Plasma kallikrein inhibitors

Abstract

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

Description

Background of the Invention

[0002] Plasma kallikrein is the zymogen of a trypsin-like serine protease and is present in plasma. Its gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein shares 58% homology with factor XI. Factor XIIIa undergoes proteolytic activation at the internal I 389-R390 bond, producing a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of plasma kallikrein is contained within 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 a complex with HMWK. Plasma kallikrein cleaves 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)).

[0003] Patients exhibiting a genetic defect on C1-esterase inhibitors have hereditary angioedema (HAE), a lifelong condition that causes intermittent swelling throughout the body, including the hands, feet, face, throat, genitals, and gastrointestinal tract. Analysis of blisters resulting from acute attacks has shown the presence of high levels of plasma kallikrein, and treatment with the protein-based, reversible plasma kallikrein inhibitor ikalatide (Kalbitor) has been approved by the FDA for the treatment of acute attacks of HAE (Schneider, L. et al., J. Allergy Clin. Immunol., 120: 416 (2007)).

[0004] Furthermore, the plasma kallikrein-kinin system is abnormally abundant in patients diagnosed with advanced diabetic macular edema (DME). Recent publications have shown that plasma kallikrein promotes 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 improved the observed retinal vascular permeability and other abnormalities related to retinal blood flow.

[0005] There is a need in this field to develop plasma kallikrein inhibitors that can be used to treat a wide range of disorders, including hereditary angioedema, diabetic macular edema, and diabetic retinopathy. Invention Overview

[0007] This invention relates to compounds of formula I:

[0008]

[0009] Compounds of Formula I and their pharmaceutically acceptable salts. 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 also be used in combination with other therapeutically effective agents, including but not limited to other drugs 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. Furthermore, the present invention relates to methods for preparing compounds of Formula I, and pharmaceutical compositions comprising compounds of Formula I and their pharmaceutically acceptable salts. Invention Details

[0011] This invention relates to compounds of formula I or their pharmaceutical salts:

[0012]

[0013] Where X is CR 2 Or N;

[0014] Y is

[0015] in Selected from

[0016]

[0017] It is a 5-membered heteroaryl ring, optionally substituted by one or two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, R. x and OR x ;

[0018] G is N or CR 7 ;

[0019] J is N or CR 8 ;

[0020] L is N or CR 7 ;

[0021] M is non-existent, N, or CR. 8 ;

[0022] Each R 1 Independently selected from the following group: halogen, cyano, R x and OR x ;

[0023] R 2 It is hydrogen, halogen, cyano, R x OR x CONH2 or heteroaryl, wherein the heteroaryl group is optionally substituted with a halogen;

[0024] R 3 It is hydrogen, deuterium, halogen, or methyl;

[0025] R 4 It is hydrogen, deuterium, halogen, hydroxyl, or methyl;

[0026] Or R 3 and R 4 It can form C together with the carbon atoms between them. 3-6 Cycloalkyl groups;

[0027] R 5 Is it hydrogen or C? 1-3 Alkyl groups, optionally substituted with one to three substituents selected from the group consisting of halogens and hydroxyl groups;

[0028] Or R 5 L and L can form C together with the carbon atoms between them. 3-6 Cycloalkyl groups;

[0029] R 6 Is it hydrogen, hydroxyl, or C? 1-3 alkyl;

[0030] Or R 5 and R 6 It can form C together with the carbon atoms between them. 3-6 Cycloalkyl groups;

[0031] Each R 7 Independently selected from the following groups: hydrogen, halogen, R x and OR x ;

[0032] Each R 8 Independently selected from the following groups: hydrogen, halogen, R x OR x and NH2;

[0033] R 9 Is it hydrogen or C? 1-3 alkyl;

[0034] R x Is it hydrogen or C? 1-6 Alkyl groups, optionally substituted with one to four substituents, said substituents being independently selected from the group consisting of halogens, hydroxyl groups, methoxy groups, and ethoxy groups;

[0035] m is 1 or 2;

[0036] n is an integer between 0 and 3.

[0037] In one embodiment of the present invention, X is CR 2 In another embodiment of the invention, X is N.

[0038] In one embodiment of the present invention, Y is... In another embodiment of the invention, Y is

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

[0040] In the implementation plan, yes

[0041] In one embodiment of the present invention, Selected from the group consisting of pyrrole, pyrazolyl, imidazole, triazolyl, isoxazolyl, and oxazolyl, wherein the pyrrole, pyrazolyl, imidazole, triazolyl, isoxazolyl, and oxazolyl groups are optionally substituted by one or two substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, and R. x and OR x In one type of the described embodiments, wherein Selected from the group consisting of pyrazolyl, triazolyl, or isoxazolyl, wherein the pyrazolyl group is optionally R x OR x Replacement. In one subclass of the described embodiments, It is a pyrazolyl group, wherein the pyrazolyl group is optionally R x ORx Replacement. In another subclass of the described implementation scheme, It is a triazole group. In one subclass of the embodiments described, It is an isoxazolyl group.

[0042] In one embodiment of the invention, G is N. In another embodiment of the invention, G is CR. 8 In one type of the described implementation scheme, G is CH.

[0043] In one embodiment of the invention, J is N. In another embodiment of the invention, J is CR. 8 In one type of the described implementation scheme, J is CH.

[0044] In one embodiment of the invention, L is N. In another embodiment of the invention, L is CR. 8 In one type of the described implementation scheme, L is CH.

[0045] In one embodiment of the invention, M is absent. In another embodiment of the invention, M is N. In yet another embodiment of the invention, M is CR. 8 In one type of the described implementation scheme, M is CH.

[0046] In one embodiment of the invention, R 1 It is chlorine, fluorine, methyl, or cyano. In one type of the embodiments described, R 1 It is chlorine. In another type of embodiment, R 1 It is fluorine. In another type of embodiment, R 1 It is methyl. In another type of embodiment, R 1 It is a cyano group.

[0047] In one embodiment of the invention, R 2 It is cyano, CONH2, fluopyrazole, R x OR x In one type of embodiment of the invention, R 2 It is cyano. In another type of embodiment of the invention, R 2 It is CONH2. In another type of embodiment of the invention, R 2 It is a fluopyrazole group. In another type of embodiment of the invention, R 2 It is R x In another type of embodiment of the invention, R 2 OR x .

[0048] In one embodiment of the invention, R 3It is hydrogen. In another embodiment of the invention, R 3 It is deuterium. In another embodiment of the invention, R 3 It is a halogen. In another embodiment of the invention, R 3 It is a methyl group.

[0049] In one embodiment of the invention, R 4 It is hydrogen. In another embodiment of the invention, R 4 It is deuterium. In another embodiment of the invention, R 4 It is a halogen. In another embodiment of the invention, R 4 It is a hydroxyl group. In another embodiment of the invention, R 4 It is a methyl group.

[0050] In one embodiment of the invention, R 3 and R 4 Together with the carbon atoms between them, they form a cyclohexyl group.

[0051] In one embodiment of the invention, R 5 It is a methyl group.

[0052] In one embodiment of the invention, R 5 L and the carbon atoms between them together form a cyclopentyl group.

[0053] In one embodiment of the invention, R 6 It is hydrogen. In one embodiment of the invention, R 6 It is a methyl group.

[0054] In one embodiment of the invention, R 9 It is hydrogen.

[0055] In one embodiment of the invention, n is 1. In another embodiment of the invention, n is 2.

[0056] In one embodiment of the invention, n is 0. In another embodiment of the invention, n is 1. In another embodiment of the invention, n is 2. In another embodiment of the invention, n is 3.

[0057] References to the preferred classes and subclasses mentioned above are intended to include all combinations of the specific and preferred groups, unless otherwise stated.

[0058] Specific embodiments of the present invention include, but are not limited to, the compounds identified herein as Examples 1 to 174 or their pharmaceutically acceptable salts.

[0059] The scope of this invention also includes pharmaceutical compositions comprising a compound of formula I as described above and a pharmaceutically acceptable carrier. The invention is also contemplated to cover pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any compound specifically disclosed in this application. These and other aspects of the invention will become apparent from the teachings contained herein.

[0060] This invention includes compositions for treating diseases or conditions involving plasma kallikrein activity. Therefore, this invention includes compositions for treating visual impairment, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood clotting during cardiopulmonary bypass surgery, and bleeding from postoperative surgery, comprising compounds of this invention in a pharmaceutically acceptable carrier. One class of this 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 composition can be added to blood, blood products, or mammalian organs to achieve the desired inhibition.

[0061] The present invention also includes compositions for the prevention or treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema in mammals, comprising compounds 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.

[0062] 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 diffusion. 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 posterior eye 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.

[0064] It should be understood that the present invention relates to compounds of structural formula I described herein, pharmaceutically acceptable salts of compounds of structural formula I, and non-pharmaceutically acceptable salts when they are used as precursors of free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[0065] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including inorganic or organic bases and inorganic or organic acids). Salts of basic compounds included in the term "pharmaceutically acceptable salt" represent non-toxic salts of the compounds of the present invention, which are typically prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of this invention include, but are not limited to, the following: acetates, ascorbic acid salts, adipates, alginates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, camphorates, camphor sulfonates, dextrorotatory camphor sulfonates, carbonates, chlorides, clavulanates, citrates, cyclopentanepropionates, diethylacetate, digluconate, dihydrochloride, dodecylsulfonate, edetate, ethanedisulfonate, etolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerol phosphate, and glycolyllarsanilate. Hemisulfate, heptanate, hexanoate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthylcarboxylate, iodide, isonicotinic acid, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucilage, 2-naphthalenesulfonate, naphthalenesulfonate, nicotinate, nitrate, N-methylreducing glucose Ammonium salts, oleates, oxalates, pyrazine (dihydroxynaphthyl salt), palmitates, pantothenates, pectinates, persulfates, phosphates / bisphosphates, pimecrolates, phenylpropionates, polygalacturonic acids, propionates, salicylates, stearates, sulfates, hypoacetates, succinates, tannates, tartrates, teoclates, thiocyanates, toluenesulfonates, triethyliodine, trifluoroacetate, undeconate, valerates, etc. Furthermore, in cases where the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, ferric manganese, ferrous manganese, potassium, sodium, zinc, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are also included.Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include salts of the following substances: 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, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. Furthermore, the included basic nitrogen-containing groups can be quaternized by reagents such as: lower alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides, such as chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearoyl; aralkyl halides such as bromides of benzyl and phenethyl, etc.

[0066] These salts can be obtained by known methods, such as by mixing the compounds of the present invention with an equal volume of a solution containing the desired acid, base, etc., and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present invention and their salts can form solvates with solvents such as water, ethanol, or glycerol. Depending on the type of side-chain substituents, the compounds of the present invention can simultaneously form acid addition salts and base salts.

[0067] If the compound of Formula I contains both acidic and basic groups in its molecule, in addition to the salt forms mentioned, the present invention also includes internal salts or internal ammonium salts (betaines) (zwitterions).

[0068] This invention includes all stereoisomers of compounds of Formula I. Unless a specific stereochemistry is specified, this invention is intended to include all such isomers of these compounds. The asymmetric centers present in compounds of Formula I may each have an independent (R) configuration or (S) configuration. When the bond with the chiral carbon is described as a straight line in the structural formula of this invention, it should be understood that the (R) and (S) configurations of the chiral carbon and therefore each individual enantiomer and mixture thereof are included in the formula. When a particular configuration is described, it means that the enantiomer ((R) or (S), located at the center). Similarly, when the name of a compound is listed without specifying the chirality of the chiral carbon, it should be understood that the (R) and (S) configurations of the chiral carbon and therefore each enantiomer and mixture thereof are included in the name. The production of specific stereoisomers or mixtures thereof can be identified in examples of obtaining such stereoisomers or mixtures, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of this invention.

[0069] Unless a specific enantiomer or diastereomer is specified, this invention encompasses all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers in all proportions, such as mixtures of enantiomers and / or diastereomers. Thus, enantiomers in the following forms are the subject of this invention: enantiomerically pure forms, as both levorotatory and dextrorotatory enantiomers, racemic forms, and mixtures of two enantiomers in all proportions. In the case of cis / trans isomerism, this invention includes cis forms and transformations, as well as mixtures of these forms in all proportions. If desired, the preparation of individual stereoisomers can be carried out by separating the mixture using conventional methods (e.g., chromatography or crystallization), by using stereochemically homogeneous synthetic starting materials, or by stereoselective synthesis. Optionally, derivatization can be performed prior to the separation of stereoisomers. The separation of stereoisomer mixtures can be carried out as an intermediate step during the synthesis of compounds of Formula I, or it can be carried out on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or intermediate, which, if necessary, is derivatized with a reagent containing a stereocenter of known configuration. Where the compounds of the present invention are tautomerizable, all tautomers and mixtures thereof are included within the scope of the present invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemates, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0070] In the compounds of this invention, the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with specific isotopes having the same number of atoms but different atomic masses or mass numbers from those that are predominantly found in nature. This invention is intended to include all suitable isotopic variants of the compounds specifically and generally described. For example, different isotopic forms of hydrogen (H) include protium (1... H ) and deuterium (2 H Protium is the dominant hydrogen isotope found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. Isotope-enriched compounds can be prepared with minimal experimentation using conventional techniques well known to those skilled in the art, or processes similar to those described in the general methodologies and examples herein, using appropriate isotope-enriching reagents and / or intermediates.

[0071] When any variable (e.g., R) 6When a substituent (e.g., a variable) appears more than once in any component, its definition for each occurrence is independent of each subsequent occurrence. Furthermore, combinations of substituents and variables are permitted only if such combinations produce stable compounds. A line drawn from a substituent to the ring system represents a specified bond that can be attached to any substituted ring atom. If the ring system is bicyclic, it means that the bond is attached to any suitable atom on either ring of the bicyclic portion.

[0072] It should be understood that those skilled in the art can incorporate one or more silicon (Si) atoms into the compounds of the present invention to replace one or more carbon atoms, providing chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art. When comparing similar C and Si element bonds, carbon and silicon have different covalent radii, leading to differences in bond lengths and spatial arrangement. These differences result in subtle variations in the size and shape of silicon-containing compounds compared to carbon. Those skilled in the art will understand that differences in size and shape can lead to subtle or significant variations 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).

[0073] It should be understood that those skilled in the art can select the substituents and substitution patterns of the compounds of the present invention to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods set forth below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure is produced. The phrase "optionally substituted" (having one or more substituents) should be understood to mean that the group in question is unsubstituted or may be substituted by one or more substituents.

