pyridine-2-thione. 2-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 minutes, the reaction was warmed to rt. After 1 hour, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with brine and concentrated in anhydrous Na 2 SO 4 Dry over medium, filter and concentrate to give a crude residue which is purified by silica gel chromatography (10-30% EtOAc / petroleum ether) to give the title compound. MS=188.0 (M+1).

[0640] Step 3: 4-Chloro-2,2-difluoro-[1,3]dioxolan[4,5-c]pyridine. 4-Chloro-[1,3]dioxolane and [4,5-c]pyridine-2-thione (2.00 g, 10.7 mmol) was dissolved in DCM (20 mL) and cooled to -78 °C. Hydrogen fluoride pyridine (20.0 mL, 155 mmol) was added dropwise, followed by 1,3-dibromo-5,5-dimethylimidazoline-2,4-dione (9.14 g, 32.0 mmol) in several portions. After 20 minutes, the reaction was warmed to -20 °C. After another 40 minutes, the reaction was adjusted to pH 7 by careful addition of 5M NaOH. Sodium thiosulfate was added, and the resulting mixture was diluted with water and extracted with DCM. The organic layer was concentrated to provide a crude residue, which was purified by silica gel chromatography (10-30% EtOAc / petroleum ether) to obtain the title compound. MS=194.0 (M+1). 1 H NMR (400 MHz, CDCl 3 )δ8.22 (d, J=5.5Hz, 1H), 7.07 (d, J=5.1Hz, 1H).

[0641] Step 4: (1R,5S)-3-(2,2-difluoro-[1,3]dioxolano[4,5-c]pyridin-4-yl)-3-azabicyclo [3.1.0] Hexan-2-one. To (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one (750 mg, 7.72 mmol), 4-chloro-2,2-difluoro-[1,3]dioxolan-[4,5-c]pyridine (1.50 g, 7.75 mmol), Cs 2 CO 3 To a solution of 1,4-dioxane (20 mL) of 2-nitropropene (7.58 g, 23.3 mmol) and XANTPHOS (224 mg, 0.388 mmol) was added Pd 2 (dba) 3 (355 mg, 0.388 mmol). The mixture was degassed and heated with N 2Backfilled and the resulting mixture was heated to 90°C for 14 hours. The reaction was cooled to rt and concentrated to provide a crude residue which was purified by silica gel chromatography (30-40% EtOAc / petroleum ether) to give the title compound. MS = 255.1 (M+1). 1 H NMR (500 MHz, CDCl 3 )δ8.15 (d, J=5.3Hz, 1H), 6.92 (d, J=5.2Hz, 1H), 4.34 (dd, J=5.1, 10.6Hz, 1H), 3.76-3.79 (m, 1H), 2.08-2.11 (m, 1H), 1.28 (br dd, J=3.1, 8.1Hz, 1H), 0.95 (q, J=4.3Hz, 1H), 0.84-0.88 (m, 1H).

[0642] Step 5: (1R,5S)-3-(7-bromo-2,2-difluoro-[1,3]dioxolano[4,5-c]pyridin-4-yl)-3-nitrogen Heterobicyclo[3.1.0]hexan-2-one. To a solution of (1R,5S)-3-(2,2-difluoro-[1,3]dioxolano[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 hours, the reaction was concentrated to provide a crude residue, which was purified by reverse phase preparative HPLC (C18 stationary phase, ACN / water + 0.1% TFA) to provide the title compound. MS = 332.9, 334.9 (M+1). 1 H NMR (400 MHz, CDCl 3 )δ8.20 (s, 1H), 4.31 (dd, J=4.9, 10.8Hz, 1H), 3.76 (d, J=11.0Hz, 1H), 2.04-2.18 (m, 2H), 1.30 (dt, J=5.1, 8.0Hz, 1H), 0.88-1.01 (m, 1H).

[0643] Step 6: (1R,5S)-3-(7-acetyl-2,2-difluoro-[1,3]dioxolano[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]dioxolano[4,5-c]pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-2-one (300 mg, 0.901 mmol) and tributyl(1-ethoxyvinyl)tin hydride (395 mL, 1.17 mmol) in toluene (5 mL) was added Pd(PPh 3 ) 2 Cl 2(63 mg, 0.090 mmol) and the resulting mixture was heated to 90 ° C. After 14 hours, the reaction was cooled to rt, 6M HCl (2 mL) was added, and the mixture was stirred for 30 minutes. The reaction was quenched by saturated KF aqueous solution, stirred for 1 hour, and extracted with EtOAc. The combined organic layers were heated to 40 ° C. 2 SO 4 Dry on ice, filter and concentrate to provide a crude residue which is purified by silica gel chromatography (30-50% EtOAc / petroleum ether) to give the title compound. MS=297.1 (M+1).

[0644] Step 7: (1R,5S)-3-(2,2-difluoro-7-(1-hydroxyethyl)-[1,3]dioxolan-[4,5-c]pyridine-4-yl)- 1-(4-(4-nitro-1-yl)-3-azabicyclo[3.1.0]hexan-2-one. To a solution of (1R,5S)-3-(7-acetyl-2,2-difluoro-[1,3]dioxolano[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) was added NaBH 4 (31.9 mg, 0.844 mmol). The resulting mixture was stirred at 0°C for 1 hour, at which time excess acetone was added and the resulting mixture was warmed to rt. After 1 hour, the reaction was concentrated to provide a crude residue, which was purified by silica gel chromatography (40-50% EtOAc / petroleum ether) to give the title compound. MS=299.1 (M+1).

[0645] Intermediates CA-6a and CA-6b

[0646]

[0647] (1S,5R)-3-Azabicyclo[3.1.0]hexan-2-one and (1R,5S)-3-Azabicyclo[3.1.0]hexan-2-one (square Case CA)

[0648] Step 1. 3-Benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione: The following sequence was carried out in parallel in two batches on an equivalent scale. These batches were combined for subsequent post-reaction processing. At 15 ° C, benzylamine (574g, 5.35mol) was added to a solution of 3-oxabicyclo [3.1.0] hexane-2,4-dione (400g, 3.57mol) in acetic acid (2.00L). The reaction mixture was stirred at 120 ° C for 12 hours. The reaction was cooled to rt and combined by pouring into water. The resulting mixture was stirred for 30 minutes and then filtered. The filtered solid was washed with water and then dissolved by adding EtOAc. The mixture was washed with water and brine and then in Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound. MS = 202.1 [M+1] +.

[0649] Step 2. 3-Benzyl-3-azabicyclo[3.1.0]hexane: The following sequence was carried out in parallel in three batches on an equivalent scale. To a suspension of LAH (87.9 g, 2.32 mol) in THF (700 mL) at 10°C was added a solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (333 g, 1.65 mol) in THF (1.40 L) dropwise. The resulting mixture was stirred at 40°C for 12 hours and then cooled to 0°C. In a sequential manner, water (87 mL), aqueous sodium hydroxide solution (87 mL, 15% by volume) and then water (261 mL) were added dropwise to the mixture. Na 2 SO 4 was added to the mixture, and the resulting mixture was stirred for 30 minutes and then filtered. The filtered solid was washed with EtOAc, and the filtrate was concentrated under reduced pressure to provide the title compound. MS = 174.2 [M + 1] + .

[0650] Step 3. tert-Butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate: The following sequence was carried out in parallel in 8 batches on an equivalent scale. 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% by weight). The reaction mixture was heated to 40°C under H 2 The mixture was stirred at 40°C under atmospheric pressure (45 psi) for 2 hours. Reactions were run in parallel and combined and purified by The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% to 20% EtOAc / petroleum ether) to provide the title compound. 1 HNMR (400 MHz, CDCl 3 )δ3.47–3.59(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).

[0651] Step 4. tert-Butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate:The following sequence is carried out in two batches in parallel on an equivalent scale. At rt, to 3-azabicyclo [3.1.0] hexane-3-tert-butyl formate (330g, 1.80mol) and ruthenium chloride (11.2g, 54.0mmol) in EtOAc (1.6L) and water (1.60L) solution, sodium periodate (770g, 3.60mol) is added portion by portion. The resulting mixture is stirred for 12 hours. The reactions carried out in parallel are combined and filtered. Each layer is separated and extracted with EtOAc aqueous layer. The organic layers are combined, and washed with saturated sodium dithionite aqueous solution, and the mixture is stirred for 12 hours. 2 SO 4 Dry over medium, filter, and then concentrate under reduced pressure to provide the title compound as a racemate. 1 HNMR (400 MHz, CDCl 3 )δ3.82–3.78 (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). By chiral chromatography (SFC, DAICEL CHIRALPAK IC; 0.1% NH 3 H 2 O-EtOH starting B 25% end B 25%) to separate the enantiomers of the title compound to provide the individual isomeric compounds in pure form. The faster eluting enantiomer of the title compound (Intermediate CA-5a). The slower eluting enantiomer of the title compound (Intermediate CA-5a): 1 H NMR (400 MHz, CDCl 3 )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).

[0652] Step 5. (1S,5R)-3-azabicyclo[3.1.0]hexan-2-one and (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one 2-Keto: 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 filtered solid was washed with EtOAc (2.0 L, 1.0 L) and then dried to provide the title compound as a mixture of enantiomers. 1 H NMR (400 MHz, DMSO-d 6)δ8.49(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).

[0653] Step 5. (1R,5S)-3-azabicyclo[3.1.0]hexan-2-one: A mixture of (1R,5S)-tert-butyl 2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate (slower eluting enantiomer from the previous step, 370 g, 1.88 mol) in HCl / EtOAc (4M, 1.4 L) at 0-10° C. for 1 hour. The reaction mixture was filtered and the filtered solid was washed with EtOAc (500 mL) and then dried to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 )δ10.0(s, 1H), 7.07(s, 1H), 3.34–3.30(m, 1H), 3.13(d, J=10.4Hz, 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] + .

[0654] Table 14. The following compounds were prepared using procedures similar to those described for intermediate CA-6 using appropriate starting materials.

[0655]

[0656] Intermediate CA-7

[0657]

[0658] (1R,5S)-3-Azabicyclo[3.1.0]hexane-2-thione (Scheme CA)

[0659] 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 Lawes' reagent (208 mg, 0.520 mmol). The lactam solution was slowly added to the Lawes' reagent solution and stirred at rt 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] + .

[0660] Examples 1 and 2

[0661]

[0662] 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)

[0663] 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 rt for 6 hours. The mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to provide the title compound. MS=280.9[M+1] + .

[0664] 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 Cs 2 CO 3 (733 mg, 2.25 mmol). The mixture was stirred at rt for 16 hours. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was concentrated to Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue is purified by silica gel column chromatography (EtOAc / hexanes) to provide the title compound. MS=284.1[M+1] + .

[0665] Step 3. (1-(1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine- tert-Butyl (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 rt, the mixture was filtered (eluting with additional EtOAc). The organic layer was stirred over Na 2 SO 4Dry over medium, filter and concentrate under reduced pressure. The crude residue is purified by silica gel column chromatography (MeOH / DCM) to provide the title compound. MS=399.3[M+1] + .

[0666] 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 similar procedure as described above in Intermediate AE-5, Step 4. MS = 299.1 [M+1] + .

[0667] 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-yl Formamide 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 at rt overnight, then saturated NaHCO 3 The organic layers were combined and washed with brine, and the mixture was purified by centrifugation at room temperature. 2 SO 4 The mixture was dried on 4% 4-nitropropene, 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 provide a mixture of diastereomeric title compounds. The isomeric title compounds were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD-H; neutral EtOH starting B 40% ending B 40%) to provide individual isomers in pure form. The faster eluting diastereomers of the title compound (Example 1): 1 H NMR (600 MHz, CD 3OD) δ8.85 (d, J=2.4Hz, 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=54.6Hz, 1H), 5.70 (q, J=7.1Hz, 1H), 4.05 (dd, J=10.2, 5 .9Hz, 1H), 3.75–3.54(m, 1H), 2.99(s, 3H), 2.36(s, 3H), 2.21–2.13(m, 1H), 2.0 9–1.97 (m, 1H), 1.93 (d, J=7.1Hz, 3H), 1.36–1.24 (m, 2H), 0.93 (d, J=3.4Hz, 1H). MS=597.1[M+1] + The slower eluting diastereomer of the title compound (Example 2): 1 H NMR (600 MHz, CD 3 OD) δ8.85 (d, J=2.4Hz, 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=54.6Hz, 1H), 5.70 (q, J=7.1Hz, 1H), 4.05 (dd, J=10.2, 5. 9Hz, 1H), 3.67 (d, J=10.2Hz, 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=7.1Hz, 3H), 1.36–1.25 (m, 1H), 0.96–0.87 (m, 1H). MS=597.1[M+1] + .

[0668] Table 15. The following compounds were prepared using procedures similar to those described in Examples 1 and 2 using appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using chiral columns (SFC or HPLC) specified in the table. For those isomer pairs or sets, the isomers are listed in elution order (i.e., the fastest eluting isomer is listed first). This convention for listing isomers separated from chiral SFC or HPLC will be used in all subsequent tables.