[0074] Furthermore, the compounds of the present invention can exist in amorphous and / or one or more crystalline forms, and therefore all amorphous and crystalline forms of the compounds of Formula I and mixtures thereof are intended to be included within the scope of the present invention. Additionally, some compounds of the present invention can 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), as well as non-solventized and anhydrous forms, are also included within the scope of the present invention.

[0075] Furthermore, in the presence of a carboxylic acid (-COOH) or hydroxyl group in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or neopentanoyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-neopentyl, O-benzoyl, and O-aminoacyl, may be used. This includes those esters and acyl groups known in the art for altering the solubility or hydrolytic characteristics of formulations used for sustained release or prodrug preparations.

[0076] Any pharmaceutically acceptable prodrug modification of the compounds of the present invention (which results in in vivo conversion to compounds within the scope of the present invention) is also within the scope of the present invention. For example, esters can optionally be prepared by esterification of a available carboxylic acid group or by forming an ester on a available hydroxyl group in the compound. Similarly, unstable amides can be prepared. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared as prodrugs, which can be hydrolyzed back to acid (or -COO). - (depending on the pH of the liquid or tissue in which the transformation occurs) or hydroxyl form, particularly in vivo, and therefore included within the scope of this invention. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 Alkyl esters and -C substituted with phenyl esters 1-6 alkyl.

[0077] Therefore, the compounds in the general structural formulas, embodiments and specific compounds described and claimed herein include their salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvates and hydrates, and any combination of these forms, as well as their salts, their prodrug forms and salts of their prodrug forms, provided such forms are possible, unless otherwise stated.

[0078] Unless otherwise stated herein, the terms “alkyl” and “alkylene” are intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. Common abbreviations for alkyl groups are used throughout this specification; for example, methyl may be represented by a symbol including “Me” or CH3 or as an extended bond of a terminal group (e.g., The abbreviations include ethyl (e.g., "Et" or CH2CH3), propyl (e.g., "Pr" or CH2CH2CH3), butyl (e.g., "Bu" or CH2CH2CH2CH3), etc. For example, "C1-4 alkyl" (or "C1-C4 alkyl") refers to a straight-chain or branched alkyl group having a specified number of carbon atoms, including all isomers. For example, the structure...

[0079]

[0080] They have the same meaning. C 1-4Alkyl groups include n-butyl, isobutyl, sec-butyl, and tert-butyl, n-propyl and isopropyl, ethyl, and methyl. If no number is specified, straight-chain or branched alkyl groups mean 1 to 4 carbon atoms.

[0081] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0082] Unless otherwise specified, the term "aryl" as used herein refers to a stable monocyclic or bicyclic ring system having up to 10 carbon atoms in each ring, wherein at least one ring is aromatic. Bicyclic aryl ring systems include fused ring systems in which two rings share two atoms; and spirocyclic systems in which two rings share one atom. Aryl groups within the scope of this definition include, but are not limited to, phenyl, indene, isoindene, naphthalene, and tetrahydronaphthalene.

[0083] Unless otherwise specified, the term "heteroaryl" as used herein refers to a stable monocyclic or bicyclic ring system having up to 10 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N, and S. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms; and spirocyclic systems in which two rings share one atom. The heteroaryl groups within this defined range include, but are not limited to: azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazoyl, carbaolinyl, cenolinyl, dihydroindenyl, furanyl, indololinyl, indolyl, indolazinyl, indolazinyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyl, naphthidyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl Pyrimidinyl, pyrroloyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazonopyridyl, thiadiazoyl, thiazolyl, thiophene, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophene, dihydrobenzooxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxazinyl, dihydropyrazolyothiazinedioxidyl, methylenedioxybenzene, benzothiazolyl, benzothiaphene, quinolinyl, isoquinolinyl, oxazolyl, tetrahydroquinoline, and 3-oxo-3,4-dihydro-2N-benzo[b][1,4]thiazine. If a heteroaryl group contains a nitrogen atom, it should be understood that its corresponding N-oxide is also included in this definition.

[0084] Unless otherwise specified, the terms “halogen” or “halogenated” refer to fluorine, chlorine, bromine, or iodine.

[0085] (Fluka) diatomaceous earth is diatomaceous earth and can also be called "celite".

[0086] Unless otherwise stated herein, structures containing substituent variables such as the variable "R" below (which is described as not being attached to any particular bicyclic carbon atom) are:

[0087]

[0088] This represents a structure in which the variable can optionally be attached to any bicyclic carbon atom. For example, the variable R shown in the structure above can be attached to any one of the six bicyclic carbon atoms i, ii, iii, iv, v, or vi.

[0089] Unless otherwise stated herein, bicyclic ring systems include fused ring systems in which two rings share two atoms; and spirocyclic systems in which two rings share one atom.

[0090] The present invention also relates to a medicament comprising at least one compound of formula I and / or a pharmaceutically acceptable salt of a compound of formula I and / or optionally a stereoisomer of a compound of formula I or a pharmaceutically acceptable salt of a stereoisomer of a compound of formula I, as well as a pharmaceutically suitable and pharmaceutically acceptable carrier, additive and / or other active substance and adjuvant.

[0091] The term "patient" as used in this article refers to mammals such as primates, humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.

[0092] The medicament according to the invention can be administered orally, by inhalation, rectal or transdermal application, or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred. It is possible to coat the stent and other surfaces in contact with blood in the body with compounds of Formula I.

[0093] The present invention also relates to a method for producing a pharmaceutical product, comprising preparing at least one compound of formula I into a suitable administration form using a pharmaceutically suitable and pharmaceutically acceptable carrier and optionally other suitable active substances, additives or adjuvants.

[0094] Suitable solid or galenal formulations include, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injectable solutions, as well as formulations with prolonged release of the active substance, prepared using conventional excipients such as mediators, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavoring agents, sweeteners, and solubilizers. Commonly used excipients that may be mentioned include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol, and solvents such as, for example, sterile water, and monohydric or polyhydric alcohols such as glycerin.

[0095] The dosing regimen for plasma kallikrein inhibitors is selected based on several factors, including patient type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt used. A general practitioner or veterinarian can easily determine and prescribe an effective amount of the drug needed to prevent, counteract, or halt disease progression.

[0096] When used for a specified effect, the oral dose range of a plasma kallikrein inhibitor is 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 stated, the amount of active ingredient is based on 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. Therefore, a suitably prepared drug suitable 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, for example, 8 mg, 10 mg, 20 mg, and 40 mg. Advantageously, the plasma kallikrein inhibitor can be administered in fractionated doses twice, three, or four times daily. For twice-daily administration, a suitably prepared drug 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, for example, 4 mg, 5 mg, 10 mg, and 20 mg.

[0097] Intravenous administration will deliver an amount 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 of the active ingredient. Such an amount can be administered in a variety of suitable manners, such as large volumes of low-concentration active ingredient administered over a prolonged period or several times daily, or small volumes of high-concentration active ingredient administered over a short period (e.g., once daily). Typically, conventional intravenous formulations can be prepared containing an active ingredient at a 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 administered daily at doses ranging from 0.01 mL / kg patient weight to 10.0 mL / kg patient weight, such as 0.1 mL / kg, 0.2 mL / kg, and 0.5 mL / kg. In one embodiment, an 80 kg patient receiving 8 mL of an intravenous formulation containing an active ingredient at a concentration of 0.5 mg / mL twice daily receives 8 mg of the active ingredient daily. Glucuronic acid, L-lactic acid, acetic acid, citric acid, or any pharmaceutically acceptable acid / conjugate base with reasonable buffering capacity within an acceptable pH range for intravenous administration can be used as a buffer. Depending on the solubility of the drug to be administered, a person skilled in the art can readily make an appropriate choice of buffer and pH for the formulation.

[0098] The compounds of Formula I can be administered as a 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.

[0099] "Anti-inflammatory agent" is any medication that, when administered at a therapeutically effective level, directly or indirectly reduces inflammation. "Anti-inflammatory agents" include, but are not limited to, steroidal anti-inflammatory agents and glucocorticoids. Suitable anti-inflammatory agents include, but are not limited to, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisolone, and triamcinolone.

[0100] "Anti-VEGF agents" are any drugs that directly or indirectly inhibit the activity of VEGF (vascular endothelial growth factor). Suitable anti-VEGF agents include, but are not limited to, bevacizumab, ranibizumab, and aflibercept.

[0101] Immunosuppressants are any medications that directly or indirectly suppress or reduce the strength of the body's immune system. Suitable immunosuppressants include, but are not limited to, corticosteroids (e.g., prednisone, budesonide, prednisolone), janus kinase inhibitors (e.g., tofacitinib), troponin inhibitors (e.g., cyclosporine, tacrolimus), mTOR inhibitors (e.g., sirolimus, everolimus), IMDH inhibitors (e.g., azathioprine, leflunomide, mycophenolate mofetil), and biologics (e.g., abatacept, adalimumab, anakinra, certolizumab, etanercept). etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab) and monoclonal antibodies (e.g., basiliximab, daclizumab)

[0102] 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 re-occlusion and restenosis after angioplasty), other anticoagulants such as aspirin, and thrombolytic agents such as plasminogen activators or streptokinase, to achieve synergistic effects in the treatment of various vascular diseases. Such anticoagulants include, for example, apixaban, dabigatran, cangrelor, ticagrelor, vorapaxar, clopidogrel, edoxaban, mipomersen, prasugrel, rivaroxaban, and semuloparin. For instance, patients with coronary artery disease and those undergoing angioplasty will benefit from the co-administration of fibrinogen receptor antagonists and thrombin inhibitors.

[0103] In some embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are used at their usual dose ranges and regimens reported in the art, including doses described, for example, in versions of the Physicians' Desk Reference, such as edition 70 (2016) and earlier. In other embodiments, the anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents described herein are used at doses below their usual dose ranges.

[0104] Alternatively or additionally, one or more other pharmacologically active agents may be administered in combination with the compounds of the present invention. The term "other active agents" is intended to refer to pharmaceutically active agents (or agents) that are active in vivo, including prodrugs that are converted to a pharmaceutically active form after administration, which differs from the compounds of the present invention, and, when such forms are commercially available or otherwise chemically possible, also include free acids, free bases, and pharmaceutically acceptable salts of the other active agents. Generally, any suitable other active agent (including, but not limited to, antihypertensive agents, additional diuretics, antiatherosclerotic agents such as lipid-regulating compounds, antidiabetic agents, and / or antiobesity agents) may be used in any combination with the compounds of the present invention in a single-dose formulation (fixed-dose drug combination), or may be administered to the patient in one or more separate-dose formulations, allowing for simultaneous or sequential administration of the active agents (co-administration of individual active agents). Examples of other active agents that may be used include, but are not limited to, angiotensin-converting enzyme inhibitors (e.g., alapril, benazepril, captopril, siropril, cilazapril, delapril, enalapril, enalapril, fosinopril, imidapril, lisinopril, movipril, perindopril, quinapril, ramipril, spiropril, temopril, or qundolipril); and angiotensin II receptor antagonists, also known as angiotensin receptor blockers or ARBs, which may be in the form of a free base, free acid, salt, or prodrug, such as azilsartan, for example, meazartan potassium. Candesartan, for example, candesartan medoxomil eprosartan, for example, eprosartan mesylate Irbesartan Losartan, for example, losartan potassium Olmesartan, for example, olmesartan medoxomil Telmisartan Valsartan and with thiazide-like diuretics such as hydrochlorothiazide (e.g., Any of these drugs used in combination (e.g., amiloride hydrochloride, spironolactone, eplerenone, triamterene, each with or without HCTZ); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors; enalkrein; RO 42-5892; A 65317; CP 80794; ES 1005; ES 8891; SQ 34017; Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]octamido hemifumarate) SPP600, SPP630 and SPP635); endothelial angiotensin receptor antagonists; vasodilators (e.g. nitroprusside); calcium channel blockers (e.g. amlodipine, nifedipine, verapamil, diltiazem, felodipine, golopamil, niludipine, nimodipine, nicardipine); potassium channel activators (e.g. Nicorandil, pinacidil, crocalin, minoxidil, alpracalin, cloprazolam); sympathetic nerve blockers; β-adrenergic blockers (e.g., acebutolol, atenolol, betalol, bisoprolol, carvedilol, metoprolol, metoprolol tartrate, nadolol, propranolol, sotalol, timolol); α-adrenergic blockers (e.g., doxazosin, prazosin, or α-methyldopa); central α-adrenergic agonists; peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors like simvastatin and lovastatin (which are available as lactone prodrugs). and (Sold and acting as an inhibitor after administration), and pharmaceutically acceptable salts of dihydroxyocyclocarboxylic acid HMG-CoA reductase inhibitors such as atorvastatin (especially in the form of...). calcium salts sold in various forms), rosuvastatin (especially in the form of calcium salts sold in various forms), calcium salts sold in various forms), pravastatin (especially in... Sodium salts sold in the form of sodium salts) and fluvastatin (especially ... Sodium salts sold in physical form; cholesterol absorption inhibitors such as ezetimibe And with any other lipid-lowering agents such as HMG-CoA reductase inhibitors mentioned above, and especially with simvastatin Ezetimibe in combination with atorvastatin calcium; niacin in immediate-release or controlled-release forms, and especially niacin in combination with DP antagonists such as laropiprant and / or with HMG-CoA reductase inhibitors; niacin receptor agonists such as acilimus and acyclofuran, and partial niacin receptor agonists; metabolic modifiers, including insulin sensitizers and related compounds used to treat diabetes such as biguanides (e.g., metformin), chloropicrins (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glibenclamide, tolazoline, tolbutamide), thiazolidinediones also known as glitazones (e.g., pioglitazone, rosiglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors (e.g., sitagliptin). Allolistin, vildagliptin, saxagliptin, liraliptin, dugliptin, giglitazone), ergot alkaloids (e.g., bromocriptine), and combination drugs such as (Sitagliptin and metformin) and injectable diabetes medications such as exenatide and prulaminide acetate; glucose uptake inhibitors, such as sodium-glucose transporter (SGLT) inhibitors and their various isomers, such as SGLT-1, SGLT-2 (e.g., ASP-1941, TS-071, BI-10773, tolpagliflozin, LX-4211, canagliflozin, dapagliflozin, elepagliflozin, etagliflozin, repaggliflozin, and soragliflozin) and SGLT-3; or other medications beneficial for the prevention or treatment of the aforementioned diseases, including but not limited to diazoxide; and including free acids, free bases, and pharmaceutically acceptable salt forms, prodrug forms, such as esters and salts of the prodrugs of the above-mentioned pharmaceutical ingredients, where chemically possible. Trademark names of the above-mentioned pharmaceutical drugs are provided to illustrate the sales forms of the active agents; such pharmaceutical drugs may be used in separate dosage forms for simultaneous or sequential administration with the compounds of the present invention, or the active agents therein may be used in fixed-dose pharmaceutical combinations comprising the compounds of the present invention.

[0105] Typical doses of the plasma kallikrein inhibitors of the present invention, when combined with other suitable agents, may be the same as, or significantly lower than, those doses of plasma kallikrein inhibitors administered without co-administration of other agents, depending on the patient’s treatment needs.

[0106] The compound is administered to mammals in a therapeutically effective amount. A "therapeutically effective amount" means an amount of the compound of the invention that, when administered to mammals alone or in combination with other therapeutic agents, is effective in treating (i.e., preventing, inhibiting, or improving) a disease condition or in treating the progression of disease in the host.

[0107] The compounds of the present invention are preferably administered alone to mammals in a therapeutically effective amount. However, the compounds of the present invention may also be administered to mammals in combination with another therapeutic agent as defined below in a therapeutically effective amount. When administered in combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. A synergistic effect occurs when the effect of the compounds (in this case, inhibition of the desired target) when administered in combination is greater than the additive effect of each compound when administered as a single agent, as described, for example, as described in Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55. Generally, synergistic effects are most clearly demonstrated at suboptimal concentrations of the compounds. Compared to individual components, synergistic effects can be reduced cytotoxicity, increased anticoagulant activity, or some other beneficial effect of the combination.

[0108] "Combined administration" or "combined therapy" refers to the parallel administration of the compounds of the present invention and one or more other therapeutic agents to a mammal being treated. When administered in combination, each component may be administered simultaneously or sequentially at different times in any order. Thus, each component can be administered individually, but close enough in time to provide the desired therapeutic effect. The administration of each component does not need to be via the same route of administration; for example, one component may be administered orally while another component may be delivered into the vitreous humor of the eye.

[0109] This invention is not limited in scope to the specific embodiments disclosed in the examples, which are intended to illustrate several aspects of the invention, and any functionally equivalent embodiments are within the scope of this invention. In fact, various modifications to the invention, in addition to those shown and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0110] General methods

[0111] The compounds of the present invention can be prepared using conventional techniques or according to the methods outlined in the general synthetic schemes below. Those skilled in the art can modify the shown procedures and reagents to obtain similar intermediates and / or final compounds.

[0112] NMR spectra were measured on VARIAN or Bruker NMR Systems (400, 500, or 600 MHz). Chemical shifts were reported in ppm low-field and high-field values ​​from tetramethylsilane (TMS), with reference to internal TMS or solvent resonances. 1 H NMR: δ7.27 (for CDCl3), δ2.50 (for (CD3)(CHD2)SO), and 13C18 NMR: δ77.02 (for CDCl3), δ39.51 (for (CD3)2SO)). Coupling constants (J) are expressed in Hertz (Hz), and spin multiplicity is given as s (singleton), d (doublet), dd (doublet), t (triplet), m (multiplet), and br (broad peak). Chiral resolution was performed on a Waters Thar 80 SFC or Berger MG II preparative SFC system. LC-MS data were recorded on a C18 column with a MeCN gradient in water containing 0.02–0.1% TFA on a SHIMADAZU LC-MS-2020, SHIMADAZU LC-MS-2010, or Agilent 1100 series LC-MS, Agilent Prime-1260, or Waters Acquity LC-MS instrument. UV detection was performed at 220 and / or 254 nm, with ESI ionization used for MS detection.

[0113] When chiral separation is achieved by chromatography using chiral columns, the chiral columns used for SFC chiral separation are listed in the table. Some of the chiral columns used are CHIRALPAK AD, CHIRALCEL OJ, CHIRALPAK AS, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK AD-H, and CHIRALPAK AS-H. These will subsequently be indicated by two or three-letter abbreviations. By convention, the fast-eluting isomer from the chiral separation is always listed first in the table, followed by the slower-eluting isomer from the same separation. If more than two isomers are separated, they will always be listed in the table in their elution order, such as peak 1, then peak 2, peak 3, etc. An asterisk (*) near the chiral center in the structure indicates that the chiral center was separated by chiral resolution, and its stereochemical configuration is not definitively determined.

[0114] Furthermore, TLC stands for Thin-Layer Chromatography; UV stands for Ultraviolet; W stands for Watts; wt% is weight percentage; xg is a multiple of gravity; α D Specific rotation of polarized light at 589 nm; ℃ is degrees Celsius; %w / v is the percentage of the weight of the former reagent relative to the volume of the latter reagent; Hz is Hertz; cpm is counts per minute; δ H d is chemical shift; dd is doublet; MHz is megahertz; MS is mass spectrometry, and the mass spectrometry obtained by ES-MS can be referred to as "LC-MS" in this paper; m / z is mass-to-charge ratio; n is normal; N is standard; nm is nanometer; nM is nanomolar.

[0115] Several catalysts and ligands were used in the following procedures. “XANTPHOS” is also known as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. “XANTPHOS Pd G3” is also known as [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate. “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)]palladium(II)methanesulfonate. “cataCXium A Pd G2” is also known as chloro[(bis(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II). These catalysts and ligands are available from Millipore Sigma.

[0116] For the purposes of this specification, the following abbreviations have the meanings indicated below:

[0117] Acetyl group

[0118] ACN Acetonitrile

[0119] AcOH or HOAc acetic acid

[0120] APCI (Atmospheric Pressure Chemical Ionization)

[0121] aq (water-based)

[0122] Bn benzyl

[0123] Boc or BOC tert-butoxycarbonyl

[0124] Brettphos 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl

[0125] BrettPhos Pd G3 [(2-dicyclohexylphosphino-3,6-dimethoxy-′,′,′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0126] Bu Butyl

[0127] Bz Benzoyl

[0128] calc′d is calculated

[0129] cataCXium A Pd G2 Chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)

[0130] cBu cyclobutyl

[0131] Cbz benzyloxycarbonyl

[0132] cHep Cyclohepyl

[0133] cHex cyclohexyl

[0134] cPen cyclopentyl

[0135] cPr cyclopropyl

[0136] DAST (diethylamino) sulfur trifluoride

[0137] dba dibenzylidene acetone

[0138] DBAD di-tert-butyl azodicarbonate

[0139] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0140] DCE 1,2-Dichloroethane

[0141] DCM dichloromethane

[0142] DIAD (Diisopropyl Azodicarbonate)

[0143] DIBAL or DIBAL-H diisobutylaluminum hydride

[0144] DIC N,N′-Diisopropylcarbodiimide

[0145] DIEA or Hünig's base N,N-diisopropylethylamine

[0146] DIPA diisopropylamine

[0147] DMA 1,2-dimethylacetamide

[0148] DMAP 4-Dimethylaminopyridine

[0149] DMF (dimethylformamide)

[0150] DMP Des Martin periodopane (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzodiazepine oxacyclopentane-3(1H)-one

[0151] DMS dimethyl sulfide

[0152] DMSO (dimethyl sulfoxide)

[0153] DPPA diphenylphosphoazide

[0154] dppf 1,1′-bis(diphenylphosphine)ferrocene

[0155] DPy 2,2′-dipyridine

[0156] DTBPY or BBBPY 4,4′-Di-tert-butyl-2,2′-dipyridyl

[0157] DTT dithiothreitol

[0158] EA (ethyl acetate)

[0159] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0160] EDTA (ethylenediaminetetraacetic acid)

[0161] ESI Electrospray Ionization

[0162] Et Ethyl

[0163] EtOH (ethanol)

[0164] EtOAc (ethyl acetate)

[0165] g gram

[0166] GST glutathione S-transferase

[0167] h hours

[0168] HATU N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate

[0169] HMDS 1,1,1,3,3,3-Hexamethyldisilazane

[0170] HOBt 1-hydroxybenzotriazole

[0171] HPLC (High Performance Liquid Chromatography)

[0172] IPA isopropanol

[0173] iPr isopropyl

[0174] LC liquid chromatography

[0175] LCMS (Liquid Chromatography-Mass Spectrometry)

[0176] LDA (Lithium diisopropylamino)

[0177] mCPBA (m-chloroperoxybenzoic acid)

[0178] Me methyl

[0179] MeOH (methanol)

[0180] mg

[0181] min minutes

[0182] μL

[0183] mL

[0184] mmol millimole

[0185] MS mass spectrometry

[0186] Ms. methanesulfonyl (methanesulfonyl)

[0187] MPLC (Medium-Pressure Liquid Chromatography)

[0188] MTBE (methyl tert-butyl ether)

[0189] NBS N-bromosuccinimide

[0190] NiCl2 ethylene glycol dimethyl ether nickel(II) chloride ethylene glycol dimethyl ether complex

[0191] NMR (Nuclear Magnetic Resonance) spectroscopy

[0192] obsv′d (observed)

[0193] Ph phenyl

[0194] Pr propyl

[0195] PS (Polystyrene)

[0196] RAC racemic mixture

[0197] RT or rt: Room temperature (around 25°C)

[0198] saturated

[0199] SFC Supercritical Fluid Chromatography

[0200] S-phos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

[0201] TBAF tert-butylammonium fluoride

[0202] TBAI Tetra-n-butylammonium iodide

[0203] TBS or TBDMS tert-butyldimethylsilyl

[0204] TBSCl tert-butyldimethylchlorosilane

[0205] TCFH Tetramethylchloromethylammonium hexafluorophosphate

[0206] tBu tert-butyl

[0207] tBu X-phos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl

[0208] TEA (Triethylamine, Et3N)

[0209] TFA (trifluoroacetic acid)

[0210] TFAA (trifluoroacetic anhydride)

[0211] THF Tetrahydrofuran

[0212] TLC (Thin Layer Chromatography)

[0213] TMS (trimethylsilyl)

[0214] Tris(hydroxymethyl)aminomethane

[0215] Ts Toluenesulfonyl (Toluyl)

[0216] TSA p-Toluenesulfonic acid

[0217] X-phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0218] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium

[0219] Xantphos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthanyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0220] General aspects

[0221] The starting materials used are derived from commercial sources or prepared in other embodiments, unless otherwise indicated.

[0222] The method for preparing the compounds of the present invention is described below. Unless otherwise stated, all starting materials used are commercially available.

[0223] Option 1.

[0224]

[0225] From acids such as 1a Compounds of formula (I) are prepared by forming an acyl chloride, followed by treatment with a reagent such as sodium azide. 1a Transform into 1bThe formation of a Boc-protected amine, followed by reduction with a reagent such as sodium borohydride, provides... 1c The formation of alkyl iodides, followed by Ni-mediated reductive coupling and deprotection with aryl halides, provides intermediates such as... I .

[0226] Option 2.

[0227]

[0228] From acids such as 2a Prepare compounds of formula (II). Make the acid... 2a Coupling with reagents such as N-hydroxyphthalimide, followed by Ni-mediated reductive coupling with aryl halides and acid-mediated deprotection, provides intermediates such as II .

[0229] Option 3.

[0230]

[0231] Scheme 3 summarizes the general synthesis of several embodiments of the present invention, which describes the process from intermediates. 3a and 3b Preparation of compounds III The alcohol was tested using reagents such as diisopropyl azodicarbonate and triphenylphosphine. 3a With pyrazoles, etc. 3b The Mitsunobu reaction, followed by ester hydrolysis, provides the acid. 3c The reaction was carried out using reagents such as N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (HATU). 3c With amines such as 3d The amide coupling, followed by oxidation, provides 3e Under alkaline conditions, amines such as... 3f Sulfone treatment 3e ,supply III .

[0232] Option 4.

[0233]

[0234] Scheme 4 summarizes the general synthesis of several embodiments of the present invention, which describes the process from intermediates. 4a and 4b Preparation of compounds IV . alcohol 4a and pyrazole 4b The Mitsunobu reaction product under alkaline conditions is reacted with amines such as... 4c Processing to provide acid 4dThe reaction was carried out using reagents such as N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (HATU). 4d With amines such as 4e The amide coupling provides IV.

[0235] Option 5.

[0236]

[0237] Scheme 5 summarizes the general synthesis of several embodiments of the present invention, which describes the process from intermediates. 5a and 5b Preparation of compounds V Under Pd-mediated carbon-nitrogen bond formation conditions, alcohols... 5a and pyrazole 5b The Mitsunobu reaction product is used with amines such as 5c Processing to provide esters 5d Ester hydrolysis under alkaline conditions 5d Subsequently, reagents such as N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (HATU) were used to react with amines such as 5e amide coupling provides V .

[0238] Option 6.

[0239]

[0240] Scheme 6 summarizes the general synthesis of several embodiments of the present invention, which describes the process from intermediates. 6a Preparation of compounds VI Using reagents such as diphenylphosphohydrin and DBU from 6a The intermediate azide is generated, which is then reacted with alkynes under Cu-catalyzed conditions. 6b Treatment, providing triazole 6c Under alkaline conditions, amines such as... 6d deal with 6c Provide acid 6e The reaction was carried out using reagents such as N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (HATU). 6e With amines such as 6f amide coupling provides VI .

[0241] Option 7.

[0242]

[0243] Scheme 7 summarizes the general synthesis of several embodiments of the invention, which describes the process from intermediates. 7a Preparation of compounds VII Using reagents such as diphenylphosphohydrin and DBU from 7a The intermediate azide is generated, which is then reacted with alkynes under Cu-catalyzed conditions. 7b Treatment, providing triazole 7c The ester is hydrolyzed, followed by the use of reagents such as HATU and amines. 7d Couplet, providing 7e Oxidation with reagents such as mCPBA, followed by oxidation with amines under alkaline conditions. 7f Process, provide VII.

[0244] Option 8.

[0245]

[0246] Scheme 8 summarizes the general synthesis of several embodiments of the present invention, which describes the process from intermediates. 8a Preparation of compounds VIII Using reagents such as diphenylphosphohydrin and DBU, or by activation with alcohol and treatment with sodium azide, from 8a The intermediate azide is generated, which is then reacted with alkynes under Cu-catalyzed conditions. 8b Treatment, providing triazole 8 c。 Ester hydrolysis and Pd-mediated carbon-nitrogen formation conditions provide the acid. 8e Using reagents such as HATU 8 e and amines such as 8f amide coupling provides VIII .

[0247] Option 9.