[0669]

[0670]

[0671]

[0672]

[0673]

[0674] Embodiment 21

[0675]

[0676] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-((1R,5S)-2-oxo-3-aza Bicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAB)

[0677] Step 1. 3-(Bromomethyl)-6-chloropyridazine: 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 CCl 4 The mixture in (26 ml) was stirred at 90 °C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane) to provide the title compound. MS = 208.9 [M+1] +

[0678] 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 rt, tert-butyl (1H-pyrazol-4-yl)carbamate (702 mg, 3.83 mmol) and cesium carbonate (2.50 g, 7.66 mmol) were added. The mixture was stirred at rt for 16 hours, diluted with EtOAc, and washed with water and then brine. The organic layer was stirred over Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to provide the title compound. MS=310.0[M+1] + .

[0679] Step 3. (1-((6-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrrolidone tert-Butyl oxazol-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) at rt was added mCPBA (441 mg, 2.0 mmol). The mixture was stirred at rt for 1 hour, diluted with DCM and washed with 1N Na 2 CO 3 The organic layer was dried (Na 2 SO 4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / hexanes 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 hours. The mixture was cooled to rt and purified by Filtered (washed with DCM). The filtrate was washed with brine and 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue is purified by silica gel column chromatography (MeOH / DCM) to provide the title compound. MS=371.1 [M+1] + .

[0680] Step 4. (1R,5S)-3-(6-((4-amino-1H-pyrazol-1-yl)methyl)pyridazin-3-yl)-3-azabicyclo [3.1.0] Hexane-2-one: The title compound was prepared following a similar procedure as described above in Intermediate AE-5, Step 4. MS = 271.1 [M+1] + .

[0681] 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 analogous to that described above in Example 1, Step 5. 1 H NMR (600 MHz, CD 3 OD) δ8.88 (d, J=1.9Hz, 1H), 8.55 (d, J=9.3Hz, 1H), 8.30 (s, 1H), 7.84 (t, J=7.8Hz , 1H), 7.76 (s, 1H), 7.69 (d, J=8.4Hz, 1H), 7.45 (d, J=9.4Hz, 1H), 6.96 (s, 1H), 5. 61 (s, 2H), 4.26 (dd, J=11.5, 5.6Hz, 1H), 4.20 (d, J=11.6Hz, 1H), 3.01 (s, 3H), 2. 22 (p, J=6.0Hz, 1H), 2.16 (d, J=4.5Hz, 1H), 1.36–1.30 (m, 1H), 0.94–0.86 (m, 1H). MS=555.3[M+1] +

[0682] Examples 22 and 23

[0683]

[0684] 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]hexyl-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAC)

[0685] Step 1. 5-(1-bromoethyl)-4-methyl-2-(methylthio)pyrimidine: The title compound was prepared following a similar procedure as described above in Example AAA-10a, Step 1. MS = 248.9 [M+1] + .

[0686] Step 2. 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)- N -(1-(1-(4-methyl-2-(methylthio)-pyrimidine- 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) at rt 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). The mixture was stirred at rt for 16 hours, diluted with EtOAc, and then washed with water and brine. The organic layer was stirred over Na2O3 for 16 hours, and the mixture was washed with water and brine. The organic layer was stirred over Na2O3 for 16 hours, and the mixture was dried over Na2O3 for 16 hours. The mixture was dried over Na2O3 for 16 hours, and the mixture was dried over Na2O3 for 16 hours. The mixture was dried over Na2O3 for 16 hours, and the mixture was dried over Na2O3 for 16 hours. The organic layer ... 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue is purified by silica gel chromatography (EtOAc / hexanes) to provide the title compound. MS=533.9 [M+1] + .

[0687] 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-carboxamide. 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, 2.00 mmol). The mixture was stirred at rt for 1 hour, diluted with DCM and washed with 1N aqueous sodium carbonate solution. The organic layer was dried (Na2SO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / hexanes to provide the title compound. MS=565.9 [M+1] + .

[0688] 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-azabiphenyl) Cyclo[3.1.0]-hexyl-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 rt and purified by reverse phase preparative HPLC (C18 stationary phase, ACN / water + 0.1% TFA) to provide the diastereomeric title compounds as a mixture. The isomeric title compound was separated by chiral chromatography (SFC, DAICEL CHIRALELIA, 0.1% DEA-EtOH starting B 35% ending B 35%) to provide the individual isomers in pure form. The faster eluting isomer of the title compound (Example 22): 1 H NMR (600 MHz, CD 3 OD) δ9.38 (s, 1H), 9.01 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.84 (t, J=7.8Hz, 1H), 7. 77 (s, 1H), 7.66 (d, J=8.5Hz, 1H), 7.00 (t, J=54.7Hz, 1H), 5.80 (q, J=7.0Hz, 1H), 4.1 8 (dd, J=11.5, 5.0Hz, 1H), 3.99 (d, J=11.5Hz, 1H), 2.43 (s, 3H), 2.10 (dt, J=8.2, 4. 5Hz, 2H), 1.89 (d, J=7.0Hz, 3H), 1.27 (td, J=7.7, 4.1Hz, 1H), 0.82 (q, J=3.7Hz, 1H). MS=583.0[M+1] + Slower eluting isomer of the title compound (Example 23): 1 H NMR (600 MHz, CD 3OD) δ9.39 (s, 1H), 9.02 (d, J = 2.0Hz, 1H), 8.41 (d, J = 3.7Hz, 1H), 8.26 (s, 1H), 7.87–7.81 (m, 1H), 7.78 (d, J=3.2Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.00 (t, J=54.7Hz, 1H), 5.85 (q, J= 7.0Hz, 1H), 4.18 (dq, J=11.3, 4.5, 4.0Hz, 1H), 4.05 (d, J=11.5Hz, 1H), 2.51 (s, 3H), 2.17 (dt, J=8.2, 4.7Hz, 2H), 1.90 (d, J=6.9Hz, 3H), 1.37–1.30 (m, 1H), 0.89 (q, J=4.1Hz, 1H). MS=583.0[M+1] + .

[0689] Table 16. The following compounds were prepared using procedures analogous to those described in Examples 22 and 23 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0690]

[0691]

[0692]

[0693] Examples 33 and 34

[0694]

[0695] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo- 3-(3-azabicyclo[3.1.0]hexyl-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]hexyl-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAD)

[0696] 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, carbon tetrabromide (1.267 mg, 3.82 mmol) and triphenylphosphine (1.00 g, 3.82 mmol) were added. 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 provide the title compound. MS = 234.9.0 [M+1] + .

[0697] Step 2. tert-Butyl (1-((4-methyl-2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)carbamate ester: To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (754 mg, 4.12 mmol) in DMF (10.0 mL), 5-(bromomethyl)-4-methyl-2-(methylthio)pyrimidine (640 mg, 2.75 mmol) and cesium carbonate (3.58 g, 11.0 mmol) were added. The mixture was stirred at rt for 16 hours, then diluted with EtOAc and washed with water and brine. The organic layer was heated to 40 ℃ and then dried over Na2O3. The resulting mixture was dried over 40 ℃ and then dried over 80 ℃. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (5 to 60% EtOAc / hexanes) to provide the title compound. MS = 336.0 [M+1] + .

[0698] Step 3. (1-((4-methyl-2-(methylsulfonyl)pyrimidin-5-yl)methyl)-1 H -pyrazol-4-yl)carbamic acid Tert-Butyl Ester: The title compound was prepared following a procedure similar to that described above in Example 22, Step 3. Aqueous MS = 368.0 [M+1] + .

[0699] Step 4. (1-((4-methyl-2-(2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)- tert-Butyl 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 rt 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 provide the title compound. MS=385.1[M+1] + .

[0700] Step 5. 3-(5-((4-amino-1 H -pyrazol-1-yl)methyl)-4-methylpyrimidin-2-yl)-3-azabicyclo [3.1.0]-Hexan-2-one: The title compound was prepared following the procedure described above for Intermediate AE-5, Step 4. MS = 285.1 [M+1] + .

[0701] 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-azepine Bicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared following a similar procedure as described above in Example 1, Step 5. The isomeric title compound was separated by chiral chromatography (SFC, DAICEL CHIRACELAS-H; MeOH start B 25% end B 25%) to provide the individual isomers in pure form. The faster eluting isomer of the title compound (Example 33): 1 H NMR (600 MHz, CD 3 OD) δ8.85 (d, J=2.4Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.84–7.78 (m, 1H), 7 .70 (s, 1H), 7.66 (d, J=8.5Hz, 1H), 6.93 (t, J=54.6Hz, 1H), 5.37 (s, 2H), 4. 19 (dd, J=11.5, 5.1Hz, 1H), 4.00 (d, J=11.1Hz, 1H), 2.98 (s, 3H), 2.46 (s, 3 H), 2.14–2.08 (m, 2H), 1.27 (dt, J=12.6, 4.4Hz, 1H), 0.83 (q, J=4.2Hz, 1H). MS=583.0[M+1] + Slower eluting isomer of the title compound (Example 34): 1 HNMR (600 MHz, CD 3 OD) δ 8.85 (d, J = 2.4Hz, 1H), 8.28 (s, 1H), 8.17 (s, 1H), 7.84–7.78 (m, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.5Hz, 1H), 6.93 (t, J = 54.6Hz, 1H), 5.37 (s, 2H), 4.19 (dd, J=11.5, 5.1Hz, 1H), 4.00 (d, J=11.1Hz, 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] + .

[0702] Table 17. The following compounds were prepared using procedures analogous to those described in Examples 33 and 34 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0703]

[0704]

[0705] Examples 37 and 38

[0706]

[0707] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexyl-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]hexyl-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

[0708] Step 1. 3-Chloro-4-methyl-6-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridazine: At 0 ° C, to 1- (6-chloro-4-methylpyridazine-3-yl) ethanol and 1- (6-chloro-5-methylpyridazine-3-yl) ethanol (480mg, 1.39mmol), 4-nitro-1H-pyrazole (377mg, 3.34mmol) and triphenylphosphine (875mg, 3.34mmol) in a THF (10mL) solution, di-tert-butyl azodicarboxylate (960mg, 4.17mmol) was added. The reaction mixture was stirred at 80 ° C 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 provide 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] + .

[0709] 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-one: To 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 rt, filtered and the filtrate was concentrated under reduced vacuum. The crude residue was purified by silica gel chromatography (30% EtOAc / petroleum ether) followed by preparative TLC (50% EtOAc / petroleum ether) to provide the title compound. MS=329.2 [M+1] + .

[0710] 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 EtOAc (0.6 mL) and MeOH (0.2 mL) was added platinum(IV) oxide (5.5 mg, 0.024 mmol). The reaction mixture was heated to 40 ℃ under H 2 Stir at rt for 2 hours under atmosphere (15 psi). The reaction mixture was filtered and then concentrated under reduced pressure to provide the title compound. MS = 299 [M+1] + .

[0711] 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-fluorobenzene base )-N-(1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabi Cyclo[3.1.0]hexyl-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide: A 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 rt 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 start B 45% end B 75%) to provide a diastereomeric mixture of the title compound. The diastereomeric title compounds were separated by chiral chromatography (SFC, DAICELCHIRALPAK AD; neutral IPA start B 55% end B 55%) to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 37): 1 H NMR (500 MHz, CD 3OD) δ9.30 (s, 1H), 8.92 (d, J = 2.0Hz, 1H), 8.24 (s, 1H), 7.74 (t, J = 7.9Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.2Hz, 1H), 7.27 (s, 1H), 7.03 –6.79 (m, 1H), 5.76 (d, J = 7.2Hz, 1H), 4.37 (dd, J = 5.8, 10.4Hz, 1H), 3.71 (d, J = 10.1Hz, 1H), 2.15–2.11 (m, 1H), 2.08 (s, 3H), 1.96 (br s, 1H), 1.90 (d, J=7.2Hz, 3H), 1.23 (dt, J=4.7, 8.0Hz, 1H), 0.90–0.86 (m, 1H). MS=583.2[M+1] + The slower eluting diastereomer of the title compound (Example 38): 1 H NMR (500 MHz, CD 3 OD) δ9.30 (s, 1H), 8.92 (d, J = 2.1Hz, 1H), 8.24 (s, 1H), 7.74 (t, J = 7.9Hz, 1H), 7.71 (s, 1H), 7.57 (d, J = 8.7Hz, 1H), 7.26 (s, 1H), 7.04 –6.78(m, 1H), 5.77(d, J=7.2Hz, 1H), 4.37(dd, J=5.9, 10.5Hz, 1H), 3.71(d, J=9.9Hz, 1H), 2.16–2.10(m, 1H), 2.08(s, 3H), 1.97(br s, 1H), 1.90 (d, J=7.0Hz, 3H), 1.27–1.22 (m, 1H), 0.91–0.86 (m, 1H). MS=583.2[M+1] + .