[0248]

[0249] Scheme 9 summarizes the general synthesis of several embodiments of the invention, which describes the process from intermediates. 9a Preparation of compounds VIII Using reagents such as diphenylphosphohydrin and DBU from 9a The intermediate azide is generated, which is then reacted with alkynes under Cu-catalyzed conditions. 9b Treatment, providing triazole 9c。 Pd-mediated interactions with amines such as 9d The formation of carbon-nitrogen bonds provides 9e Ester hydrolysis under alkaline conditions and the use of reagents such as HATU with amines. 9f The amide coupling provides IX.

[0250] Option 10.

[0251]

[0252] Scheme 10 summarizes the general synthesis of several embodiments of the present invention, which describes the process from intermediates. 10a Preparation of compounds X Using reagents such as HATU to react with acids such as... 10a With amine 10b amide coupling provides X .

[0253] intermediate

[0254] Intermediate A

[0255]

[0256] 1-(1-(trifluoro-14-boronyl)ethyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester, potassium salt

[0257] Step 1. (1-(4-(tert-butoxycarbonyl)-1H-pyrazol-1-yl)ethyl)boronic acid:

[0258] NaH (27.1 g, 678 mmol, 1.20 g) was added to a solution of tert-butyl 1H-pyrazole-4-carboxylate (95 g, 565 mmol) in DMF (1 L) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and then 2-(1-iodoethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (239 g, 847 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 15 h. MTBE (1.00 L) was added and the mixture was stirred at 25 °C for 30 min. The mixture was filtered and the filtrate was concentrated to the title compound. MS = 241.3 (M+1).

[0259] Step 2.1-(1-(trifluoro-14-boronyl)ethyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester, potassium salt: KHF2 (234 g, 3.00 mmol) in H2O (900 mL) was added to a solution of (R)-(1-(4-(tert-butoxycarbonyl)-1H-pyrazol-1-yl)ethyl)boronic acid and (S)-(1-(4-(tert-butoxycarbonyl)-1H-pyrazol-1-yl)ethyl)boronic acid (180 g, 750 mmol) in MeOH (1.80 L). The solution was stirred at 25 °C for 12 h and concentrated to produce a residue. Acetone (2.50 L) was added and the mixture was kept at 25 °C for 1 h. The mixture was filtered and concentrated, and then purified by recrystallization from MTBE to provide the title compound. 1 H NMR (400MHz DMSO, ppm) δ7.86 (s, 1H), 7.56 (s, 1H), 3.21 (br d, J=3.4Hz, 1H), 1.45 (s, 9H), 1.12 (d, J=7.2Hz, 3H)

[0260] Intermediate B

[0261]

[0262] 1-(6-chloro-4,5-dimethylpyridin-3-yl)ethane-1-ol

[0263] Step 1.5-Bromo-2-chloro-3,4-dimethylpyridine: 5-Bromo-3,4-dimethylpyridin-2-amine (6.0 g, 29.8 mmol) was suspended in 120 mL of 36% HCl (aqueous solution) and cooled to -15 °C. Sodium nitrite (10.29 g, 149 mmol) was added, and the reaction mixture was slowly heated to 25 °C and stirred for 15 h. The reaction mixture was quenched by adding water (100 mL) and extracted with DCM (5 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by rapid silica gel chromatography (0–21% ethyl acetate / petroleum ether) to yield the title compound. MS = 219.9, 221.9 (M+1).

[0264] Step 2.1 - (6-chloro-4,5-dimethylpyridin-3-yl)acetone: Pd(PPh3)2Cl2 (0.637 g, 0.907 mmol) was dissolved in toluene (20 mL), and then tributyl(1-ethoxyvinyl)stanane (4.06 mL, 12.02 mmol) and 5-bromo-2-chloro-3,4-dimethylpyridine (2 g, 9.07 mmol) were added at 20 °C. The resulting mixture was stirred at 90 °C under N2 for 16 h. The reaction mixture was cooled to 20 °C, and 6 M HCl (8 mL) was added and stirred for 1 h. NaHCO3 (aqueous solution, 20 mL) was added, and the mixture was washed with KF aqueous solution (saturated, 3 x 10 mL). The mixture was extracted with DCM (3 x 30 mL). The combined organic fractions were washed with brine (saturated, 50 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified to the title compound by rapid silica gel chromatography (0–12% ethyl acetate / petroleum ether). 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.50 (s, 1H), 2.60 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H).

[0265] Step 3.1 - (6-chloro-4,5-dimethylpyridin-3-yl)ethane-1-ol:NaBH4 (0.402 g, 10.62 mmol) was added to a stirred solution of 1-(6-chloro-4,5-dimethylpyridin-3-yl)acetone (1.3 g, 7.08 mmol) in MeOH (20 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 h. A saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to yield the title compound. MS = 186.0 (M+1).

[0266] Intermediate C

[0267]

[0268] (5-Bromo-6-methylpyridin-3-yl)methanol

[0269] Step 1. 5-Bromo-6-iodonicotinic acid methyl ester: Trimethyliodosilane (3.99 g, 19.96 mmol) was added to a stirred solution of methyl 5-bromo-6-chloronicotinate (5 g, 19.96 mmol) and sodium iodide (8.98 g, 59.9 mmol) in MeCN (40 mL). After the addition was complete, the reaction mixture was stirred at 30 °C for 14 h. The reaction mixture was concentrated and diluted with water (20 mL). The pH of the solution was adjusted to 7 with 2N NaOH. The reaction mixture was extracted with DCM (15 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum to provide crude methyl 5-bromo-6-iodonicotinate, which was used without further purification. MS = 341.8, 343.8 (M+1).

[0270] Step 2.5-Bromo-6-methylnicotinic acid methyl ester: K₂CO₃ (4.12 g, 29.8 mmol) and Pd(DPPF)Cl₂ (0.812 g, 0.994 mmol) were added to a stirred solution of methyl 5-bromo-6-iodonicotinate (3.4 g, 9.94 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboroxane (3.74 g, 29.8 mmol) in dioxane (25 mL). After the addition was complete, the reaction mixture was stirred at 75 °C under N₂ for 12 h. The mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (25 mL x 3). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by rapid silica gel chromatography (0–30% EtOAc / Pet.) to yield the title compound. MS = 229.9, 231.9 (M+1).

[0271] Step 3. (5-Bromo-6-methylpyridin-3-yl)methanol:NaBH4 (0.419 g, 11.08 mmol) was added to a stirred solution of methyl 5-bromo-6-methylnicotinate (1.7 g, 7.39 mmol) in THF (10 mL) and MeOH (10 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 13 h. A saturated aqueous solution of ammonium chloride (20 mL) was added, and the mixture was extracted with EtOAc (15 mL x 3). The combined organic fractions were washed with saturated brine (15 mL), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (0–36% EtOAc / Pet.) to yield the title compound. MS = 201.9, 203.9 (M+1).

[0272] Intermediate D

[0273]

[0274] 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)ethane-1-ol

[0275] Step 1.2-Chloro-3-fluoro-5-iodo-4-methylpyridine: LDA (2M in THF and hexane) (11.65 mL, 23.31 mmol) was added to a solution of 2-chloro-3-fluoro-4-iodopyridine (5 g, 19.42 mmol) in THF (50 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min. Iodomethane (9.61 mL, 154 mmol) was added at -78 °C, and the reaction mixture was stirred at -78 °C for 1.5 h. The mixture was quenched with NH4Cl and extracted with EtOAc. The organic layer was washed with saturated NaCl (20 mL), dried over Na2SO4, and concentrated. The residue was purified by rapid silica gel chromatography (0–3% ethyl acetate / petroleum ether) to yield the title compound. MS = 271.9 (M+1).

[0276] Step 2.1 - (6-chloro-5-fluoro-4-methylpyridin-3-yl)ketene:Tributyl(1-ethoxyvinyl)stanane (5.97 mL, 17.69 mmol) and 2-chloro-3-fluoro-5-iodo-4-methylpyridine (4.48 g, 16.50 mmol) were added to a solution of (PPh3)2PdCl2 (1.158 g, 1.650 mmol) in toluene (40 mL) at 20 °C. The resulting mixture was stirred at 90 °C for 16 h under N2. The reaction mixture was cooled to 20 °C, 6 M HCl (20 mL) was added, and the mixture was stirred at 20 °C for 1 h. NaHCO3 (aqueous solution, 20 mL) was added, and the mixture was washed with KF aqueous solution (saturated, 3 x 10 mL). The mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0–12% ethyl acetate / petroleum) to yield the title compound. MS = 188.0 (M+1).

[0277] Step 3.1 - (6-chloro-5-fluoro-4-methylpyridin-3-yl)ethane-1-ol: NaBH4 (0.504 g, 13.31 mmol) was added to a solution of 1-(6-chloro-5-fluoro-4-methylpyridin-3-yl)acetone (1.665 g, 8.88 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was quenched with acetone (10 mL), concentrated, and water (20 mL) and EtOAc (10 mL) were added. The organic layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to produce a crude product. The crude product was purified by rapid silica gel chromatography (0–30% ethyl acetate / petroleum ether) to produce the title compound. MS = 190.0 (M+1).

[0278] Intermediate E

[0279]

[0280] 1-(6-chloro-4,5-dimethylpyridazin-3-yl)ethane-1-ol

[0281] Step 1.1 - (6-chloro-4,5-dimethylpyridazin-3-yl)ketene:Tributyl(1-ethoxyvinyl)stanane (0.842 mL, 2.49 mmol) and Pd(Ph3P)2Cl2 (0.083 g, 0.119 mmol) were added to a solution of 3,6-dichloro-4,5-dimethylpyridazine (0.42 g, 2.37 mmol) in toluene (10 mL). The mixture was then degassed three times and purged with nitrogen. The mixture was stirred at 90 °C for 12 h and then quenched by adding an aqueous solution of KF (30 mL). The mixture was filtered, and the filtrate was extracted with EtOAc (2 x 20 mL). The organic layer was concentrated under vacuum to produce a residue, which was dissolved in an aqueous solution of THF (10 mL) and HCl (5 mL, 4 M). The mixture was stirred at room temperature (26 °C) for 0.5 h and then concentrated under vacuum to produce the title compound, which was used directly without further purification. MS = 185.0 (M+1).

[0282] Step 2.1 - (6-chloro-4,5-dimethylpyridazin-3-yl)ethane-1-ol: Sodium borohydride (0.082 g, 2.167 mmol) was added to a solution of 1-(6-chloro-4,5-dimethylpyridazin-3-yl)ethyl ketone (0.4 g, 2.17 mmol) in MeOH (1 mL) and THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then acetone (5 mL) was added, and the mixture was stirred at 26 °C (room temperature) for 1 h. The mixture was concentrated under vacuum to produce a residue, which was purified by rapid silica gel chromatography (0–50% EtOAc / petroleum ether) to yield the title compound. 1 H NMR (400MHz, CDCl3) δ5.13 (br d, J=5.9Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 1.50 (d, J=6.3Hz, 3H). MS=187.1(M+1).

[0283] intermediate F

[0284]

[0285] 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethane-1-ol

[0286] Step 1.2-Chloro-3-fluoro-5-iodo-4-methylpyridine:LDA (2M, in THF and hexane) (6.99mL, 13.98mmol) was added to a solution of 2-chloro-3-fluoro-4-iodopyridine (3g, 11.65mmol) in THF (40mL) at -78°C. The mixture was stirred at -78°C for 30min, followed by the addition of iodomethane (3.95mL, 63.4mmol) at -78°C, and the reaction mixture was stirred at -78°C for 2h. The mixture was quenched with NH4Cl (40mL aqueous solution) and extracted with EtOAc (30mL x 3). The combined organic layers were washed with saturated NaCl (20mL), dried over Na2SO4, and concentrated. The residue was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 271.9 (M+1).

[0287] Step 2.2-Chloro-5-iodo-3-methoxy-4-methylpyridine: Sodium methoxide (0.687 g, 12.71 mmol) was added to a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine (2.3 g, 8.47 mmol) in MeOH (40 mL) at 27 °C. The mixture was stirred at 80 °C for 48 h, water (aqueous solution, 30 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated, and the residue was purified by rapid silica gel chromatography (0–7% petroleum ether / EtOAc) to yield the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 3.86 (s, 3H), 2.45ppm (s, 3H). MS=283.9(M+1)

[0288] Step 3.1 - (6-chloro-5-methoxy-4-methylpyridin-3-yl)ethane-1-one: Tributyl(1-ethoxyvinyl)stanane (3.71 mL, 11.01 mmol) and (PPh3)2PdCl2 (0.644 g, 0.917 mmol) were added to a solution of 2-chloro-5-iodo-3-methoxy-4-methylpyridine (2.6 g, 9.17 mmol) in toluene (40 mL) at 20 °C. The resulting mixture was stirred at 90 °C under N2 for 16 h, then cooled to 20 °C and 6 M HCl (40 mL) was added. The mixture was stirred at 20 °C for 1 h and then quenched with a saturated 25 mL KF aqueous solution. The mixture was extracted with EtOAc (3 x 15 mL). The combined organic fractions were washed with saturated brine (50 mL), dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (0–50% petroleum ether / EtOAc) to yield the title compound. 1H NMR (400MHz, CDCl3) δ8.50 (s, 1H), 3.86 (s, 3H), 2.62 (s, 3H), 2.52ppm (s, 3H). MS=200.1(M+1).

[0289] Step 4.1 - (6-chloro-5-methoxy-4-methylpyridin-3-yl)ethane-1-ol: Sodium tetrahydroborate (0.318 g, 8.42 mmol) was added to a solution of 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)acetone (1.4 g, 7.01 mmol) in THF (20 mL) and MeOH (2 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. Saturated NH4Cl (5 mL) was added, and the aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layers were concentrated, and the residue was purified by rapid silica gel chromatography (0–50% petroleum ether / EtoAc) to yield the title compound. 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 5.02-5.14 (m, 1H), 3.84 (s, 3H), 2.33 (s, 3H), 1.53ppm (d, J = 6.6Hz, 3H). MS=202.1(M+1).

[0290] intermediate G

[0291]

[0292] 1-(6-chloro-4-methylpyridin-3-yl)ethane-1-ol

[0293] Step 1.1 - (6-chloro-4-methylpyridin-3-yl)ketene: 5-Bromo-2-chloro-4-methylpyridine (1 g, 4.84 mmol) was dissolved in toluene (20 mL), and then tributyl(1-ethoxyvinyl)stanane (2.495 mL, 7.39 mmol) and (PPh3)2PdCl2 (0.340 g, 0.484 mmol) were added at 20 °C. The resulting mixture was stirred at 90 °C under N2 for 16 h. The reaction mixture was cooled to 20 °C, 6 M HCl (4 mL) was added, and the mixture was stirred at 20 °C for 1 h. NaHCO3 (aqueous solution, 20 mL) was added to the mixture, and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with KF aqueous solution (saturated, 3 x 10 mL) and brine (saturated, 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0–12% ethyl acetate / petroleum ether) to yield the title compound. (400MHz, CDCl3, ppm) δ8.71 (s, 1H), 7.22 (s, 1H), 2.60 (s, 3H), 2.54 (s, 3H). MS=170.1(M+1).

[0294] Step 2.1 - (6-chloro-4-methylpyridin-3-yl)ethane-1-ol: To a solution of 1-(6-chloro-4-methylpyridin-3-yl)acetone (430 mg, 2.54 mmol) in MeOH (5 mL), NaBH4 (96 mg, 2.54 mmol) was added. The mixture was stirred at 20 °C for 0.5 h, then quenched with CH3COCH3 (10 mL). The mixture was concentrated, diluted with H2O (15 mL), and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–50% ethyl acetate / petroleum ether) to yield the title compound. 1 H NMR (400MHz, CDCl3) δ 8.40 (s, 1H), 7.07 (s, 1H), 5.08 (q, J=6.4Hz, 1H), 2.33 (s, 3H), 1.49 (d, J=6.6Hz, 3H).

[0295] intermediate H

[0296]

[0297] 1-(5-chloro-6-methoxypyrazin-2-yl)ethane-1-ol

[0298] Step 1.1 - (5-chloro-6-methoxypyrazin-2-yl)ketene: Pd(Ph3P)4 (228 mg, 0.197 mmol) was added to 5-bromo-2-chloro-3-methoxypyrazine (440 mg, 1.969 mmol) and tributyl(1-ethoxyvinyl)tin (0.665 mL, 1.969 mmol) in toluene (14 mL), and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to 20 °C, HCl (4 M, 3 mL) was added, and the mixture was stirred at 20 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0–17% EA / PE) to yield the title compound. MS = 187.1 (M+1).

[0299] Step 2.1 - (5-chloro-6-methoxypyrazin-2-yl)ethane-1-ol: Sodium borohydride (38.5 mg, 1.017 mmol) was added to a solution of 1-(5-chloro-6-methoxypyrazin-2-yl)acetone (271 mg, 1.452 mmol) in THF (5 mL) and MeOH (1 mL) at 0 °C. The mixture was stirred at 25 °C (room temperature) for 1 h. The reaction mixture was quenched with acetone (10 mL), concentrated, and the residue was purified by rapid silica gel chromatography (0–25% EA / PE) to yield the title compound. MS = 189.1 (M+1).

[0300] Intermediate I

[0301]

[0302] 3-(5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl)cyclobutane-1-amine

[0303] Step 1. (3-(5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl)cyclobutyl)carbamate: Potassium trifluoroborate (202 mg, 0.650 mmol), 1-(2-bromo-4-chlorophenyl)-4-fluoro-1H-pyrazole (138 mg, 0.5 mmol), cesium carbonate (244 mg, 0.750 mmol), and [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine]nickel(II) dichloride (99 mg, 0.250 mmol) were added. A mixture of [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (14.02 mg, 0.013 mmol) was added to a flask, purged with N2 for 10 min, then sealed and irradiated with 450 nM light for 12 h using a photoreactor (full power, full fan speed). The mixture was then diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried and purified by rapid silica gel chromatography (0-100% EtOAc / hexane) to provide the title compound. MS = 399.0 (M+1).

[0304] Step 2.3-(5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl)cyclobutane-1-amine: Water was added to (3-(5-chloro-2-(4-fluoro-1H-pyrazol-1-yl)phenyl)cyclobutyl)carbamate (39 mg, 0.098 mmol) in MeOH, followed by potassium hydroxide (192 mg, 3.41 mmol). The mixture was stirred overnight at 65 °C, then stirred at 90 °C for 3 h, and then partitioned between EtOAc and NH4Cl (saturated aqueous solution). The aqueous layer was extracted with EtOAc, dried (MgSO4), filtered, and concentrated. The crude product was used for the next step without further purification. MS = 266.0 (M+1)

[0305] Intermediate J

[0306]

[0307] 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile with 2,2,2-trifluoroacetic acid (Scheme 1)

[0308] Step 1.3 - Oxycyclobutane-1-carbonyl chloride:SOCl2 (233 mL, 3210 mmol, 3.0 equivalent) was added dropwise to a solution of 3-oxocyclobutanecarboxylic acid (122 g, 1070 mmol, 1.0 equivalent) in dry DCM (1200 mL) at 0 °C. The mixture was heated to reflux and held for 1.5 h, and then evaporated under vacuum to provide the title compound.

[0309] Step 2.3 -Oxycyclobutane-1-carbonyl azide: A solution of 3-oxocyclobutanecarbonyl chloride (99 g, 749 mmol, 1.0 equivalent) in acetone (1000 mL) was added dropwise to a solution of NaN3 (58.4 g, 898.8 mmol, 1.2 equivalent) in H2O (200 mL) at 0 °C. After addition, the mixture was stirred for 1 h and treated with ice (110 g). The resulting mixture was extracted with Et2O (2 x 1000 mL). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, and concentrated to approximately 15 mL of solution. Toluene (2 x 30 mL) was added to the residue, and the mixture was evaporated twice to remove Et2O (leaving approximately 30 mL of solution each time to avoid explosion), which yielded the title compound.

[0310] Step 3. (3-O-cyclobutyl)carbamate tert-butyl ester: Add 800 mL of toluene to the solution of the 3-oxocyclobutane-1-carbonyl azide from the previous step in toluene. Heat the resulting solution to 90 °C until N2 production ceases. Next, add 500 mL of t-BuOH to the reaction mixture, and stir the resulting mixture overnight at 90 °C. Cool the mixture and concentrate it. Purify the crude residue using rapid silica gel chromatography (17% ethyl acetate / petroleum ether) to provide the title compound.

[0311] Step 4. (3-Hydroxycyclobutyl)carbamate tert-butyl ester NaBH4 (38 g, 1005.8 mmol, 1.0 equivalent) was added fractionally to a solution of N-(3-oxocyclobutyl)carbamate (95 g, 502.9 mmol, 1.0 equivalent) cooled to 0 °C in THF (950 mL) and MeOH (475 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was quenched by adding 1 L of NH4Cl (aqueous solution), and the THF and MeOH in the solution were evaporated and extracted with DCM (3 × 1 L). The organic layers were combined and washed with brine (2 × 1 L). The organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound.

[0312] Step 5. (3-Iodocyclobutyl)carbamate tert-butyl esterTo a solution of N-(3-hydroxycyclobutyl)carbamate tert-butyl ester (88.9 g, 472.8 mmol, 1.0 equivalent) in DCM (900 mL), I₂ (144 g, 567.4 mmol, 1.2 equivalent), PPh₃ (148.6 g, 567.4 mmol, 1.2 equivalent), and imidazole (38.6 g, 567.4 mmol, 1.2 equivalent) were added. The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with 2 L H₂O, filtered, and the liquid was extracted with DCM (2 x 1 L). The organic layers were combined and washed with brine (2 x 1 L). The organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (3% ethyl acetate / petroleum ether) to provide the title compound.

[0313] Step 6. (3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate tert-butyl ester: DPy (11.55 g, 73.97 mmol, 0.2 equivalents) was added to a solution of NiCl2 (DME) (16.25 g, 73.97 mmol, 0.2 equivalents) in DMA (1000 mL), and the mixture was degassed with N2 (x3) and stirred at room temperature for 30 min. N-(3-iodocyclobutyl)carbamate tert-butyl ester (109.9 g, 369.86 mmol, 1.0 equivalents), 2-bromo-4-chlorobenzyl nitrile (96.07 g, 443.84 mmol, 1.2 equivalents), and zinc powder (36.29 g, 554.8 mmol, 1.5 equivalents) in DMA (4000 mL) were added. The mixture was degassed with N2 (x3). The reaction mixture was stirred at room temperature for 3 h and 5 L of water was added. The resulting solution was extracted with ethyl acetate (3 x 2 L) and the organic layers were combined. The resulting mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (2% to 3% ethyl acetate / petroleum ether) to provide a mixture of isomers. The title compound was resolved by preparative SFC under the following conditions: EnantioPak-A1-5(02); IPA 40%. This yielded a faster-eluting isomer (cis-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate tert-butyl ester: MS: 305, obtained as a solid. 1¹H NMR (300 MHz, CD₃OD): δ 7.66 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 4.10 (p, J = 8.3 Hz, 1H), 3.48 (tt, J = 10.1, 7.6 Hz, 1H), 2.92–2.74 (m, 2H), 2.18–2.01 (m, 2H), 1.46 (s, 9H). [M⁻¹]⁻. The slower-eluting isomer (trans-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate obtained as a solid: MS: 305 [M⁻¹] 1 H NMR (300MHz, CD3OD): δ7.69 (d, J=8.2Hz, 2H), 7.42 (dd, J=8.3, 2.0Hz, 1H), 4.17 (dt, J=14.2, 6.4Hz, 1H), 3.91 (p, J=7.6, 7.2Hz, 1H), 2.54 (t, J=7.3Hz, 4H), 1.47 (s, 9H).

[0314] Step 7.2: ((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile compound with 2,2,2-trifluoroacetic acid (1:1) Trifluoroacetic acid (6.03 mL, 78 mmol) was added to a stirred solution of tert-butyl cis-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate (3.0 g, 9.78 mmol) in dichloromethane at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 207.2 (M+1).

[0315] Table 1. The following compounds were prepared using appropriate starting materials according to procedures similar to those described for intermediate J.

[0316]

[0317] intermediate P

[0318]

[0319] 2-(cis)-3-aminocyclobutyl)-4-methylbenzylnitrile

[0320] Step 1.3 - Oxycyclobutane-1-carbonyl chloride: SOCl2 (233 mL, 3210 mmol, 3.0 equivalent) was added dropwise to a solution of 3-oxocyclobutanecarboxylic acid (122 g, 1070 mmol, 1.0 equivalent) in dry DCM (1200 mL) at 0 °C. The mixture was heated to reflux and held for 1.5 h, and then evaporated under vacuum to provide the title compound.

[0321] Step 2.3 -Oxycyclobutane-1-carbonyl azide:A solution of 3-oxocyclobutanecarbonyl chloride (99 g, 749 mmol, 1.0 equivalent) in acetone (1000 mL) was added dropwise to a solution of NaN3 (58.4 g, 898.8 mmol, 1.2 equivalent) in H2O (200 mL) at 0 °C. After addition, the mixture was stirred for 1 h and treated with ice (110 g). The resulting mixture was extracted with Et2O (2 x 1000 mL). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, and concentrated to approximately 15 mL of solution. Toluene (2 x 30 mL) was added to the residue, and the mixture was co-evaporated twice to remove Et2O (leaving approximately 30 mL of solution each time to avoid explosion), which yielded the title compound.

[0322] Step 3. (3-O-cyclobutyl)carbamate tert-butyl ester: Add 800 mL of toluene to the solution of the 3-oxocyclobutane-1-carbonyl azide from the previous step in toluene. Heat the resulting solution to 90 °C until N2 production ceases. Next, add 500 mL of t-BuOH to the reaction mixture, and stir the resulting mixture overnight at 90 °C. Cool the mixture and concentrate it. Purify the crude residue using rapid silica gel chromatography (17% ethyl acetate / petroleum ether) to provide the title compound.

[0323] Step 4. (3-Hydroxycyclobutyl)carbamate tert-butyl ester NaBH4 (38 g, 1005.8 mmol, 1.0 equivalent) was added fractionally to a solution of N-(3-oxocyclobutyl)carbamate (95 g, 502.9 mmol, 1.0 equivalent) cooled to 0 °C in THF (950 mL) and MeOH (475 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was quenched by adding 1 L of NH4Cl (aqueous solution), and the THF and MeOH in the solution were evaporated and extracted with DCM (3 × 1 L). The organic layers were combined and washed with brine (2 × 1 L). The organic layers were dried over Na2SO4 and concentrated under vacuum to provide the title compound.

[0324] Step 5. (3-Iodocyclobutyl)carbamate tert-butyl esterTo a solution of N-(3-hydroxycyclobutyl)carbamate tert-butyl ester (88.9 g, 472.8 mmol, 1.0 equivalent) in DCM (900 mL), I₂ (144 g, 567.4 mmol, 1.2 equivalent), PPh₃ (148.6 g, 567.4 mmol, 1.2 equivalent), and imidazole (38.6 g, 567.4 mmol, 1.2 equivalent) were added. The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with 2 L H₂O, filtered, and the liquid was extracted with DCM (2 x 1 L). The organic layers were combined and washed with brine (2 x 1 L). The organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (3% ethyl acetate / petroleum ether) to yield the title compound.

[0325] Step 6. (3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate tert-butyl ester: DPy (11.55 g, 73.97 mmol, 0.2 equivalents) was added to a solution of NiCl2 (DME) (16.25 g, 73.97 mmol, 0.2 equivalents) in DMA (1000 mL), and the mixture was degassed with N2 (x3) and stirred at room temperature for 30 min. N-(3-iodocyclobutyl)carbamate tert-butyl ester (109.9 g, 369.86 mmol, 1.0 equivalents), 2-bromo-4-chlorobenzyl nitrile (96.07 g, 443.84 mmol, 1.2 equivalents), and zinc powder (36.29 g, 554.8 mmol, 1.5 equivalents) in DMA (4000 mL) were added. The mixture was degassed with N2 (x3). The reaction mixture was stirred at room temperature for 3 h and 5 L of water was added. The resulting solution was extracted with ethyl acetate (3 x 2 L) and the organic layers were combined. The resulting mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (2% to 3% ethyl acetate / petroleum ether) to produce a mixture of isomers. The title compound was resolved by preparative SFC under the following conditions: EnantioPak-A1-5(02); IPA 40%). This yielded a faster-eluting isomer (cis-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate tert-butyl ester: MS: 305 [M-1]- as a solid. A slower-eluting isomer (trans-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate tert-butyl ester: MS: 305 [M-1]- as a solid.

[0326] Step 7. ((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)carbamate tert-butyl esterPd(dppf)Cl2 (239 mg, 0.293 mmol) was added to a solution of (cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)carbamate (500 mg, 1.630 mmol), potassium phosphate (1038 mg, 4.89 mmol), and methylboronic acid (293 mg, 4.89 mmol) in dioxane (8 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 90 °C. After the reaction was complete, the mixture was diluted with ethyl acetate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–100% ethyl acetate / hexane) to provide the title compound. MS = 287.0 (M+1).