[0712] Examples 39 and 40

[0713]

[0714] 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-carboxylate Amine 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)

[0715] 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-yl Formamide 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-carboxylate amine:To 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 rt 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 start B 37% end B 67%) to provide a diastereomeric mixture of the title compound. The precipitate was purified by chiral chromatography (SFC, DAICEL CHIRALPAK AD; 0.1% NH 3 H 2 O-IPA start B 50% end B 50%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 39): 1 H NMR (400 MHz, CD 3 OD) δ8.79 (s, 1H), 8.32 (s, 1H), 7.77 (s, 1H), 7.74–7.68 (m, 1H), 7.36 (d, J=0.8Hz, 1H) , 7.25 (d, J=9.0Hz, 1H), 6.93 (t, J=72.8Hz, 1H), 5.85 (q, J=7.3Hz, 1H), 4.47 (dd, J=10. 6, 5.9Hz, 1H), 3.82 (d, J = 9.4Hz, 1H), 2.98 (s, 3H), 2.27–2.20 (m, 1H), 2.18 (d, J = 0.8Hz , 3H), 2.10–2.03 (m, 1H), 2.00 (d, J=7.4Hz, 3H), 1.37–1.32 (m, 1H), 1.01–0.96 (m, 1H). MS=613.2[M+1] + The slower eluting diastereomer of the title compound (Example 40): 1 H NMR (400 MHz, CD 3OD) δ8.79 (s, 1H), 8.31 (s, 1H), 7.77 (s, 1H), 7.71 (t, J=8.6Hz, 1H), 7.35 (s, 1H), 7 .25 (d, J=9.0Hz, 1H), 6.93 (t, J=72.8Hz, 1H), 5.86 (q, J=7.0Hz, 1H), 4.47 (dd, J=10 .6, 5.9Hz, 1H), 3.81 (d, J=9.4Hz, 1H), 2.98 (s, 3H), 2.27–2.20 (m, 1H), 2.18 (s, 3H ), 2.10–2.04(m, 1H), 2.00(d, J=7.0Hz, 3H), 1.37–1.33(m, 1H), 1.01–0.96(m, 1H). MS=613.2[M+1] + .

[0716] Embodiment 41

[0717]

[0718] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5-methyl-6-((1R,5S)-2-oxo- (3-(4-((3-( ... AAE)

[0719] Step 1. 2-Bromo-3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridine: To a THF (200 mL) 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) cooled to 0°C, diisopropyl azodicarboxylate (14.4 mL, 74.2 mmol) was added. After the addition was complete, the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc / hexane) to provide the title compound. MS=297.0, 299.0 [M+1] + .

[0720] Step 2. (1R,5S)-3-(3-methyl-5-((4-nitro-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-3-nitropropane Heterobicyclo[3.1.0]hexan-2-one:Under nitrogen atmosphere, to a vessel containing [(4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (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) at rt, 1,4-dioxane (200 mL) was added. The resulting mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 6% MeOH / DCM) to provide the title compound. MS = 314.1 [M+1] + .

[0721] Step 3. (1R,5S)-3-(5-((4-amino-1H-pyrazol-1-yl)methyl)-3-methylpyridin-2-yl)-3-nitrogen Heterobicyclo[3.1.0]hexan-2-one: At rt, a mixture 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 NH 4 Cl (9.34 g, 175 mmol) was added to a container, EtOH (70 mL) and water (18 mL). The resulting mixture was stirred at 80 ° C for 6 hours. The reaction mixture was cooled to rt and Filter 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 provide the title compound. MS = 284.1 [M+1] + .

[0722] 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-carboxamide: To 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 rt 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, CDCl 3 )δ9.77 (s, 1H), 8.95 (d, J = 3.4Hz, 1H), 8.25 (d, J = 2.1Hz, 1H), 8.15 (s, 1H), 7.75–7.66(m, 2H), 7.60(s, 1H), 7.46(d, J=1.9Hz, 1H), 6.60(t, J=54.0Hz, 1H), 5.27(s, 2H), 4.42–4.33(m, 1H), 3.68(d, J=10.0Hz, 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=3.8Hz, 1H). MS=582.0[M+1] + .

[0723] Examples 42 and 43

[0724]

[0725] 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)

[0726] Step 1. 2-Chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine: Under nitrogen atmosphere, to 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) 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 / hexane) to provide the title compound. MS=268.0[M+1] + .

[0727] 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:Under nitrogen atmosphere, to 2-chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine (185mg, 0.691mmol), (1R, 5S)-3-azabicyclo [3.1.0] hexan-2-ketone (87.0mg, 0.898mmol), cesium carbonate (450mg, 1.38mmol) in dioxane (5.0mL) mixture, add tris (dibenzylideneacetone) dipalladium (63mg, 69μmol) and Xantphos (40mg, 69μmol). The reaction mixture was stirred at 90°C for 16 hours, then cooled to rt and concentrated under reduced pressure. Water was added to the resulting mixture, and it was extracted with EtOAc. The organic layers were merged, and 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] + .

[0728] 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-one: To 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 EtOAc (3.0 mL) and MeOH (1.0 mL) was added platinum (IV) oxide (5.5 mg, 0.024 mmol). The resulting mixture was stirred at 15° C. for 1 hour under a hydrogen atmosphere (pressure: 15 psi). The mixture was then filtered and the filtrate was concentrated under reduced pressure to provide the title compound. MS=299.0[M+1] + .

[0729] 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-carboxylate amine: The title compound was prepared as an initial mixture of diastereomers following a similar procedure as described above in Intermediate AL-5a, Step 3. The diastereomers of the title compound were separated by chiral chromatography (SFC, DAICEL CHIRALPAK AD; neutral EtOH starting B 50% ending B 50%) to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 42): 1 H NMR (400 MHz, CD 3OD)δ8.83(d, J=2.5Hz, 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 = 8.6Hz, 1H), 7.05–6.77 (m, 1H), 5.77 (q, J = 6.9Hz, 1H), 4.22–4.09(m, 1H), 4.03–3.91(m, 1H), 2.95(s, 3H), 2.41(s, 3H), 2.12–2.0 3 (m, 2H), 1.86 (d, J=7.1Hz, 3H), 1.25 (dt, J=4.7, 8.0Hz, 1H), 0.84–0.77 (m, 1H). MS=597.2[M+1] + The slower eluting diastereomer of the title compound (Example 43): 1 H NMR (400 MHz, CD 3 OD) δ8.83(d, J=2.5Hz, 1H), 8.36(s, 1H), 8.16(s, 1H), 7.82–7.75(m, 1H), 7.68( s, 1H), 7.63 (d, J=8.6Hz, 1H), 7.17–6.68 (m, 1H), 5.77 (q, J=7.10Hz, 1H), 4.24– 4.11(m, 1H), 3.96(d, J=11.3Hz, 1H), 2.95(s, 3H), 2.41(s, 3H), 2.14–2.02(m, 2 H), 1.86 (d, J=7.1Hz, 3H), 1.25 (td, J=3.9, 8.01Hz, 1H), 0.80 (q, J=4.1Hz, 1H). MS=597.2[M+1] + .

[0730] Examples 44 and 45

[0731]

[0732] 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-nitrogen Heterobicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAE)

[0733] 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] + .

[0734] Step 2. (1R, 5S)-3-(4-bromo-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one:N-Bromosuccinimide (4.00 g, 22.5 mmol) was added to a stirred 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 rt and concentrated under reduced pressure. The resulting crude mixture was heated to saturated NaHCO 3 Partition between aqueous solution and EtOAc. Separate the layers and extract the aqueous layer with EtOAc. Concentrate the combined organics to provide a crude residue that is purified by silica gel chromatography (0 to 80% EtOAc / hexanes) to provide the title compound. MS = 284.9, 286.9 [M+1, M+3] + .

[0735] Step 3. (1R,5S)-3-(5-Acetyl-3-fluoro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane- 2-Keto: (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 with N 2 The atmosphere was replaced. 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 rt, quenched with concentrated HCl, and allowed to stir at rt for 1 hour. The mixture was then added to saturated NaHCO 3 The product was dissolved in water and extracted with EtOAc. The combined organics were concentrated to provide a crude residue which was purified by silica gel chromatography (0 to 10% MeOH / DCM) to provide the title compound. MS = 249.0 [M+1] + .

[0736] Step 4. (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0] Hexane-2-one: Sodium borohydride (220 mg, 5.81 mmol) was added to 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). The resulting mixture was stirred at rt for 30 minutes, at which time the reaction was concentrated to provide a crude mixture, which was added saturated NaHCO 3 The combined organics were dried (MgSO 4), filtered and concentrated to provide a crude residue to provide the title compound. MS = 251.0 [M + 1] + .

[0737] Step 5. (1R,5S)-3-(3-fluoro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine-2-yl 1-(2-nitro-3-nitro-1-yl)-3-azabicyclo[3.1.0]hexan-2-one: (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) was added to a stirred solution of 4-nitro-1H-pyrazole (529 mg, 4.67 mmol) and triphenylphosphine (1.23 g, 4.67 mmol) in THF (18 mL). DIAD (910 mL, 4.7 mmol) was added and the resulting mixture was heated to 50 °C for 1 hour. The reaction was cooled to rt and concentrated to provide a crude residue which was purified by silica gel chromatography (0 to 10% MeOH / DCM) to provide the title compound. MS=346.0[M+1] + .

[0738] 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-carboxamide: (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) was added to 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). The resulting mixture was heated to 50 °C for 2 hours, at which time the reaction was cooled to rt and filtered. The filtrate was concentrated and saturated NaHCO 3 The combined organics were dried (MgSO 4 ), filtered and concentrated to provide the title compound, which was directly carried forward and combined with HATU (1.37 g, 3.60 mmol) and dissolved 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 allowed to stir at rt overnight. The reaction was diluted with EtOAc and the organics were washed with water and brine and concentrated to provide a crude residue that was purified by silica gel chromatography (0 to 10% MeOH / DCM) to provide 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 provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 44): 1 H NMR (400 MHz, CD 3 OD) δ9.40 (s, 1H), 9.02 (d, J = 2.0Hz, 1H), 8.23 ​​(s, 1H), 8.03 (s, 1H), 7.85 (t, J = 7.8Hz, 1H), 7.79 (s, 1H), 7.67 (d, J = 8.6Hz, 1H), 6.86-7.1 7 (m, 1H), 5.85 (q, J=7.3Hz, 1H), 4.29 (dd, J=10.2, 5.9Hz, 1H), 3.68 (d, J=10.6Hz, 1H), 2.28 (d, J=2.0Hz, 3H), 2.14-2.21 (m, 1H), 2.03 (br s, 1H), 1.92 (d, J=7.0Hz, 3H), 1.29-1.31 (m, 1H), 0.86-0.91 (m, 1H). MS=600.1[M+1] + The slower eluting diastereomer of the title compound (Example 45): 1 H NMR (400 MHz, CD 3 OD) δ9.39 (s, 1H), 9.02 (d, J = 2.3Hz, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.81-7.88 (m, 1H), 7.79 (s, 1H), 7.67 (d, J = 8.6Hz, 1H), 6.86-7.17 ( m, 1H), 5.85 (q, J=6.9Hz, 1H), 4.27 (dd, J=10.6, 5.9Hz, 1H), 3.70 (d, J=11.0Hz, 1H), 2.28 (d, J=2.0Hz, 3H), 2.13-2.20 (m, 1H), 2.03 (br s, 1H), 1.92 (d, J=7.0Hz, 3H), 1.32 (br d, J=3.5Hz, 1H), 0.89 (br d, J=3.1Hz, 1H). MS=600.1[M+1] + .

[0739] Table 18. The following compounds were prepared using procedures analogous to those described in Examples 37-45 using appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768] Examples 150 and 151

[0769]

[0770] 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-nitrogen Heterobicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAF)

[0771] Step 1. (1R, 5S)-3-(3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To 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), Xantphos (0.398 g, 0.687 mmol) and tris (dibenzylideneacetone) dipalladium (556 mg, 0.687 mmol) were added. The reaction mixture was stirred at 100 ° C for 12 hours. The mixture was cooled to rt, and water was added to the mixture, and the resulting mixture was then extracted with EtOAc. The organic layer was stirred at 40 ° C for 12 hours. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc / petroleum ether) to provide the title compound. MS = 207.1 [M+1] + .

[0772] 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 rt and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 30% EtOAc / petroleum ether) to provide the title compound. MS = 284.9, 286.9 [M + 1] + .

[0773] Step 3. (1R,5S)-3-(5-Acetyl-3-fluoro-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane- 2-Keto: The title compound was prepared following a similar procedure as described above in Intermediate BI-4a, Step 1. MS = 249.2 [M+1] + .

[0774] Step 4. (1R,5S)-3-(3-fluoro-5-(1-hydroxyethyl)-6-methylpyridin-2-yl)-3-azabicyclo[3.1.0] Hexane-2-one:The title compound was prepared following a similar procedure as described above in Intermediate BJ-5a, Step 3. MS = 251.1 [M+1] + .

[0775] Step 5: (1R,5S)-3-(3-fluoro-6-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine-2-yl 1-(2-nitro-3-nitro-1-yl)-3-azabicyclo[3.1.0]hexan-2-one: At 0°C, 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 diisopropyl azodicarboxylate (0.699 mL, 3.60 mmol). 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 provide the title compound. MS=346.2[M+1] + .

[0776] Step 6. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-fluoro-6-methylpyridine-2-yl 1-(2-nitro-3-nitro-1-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] + .