[0327] Step 8.2 - ((cis)-3-aminocyclobutyl)-4-methylbenzylnitrile Hydrogen chloride (5 mL, 20.00 mmol) (4 N, in dioxane) was added to a stirred solution of ((cis)-3-(2-cyano-5-methylphenyl)cyclobutyl)carbamate (384 mg, 1.341 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure to provide the title compound as an HCl salt. MS = 187.1 (M+1).

[0328] intermediate Q

[0329]

[0330] 2-((1S,3R)-3-aminocyclopentyl)-4-chlorobenzylnitrile (Scheme 2)

[0331] Step 1. (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid 1,3-dioxoisoindoline- 2-yl ester: To a solution of (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (750 mg, 3.27 mmol), N-hydroxyphthalimide (640 mg, 3.93 mmol), and DMAP (40.0 mg, 0.327 mmol) in DCM (16.400 mL), DIC (0.663 mL, 4.25 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then filtered through a celite filter and concentrated. The residue was purified by silica gel chromatography (0–100% EtOAc in hexane) to yield the title compound. MS = 375.1 (M+1)

[0332] Step 2. ((1R,3R)-3-(5-chloro-2-cyanophenyl)cyclopentyl)carbamate tert-butyl ester and ((1R,3S)-3- (5-Chloro-2-cyanophenyl)cyclopentyl)tert-butyl carbamate:In a glove box, (1S,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid 1,3-dioxoisoindoline-2-yl ester (250 mg, 0.668 mmol), 2-bromo-4-chlorobenzyl nitrile (289 mg, 1.335 mmol), and activated zinc (87 mg, 1.335 mmol) were added to a solution of nickel(II) hexahydrate (31.7 mg, 0.134 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (35.8 mg, 0.134 mmol) in DMA (2226 μl). The reaction mixture was stirred at room temperature for 6 h, then diluted with 1 M HCl and EtOAc. The aqueous layer was extracted with EtOAc (x2), and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0–100% EtOAc / Hex) to yield the title compound. The enantiomerically pure title compound was resolved by Chiral SFC (AD-H, 21 x 250 mm; 10% MeOH). The rapidly eluting enantiomer of the title compound (2-((1R,3R)-3-aminocyclopentyl)-4-chlorobenzyl nitrile) was given as a solid: MS = 265.4 (M+1–56).

[0333] Step 3.2 - ((1S,3R)-3-aminocyclopentyl)-4-chlorobenzyl nitrile: To a solution of ((1R,3S)-3-(5-chloro-2-cyanophenyl)cyclopentyl)carbamate tert-butyl (23.8 mg, 0.074 mmol)) in DCM (371 μl), 4N HCl in dioxane (185 μl, 0.742 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was used directly. MS = 221.0

[0334] Table 2. The following compounds were prepared using appropriate starting materials according to procedures similar to those described for intermediate P.

[0335]

[0336] intermediate U

[0337]

[0338] 2-(3-amino-1-methylcyclobutyl-3-d)-4-chlorobenzylnitrile

[0339] Step 1. 4-Chloro-2-(1-Methyl-3-oxocyclobutyl)benzylnitrileIn a glove box, 1-methyl-3-oxocyclobutane-1-carboxylic acid 1,3-dioxoisoindoline-2-yl ester (3500 mg, 12.81 mmol), 2-bromo-4-chlorobenzyl nitrile (5545 mg, 25.6 mmol), and zinc (1675 mg, 25.6 mmol) were added to a solution of nickel(II) hexahydrate (609 mg, 2.56 mmol) and 4,4′-di-tert-butyl-2,2'-bipyridine (1375 mg, 5.12 mmol) in DMA (42.700 mL). The reaction mixture was stirred at room temperature for 6 h, filtered through a celite filter, and diluted with 1 M HCl and EtOAc. The aqueous layer was extracted with EtOAc (x2), and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0–100% EtOAc / Hex.) to yield the title compound. 1 H NMR (500MHz, CD3OD, ppm) δ7.78 (d, J=8.3Hz, 1H), 7.61 (d, J=2.0Hz, 1H), 7.50 (dd, J=8.3, 2.0Hz, 1H), 3.72-3.63 (m, 2H), 3.29-3.20 (m, 2H), 1.69 (s, 3H).

[0340] Step 2.2 - (3-amino-1-methylcyclobutyl-3-d)-4-chlorobenzyl nitrile: Titanium isopropoxide (IV) (162 μl, 0.546 mmol) was added to a solution of 4-chloro-2-(1-methyl-3-oxocyclobutyl)benzyl nitrile (60 mg, 0.273 mmol) in ammonia / methanol (683 μl, 1.366 mmol). The reaction mixture was stirred at room temperature for 4 h, sodium borodeuteride (14.41 μl, 0.410 mmol) was added, and the mixture was stirred at room temperature for 2 h. Ammonium hydroxide (200 μL, 0.4 mmol) (2 M in MeOH) was added, the solution was diluted with EtOAc, filtered through a celite filter, and concentrated. The residue was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 222.3 (M+1).

[0341] intermediate V

[0342]

[0343] 2-(3-aminocyclobutyl-1-d)-4-chlorobenzylnitrile

[0344] Step 1. Tert-butyl(3-iodocyclobutoxy-3-d)dimethylsilane:To a solution of 3-((tert-butyldimethylsilyl)oxy)cyclobutane-1-d-1-ol (2.34 g, 11.5 mmol, 1.0 equivalent) in DCM (46 mL), I₂ (3.5 g, 13.8 mmol, 1.2 equivalent), PPh₃ (3.92 g, 15.0 mmol, 1.3 equivalent), and imidazole (1.18 g, 17.3 mmol, 1.5 equivalent) were added. The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with H₂O and filtered through a celite filter. The layers in the filtrate were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by rapid silica gel chromatography (EtOAc / hexane) to provide the title compound.

[0345] Step 2.2-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl-1-d)-4-chlorobenzyl nitrile: Add DMA (4 mL) to a tubular flask containing NiCl2 (DME) (44 mg, 0.2 mmol, 0.2 equivalent) and 2,2'-bipyridine (31 mg, 0.2 mmol, 0.2 equivalent). Degas the mixture with N2 and stir at room temperature for 30 min. Add this solution to another tubular flask (under N2) containing tert-butyl(3-iodocyclobutoxy-3-d)dimethylsilane (313 mg, 1.0 mmol, 1.0 equivalent), 2-bromo-4-chlorobenzyl nitrile (325 mg, 1.50 mmol, 1.5 equivalent), TBAI (369 mg, 1.0 mmol, 1.0 equivalent), and zinc powder (98 mg, 1.50 mmol, 1.5 equivalent) in DMA (1.6 mL). Degas the mixture with N2 for 5 min and then stir at room temperature for 4 h. Quench the reaction with H2O and dilute with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by rapid silica gel chromatography (EtOAc / hexane) to yield the title compound.

[0346] Step 3.4-Chloro-2-(3-hydroxycyclobutyl-1-d)benzylnitrile: In an ice bath, 1.0 M TBAF (0.61 mL, 0.61 mmol, 1.5 equivalence) in THF was added to a solution of 2-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl-1-d)-4-chlorobenzyl nitrile (132 mg, 0.41 mmol, 1.0 equivalence) in THF (4 mL). The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was quenched with H2O and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound. The crude alcohol was used for the next step without any further purification.

[0347] Step 4.4-Chloro-2-(3-oxocyclobutyl-1-d)benzylnitrile:To a solution of 4-chloro-2-((cis)-3-hydroxycyclobutyl-1-d)benzyl nitrile and 4-chloro-2-((trans)-3-hydroxycyclobutyl-1-d)benzyl nitrile (83 mg, 0.4 mmol, 1.0 equivalent), NaHCO3 (67 mg, 0.80 mmol, 2.0 equivalent) in DCM (2.0 mL), Dysmart periodide (187 mg, 0.44 mmol, 1.1 equivalent) was added. The mixture was stirred at room temperature for 1 h. DCM was removed under reduced pressure, and the crude residue was purified by rapid silica gel chromatography (EtOAc / hexane) to provide the title compound.

[0348] Step 5.2 - (3-aminocyclobutyl-1-d)-4-chlorobenzyl nitrile: Ti(O) was added to a solution of 4-chloro-2-(3-oxocyclobutyl-1-d)benzyl nitrile (90 mg, 0.44 mmol, 1.0 equivalent) in NH3 (7 M in MeOH, 1.2 mL, 8.7 mmol, 20 equivalent) 1 Pr)4 (0.16 mL, 0.52 mmol, 1.2 equivalents). The mixture was stirred at room temperature for 16 h, during which time it was cooled to 0 °C. NaBH4 (132 mg, 3.5 mmol, 8 equivalents) was added to the solution, and the mixture was warmed to room temperature and stirred for 12 h. MeOH was removed under reduced pressure, followed by the addition of H2O and EtOAc. The mixture was filtered through a celite filter to separate the layers, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound. The crude amine was used for the next step without any further purification. MS = 208.1 (M+1)

[0349] intermediate W

[0350]

[0351] 2-(3-aminocyclobutyl-3-d)-4-chlorobenzylnitrile

[0352] Step 1. 4-Chloro-2-(3-oxocyclobutyl)benzyl nitrile.4,4'-di-tert-butyl-2,2'-bipyridine (0.54 g, 2.02 mmol) was added to a solution of NiCl2 (DME) (0.42 g, 1.9 mmol) in DMA (10 mL), and the mixture was degassed with N2 (x3) and stirred at room temperature for 30 min. 1,3-dioxoisoindoline-2-yl ester of 3-oxocyclobutane-1-carboxylic acid (5 g, 19.2 mmol), 2-bromo-4-chlorobenzyl nitrile (6.26 g, 28.9 mmol), and zinc powder (2.52 g, 38.6 mmol) were added to DMA (10 mL). The mixture was degassed with N2 (x3). The reaction mixture was stirred at room temperature for 3 h and water was added. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The resulting mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (0% to 50% ethyl acetate / hexane) to yield the title compound.

[0353] Step 2.2 - (3-aminocyclobutyl-3-d)-4-chlorobenzyl nitrile: Ti(O) was added to a solution of 4-chloro-2-(3-oxocyclobutyl)benzyl nitrile (130 mg, 0.63 mmol, 1.0 equivalent) in NH3 (7 M in MeOH, 1.8 mL, 12.6 mmol, 20 equivalent) 1 pr)4 (0.23 mL, 0.76 mmol, 1.2 equivalents). The mixture was stirred at room temperature for 16 h, during which time it was cooled to 0 °C. NaBD4 (212 mg, 5.1 mmol, 8 equivalents) was added to the solution, and the mixture was warmed to room temperature and stirred for 12 h. MeOH was removed under reduced pressure, followed by the addition of H2O and EtOAc. The mixture was filtered through a celite filter to separate the layers, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound. The crude amine was used for the next step without any further purification. MS = 208.1 (M+1).

[0354] Intermediate X

[0355]

[0356] (1S,2S,4S)-2-amino-4-(3-chlorophenyl)cyclobutane-1-ol and (1R,2R,4R)-2-amino-4-(3-chlorophenyl)cyclobutane-1-ol (Phenyl)cyclobutane-1-ol

[0357] Step 1. (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate tert-butyl ester:To a solution of 1-bromo-3-chlorobenzene (3.10 g, 16.20 mmol) in dry THF (20 mL), n-butyllithium (6.48 mL, 16.20 mmol) was added dropwise at -78 °C. The mixture was then degassed three times and stirred at -78 °C for 20 min under nitrogen atmosphere. Tert-butyl (3-oxocyclobutyl)carbamate (1.5 g, 8.10 mmol) (dissolved in 1.5 mL of THF) was added dropwise to the reaction mixture, and the mixture was stirred at -78 °C for 1 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (30 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to produce a crude product, which was purified by rapid silica gel chromatography (0–30% EtOAc / Pet.) to produce the title compound. MS = 223.9 (M+1 -56 -18).

[0358] Step 2.3-(3-Chlorophenyl)cyclobut-2-enamine: A mixture of tert-butyl (3-(3-chlorophenyl)-3-hydroxycyclobutyl)carbamate (250 mg, 0.840 mmol) and methanesulfonic acid (0.545 mL, 8.40 mmol) in DCM (6 mL) was stirred at 25 °C for 2 h. The solvent was evaporated, and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide the title compound as a TFA salt. MS = 163.0 (M+1-17).

[0359] Step 3. (1S,2S,4S)-2-amino-4-(3-chlorophenyl)cyclobutane-1-ol and (1R,2R,4R)-2-amino-4- (3-Chlorophenyl)cyclobutane-1-ol (racemic 2-amino-4-(3-chlorophenyl)cyclobutanol, the amide and phenyl rings are in the same...) (The OH and phenyl rings are on different sides): Under N2, BH3 DMS (0.187 mL, 1.873 mmol) (10 M in DMS) was added dropwise to a 0°C solution of 3-(3-chlorophenyl)cyclobut-2-enamine TFA salt (110 mg, 0.375 mmol) in THF (4 mL). The mixture was stirred at 0°C for 5 min and then at 25°C for 4 h. Sodium perborate (153 mg, 1.873 mmol) and water (1 mL) were carefully added to the reactants, and the resulting mixture was stirred at 25°C for another 1 h. The solvent was evaporated, and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to produce 2-amino-4-(3-chlorophenyl)cyclobutanol TFA salt (faster elution peak, racemic, amide and phenyl ring are cis, OH and phenyl ring are trans): MS = 198.0 (M+1) and 2-amino-4-(3-chlorophenyl)cyclobutanol TFA salt (slower elution peak, racemic, amine and phenyl ring are trans, OH and amine are cis): MS = 198.0 (M+1).

[0360] intermediate Y

[0361]

[0362] (cis)-3-(4-methylpyridin-2-yl)cyclobutane-1-amine

[0363] Step 1. ((cis)-3-(4-chloropyridin-2-yl)cyclobutyl)carbamate tert-butyl ester: To a solution of 2,2′-bipyridine (0.105 g, 0.673 mmol), nickel(II) glycol dimethyl ether complex (0.148 g, 0.673 mmol), TBAI (1.243 g, 3.37 mmol), and zinc (0.330 g, 5.05 mmol) in DMA (5 mL), tert-butyl 3-iodocyclobutyl)carbamate (1 g, 3.37 mmol) and 2-bromo-4-chloropyridine (0.648 g, 3.37 mmol) were added. The mixture was stirred at 27 °C for 12 h. Water was added, and the reaction mixture was extracted with EtOAc. The organic layer was concentrated and purified by rapid silica gel chromatography (0–40% petroleum ether / EtOAc gradient) to yield the title compound as a mixture of cis and trans isomers. Isomers were separated by SFC (OD-H; mobile phase 15% EtOH (0.1% NH3H2O)) to provide faster elution of the isomer ((cis)-3-(4-chloropyridin-2-yl)cyclobutyl)carbamate and slower elution of the isomer ((trans)-3-(4-chloropyridin-2-yl)cyclobutyl)carbamate.