[0777] 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: The title compound was prepared as a starting mixture of diastereomers following a procedure analogous to that described above in Example 1, Step 5. The isomers were purified by chiral chromatography (SFC, DAICEL CHIRALPAK AD; 0.1% NH 3 H 2 O EtOH start B 35% end B 35%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 150): 1 H NMR (400 MHz, CD 3OD) δ9.39 (s, 1H), 9.02 (d, J = 2.0Hz, 1H), 8.22 (s, 1H), 7.86–7.84 (m, 1H), 7.78 (s, 1H), 7.67 (d, J = 8.6Hz, 1H), 7.41 (d, J = 10.6Hz, 1 H), 7.18–6.84 (m, 1H), 5.81 (d, J = 7.0Hz, 1H), 4.29 (dd, J = 10.6, 5.9Hz, 1H), 3.67 (d, J = 10.2Hz, 1H), 2.48 (d, J = 0.8Hz, 3H), 2.15 (br d, J=7.4Hz, 1H), 2.01(br s, 1H), 1.86 (d, J=7.0Hz, 3H), 1.32–1.26 (m, 1H), 0.91–0.84 (m, 1H).MS=600.1[M+1] + The slower eluting diastereomer of the title compound (Example 151): 1 H NMR (400 MHz, CD 3 OD) δ9.39 (s, 1H), 9.01 (d, J = 2.0Hz, 1H), 8.20 (s, 1H), 7.88–7.81 (m, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.6Hz, 1H), 7.44 (d, J = 10.6Hz, 1H), 7 .18–6.83 (m, 1H), 5.81 (d, J=7.0Hz, 1H), 4.28 (dd, J=10.6, 5.9Hz, 1H), 3.70 (d, J=9.4Hz, 1H), 2.48 (s, 3H), 2.20–2.13 (m, 1H), 2.02 (br d, J=7.0Hz, 1H), 1.86 (d, J=7.0Hz, 3H), 1.32–1.26 (m, 1H), 0.92–0.85 (m, 1H). MS=600.2[M+1] + .

[0778] Table 19. The following compounds were prepared using procedures analogous to those described in Examples 150 and 151 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0779]

[0780]

[0781] Embodiment 156

[0782]

[0783] 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)

[0784] 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]hex-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide (120 mg, 0.202 mmol) in DMF (2.0 mL) cooled to 0°C, sodium hydride (16 mg, 0.40 mmol, 60% dispersion in oil) was added. 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 saturated with NH 4 The mixture was quenched with aqueous Cl solution and extracted with EtOAc. The organic layers were combined and washed with brine and concentrated into Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc / hexanes) to provide the title compound. MS=752.2[M+1] + .

[0785] 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-(trimethyl (methylsilyl)ethoxy)methyl)pyrazine-2-carboxamide: The title compound was prepared following a similar procedure as described above in Intermediate AE-5, Step 2. MS = 745.1 [M+H 2 O+1] + .

[0786] 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-(Triple A (methylsilyl)ethoxy)methyl)pyrazine-2-carboxamide: The title compound was prepared following a similar procedure as described above in Intermediate BA-1a, Step 2. MS = 731.2 [M+1] + .

[0787] 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-carboxylic acid amine : Prepared following a procedure similar to that described above in Intermediate AE-5, Step 4. 1 H NMR (600 MHz, CD 3OD) δ8.98 (d, J=2.0Hz, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.83 (t, J=7. 8Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=8.5Hz, 1H), 6.95 (t, J=54.6Hz, 1H), 5.37 (s, 2H) , 5.23 (s, 2H), 4.19 (dd, J=11.5, 5.0Hz, 1H), 4.00 (d, J=11.5Hz, 1H), 2.45 (s, 3H) , 2.10 (dt, J=8.0, 4.6Hz, 2H), 1.27 (dq, J=8.0, 4.4Hz, 1H), 0.83 (q, J=4.0Hz, 1H). MS=599.4[M+1] + .

[0788] Examples 157-160

[0789]

[0790] 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]hexyl-3-yl)pyrimidin-5-yl)ethyl)-1 H -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]hexyl-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide and 6-(3-chloro-6-(difluoromethane) 1-((R)-2-hydroxy-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0] Hexyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAH)

[0791] Step 1. 2-Chloro-4-methyl-5-vinylpyrimidine: 5-Bromo-2-chloro-4-methylpyrimidine (7.00 g, 33.7 mmol), TEA (7.05 mL, 50.6 mmol), potassium vinyl trifluoroborate (4.97 g, 37.1 mmol) and bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.741 g, 1.01 mmol) in ethanol (100 mL) were stirred at 90 ° C for 3 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, and the mixture was concentrated in Na 2 SO 4 Dry over 400 °C, filter and concentrate 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, CD 3 OD) δ8.64 (s, 1H), 6.93–6.83 (m, 1H), 5.90–5.85 (m, 1H), 5.58–5.52 (m, 1H), 2.52 (d, J=1.2Hz, 3H).

[0792] 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 for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to rt and concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, and the residue was purified by column chromatography on Na 20% HPLC elution. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 95% EtOAc / petroleum ether) to provide the title compound. MS = 216.0 [M+1] + .

[0793] Step 3. 3-(5-(1,2-dihydroxyethyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To 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 acetonitrile (15 mL) and water (5.0 mL) was added an aqueous solution of 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 rt for 12 hours. The mixture was cooled to 0 ° C and then saturated Na 2 S 2 O 3 The aqueous solution was added to the reaction and the resulting mixture was stirred for 30 minutes. The mixture was then filtered through a pad of celite (eluted with acetonitrile) and the filtrate was concentrated under reduced pressure to provide the title compound. MS = 250.3 [M+1] + .

[0794] Step 4. 3-(5-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-methylpyrimidine-2-yl)- 1-(2-nitro-3-nitro-1-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 hours. The reaction mixture was cooled to rt. Water was added to the mixture, and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with brine, and the mixture was concentrated in Na 2 SO 4Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 95% EtOAc / petroleum ether, then 0 to 10% MeOH / DCM) to provide the title compound. MS = 488.2 [M+1] + .

[0795] Step 5: 3-(5-(2-((tert-butyldiphenylsilyl)oxy)-1-(4-nitro-1 H -pyrazol-1-yl)ethyl 1-(4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one: To 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 rt 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. MS=583.6[M+1] + .

[0796] Step 6: 3-(5-(1-(4-amino-1H-pyrazol-1-yl)-2-((tert-butyldiphenylsilyl)oxy)ethyl 1-(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] + .

[0797] Step 7. N-(1-(2-((tert-butyldiphenylsilyl)oxy)-1-(4-methyl-2-(2-oxo-3-aza)- Bicyclo[3.1.0]hexyl-3-yl)pyrimidin-5-yl)ethyl)-1 H -pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorobenzene 1-(2-Yl)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] + .

[0798] 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-yl Formamide, 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)-1 H -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]hexyl-3-yl)pyrimidin-5-yl)ethyl)-1 H -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] hexyl-3-yl) pyrimidin-5-yl) ethyl) -1H-pyrazol-4-yl) pyrazine-2-carboxamide: The title compound was prepared as a starting mixture of diastereomers following a procedure analogous to that described above for Intermediate AE-5, Step 4. The isomers were purified by chiral chromatography (SFC, REGIS (S,S) WHELK-O1; 0.1% NH 3 H 2O EtOH start B 40% end B 40%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 157): 1 H NMR (400 MHz, CD 3 OD) δ9.29 (s, 1H), 8.92 (d, J = 2.1Hz, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.74 (t, J = 7.7H z, 1H), 7.71 (s, 1H), 7.57 (d, J=8.5Hz, 1H), 7.03–6.80–(m, 1H), 5.61–5.56 (m, 1H), 4 .21 (dd, J=11.8, 7.2Hz, 1H), 4.09 (dd, J=11.6, 5.2Hz, 2H), 3.89 (d, J=11.3Hz, 1H), 2.40 (s, 3H), 2.05–1.96 (m, 2H), 1.18 (dd, J=8.1, 4.4Hz, 1H), 0.72 (q, J=4.1Hz, 1H). MS=599.1[M+1] + The second eluting diastereomer of the title compound (Example 158): 1 HNMR (400 MHz, CD 3 OD)δ9.41 (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=8.5Hz, 1H), 7.16–6.92 (m, 1H), 5.73 (br t, J=5.8Hz, 1H), 4.33(dd, J=11.9, 7.0Hz, 1H), 4.27–4.17(m, 2H), 4.05(br d, J=11.6Hz, 1H), 2.55(s, 3H), 2.16(br d, J=4.3Hz, 2H), 1.38–1.29(m, 1H), 0.89(br d, J=3.7Hz, 1H). MS=599.1[M+1] + The third eluting diastereomer of the title compound (Example 159): 1 H NMR (400 MHz, CD 3OD) δ9.29 (s, 1H), 8.92 (d, J = 2.1Hz, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.74 (t, J = 7.8Hz, 1H), 7.71 (s, 1H), 7.57 (d, J=8.2Hz, 1H), 7.04–6.80 (m, 1H), 5.60–5.56 (m, 1H), 4.21 ( dd, J=11.8, 7.2Hz, 1H), 4.09 (dd, J=11.6, 5.2Hz, 2H), 3.89 (d, J=11.3Hz, 1H), 2.40 (s , 3H), 2.00 (dd, J=7.5, 4.1Hz, 2H), 1.18 (dt, J=7.9, 4.0Hz, 1H), 0.72 (q, J=4.0Hz, 1H). MS=599.2[M+1] + The fourth eluting isomer of the title compound (Example 160): 1 H NMR (400 MHz, CD 3 OD)δ9.29(s,1H),8.92(s,1H),8.38(s,1H),8.19(s,1H),7.74(br t, J=7.5Hz, 1H), 7.72–7.70 (m, 1H), 7.57 (d, J=8.2Hz, 1H), 7.03–6.80 (m, 1H), 5.57 (t, J=6.3Hz, 1H), 4. 21 (dd, J=11.4, 7.2Hz, 1H), 4.09 (dd, J=11.6, 5.2Hz, 2H), 3.89 (d, J=11.6Hz, 1H), 2.39 (s, 3H), 2.00 (br d, J=4.6Hz, 2H), 1.18 (brd, J=9.2Hz, 1H), 0.72 (brd, J=4.0Hz, 1H). MS=599.1[M+1] + .

[0799] Table 20. The following compounds were prepared using procedures analogous to those described in Examples 157-160 using appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0800]

[0801]

[0802] Embodiment 169

[0803]

[0804] 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

[0805] Step 1. 1-(4-(tert-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) 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) at rt. After the addition was complete, the mixture was stirred at 6 °C for 1 hour. The mixture was poured into water and extracted with EtOAc. The organic layers were combined and heated to 40 °C for 1 h. 2 SO 4 Dry over medium, filter and concentrate under reduced vacuum. The crude residue was purified by silica gel chromatography (0 to 8% EtOAc / petroleum ether) to provide the title compound. MS = 243.3 [M+1] + .

[0806] Step 2. 1-(4-(tert-Butoxymethyl)-2-chloropyrimidin-5-yl)ethanol: The title compound was prepared following a similar procedure as described above in Intermediate BJ-5a, Step 3. MS = 245.1 [M+1] + .

[0807] Step 3. 4-(tert-Butoxymethyl)-2-chloro-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine: Under nitrogen atmosphere and cooled to 0 ℃, to 1-(4-(tert-butoxymethyl)-2-chloropyrimidin-5-yl)ethanol (150mg, 0.613mmol), 4-nitro-1H-pyrazole (90mg, 0.80mmol) and triphenylphosphine (241mg, 0.919mmol) in toluene (5.0mL) solution, diisopropyl azodicarboxylate (186mg, 0.919mmol) was added. After the addition was complete, the reaction was stirred at rt for 15 hours. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined and heated to 40 ℃ for 15 hours. 2 SO 4 Dry over medium, filter and concentrate under reduced vacuum. The crude residue was purified by silica gel chromatography (0 to 18% EtOAc / petroleum ether) to provide the title compound. MS = 339.9 [M+1] + .

[0808] Step 4. (1S,5R)-3-(4-(tert-butoxymethyl)-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidine Pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-2-one:At rt, 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), tris(dibenzylideneacetone)dipalladium (25 mg, 27 μmol) was added. The reaction mixture was stirred at 100 ° C for 15 hours. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (1:1 EtOAc / petroleum ether) to provide the title compound. MS=401.1[M+1] + .

[0809] 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-one: The title compound was prepared following a procedure similar to that described above in Example 41, Step 3. MS = 371.5 [M+1] + .

[0810] Step 6. N-(1-(1-(4-(tert-butoxymethyl)-2-(2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine (2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-5-carboxamide)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide : The title compound was prepared following a similar procedure as described above in Example 1, Step 5. MS = 655.2 [M+1] + .

[0811] 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 similar procedure as described above in Intermediate AE-5, Step 4. 1 H NMR (500 MHz, CDCl 3 )δ9.51–9.48 (m, 1H), 9.06 (d, J=2.9Hz, 1H), 8.55 (br d, J=7.6Hz, 1H), 8.14 (s, 1H), 7.70–7.76 (m, 1H), 7.65 (d, J=8.2Hz, 1H), 7.61 (br s, 1H), 6.73–6.46 (m, 1H), 5.57 (br d, J=7.2Hz, 1H), 4.82–4.69 (m, 1H), 4.60 (br s, 1H), 4.18 (br d, J=3.5Hz, 1H), 4.07 (br d, J=10.4Hz, 1H), 2.17(br s, 1H), 2.07(br s, 1H), 1.93 (br d, J=7.0Hz, 3H), 1.27 (br d, J=6.1Hz, 1H), 0.90 (br s, 1H). MS=599.2[M+1] +.