[0364] Step 2. ((cis)-3-(4-methylpyridin-2-yl)cyclobutyl)carbamate tert-butyl ester: To a solution of (cis)-3-(4-chloropyridin-2-yl)cyclobutyl)carbamate (150 mg, 0.530 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (133 mg, 1.061 mmol), and potassium phosphate (338 mg, 1.591 mmol) in dioxane (3 mL) and H₂O (0.6 mL), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (34.6 mg, 0.053 mmol) was added. The reaction mixture was stirred at 110 °C for 12 h, and water was added. The mixture was then extracted with EA. The organic layer was concentrated and purified by rapid silica gel chromatography (petroleum ether: EA = 3:1) to yield the title compound. MS = 263.1 (M+1).

[0365] Step 3. (cis)-3-(4-methylpyridin-2-yl)cyclobutane-1-amine: TFA (0.5 mL) was added to a stirred solution of (cis)-3-(4-methylpyridin-2-yl)cyclobutyl)carbamate (110 mg, 0.419 mmol) in DCM (5 mL) at 25 °C. After the addition was complete, the reaction was stirred at 25 °C for 12 h. The mixture was concentrated to obtain the title compound, which was used without further purification. MS = 163.1 (M+1).

[0366] Intermediate Z

[0367]

[0368] 2-(cis)-3-amino-1-methylcyclobutyl)-4-chlorobenzamide

[0369] Step 1.2-((cis)-3-amino-1-methylcyclobutyl)-4-chlorobenzamide: Sodium hydroxide (2.333 mL, 11.67 mmol, 5 N in water) was added to a solution of 2-((cis)-3-amino-1-methylcyclobutyl)-4-chlorobenzyl nitrile hydrochloride (20 mg, 0.078 mmol) in MeOH (0.3 mL) and THF (0.3 mL). The reaction mixture was stirred at 90 °C for 16 h. The mixture was concentrated under reduced pressure to remove the organic solvent. The mixture was neutralized with TFA and purified by preparative reversed-phase HLC (ACN / water containing 0.05% TFA modifier) ​​to provide the title compound as a TFA salt. MS = 238.9 (M+1).

[0370] Intermediate AA

[0371]

[0372] (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one

[0373] Step 1. (1R,2S)-Cyclopropane-1,2-dimethyl dicarboxylate: H₂SO₄ (68 g, 679 mmol) was added to a solution of (1R, 5S)-3-oxabicyclo[3.1.0]hexane-2,4-dione (680 g, 6067 mmol) in MeOH (6.8 L) under stirring at 30 °C, and the solution was heated to 70 °C and maintained for 16 h. The reactants were concentrated under vacuum, diluted with EtOAc, and washed with water (x2). The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO₃ and brine. The organic phases were concentrated under vacuum and purified by rapid silica gel chromatography (1–10% EtOAc / petroleum ether) to yield the title compound. 1 ¹H NMR (400 MHz, chloroform-d) δ 3.69 (s, 6H), 2.06 (dd, J = 6.9, 8.1 Hz, 2H), 1.76–1.61 (m, 1H), 1.24 (dt, J = 5.1, 8.4 Hz, 1H).

[0374] Step 2. (1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid:Dimethyl (1R,2S)-cyclopropane-1,2-dicarboxylate (67 g, 424 mmol) was added to a solution of porcine liver esterase (2 g, 3 wt% loading) in buffer (3.35 L, 0.1 M phosphate buffer, pH 7.0) in MeCN (335 mL). The mixture was stirred at 30 °C for 48 h while maintaining a pH of 6.8–7.2. NaCl (2 kg) was added and the pH was adjusted from 7 to 2. The solution was filtered through diatomaceous earth and extracted with isopropyl acetate (1.2 L x 4). The combined organic matter was washed with brine (300 mL x 3), dried over Na₂SO₄, filtered, and concentrated to provide the title compound. MS = 145.2 (M+1).

[0375] Step 3. Methyl (1R,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate: BH3·DMS (305 mL, 3053 mmol) was added dropwise to a solution of (1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (220 g, 1526 mmol) in THF (2.2 L) at 40 °C. The reaction mixture was stirred at 45 °C for 2 h, and MeOH (500 mL) was added at 0 °C. The mixture was then heated to 50 °C and held for 4 h. The mixture was dried over Na2SO4, concentrated, and purified by rapid silica gel chromatography (1–10% EtOAc / petroleum ether) to yield the title compound. 1 H NMR (400 MHz, CDCl3) δ3.92 (br dd, J=4.9, 11.7Hz, 1H), 3.81-3.64 (m, 4H), 2.41-2.19 (m, 1H), 1.83-1.73 (m, 1H), 1.60 (dquin, J=5.3, 8.1Hz, 1H), 1.15-1.07 (m, 2H).

[0376] Step 4. (1R, 5S)-3-azabicyclo[3.1.0]hexane-2-one:TEA (471 mL, 3381 mmol) and MsCl (290 g, 2536 mmol) were added to a solution of methyl (1R, 2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (220 g, 1690 mmol) in DCM (2.2 L) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h. The solution was diluted with DCM (1.0 L) and washed with water (300 mL x 3) and saturated NaCl (300 mL). The organic matter was dried over MgSO4, filtered, and concentrated. The residue was dissolved in THF (900 mL) and loaded into a 5 L autoclave. NH3·H2O (2.1 L) was added to the mixture and the mixture was stirred at 50 °C for 12 h. The aqueous phase was extracted with CHCl3 / i-PrOH (3V / 1V, 500 mL x 4) and the combined organic matter was washed with brine. The organic matter was dried over MgSO4, filtered, and concentrated. The residue was suspended in MTBE and stirred at 25°C for 16 hours, then filtered to provide the title compound. MS = 98.3 (M+1) 1 H NMR (400MHz, DMSO-d6) δ7.022 (s, 1H), 3.37-3.28 (d, 1H), 3.14 (d, J=10.4Hz, 1H), 1.90 (m, household 4.5 , 5.9Hz, 1H), 1.61 (m, J=1.5, 3.1, 6.5Hz, 1H), 1.00 (m, J=4.2, 8.0Hz, 1H), 0.44 (m, J=4.0Hz, 1H).

[0377] Intermediate AB

[0378]

[0379] 1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine-3- (ethyl)-1H-1,2,3-triazol-4-carboxylic acid

[0380] Step 1.5-Bromo-4-methylpyridine-2-amine: Bromine (369 g, 2.31 mol) was added dropwise to a solution of 4-methylpyridin-2-amine (250 g, 2.31 mol) in AcOH (1.50 L) at a temperature below 10 °C. The reaction mixture was stirred at 25 °C for 2 hours. The solution was concentrated under reduced pressure to remove the solvent. H₂O (5.00 L) was added, and the pH was adjusted to 7–8 with NaHCO₃. The resulting mixture was extracted with ethyl acetate (2.00 L x 3), washed with saturated NaCl (2.00 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was ground together with MTBE (5.00 L) and filtered to yield the title compound. 1 HNMR: (400MHz, CDCl3) δ8.09 (s, 1H) 6.42 (s, 1H) 4.43 (br s, 2H) 2.29 (s, 3H).

[0381] Step 2.5-Bromo-2-fluoro-4-methylpyridine: (Under nitrogen) 5-Bromo-4-methylpyridin-2-amine (250 g, 1.34 mol) was added to a solution of nitrosotetrafluoroborate (234 g, 2.00 mol) in CHCl3 (1.00 L) at 0 °C. After stirring at 0 °C for 30 min, the reaction mixture was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMSO (1.0 L) and stirred at 145 °C for 14 h. The reaction solution was cooled to room temperature and the reaction liquid was made alkaline with saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (2.00 L x 5), washed with saturated NaCl (5.00 L x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (10–100% EtOAc / Pet.) to yield the title compound. 1 HNMR: (400MHz, CDCl3) δ8.27 (s, 1H) 6.86 (d, J = 2.40Hz, 1H) 2.45 (s, 3H).

[0382] Step 3.1 - (6-fluoro-4-methylpyridin-3-yl)ethane-1-ol: Under helium, at 25°C, dry Mg (51.2 g, 2.11 mol) and dry LiCl (74.5 g, 1.76 mol) were added to a 3 L three-necked flask, followed by THF (1.5 L). DIBAL-H (1 M, 14.0 mL) was then added, and the reaction mixture was purified and degassed three times with nitrogen. 5-Bromo-2-fluoro-4-methylpyridine (267 g, 1.41 mol) was added dropwise over 2 hours at 25°C under N2, while maintaining the temperature below 35°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was cooled to 0°C, and acetaldehyde (5 M, 422 mL) was added dropwise over 30 minutes under N2. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with 50% NH4Cl (1.00 L) and then extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine (1.00 L), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (20–50% EtOAc / petroleum ether) to yield the title compound. 1 H NMR: (400MHz, DMSO-d6) δ 8.18 (s, 1H) 6.95 (s, 1H) 5.28 (d, J = 4.4Hz, 1H) 4.79-5.02 (m, 1H) 2.36 (s, 3H) 1.35 (d, J = 6.4Hz, 3H).

[0383] Step 4.5-(1-Azide-ethyl)-2-fluoro-4-methylpyridineDBU (257 g, 1.69 mol) was added dropwise to a solution of 1-(6-fluoro-4-methylpyridin-3-yl)ethane-1-ol (250 g, 1.61 mol), DPPA (466 g, 1.69 mol), and DMAP (197 g, 1.61 mol) in THF (1.00 L) cooled to 0 °C. The reaction mixture was stirred at 25 °C for 24 h. H₂O (500 mL) was added, and the aqueous phase was extracted with MTBE (200 mL x 3), washed with saturated NaCl (200 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (10–20% EtOAc / Pet.) to yield the title compound. 1 H NMR: (400 MHz, CDCl3) δ 8.16 (s, 1H) 6.75 (d, J = 0.8Hz, 1H) 4.77 (q, J = 6.8Hz, 1H) 2.41 (s, 3H) 1.59 (d, J = 6.8Hz, 3H).

[0384] Step 5. 1-(1-(6-fluoro-4-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid ethyl ester To a solution of 5-(1-azidoethyl)-2-fluoro-4-methylpyridine (230 g, 1.28 mol) and HCCCO2Et (250 g, 2.55 mol) in MeOH (1.50 L), CuSO4·5H2O (79.68 g, 319 mmol) and sodium ascorbate (129 g, 638 mmol) in H2O (500 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and saturated NaCl (200 mL) was added. The aqueous phase was extracted with EtOAc (300 mL x 5), washed with saturated NaCl (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by filtration from MTBE / PE (1:1) to provide the title compound. The remaining solution was purified by rapid silica gel chromatography (10–100% EtOAc / Pet.) to produce the title compound. MS = 279.2(M+1). 1 H NMR: (400MHz, CDCl3) δ8.23 (br s, 1H) 7.89 (s, 1H) 6.81 (br s, 1H) 6.11 (q, J=6.8Hz, 1H) 4.40 (q, J=7.2Hz, 2H) 2.27 (s, 3H) 2.03 (d, J=7.2Hz, 3H) 1.38 (t, J=7.2Hz, 3H).

[0385] Step 6.1-((R)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl) ethyl pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate and 1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo- Ethyl 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate:To a solution of ethyl 1-(1-(6-fluoro-4-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (31.5 g, 113 mmol) and (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (intermediate AA) (11.0 g, 113 mmol) in DMA (80 mL), NaH (4.76 g, 119 mmol, 60% purity) was added. The reaction mixture was heated at 90 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent. 500 mL of EtOAc was then added, and the mixture was washed with saturated NaCl (100 mL x 3). The organic layer was extracted and concentrated. The reaction mixture was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers. The title compound was resolved by chiral SFC (Chiralpak AD, 250*50mm id10um; 45% MeOH; gradient: B% = 45%) to provide enantiomerically pure compounds. Faster elution diastereomers of the title compound: MS = 356.1 (M+1). 1 ¹H NMR: (400 MHz, DMSO-d⁶) δ 8.91 (s, 1H) 8.31 (s, 1H) 8.01 (s, 1H) 6.20 (q, J = 6.8 Hz, 1H) 4.30 (q, J = 7.2 Hz, 2H) 3.92–4.04 (m, 2H) 2.28 (s, 3H) 2.04–2.11 (m, 2H) 1.93 (d, J = 7.2 Hz, 3H) 1.29 (t, J = 7.2 Hz, 3H) 1.19 (td, J = 8.0, 4.22 Hz, 1H) 0.73 (q, J = 4.0 Hz, 1H). Slower eluting diastereomer of the title compound: MS = 356.2 (M+1). 1 H NMR: (400MHz, DMSO-d6) δ8.90 (s, 1H) 8.34 (s, 1H) 8.01 (s, 1H) 6.21 (q, J = 6.8Hz, 1H), 4.30 (q, J=7.2Hz, 2H) 4.03 (dd, J=11.2, 4.83Hz, 1H) 3.93 (d, J=11.6Hz, 1H) 2.28 (s, 3H) 2.07 (br dd, J=7.6, 3.24Hz, 2H) 1.88-2.00 (m, 3H) 1.29 (t, J=7.2Hz, 3H) 1.17 (td, J=8.0, 4.28Hz, 1H) 0.72 (q, J=4.0Hz, 1H).

[0386] Step 7.1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl) Pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid:LiOH (37.1 mg, 1.548 mmol) was added to a solution of ethyl 1-((S)-1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (500 mg, 1.407 mmol, from the slower-eluting isomer from the previous step) in dioxane (21.10 mL) and water (7.034 mL). The reaction mixture was stirred overnight at room temperature. Toluene (20 mL) was added and the reaction mixture was concentrated under reduced pressure. Another 20 mL of toluene was added and the reaction mixture was concentrated under reduced pressure to provide the title compound. MS = 327.9 (M+1).