[0812] Examples 170 and 171

[0813]

[0814] N-(1-((S)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine- 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)

[0815] Step 1. 1-(2,4-dichloropyrimidin-5-yl)ethanol: Under nitrogen atmosphere, to a solution of 2,4-dichloro-5-iodopyrimidine (8.00 g, 29.1 mmol) in THF (100 mL) cooled to -78 ° C, isopropylmagnesium chloride (17.5 mL, 34.9 mmol, 2 M in THF) was added dropwise. The resulting mixture was stirred at -78 ° C for 20 minutes, then acetaldehyde (11.6 mL, 58.2 mmol, 5 M in THF) was added dropwise, and the resulting mixture was stirred at -78 ° C for 2 hours and at rt for another 1 hour. The reaction mixture was stirred by adding saturated NH 4 The quenching was carried out with aqueous Cl solution, and the resulting mixture was extracted with EtOAc. The organic layers were combined and 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 25% EtOAc / petroleum ether) to provide the title compound. MS = 192.6 [M+1] + .

[0816] 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 rt for 14 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified sequentially by silica gel chromatography (0 to 15% EtOAc / petroleum ether) and then by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 40%, end B 70%) to provide the title compound. 1 H NMR (400 MHz, CDCl 3 , ppm) δ8.55 (d, J=3.2Hz, 1H), 8.31 (d, J=3.2Hz, 1H), 8.11 (d, J=3.2Hz, 1H), 5.81 (m, 1H), 1.98 (dd, J=3.3, 7.0Hz, 3H).

[0817] Step 3. 2-Chloro-5-(1-(4-nitro-1 H -pyrazol-1-yl)ethyl)pyrimidin-4-amine: A 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 rt for 14 h. The reaction mixture was washed with saturated NH 4 Dilute with aqueous Cl solution and extract with DCM. Combine the organic layers and add Na 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 24%, end B 44%) to provide the title compound. MS = 268.6 [M+1] + .

[0818] 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)]methanesulfonate palladium(II) (Xantphos-Pd-G3, 113 mg, 0.119 mmol) in dioxane (6.0 mL) was stirred at 100° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to rt 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 provide the title compound. MS = 329.6 [M+1] + .

[0819] 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] + .

[0820] 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]hex-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 as a starting mixture of diastereomers following a procedure analogous to that described above in Example 41, Step 4. The isomers were purified by chiral chromatography (SFC, DAICEL CHIRALPAK AD; 0.1% NH 3 H 2O IPA start B 60% end B 60%) separation of diastereomeric title compounds to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 170): 1 H NMR (400 MHz, CD 3 OD) δ9.29 (s, 1H), 8.92 (d, J = 2.2Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.71-7.78 (m, 1H), 7.69 (s, 1H), 7.57 (d, J = 8.1Hz, 1H), 7.05–6.64 (m, 2H), 5.44 (m, 1H), 4.00 (m, 1H), 3.82 (d, J=11.0Hz, 1H), 1.97–1.94 (m, 2H), 1.76 (d, J=7.1Hz, 3H), 1.14 (m, 1H), 0.83–0.81 (m, 1H). MS=584.2[M+1] + The slower eluting diastereomer of the title compound (Example 171): 1 H NMR (400 MHz, CD 3 OD) δ9.29 (s, 1H), 8.92 (d, J = 2.2Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.77–7.71 (m, 1H), 7.69 (s, 1H), 7.57 (d, J = 8.3Hz, 1H), 7.06–6. 78 (m, 2H), 5.49–5.39 (m, 1H), 4.01 (m, 1H), 3.82 (d, J=11.5Hz, 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] + .

[0821] Embodiment 172

[0822]

[0823] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-aza Bicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAK)

[0824] 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). After the addition was complete, the resulting mixture was stirred at 0°C for 10 minutes, then the reaction mixture was concentrated under reduced pressure. DCM was added to the crude residue, and the mixture was stirred, then filtered and concentrated under reduced pressure to provide the title compound. TLC (R f = 0.7, 1:4 EtOAc / petroleum ether).

[0825] 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) and 4-nitro-1H-pyrazole (201 g, 1.78 mol) in DMF (1.69 L) cooled to 0°C, cesium carbonate (1.74 kg, 5.34 mol) was added. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with EtOAc and washed with water and then brine. The organic layer was stirred at room temperature for 14 hours. The reaction mixture was stirred for 2 hours. The organic layer was stirred for 3 hours. The reaction mixture was stirred for 2 hours. The organic layer was stirred for 3 hours. The organic layer ...3 hours. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc / petroleum ether) to provide the title compound. TLC (R f =0.15, 1:5 EtOAc / petroleum ether).

[0826] 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] + .

[0827] Step 4. tert-Butyl (1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate: The title compound was prepared following a similar procedure as described above in Intermediate AE-5, Step 1. MS = 336.1 [M+1] + .

[0828] Step 5. tert-Butyl (1-(1-(2-(methylsulfonyl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamate ester: The following sequence was carried out in parallel in two batches on an equivalent scale. These batches were combined for subsequent post-reaction processing. Under a nitrogen atmosphere, mCPBA (326 g, 1.49 mol, 80% purity) was added portionwise 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. The resulting mixture was stirred at rt for 1 hour. The reaction mixtures were combined and quenched by adding saturated aqueous sodium chloride solution and extracted with DCM. The organic layers were combined and washed with brine, and the mixture was concentrated to 4% by volume.2 SO 4 Dry over medium, filter and concentrate under reduced pressure to provide the title compound. 1 HNMR (400 MHz, DMSO-d 6 )δ9.20 (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=7.2Hz, 3H), 1.45 (s, 9H).

[0829] Step 6. (1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-5-yl) tert-Butyl (1H-pyrazol-4-yl)ethyl)carbamate: To 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 hours. The reaction mixture was cooled to rt, then quenched by adding brine, and extracted with MTBE. The organic layers were combined and precipitated over Na 2 SO 4 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 residue was purified by chiral chromatography (SFC, DAICEL CHIRALPAK AY; 0.1% NH 3 H 2 The diastereomeric compounds were separated by 2% EtOH starting B 45% end B 45%) to provide the individual isomeric compounds in pure form. The title compound is the slower eluting diastereomer, which was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.05% HCl)-ACN starting B 5%, end B 45%) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 )δ9.17 (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= 12Hz, 1H), 2.06–1.99 (m, 2H), 1.78 (d, J=7.2Hz, 3H), 1.43 (s, 9H), 1.17–1.15 (m, 1H), 0.78–0.76 (m, 1H).

[0830] Step 7. (1R,5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidin-2-yl)-3-azepine Bicyclo[3.1.0]hexan-2-one: To a solution of tert-butyl (1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-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 (4M 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] + .

[0831] 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 sequence was carried out in parallel in three batches on an equivalent scale. These batches were combined for subsequent post-reaction processing. 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-propanephosphoric 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 sequentially. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixtures were combined and saturated NaHCO was added to the mixture. 3 The aqueous solution was quenched and extracted with DCM. The organic layers were combined and washed with brine and purified by Na 2 SO 4 Dry over , filter and concentrate under reduced pressure.The crude residue was purified by silica gel chromatography (0 to 100% EtOAc / petroleum ether) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6)δ10.8 (s, 1H), 9.34 (s, 1H), 9.16 (s, 1H), 8.61 (s, 2H), 8.30 (s, 1H), 7.99 (t, J=7.2Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=8.8Hz, 1H), 7.20 (t, J=54Hz , 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=6.8Hz, 3H), 1.19–1.15 (m, 1H), 0.78–0.76 (m, 1H). MS=569.1[M+1] + .

[0832] Table 21. The following compounds were prepared using procedures analogous to those described in Example 172 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0833]

[0834]

[0835]

[0836] Embodiment 180

[0837]

[0838] 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-yl Formamide (Scheme AAK)

[0839] To a toluene (0.5 mL) solution of (1R, 5S)-3-(5-((S)-1-(4-amino-1H-pyrazol-1-yl)ethyl)pyrimidine-2-yl)-3-azabicyclo[3.1.0]hexan-2-one (16 mg, 0.056 mmol), trimethylaluminum (0.084 mL, 0.17 mmol) was added. The reaction mixture was stirred at rt for 30 minutes, and then a toluene (0.5 mL) solution of 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H-pyrans and [3,4-b]pyrazine-5-one (20 mg, 0.056 mmol) was added. The resulting mixture was stirred at rt 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 start B 37%, end B 67%) to provide the title compound. 1HNMR (400 MHz, CD 3 OD)δ8.93(d, J=2.4Hz, 1H), 8.54(s, 2H), 8.29(s, 1H), 7.83–7.75(m, 1H), 7.70(s, 1H), 7.65(d, J=8.6Hz, 1H), 6.92( t, J=54.4Hz, 1H), 5.64 (q, J=6.8Hz, 1H), 4.15 (dd, J=10.9, 4.8Hz, 1H), 3.98 (d, J=11.7Hz, 1H), 3.57 (s, 2H), 2.09 (br dd, J=7.8, 3.2Hz, 2H), 1.90 (d, J=7.1Hz, 3H), 1.32–1.21(m, 7H), 0.82(br d, J=4.2Hz, 1H). MS=641.2[M+1] + .

[0840] Table 22. The following compounds were prepared using a procedure similar to that described in Example 180 using the appropriate starting materials.

[0841]

[0842] Embodiment 183

[0843]

[0844] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo- 3-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide (Solution AAL)

[0845] 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 was added diisopropyl azodicarboxylate (0.92 mL, 4.7 mmol). The reaction mixture was stirred at rt 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 provide the regioisomeric title compounds in individual forms. The faster eluting regioisomer was 2-chloro-4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine: 1 H NMR ((500 MHz, CDCl 3 )δ8.45 (s, 1H), 8.43 (s, 1H), 6.00 (s, 2H), 2.68ppm (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, CDCl 3 )δ8.58 (s, 1H), 8.21 (s, 1H), 5.68 (s, 2H), 2.66ppm (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: 1 H NMR (500 MHz, CDCl 3 ,)δ8.53 (s, 1H), 8.27 (s, 1H), 5.66 (s, 2H), 2.61ppm (s, 3H). MS=254.9[M+1] + .

[0846] Step 2. (1R,5S)-3-(4-methyl-5-((4-nitro-1H-1,2,3-triazol-1-yl)methyl)pyrimidine-2-yl 1-(2-nitro-3-nitro-1-yl)-3-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)]methanesulfonate palladium(II) (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 provide the title compound. MS=316.0[M+1] + .

[0847] Step 3. (1R,5S)-3-(5-((4-amino-1H-1,2,3-triazol-1-yl)methyl)-4-methylpyrimidine-2-yl 1-(2-nitro-3-nitro-1-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] + .

[0848] 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-carboxylic acid Amide:To 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 N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (11 mg, 0.038 mmol). The reaction mixture was stirred at rt for 2 hours. The mixture was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.2 m MHFBA + 0.1% TFA) - ACN start B 40% end B 70%) to provide the title compound. 1 H NMR (400 MHz, CD 3 OD) δ 8.92 (d, J = 2.7Hz, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 7.87–7.77 (m, 1H), 7.68 (d, J = 9.4Hz, 1H), 7.11–6.76 (m, 1H), 5.70 ( s, 2H), 4.20 (dd, J=11.3, 5.1Hz, 1H), 4.04 (d, J=11.0Hz, 1H), 2.99 (s, 3H), 2.53 (s, 3H), 2.18–2.07 (m, 2H), 1.36–1.22 (br m, 1H), 0.87ppm (br d, J=3.9Hz, 1H). MS=584.2[M+1] + .

[0849] Table 23. The following compounds were prepared using procedures similar to those described in Example 183 using appropriate starting materials.

[0850]

[0851]

[0852] Embodiment 188

[0853]

[0854] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-((1R,5S)-2-oxo- (3-(4-(2-nitro-3-nitro-1-nitro-2-yl)pyrimidin-5-yl)cyclobutyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAM)

[0855] Step 1. (1R,5S)-3-(5-(1-hydroxycyclobutyl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0] Hexane-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), Xantphos (58 mg, 0.10 mmol) and tris(dibenzylideneacetone)dipalladium (81. mg, 0.10 mmol) were added. 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 provide the title compound. MS=260.0[M+1] + .

[0856] 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 toluene (3.0 mL) 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) 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 rt and concentrated under reduced pressure. The crude residue was purified by preparative TLC (1:0 EtOAc / petroleum ether) to provide the title compound. MS=355.0[M+1] + .

[0857] 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] + .

[0858] 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-carboxylic acid Amide: The title compound was prepared following a procedure similar to that described in Example 1, Step 5, above. 1 H NMR (500 MHz, CD 3OD) δ 8.88 (d, J = 2.4Hz, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 7.84 (t, J = 7.8Hz, 1H), 7.75 (s, 1H), 7.68 (d, J = 8.5Hz, 1H), 7.08–6.81(m, 1H), 4.30–4.17(m, 1H), 4.07(d, J=11.6Hz, 1H), 3.18–3.06(m, 2H), 3.00(s, 3H), 2.95(br d, J=8.9Hz, 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, 4.9Hz, 1H), 0.91 (br d, J=4.0Hz, 1H). MS=623.2[M+1] + .

[0859] Examples 189 and 190

[0860]

[0861] N-(1-((S)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridine- 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 1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide (Scheme AAN)

[0862] The title compound was prepared as a starting mixture of diastereomers following a procedure analogous to that described above for Intermediate AE-5, Step 4. The isomers were purified by chiral chromatography (SFC, REGIS (S,S) WHELK-O1; 0.1% NH 3 H 2 O EtOH start B 55% end B 55%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 189): 1 H NMR (500 MHz, CD 3OD) δ8.88 (d, J=2.4Hz, 1H), 8.26 (s, 1H), 7.84 (t, J=7.8Hz, 1H), 7.75 (s, 1H), 7 .74(d, J=1.8Hz, 1H), 7.69(d, J=8.5Hz, 1H), 7.18(s, 1H), 6.96(s, 1H), 5.60(br d, J=7.0Hz, 1H), 4.22 (dd, J=10.5, 6.0Hz, 1H), 3.69 (d, J=10.7Hz, 1H), 3.01 ( s, 3H), 2.13–2.23 (m, 1H), 2.08–1.99 (m, 1H), 1.91 (d, J=7.3Hz, 3H), 1.30 (br dd, J=8.2, 4.6Hz, 1H), 1.04–0.97 (m, 1H). MS=597.0[M+1] + The slower eluting diastereomer of the title compound (Example 190): 1 H NMR (500 MHz, CD 3 OD) δ8.88 (d, J=2.4Hz, 1H), 8.26 (s, 1H), 7.84 (t, J=7.8Hz, 1H), 7.76–7.74 (m, 1H), 7.7 3(d, J=1.8Hz, 1H), 7.69 (d, J=8.2Hz, 1H), 7.17 (d, J=1.8Hz, 1H), 7.11–6.81 (m, 1H), 5.6 0 (q, J=7.0Hz, 1H), 4.22 (dd, J=10.7, 5.8Hz, 1H), 3.69 (d, J=10.4Hz, 1H), 3.01 (s, 3H), 2 .19–2.10(m, 1H), 2.10–2.02(m, 1H), 1.91(d, J=7.3Hz, 3H), 1.32–1.23(m, 1H), 1.01(br d, J=3.4Hz, 1H). MS=597.0[M+1] + .

[0863] Table 24. The following compounds were prepared using procedures similar to those described in Examples 189 and 190 using appropriate starting materials.

[0864]

[0865] Embodiment 192

[0866]

[0867] 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-carboxylate Amine (Scheme AAO)

[0868] The title compound was prepared following a procedure analogous to that described in Example 41, step 4, above. 1 H NMR (400 MHz, CD 3 OD) δ 8.90 (d, J = 2.5Hz, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.80 (t, J = 7.8Hz, 1H), 7.70 (s, 1H), 7.64 (d, J = 8.3Hz, 1H), 7.09–6.78 (m, 1H), 5.64 (d, J=7.1Hz, 1H), 5.06 (s, 2H), 4.15 (dd, J=4.3, 11.6Hz, 1H), 3.97 (d, J=11.5Hz, 1H), 2.09 (dd, J=3.4, 8.1Hz, 2H), 1.90 (d, J=7.1Hz, 3H), 1.26 (br s, 1H), 1.24 (s, 9H), 0.85–0.76 (m, 1H). MS=655.1[M+1] + .

[0869] Embodiment 193

[0870]

[0871] 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)

[0872] The title compound was prepared following a similar procedure as described in Intermediate AE-5, Step 4 above. 1 H NMR (400 MHz, CDCl 3 )δ9.82(br s, 1H), 8.99 (d, J=2.5Hz, 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=7.0Hz, 1H), 5.28 (s, 2H), 4.14 (dd, J=5.7, 11.37Hz, 1H), 3.98 (br s, 1H), 2.15 (br s, 1H), 2.07–1.99 (m, 1H), 1.93 (br d, J=6.8Hz, 3H), 1.28–1.17 (m, 1H), 0.86 (br d, J=3.4Hz, 1H). MS=599.2[M+1] + .

[0873] Table 25. The following compounds were prepared using procedures analogous to those described in Examples 192 and 193 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0874]

[0875]

[0876]

[0877]

[0878] Embodiment 207

[0879]

[0880] (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(3-methyl- 2-Oxoimidazolin-1-yl)pyrimidin-5-yl)ethyl)-1 H -pyrazol-4-yl)pyrazine-2-carboxamide (Scheme AAP)

[0881] Step 1. ()-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methyl)- (thio)pyrimidin-5-yl)ethyl)-1 H -pyrazol-4-yl)pyrazine-2-carboxamide: The title compound was prepared following a similar procedure as described above in Example AAA-10a, Step 5. MS = 548.1 [M+1] + .

[0882] Step 2. (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(methyl)- (2-(4-(2-(4-(2-(4-(2-pyrazol-4-yl)pyrazine-2-carboxamide)))-1H-pyrazol-4-yl)-2-carboxamide) To 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 (240 mg, 0.38 mmol). The reaction mixture was stirred at rt for 2 hours. Water was added to the mixture and the resulting mixture was extracted with EtOAc. The organic layers were combined and washed with water. 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by preparative TLC (1:1 EtOAc / petroleum ether) to provide the title compound. MS=580.1[M+1] + .

[0883] Step 3. (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(3- methyl-2-oxoimidazolin-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-methylimidazolin-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 start B 33%, end B 63%) to provide the title compound. 1 H NMR (400 MHz, CD 3 OD) δ8.86 (d, J=2.3Hz, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.86–7.77 (m, 1H), 7.73 ( s, 1H), 7.66 (d, J=8.6Hz, 1H), 7.08–6.75 (m, 1H), 5.87 (d, J=6.7Hz, 1H), 4.10 (br d, J=8.2Hz, 2H), 3.66–3.56 (m, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.56 (s, 3H), 1.90 (d, J=7.0Hz, 3H). MS=600.2[M+1] + .

[0884] Examples 208 and 209

[0885]

[0886] 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-carboxylic acid Amine 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]hexyl-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide (square Case AAQ)

[0887] 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 uL, 0.70 mmol) in DCM (10 mL) was added (1R, 5S)-3-(6-((4-amino-1H-pyrazol-1-yl)methyl)-4-methylpyridazine-3-yl)-3-azabicyclo[3.1.0]hexan-2-one (100 mg, 0.352 mmol). The mixture was stirred at rt 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 provide the title compound. MS=595.1[M+1] + .

[0888] 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-yl Formamide: At rt, under an oxygen atmosphere, to a solution of 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-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-heptanedione)manganese(III) (12 mg, 0.020 mmol). The reaction mixture was stirred at rt 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 and washed with brine and heated to 40 ℃ for 10 minutes. 2 SO 4 The crude residue was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN starting B 35% ending B 55%) to provide a mixture of diastereomeric title compounds. The residue was purified by chiral chromatography (SFC, DAICEL CHIRALCEL OJ-H; 0.1% NH 3 H 2 O MeOH start B 25% end B 25%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 208): 1 H NMR (400 MHz, CD 3OD) δ8.98 (d, J=2.5Hz, 1H), 8.31 (s, 1H), 7.81 (t, J=7.7Hz, 1H), 7.74 (s, 1H), 7.66 (d , J=8.6Hz, 1H), 7.36 (s, 1H), 6.93 (t, J=54.4Hz, 1H), 5.80 (q, J=6.6Hz, 1H), 5.60 (s, 2 H), 4.45 (dd, J=5.7, 10.39Hz, 1H), 3.80 (d, J=9.5Hz, 1H), 2.25–2.18 (m, 1H), 2.17 (s, 3H), 2.09–2.01(m, 1H), 1.60(d, J=6.4Hz, 3H), 1.35–1.31(m, 1H), 1.00–0.93(m, 1H). MS=613.2[M+1] + The slower eluting diastereomer of the title compound (Example 209): 1 H NMR (400 MHz, CD 3 OD) δ8.97 (d, J=2.5Hz, 1H), 8.30 (s, 1H), 7.81 (t, J=7.7Hz, 1H), 7.74 (s, 1H), 7.65 (d, J=8.3Hz, 1H), 7.36 (s, 1H), 6.95 (t, J=54. 8Hz, 1H), 5.80 (q, J=6.6Hz, 1H), 5.60 (s, 2H), 4.45 (dd, J=5.7, 10.39Hz, 1H), 3.80 (d, J=10.5Hz, 1H), 2.26–2.15 (m, 4H), 2.05 (br t, J=5.6Hz, 1H), 1.60 (d, J=6.4Hz, 3H), 1.36–1.31 (m, 1H), 1.01–0.93 (m, 1H). MS=613.2[M+1] + .

[0889] Table 26. The following compounds were prepared using procedures analogous to those described in Examples 208 and 209 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0890]

[0891]

[0892]

[0893] Embodiment 215

[0894]

[0895] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-4-methyl-5-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexyl-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide (square (AAR)

[0896] Step 1. (1R,5S)-3-(6-chloro-5-fluoro-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0]hexan-2-one: At rt, in a nitrogen-filled glove box, to 2-chloro-3-fluoro-5-iodo-4-methylpyridine (300mg, 1.11mmol), (1R, 5S)-3-azabicyclo [3.1.0] hexan-2-one (150mg, 1.55mmol) and cesium carbonate (1.08g, 3.32mmol) in toluene (5.0mL) solution, add [(4,5-bis (diphenylphosphine) -9,9- dimethylxanthene) -2- (2'-amino -1,1'- biphenyl)] methanesulfonate palladium (II) (Xantphos-Pd-G3, 60mg, 58μmol). After addition, the reaction vessel was sealed and stirred at 80 ° C for 15 hours. The reaction mixture was cooled to rt and then filtered, and the filtrate was concentrated under reduced pressure. By preparative TLC (SiO 2 The crude residue was purified by evaporation with 2:1 EtOAc / petroleum ether to provide the title compound. MS = 241.0 [M+1] + .

[0897] Step 2. (1R,5S)-3-(5-Fluoro-4-methyl-6-vinylpyridin-3-yl)-3-azabicyclo[3.1.0]hexane- 2-Keto: To 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 vinyl trifluoroborate (111 mg, 0.831 mmol) and TEA (126 mg, 1.25 mmol) in ethanol (5.0 mL), bis(di-tert-butylphosphino)ferrocenepalladium dichloride (30 mg, 41 μmol) was added. The reaction mixture was stirred at 80 ° C for 15 hours under a nitrogen atmosphere. The reaction was cooled to rt and then filtered, and the filtrate was concentrated under reduced pressure. By preparative TLC (SiO 2 The crude residue was purified by evaporation with 5% paraformaldehyde (EtOAc / petroleum ether, 3:2) to provide the title compound. MS = 233.1 [M+1] + .

[0898] Step 3. 3-Fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridine aldehyde: The title compound was prepared following a similar procedure as described above in Intermediate AE-5, Step 2. MS = 235.1 [M+1] + .

[0899] Step 4. (1R,5S)-3-(5-fluoro-6-(hydroxymethyl)-4-methylpyridin-3-yl)-3-azabicyclo[3.1.0] Hexane-2-one: The title compound was prepared following a similar procedure as described above in Intermediate BJ-5a, Step 3. MS = 237.1 [M+1] +.

[0900] 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] + .

[0901] 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] + .

[0902] 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-carboxylate amine: The title compound was prepared following a procedure similar to that described in Example 1, step 5, above. 1 H NMR (400 MHz, CDCl 3 )δ9.76(s, 1H), 8.94(d, J=3.1Hz, 1H), 8.24(br d, J=15.7Hz, 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, 5.3Hz, 1H), 3.64 (br d, J=10.2Hz, 1H), 3.15 (s, 3H), 2.19–2.08 (m, 5H), 1.34 (td, J=8.0, 5.5Hz, 1H), 0.90 (q, J=4.2Hz, 1H). MS=600.2[M+1] + .

[0903] Examples 216 and 217

[0904]

[0905] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-hydroxy-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexyl-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-azabiphenyl) Cyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide (Scheme AAS)

[0906] Step 1. (1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-1H-pyrazole- 4-yl) tert-butyl carbamate:The following sequence is carried out in three batches in parallel on an equivalent scale. These batches are combined for subsequent post-reaction processing. At 0 ° C, to (1H-pyrazole-4-yl) tert-butyl carbamate (65.0g, 355mmol) in DMF (1.30L) solution, sodium hydride (17.0g, 426mmol, 60% dispersion in mineral oil) is added. The resulting mixture is then dropwise added 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130g, 461mmol) at 0 ° C for 1 hour. After addition was completed, the reaction mixture was stirred at rt for 11 hours. The reaction mixture was merged and by adding saturated NH 4 The solution was quenched with aqueous Cl solution and extracted with a 10:1 mixture of EtOAc / MeOH. The organic layers were combined and washed with water then brine and concentrated in Na 2 SO 4 The reaction mixture was dried over medium, filtered and concentrated under reduced pressure to provide (1-(4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)boronic acid. The following sequence was carried out in parallel in two batches on an equivalent scale. These batches were combined for subsequent post-reaction processing. 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 provide the title compound.

[0907] Step 2. Potassium (1-(4-((tert-Butoxycarbonyl)amino)-1H-pyrazol-1-yl)ethyl)trifluoroborate: The following sequence is carried out in three batches in parallel on an equivalent scale. These batches are merged for subsequent post-reaction processing. To (1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) ethyl)-1H-pyrazole-4-yl) MeOH (1.35L) solution of tert-butyl carbamate (135g, 400mmol), potassium bifluoride (125g, 1.60mol) is added. The resulting mixture was stirred for 12 hours at rt. The reaction mixture is merged, and concentrated under reduced pressure. The thick residue is suspended in EtOAc and filtered. The solid is washed with acetone, and the filtrate combined is concentrated under reduced pressure, to provide the title compound: 1 H NMR: (400 MHz, DMSO-d 6 ) δ 8.85 (s, 1H), 7.56 (s, 1H), 7.09 (s, 1H), 3.13 (br d, J = 3.2Hz, 1H), 1.44 (s, 9H), 1.10 (d, J = 7.2Hz, 3H).

[0908] Step 3. (1-(1-(6-chloro-5-((4-methoxybenzyl)oxy)pyridin-3-yl)ethyl)-1 H -pyrazol-4-yl) Tert-Butyl Carbamate: In a nitrogen-filled glove box, lithium hydroxide (109 mg, 4.56 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (49 mg, 0.18 mmol), [Ir{dFCF] were added 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). 3 ppy} 2 (bpy)]PF 6 (33 mg, 38 μmol). The reaction mixture was stirred at rt for 6 hours in front of a single blue LED (450 nm). The mixture was quenched by adding water and extracted with EtOAc. The organic layers were combined and washed with brine and heated to 40 ℃ for 10 minutes. 2 SO 4 Dry over medium, filter and then concentrate under reduced pressure. The crude residue is purified by silica gel chromatography (0 to 30% EtOAc / petroleum ether) to provide the title compound. MS = 459.2 [M+1] + .

[0909] Step 4. (1-(1-(5-((4-methoxybenzyl)oxy)-6-((1R,5S)-2-oxo-3-azabicyclo [3.1.0] tert-butyl (hexyl)-3-yl)-pyridin-3-yl)-ethyl)-1H-pyrazol-4-yl)carbamate: A 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) and (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 for 14 hours under a nitrogen atmosphere. The mixture was cooled to rt, then quenched by adding water and extracted with EtOAc. The organic layers were combined and washed with brine, and the mixture was concentrated to 4% by volume. 2 SO 4 Dry over medium, filter and then concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 10% MeOH / DCM) to provide the title compound. MS = 520.3 [M+1] + .

[0910] 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 similar procedure as described above in Intermediate AE-5, Step 4. MS = 300.1 [M+1] + .

[0911] 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-carboxylic acid Amide and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexyl-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide: The title compound was prepared as a starting mixture of diastereomers following a procedure analogous to that described above in Example 1, Step 5. The isomers were purified by chiral chromatography (SFC, DAICEL CHIRALCEL AD; 0.1% NH 3 H 2 O IPA start B 40% end B 40%) separation of diastereomeric title compounds to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 216): 1 H NMR (500 MHz, CD 3 OD) δ8.88 (d, J=2.4Hz, 1H), 8.26 (s, 1H), 7.85 (dd, J=15.3, 7.2Hz, 2H), 7.78–7.64 (m, 2H), 7.18 (s, 1H), 7.12–6.73 (t, J=54.4Hz, 1H), 5.63 (q, J=7.0Hz, 1H), 4.24(br dd, J=10.9, 6.0Hz, 1H), 3.86 (br d, J=11.0Hz, 1H), 3.01 (s, 3H), 2.24–2.04 (m, 2H), 1.92 (d, J=7.2Hz, 3H), 1.39–1.31 (m, 1H), 0.95 (br d, J=3.4Hz, 1H). MS=598.2[M+1] + The slower eluting diastereomer of the title compound (Example 217): 1 H NMR (400 MHz, CD 3OD): δ8.84 (d, J=2.4Hz, 1H), 8.21 (s, 1H), 7.90–7.75 (m, 2H), 7.71 (s, 1H), 7.64 (d, J =8.6Hz, 1H), 7.13(s, 1H), 7.07–6.77(t, J=54.4Hz, 1H), 5.65–5.53(m, 1H), 4.20(br dd, J=11.1, 6.0Hz, 1H), 3.81 (br d, J=11.0Hz, 1H), 2.97 (s, 3H), 2.17–2.02 (m, 2H), 1.87 (d, J=7.1Hz, 3H), 1.30–1.25 (m, 1H), 0.91 (br d, J=3.4Hz, 1H). MS=598.2[M+1] + .

[0912] Table 27. The following compounds were prepared using procedures analogous to those described in Examples 216 and 217 using the appropriate starting materials. In some embodiments, racemic products or diastereomeric mixtures were separated using a chiral column (SFC or HPLC) as specified in the table.

[0913]

[0914]

[0915] Embodiment 220

[0916]

[0917] 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(6-methyl-5-((1R,5S)-2-oxo- (Scheme) AAT)

[0918] 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 trifluoromethanesulfonate (486 mg, 1.34 mmol) and DBU (0.30 mL, 2.0 mmol). The reaction mixture was stirred at rt for 14 hours under a nitrogen atmosphere. EtOAc was added to the mixture, and the resulting mixture was washed with water and brine, and then heated to room temperature under Na 2 0 0 4 0 4 0 0 4 0 0 4 0 0 4 0 0 4 0 0 4 0 0 4 0 0 4 0 0 2 SO 4 Dry over medium, filter and concentrate under reduced pressure. The crude residue was purified by silica gel chromatography (0 to 25% EtOAc / petroleum ether) to provide the title compound. MS = 324.0, 326.0 [M+1] + .

[0919] 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-one:Under nitrogen atmosphere, to (1R, 5S) -3- azabicyclo [3.1.0] hexan-2-one (81.0mg, 0.833mmol), 2- bromo-3-methyl -5- (1- (4- nitro -1H- pyrazol -1- base) cyclopropyl) pyrazine (180mg, 0.555mmol) and cesium carbonate (543mg, 1.67mmol) mixture, add tri (dibenzylideneacetone) dipalladium (51mg, 56μmol) and Xantphos (32mg, 56μmol). The reaction mixture was stirred at 100 ℃ for 14 hours. The mixture was cooled to rt and concentrated under reduced pressure. Water was added to the mixture, and the resulting mixture was then extracted with DCM. The organic layers were combined and heated to 40 ℃ for 14 hours. 2 SO 4 Dry over medium, filter and concentrate 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] + .

[0920] 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 at rt for 2 hours under a hydrogen atmosphere (pressure: 15 psi). The crude mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound. MS=311.1 [M+1] + .

[0921] 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-carboxylic acid Amide: The title compound was prepared following a procedure analogous to that described above in Example 41, Step 4. 1 H NMR (400 MHz, CD 3OD) δ8.87 (d, J=2.4Hz, 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=54.8Hz, 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] + .

[0922] Table 28. The following compounds were prepared using a procedure similar to that described in Example 220 using the appropriate starting materials.

[0923]

[0924]

[0925] Examples 224 and 225

[0926]

[0927] 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-methyl Pyrazine-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-pyrazole-4- 1-Methyl-2-pyrazine-3-carboxamide (Scheme AAU)

[0928] Step 1. 2-Chloro-5-iodo-3-methoxy-4-methylpyridine: At rt, to a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (2.3 g, 8.5 mmol) in MeOH (40 mL), sodium methoxide (0.69 g, 13 mmol) was added. The reaction mixture was stirred at 80 ° C for 48 hours. The reaction mixture was cooled to rt and water was added to the mixture. The resulting mixture was extracted with EtOAc, and the organic layers were then combined and washed with brine. 2 SO 4 The product was dried over 400 °C, filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography (0 to 7% EtOAc / petroleum ether) and then by reverse phase preparative HPLC (C18 stationary phase, 30% ACN / H 2 The crude residue was purified by HPLC (0 + 0.5% TFA) to provide the title compound. MS = 283.9 [M + 1] + .

[0929] Step 2. 1-(6-Chloro-5-methoxy-4-methylpyridin-3-yl)ethan-1-one:The title compound was prepared following a similar procedure as described above in Intermediate BI-4a, Step 1. Aqueous MS = 200.1 [M+1] + .

[0930] 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) was added sodium borohydride (0.32 g, 8.4 mmol) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was heated to 40°C by adding saturated NH 4 The mixture was quenched with aqueous Cl solution 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 provide the title compound. MS = 202.1 [M+1] + .

[0931] 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 Example 183, Step 1. MS = 297.0 [M+1] + .

[0932] Step 5. 2-Chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-3-ol: To a stirred 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) at 0°C, boron tribromide (1.0 mL, 11 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at rt for 12 hours. 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 to 30% EtOAc / petroleum ether) to provide the title compound. MS=283.0[M+1] + .

[0933] Step 6. 2-Chloro-3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridine:At rt, to a stirred solution of 2-chloro-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl)pyridin-3-ol (420mg, 1.49mmol) in DMF (8.0mL), 2-chloro-2,2-difluoroacetic acid sodium (340mg, 2.23mmol) and cesium carbonate (968mg, 2.97mmol) were added, 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 provide the title compound. MS=333.0[M+1] + .

[0934] Step 7. (1R,5S)-3-(3-(difluoromethoxy)-4-methyl-5-(1-(4-nitro-1H-pyrazol-1-yl)ethyl 1-Azabicyclo[3.1.0]hexan-2-one: To 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 rt, 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] + .

[0935] Step 8. (1R,5S)-3-(5-(1-(4-amino-1H-pyrazol-1-yl)ethyl)-3-(difluoromethoxy)-4-methyl 2-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] + .

[0936] 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-methyl Pyrazine-2-carboxamide: The title compound was prepared as a starting mixture of diastereomers following a procedure analogous to that described above in Example 1, Step 5. The product was purified by chiral chromatography (SFC, Phenomenex-Cellulose-2; 0.1% NH 3 H 2 O EtOH start B 55% end B 55%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 224): 1H NMR (400 MHz, CD 3 OD) δ8.85 (d, J=2.4Hz, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.78–7.85 (m, 1H), 7.74 (s, 1H), 7.66 ( d, J=8.6Hz, 1H), 7.10–6.78 (t, J=54.8Hz, 1H), 6.76–6.36 (t, J=72.8Hz, 1H), 5.86 (q, J=7.0Hz , 1H), 4.26 (dd, J=10.3, 5.9Hz, 1H), 3.67 (d, J=10.3Hz, 1H), 2.98 (s, 3H), 2.34 (s, 3H), 2.21– 2.12 (m, 1H), 2.05–1.97 (m, 1H), 1.92 (d, J=6.8Hz, 3H), 1.28–1.22 (m, 1H), 1.00–0.93 (m, 1H). MS=662.2[M+1] + The slower eluting diastereomer of the title compound (Example 225): 1 H NMR (400 MHz, CD 3 OD) δ8.86 (d, J=2.4Hz, 1H), 8.23 ​​(s, 1H), 8.14 (s, 1H), 7.81 (t, J=7.8Hz, 1H), 7.72 (s, 1H), 7.66 ( d, J=8.6Hz, 1H), 7.09–6.77 (t, J=54.8Hz, 1H), 6.73–6.33 (t, J=73.2Hz, 1H), 5.86 (q, J=7.1Hz, 1 H), 4.28(dd, J=10.3, 5.9Hz, 1H), 3.65(d, J=10.5Hz, 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=7.1Hz, 3H), 1.25 (dt, J=8.0, 3.9Hz, 1H), 1.00–0.93 (m, 1H). MS=662.2[M+1] + .

[0937] Examples 226 and 227

[0938]

[0939] 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-yl Formamide 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-yl Formamide (Scheme AAV)

[0940] 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, 2M in toluene). The reaction mixture was stirred at rt for 30 minutes, then a solution 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) was added. The resulting mixture was stirred at rt 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 provide a mixture of diastereomeric title compounds. By chiral chromatography (SFC, DAICEL CHIRALCEL AD; 0.1% NH 3 H 2 O EtOH start B 45% end B 45%) to separate the diastereomeric title compound to provide the individual isomeric compounds in pure form. The faster eluting diastereomer of the title compound (Example 226): 1 H NMR (400 MHz, CD 3 OD) δ8.90 (s, 1H), 8.26 (s, 1H), 8.16 (d, J = 1.7Hz, 1H), 7.77–7.67 (m, 2H) , 7.61(d, J=1.7Hz, 1H), 7.24(d, J=9.1Hz, 1H), 7.13–6.72(m, 1H), 5.62(d , J=7.1Hz, 1H), 5.21 (s, 2H), 4.22 (dd, J=5.9, 10.5Hz, 1H), 3.65 (d, J=10. 3Hz, 1H), 2.13 (s, 4H), 2.03–1.96 (m, 1H), 1.89 (d, J=7.1Hz, 3H), 1.26 (br s, 1H), 0.94–0.87 (m, 1H). MS=628.2[M+1] + The slower eluting diastereomer of the title compound (Example 227): 1 H NMR (400 MHz, CD 3OD)δ8.82(br s, 1H), 8.18 (s, 1H), 8.09 (d, J=1.9Hz, 1H), 7.66 (s, 1H), 7.62 (t, J=8.7Hz, 1H), 7.5 2(d, J=1.7Hz, 1H), 7.16(d, J=9.1Hz, 1H), 7.04–6.65(m, 1H), 5.54(q, J=7.1Hz, 1H), 5.13 (s, 2H), 4.14 (dd, J=6.0, 10.4Hz, 1H), 3.57 (d, J=10.3Hz, 1H), 2.10–2.02 (m, 4 H), 1.96–1.88 (m, 1H), 1.81 (d, J=7.1Hz, 3H), 1.21–1.19 (m, 1H), 0.85–0.80 (m, 1H). MS=628.2[M+1] + .

[0941] Embodiment 228

[0942]

[0943] 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)

[0944] 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]hex-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 rt for 12 hours. The mixture was concentrated under reduced pressure and the crude product was purified by reverse phase preparative HPLC (C18 stationary phase, water (0.1% TFA)-ACN start B 45% end B 75%) to provide a mixture of diastereomeric title compounds. 1 H NMR (500 MHz, CD 3OD)δ8.87(s,1H),8.28(s,1H),8.21(br d,J=5.3Hz,1H),7.72–7.76(m,2H),7.64(br s,1H),7.27(br d, J=9.3Hz, 1H), 7.10–6.77 (m, 1H), 5.73–5.64 (m, 1H), 5.09 (s, 2H), 4.26 (dd, J=5.9, 10.3Hz, 1H), 3.70 (d, J=11.4Hz, 1H), 2.18 (s, 4H), 2.04 (br d, J=5.2Hz, 1H), 1.94 (d, J=7.2Hz, 3H), 1.33–1.31 (m, 1H), 1.28 (s, 9H), 0.96 (br s, 1H). MS=684.0[M+1] + .

[0945] Table 29. The following compounds were prepared using procedures analogous to any of the above using appropriate starting materials.

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956] Factor XIa assay

[0957] The effectiveness of the compounds of the present invention as inhibitors of coagulation factor XIa can be determined using the relevant purified serine proteases and appropriate synthetic substrates. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the relevant serine protease is measured in the absence and presence of the compounds of the present invention. The assay is performed at room temperature or 37°C. The hydrolysis of the substrate results in the release of aminotrifluoromethylcoumarin (AFC), which is monitored by spectrofluorometry by measuring the increase in emission at 510nm accompanied by excitation at 405nm. In the presence of an inhibitor, a decrease in the rate of change of fluorescence indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of the assay are expressed as half maximal inhibitory concentration (IC50) or inhibition constant K i .

[0958] Compounds were pre-incubated with human (0.04 nM) factor XIa at 25°C in 50 mM HEPES buffer with 150 mM sodium chloride, 5 mM calcium chloride, 0.1% PEG 8000, pH 7.4 for 30 minutes. Factor XIa enzymatic activity was determined by adding the substrate glycine-proline-arginine-7-amido-4-trifluoromethylcoumarin (GPR-AFC) and measuring the fluorescence at 400 / 505 nm after a 60 minute incubation at 25°C. The % inhibition for each data point was calculated from the data and analyzed using the log(inhibitor) versus response four-parameter equation to determine the half maximal inhibitory concentration (IC50). The IC50 was converted to an equilibrium inhibition constant (Ki) using the Cheng-Prusoff equation.

[0959] The activity demonstrated by this assay indicates that the compounds of the invention may be used therapeutically to treat or prevent a variety of cardiovascular and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndrome, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, stroke such as thrombotic stroke or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation and reocclusion or restenosis of recanalized vessels.

[0960] Kallikrein assay

[0961] The effectiveness of the compounds of the present invention as inhibitors of kallikrein can be determined using the relevant purified serine proteases and appropriate synthetic substrates. The rate of hydrolysis of a chromogenic or fluorogenic substrate by the relevant serine protease is measured in the absence and presence of the compounds of the present invention. The assay is performed at room temperature or 37°C. The hydrolysis of the substrate results in the release of aminotrifluoromethylcoumarin (AFC), which is monitored by spectrofluorometry by measuring the increase in emission at 510nm accompanied by excitation at 405nm. In the presence of an inhibitor, a decrease in the rate of change of fluorescence indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of the assay are expressed as half-maximal inhibitory concentration (IC50) or inhibition constant K i .

[0962] In the presence of 150 mM NaCl, 5 mM CaCl 2 Kallikrein assays were performed in 50 mM HEPES buffer (pH 7.4) with 0.1% PEG 8000 (polyethylene glycol; Fisher Scientific). The assays were performed using purified human plasma kallikrein at a final concentration of 0.5 nM (Enzyme Research Laboratories) and the synthetic substrate acetyl-KPR-AFC (Sigma #C6608) at a concentration of 100 mM.

[0963] Activity assays are performed by diluting a stock solution of substrate at least ten-fold to a final concentration ≤ 0.2 Km into a solution containing the enzyme or the enzyme equilibrated with an inhibitor. The time required to achieve equilibrium between the enzyme and the inhibitor is determined in control experiments. Reactions are performed under linear progress curve conditions and the fluorescence increase is measured at 405Ex / 510Em nm. Values ​​are converted to percent inhibition of the control reaction (after subtracting the 100% inhibition value). IC 50 Determined by the inflection point from a four-parameter logistic curve fit. Ki was calculated using the Cheng Prusoff equation, Ki = IC 50 / (1+([S] / Km)).

[0964] The activity demonstrated by this assay indicates that the compounds of the invention may be therapeutically useful for treating or preventing a variety of ocular, cardiovascular and / or cerebrovascular thromboembolic conditions in patients suffering from unstable angina, acute coronary syndrome, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, stroke such as thrombotic stroke or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, reocclusion or restenosis of recanalized vessels, hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion.

[0965] The plasma kallikrein (PKal) and factor XIa (FXIa) IC50 (nM) for the selected compounds are as follows:

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: in Selected from for in V is CH or N; X is CH or N; Y is N or NO; and Z is CR 4 ;or for in V is N; and Z is C-CH3; E is N or CH; Q is N or CH; G is N or CR 7 ; J is N or CR 7 ; L is N or CR 7 ; M is N or CR 8 ; R 1 is selected from hydrogen, halogen, cyano, R x , OR x and SO2R x ; R 2 is hydrogen or a halogen; R 3 is hydrogen or a halogen; 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 1-3 Alkyl, which is optionally substituted with 1 to 3 substituents selected from halogen and hydroxy; R 6 is hydrogen or C 1-3 alkyl; or R 5 and R 6 Together with the carbon atoms between them, they form C 3-6 Cycloalkyl; Each R 7 are independently selected from halogen, R x , OR x , C 1-3 Alkyl-OR x 、NH(C=O)OR x and NH2; R 8 Selected from R x OR x ; or R 7 and R 8 Together with the carbon atoms between them, they form a 5-membered cycloalkyl or heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 2 substituents independently selected from halogen, methyl and ethyl; R 9 is hydrogen or C 1-3 alkyl; R 10 is hydrogen, hydroxyl or C 1-3 alkyl; R x is hydrogen or C 1-6 Alkyl which is optionally substituted with 1 to 4 substituents selected from halogen and hydroxy.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein E is CH and when for When , Z is CH.

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein yes 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, CH3, CHF2, CF3, OCHF2 and SO2CH3.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from cyano, CH3, CHF2, CH2OH, CH2OCH3, CH2OC(CH3)3, CH2O(cyclopropyl), CH(OH)CF3, CH2C(CH3)2OH, CD2OH, CH(CH3)OH and OCH3.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, CH3 or CH2OH.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein for When X is N, Y is N, and V is CH.

8. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R 7 independently selected from hydrogen, chlorine, fluorine, CH3, OCH3, CHF2, OCHF2, CH2OH, NH2 and NH(C=O)OR x .

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 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]hex-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((R or S)-1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-((5-chloro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide; N-(1-((5-chloro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(6-((1R,5S or 1S,5R)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((2-((1R,5S)-2-oxo-3-azabicyclo-[3.1.0]hex-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; (S and R)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(2-(7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; (S and R)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(2-(5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; (S and R)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(2-(3-methyl-2-oxoimidazolin-1-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(2-((1R,5S)-2-thioxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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; 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-3-vinylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-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; 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; 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; 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; 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(2,3-dimethyl-4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)benzyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(3-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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)cyclopropyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(6-ethyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(3-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S and R)-1-(4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)phenyl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)-N-(1-((S or R)-1-(2-((1R,5S or 1S,5R)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((S or R)-1-(2-((1R,5S or 1S,5R)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(6-((1R,5S or 1S,5R)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-(difluoromethyl)-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-N-(1-((S or R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-1-methyl-N-(1-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyrimidine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 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)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-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; 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-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; 6-(3-chloro-2-fluoro-6-(methylsulfonyl)phenyl)-N-(1-((S or R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(2-((R or S)-3-hydroxy-2-oxopyrrolidin-1-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-cyano-2-fluorophenyl)-N-(1-((S or R)-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-((S)-1-(5-chloro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)-N-(1-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((4-methoxy-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; tert-butyl (5-((S and R)-1-(4-(6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamido)-1H-pyrazol-1-yl)ethyl)-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)carbamate; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(2-methyl-4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)phenyl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(2-methyl-4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)phenyl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or 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; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-2-fluoro-6-methylphenyl)-N-(1-((S or R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-2-fluoro-6-methylphenyl)-N-(1-((4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-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; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((S or 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(cyclopropyloxymethyl)-N-(1-((2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-((S or R)-1-(3-amino-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyridazine-4-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxymethyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-N-(1-((R or S)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-cyano-2-fluorophenyl)-N-(1-((S or R)-1-(5-fluoro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-cyano-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(1-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)benzyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R or S)-1-(3-fluoro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-((R or S)-1-(3-chloro-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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; 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]hex-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-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-2-hydroxy-1-(2-((1S,5R or 1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-2-hydroxy-1-(6-((1S,5R or 1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-2-hydroxy-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-cyano-2-fluorophenyl)-N-(1-((R or S)-2-hydroxy-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)-2-hydroxyethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-(1-(4-(hydroxymethyl)-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-((S)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide; N-(1-((R)-1-(4-amino-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-5-((1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)carbamoyl)pyridine 1-oxide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(difluoromethyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxymethyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)-3-((S or R)-2,2,2-trifluoro-1-hydroxyethyl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S)-1-(4-methyl-2-((1R,5S or 1S,5R)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl-4,4-d2)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(2-hydroxypropan-2-yl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl-d2)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(2-((4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)methyl)-2H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(2-((6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(2-((5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-2H-1,2,3-triazol-4-yl)pyrazine-2-carboxamide; 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; N-(1-((S)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide; N-(1-((R)-1-(5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide; N-(1-((5-amino-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methylpyrazine-2-carboxamide; 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S or R)-1-(4-methyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-(tert-butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S and R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-(hydroxymethyl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-N-(1-((S or R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-fluoro-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-(hydroxymethyl)pyrazine-2-carboxamide; (S)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-(1-(4-methyl-2-(3-methyl-2-oxoimidazolin-1-yl)pyrimidin-5-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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; 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((S or R)-1-hydroxyethyl)-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethyl-N-(1-((S and R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((3-fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S)-1-(5-hydroxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(5-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(methoxymethyl)-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; 3-(tert-Butoxymethyl)-6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(hydroxymethyl)-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; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 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]hex-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((R or S)-1-hydroxyethyl)-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethyl-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; 6-(3-chloro-6-cyano-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-cyano-2-fluorophenyl)-3-methyl-N-(1-((S or 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; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethyl-N-(1-((S or R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-methoxy-N-(1-((S or R)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyrazin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R or S)-1-(3,4-dimethyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(3-fluoro-4-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(2,2-difluoro-4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)ethyl)-1H-pyrazol-4-yl)-3-methylpyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((S or R)-1-(2,2-difluoro-4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-N-(1-((R or S)-1-(4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-methyl-N-(1-((S or R)-1-(4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hex-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-((R or S)-1-hydroxyethyl)-N-(1-((4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide; and 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-3-ethyl-N-(1-((4-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-[1,3]dioxolano[4,5-c]pyridin-7-yl)methyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide.

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

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

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

13. Use of the composition of claim 11 in the preparation of a medicament for treating impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from postoperative surgery in a mammal.

14. The use according to claim 13, wherein the medicament is for treating inflammatory bowel disease or arthritis.

15. The use of claim 13, wherein the composition is further administered in combination with 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.

16. Use of the composition of claim 11 in the preparation of a medicament for treating uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal.

17. Use of the composition of claim 11 in the preparation of a medicament for treating diabetic retinopathy or diabetic macular edema in a mammal.

18. Use of the composition of claim 11 in the preparation of a medicament for treating retinal vein occlusion in a mammal.

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