[0387] intermediate AC

[0388]

[0389] 1-(,(S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine (Pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid

[0390] Step 1.5-Bromo-2-chloro-3,4-dimethylpyridine: 5-Bromo-3,4-dimethylpyridin-2-amine (175 g, 870 mmol, 1.00 equivalence) was added to HCl (12 M, 3.50 L, 48.3 equivalence) at -15 °C, followed by the addition of a solution of NaNO2 (300 g, 4.35 mol, 5.00 equivalence) in H2O (150 mL). The reaction mixture was stirred at -15 °C for 0.5 h, then warmed to room temperature and stirred for 10 h. The reaction mixture was poured into water (3.50 L) and the aqueous phase was extracted with dichloromethane (3.00 L x 3). The organic layer was washed with saturated NaCl (1.50 L x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude extract was purified by rapid silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to provide the title compound. MS = 219.8, 221.9 (M+1). 1 HNMR: (400MHz, MeOD) δ: 8.28 (s, 1H), 2.48 (s, 3H), 2.43 (s, 3H).

[0391] Step 2.1 - (6-chloro-4,5-dimethylpyridin-3-yl)ethane-1-one:A solution of 5-bromo-2-chloro-3,4-dimethylpyridine (230 g, 1.04 mol, 1.00 equivalent) in toluene (2.30 L) was degassed and purified three times with N2. Tributyl(1-ethoxyvinyl)stanane (501 g, 1.39 mol, 468 mL, 1.33 equivalent) and (PPh3)2PdCl2 (73.2 g, 104.3 mmol, 0.10 equivalent) were added to the mixture under N2 atmosphere. The reactants were degassed and purified three times with N2 and stirred at 90 °C for 12 h. The reactants were then cooled to 20 °C and 6.0 M hydrochloric acid aqueous solution (1.00 L) was added to the mixture. The mixture was stirred at 20 °C for 1 h. The mixture was then filtered, and the filtrate was extracted with EtOAc (600 mL x 3). The combined organic phases were washed with saturated sodium bicarbonate solution (300 mL x 2), KF solution (saturated, 150 mL x 3), and brine (500 mL x 2). The organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (2–10% EtOAc / Pet.). The purified material was then concentrated under reduced pressure and ground with petroleum ether (450 mL) at 25 °C for 0.5 h. The mixture was filtered, and the filter cake was washed with petroleum ether (100 mL). The filter cake was then collected and dried under reduced pressure to provide the title compound. 1 HNMR: (400MHz, MeOD) δ: 8.50 (s, 1H), 2.60 (s, 3H), 2.46 (s, 3H), 2.42 (s, 3H).

[0392] Step 3.1 - (6-chloro-4,5-dimethylpyridin-3-yl)ethane-1-ol: NaBH4 (24.7 g, 653 mmol, 1.50 equivalent) was added to a solution of 1-(6-chloro-4,5-dimethylpyridin-3-yl)ethane-1-one (80.0 g, 436 mmol, 1.00 equivalent) in THF (320 mL) and EtOH (80 mL) (in three fractions) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, then warmed to room temperature and stirred for 5 h. The mixture was poured into a saturated aqueous solution of ammonium chloride (400 mL) at 0 °C and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated NaCl (150 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. 1 HNMR: (400MHz, MeOD) δ: 8.26 (s, 1H), 5.10 (q, J=6.4Hz, 1H), 2.38 (s, 3H), 2.36 (s, 3H), 1.45 (d, J=6.4Hz, 3H).

[0393] Step 4. 2-Chloro-5-(1-Chloroethyl)-3,4-DimethylpyridineTriethylamine (131 g, 1.29 mol, 180 mL, 3.00 equivalent) was added to a solution of 1-(6-chloro-4,5-dimethylpyridin-3-yl)ethane-1-ol (80.0 g, 431 mmol, 1.00 equivalent) in dry DCM (1.25 L) under N2 atmosphere. Then, MsCl (182 g, 1.59 mol, 123 mL, 3.68 equivalent) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 0 °C for 5 min, then heated to 20 °C and stirred for 12 h. The mixture was poured into a saturated aqueous solution of ammonium chloride (1.00 L). The aqueous layer was extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with saturated sodium bicarbonate solution (300 mL x 3) and brine (300 mL x 3). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. MS = 203.9(M+1).

[0394] Step 5.5-(1-Azideylethyl)-2-chloro-3,4-dimethylpyridine: A solution of NaN3 (14.3 g, 220 mmol, 1.50 equivalent) in DMF (150 mL) was degassed and purified with N2 at 20 °C. A solution of 2-chloro-5-(1-chloroethyl)-3,4-dimethylpyridine (30.0 g, 147 mmol, 1.00 equivalent) in DMF (100 mL) was added dropwise to the mixture. The reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was cooled to room temperature and poured into ice water (750 mL) and stirred for 5 min. MTBE (750 mL) was added to the mixture and stirred for 15 min. The mixture was filtered, and the filter cake was washed with MTBE (750 mL x 2). The filtrate was extracted with MTBE (750 mL x 2). The organic layer was then washed with saturated NaCl (300 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. 1 HNMR: (400MHz, MeOD) δ: 8.17 (s, 1H), 5.03 (q, J=6.8Hz, 1H), 2.40 (s, 3H), 2.39 (s, 3H), 1.56 (d, J=6.8Hz, 1H).

[0395] Step 6.1-(1-(6-chloro-4,5-dimethylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester:Under nitrogen atmosphere, tert-butyl propionate (42.8 g, 339 mmol, 46.6 mL, 1.30 equivalent) was added to a solution of 5-(1-azidoethyl)-2-chloro-3,4-dimethylpyridine (55.0 g, 261 mmol, 1.00 equivalent) in t-BuOH (1.38 L) and H₂O (1.38 L). Sodium ascorbate (103 g, 522 mmol, 2.00 equivalent) and CuSO₄·5H₂O (6.52 g, 26.1 mmol, 0.10 equivalent) were then added to the solution. The reactants were degassed, purified with N₂, and stirred at room temperature for 12 h. EtOAc (1.50 L) and water (1.50 L) were added to the mixture, and it was stirred at room temperature for 5 min. The mixture was filtered, and the filtrate was extracted with ethyl acetate (1.50 L x 3). The organic layer was washed with saturated NaCl (1.00 L x 3) and dried under sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate: DCM = 5:1:1 to 1:1:1). The purified material was then concentrated under reduced pressure and tritized with MTBE (250 mL) at room temperature for 0.5 h. The mixture was filtered, and the filter cake was washed with MTBE (100 mL). The filter cake was then collected and dried under reduced pressure to provide the title compound. MS = 337.2 (M+1). 1 HNMR: (400MHz, MeOD) δ: 8.50 (s, 1H), 8.12 (s, 1H), 6.30 (q, J=7.2Hz, 1H), 2.40 (s, 3H), 2.34 (s, 3H), 2.01 (d, J=7.2Hz, 1H), 1.57 (s, 9H).

[0396] Step 7.1-((R)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3- 1-((S)-1-(4,5-dimethyl-6-((1R, )pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester and 1-((S)-1-(4,5-dimethyl-6-((1R, 5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert- Butyl ester:Cs₂CO₃ (322 g, 987 mmol, 3.50 equivalence) was added to a solution of 1-(1-(6-chloro-4,5-dimethylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (95.0 g, 282 mmol, 1.00 equivalence) and (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (intermediate AA) (39.6 g, 296 mmol, 1.05 equivalence, HCl) in dioxane (1.35 L). The reactants were degassed and purified three times with N₂. Xantphos (16.3 g, 28.2 mmol, 0.10 equivalence) and Pd₂(dba)₃ (25.8 g, 28.2 mmol, 0.10 equivalence) were added to the mixture. The reactants were degassed and purified three times with N₂. The reactants were stirred at 100 °C for 12 hours. EtOAc (500 mL) and DCM (500 mL) were added to the mixture, and it was stirred for 10 min. The mixture was filtered, and the filter cake was washed with ethyl acetate / DCM (1:1) (1.50 L). The organic layer was concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography (20–50% EtOAc / petroleum ether) to provide a mixture of diastereomers. The racemic title compound was resolved by chiral SFC (DAICEL CHIRALCEL OD, 250*50 mm id 10 u; 55% IPA (0.1% NH3H2O) to provide an enantiomerically pure compound. Faster elution of the title compound enantiomers: MS = 398.4 (M+1). 1 ¹H NMR: (400 MHz, MeOD) δ: 8.45 (s, 1H), 8.22 (s, 1H), 6.31 (q, J = 7.2 Hz, 1H), 4.19 (br. s, 1H), 3.69–3.73 (m, 1H), 2.31 (s, 3H), 2.17–2.18 (m, 1H), 2.16 (s, 3H), 2.05–2.10 (m, 1H), 2.01–2.02 (m, 3H), 1.57 (s, 9H), 1.30–1.32 (m, 1H), 0.97–1.15 (m, 1H). Slower eluting enantiomers of the title compound: MS = 398.4 (M+1). 1HNMR: (400MHz, MeOD) δ: 8.48 (s, 1H), 8.22 (s, 1H), 6.32 (q, J=6.8Hz, 1H), 4.22-4.26 (br.s, 1H), 3.69-3.72 (m, 1H), 2.31 (s, 3 H), 2.18-2.19(m, 1H), 2.17(s, 3H), 2.05-2.10(m, 1H), 2.01-2.03(m, 3H), 1.58(s, 9H), 1.29-1.33(m, 1H), 0.97-1.15(m, 1H).

[0397] Step 8.1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3- 3-(3-)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid: TFA (377 g, 3.31 mol, 245 mL, 37.6 equivalents) was added to a solution of tert-butyl 1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (35.0 g, 88.1 mmol, 1.00 equivalents, from the slower-eluting isomer of the previous step) in DCM (245 mL). The reactants were degassed and purified with N2 and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure at 40 °C. MTBE (200 mL) was added to the mixture and it was stirred for 30 min. The mixture was filtered and the filter cake was washed with MTBE (20.0 mL x 2). The filter cake was collected and ground together with MTBE:EtOAc (6:1) (120 mL) at 20 °C for 30 min. The mixture was filtered again, and the filter cake was washed with MTBE (30.0 mL x 2). The filter cake was collected and dried under reduced pressure to provide the title compound. MS = 342.1 (M+1). 1 HNMR: (400MHz, DMSO-d6) δ: 8.85 (s, 1H), 8.22 (s, 1H), 6.29 (q, J=7.2Hz, 1H), 4.20-4.23 (m, 1H), 3.56- 3.58 (m, 1H), 2.25 (s, 3H), 2.09-2.12 (m, 1H), 1.92-1.99 (m, 7H), 1.10-1.22 (m, 1H), 0.78-0.80 (m, 1H). Example

[0398] Example 1

[0399]

[0400] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-((1S,5R)-2-oxo-3-azabi) Cyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (Scheme 3)

[0401] Step 1. 5-(bromomethyl)-2-(methylthio)pyrimidine:Carbon tetrabromide (3.28 g, 9.90 mmol) and triphenylphosphine (2.60 g, 9.90 mmol) were added to a stirred solution of (2-(methylthio)pyrimidin-5-yl)methanol (1.19 g, 7.62 mmol) in DCM (25 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated, and the residue was purified by rapid silica gel column chromatography (0–20% EtOAc / hexane) to yield the title compound. MS = 219.0 (M+1).

[0402] Step 2.1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid methyl ester: Methyl 1H-pyrazole-4-carboxylate (0.760 g, 6.02 mmol) and Cs₂CO₃ (5.35 g, 16.43 mmol) were added to a stirred solution of 5-(bromomethyl)-2-(methylthio)pyrimidine (1.2 g, 5.48 mmol) in DMF (36.5 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0–60% EtOAc / hexane) to yield the title compound. MS = 265.2 (M+1).

[0403] Step 3.1 -((2-(methylthio-1-pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid: Lithium hydroxide (0.299 g, 12.49 mmol) was added to methyl 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylate (1.1 g, 4.16 mmol) in THF (35 mL) and water (7 mL) at room temperature, and the mixture was stirred overnight at 60 °C. The mixture was acidified to pH 2 with 1 N HCl. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The title compound was used directly in subsequent steps. MS = 251.2 (M+1).

[0404] Step 4. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin-5-yl)methyl 1H-pyrazole-4-carboxamide:Hunig's base (3.01 mL, 17.26 mmol) and HATU (2.188 g, 5.75 mmol) were added to a stirred solution of 1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazol-4-carboxylic acid (0.72 g, 2.88 mmol) at room temperature, followed by the addition of 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile 2,2,2-trifluoroacetate (1.85 g, 5.75 mmol) in DMF (25 mL). The mixture was stirred at room temperature for 4 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0–80% heptane / ethanol (3:1)) to yield the title compound. MS = 439.2 (M+1).

[0405] Step 5. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-(methylsulfonyl)pyrimidine-5- )methyl)-1H-pyrazole-4-carboxamide: mCPBA (345 mg, 1.540 mmol) was added to a stirred solution of N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-(methylthio)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (520 mg, 1.185 mmol) in DCM (11 mL), and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0–80% EtOAc / Pet.) to yield the title compound. MS = 471.3 (M+1).

[0406] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-((1S,5R)-2-oxo-3-nitrogen) Heterobicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide: Cs₂CO₃ (86 mg, 0.265 mmol) and (1R, 5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (28.4 mg, 0.212 mmol) were added to a stirred solution of N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((2-(methanesulfonyl)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxamide (25 mg, 0.053 mmol) in DMSO (531 μl) at room temperature. The reaction mixture was stirred at 110 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 488.2(M+1). 1H NMR (500MHz, chloroform-d) δ8.59 (d, J=6.2Hz, 2H), 7.94 (s, 1H), 7.85 (s, 1H), 7.58 (dd, J=8.3, 3.8Hz, 1H), 7.47-7.39 (m , 1H), 7.33 (td, J=8.5, 2.0Hz, 1H), 6.46 (d, J=7.5Hz, 1H), 5.28 (d, J=6.1Hz, 2H), 4.67-4.58 (m, 1H), 4.18 (dd, J=1 1.4, 5.7Hz, 1H), 4.02 (d, J=11.5Hz, 1H), 3.61-3.50 (m, 1H), 3.02 (dt, J=11.7, 7.3Hz, 2H), 2.65 (d, J=8.2Hz, 1H) , 2.27 (q, J=10.0Hz, 2H), 2.20 (s, 1H), 2.08 (p, J=6.0Hz, 1H), 1.29 (td, J=8.1, 4.9Hz, 1H), 0.91 (q, J=4.4Hz, 1H).

[0407] The following compounds were prepared using suitable starting materials and procedures similar to those described in Example 1. Racemic products were separated using the chiral columns specified in the table. For enantiomer pairs, the isomers that eluted rapidly were listed first. This convention of listing enantiomers separated by chiral HPLC will be used in all subsequent tables.

[0408]

[0409]

[0410] Examples 5 and 6

[0411]

[0412] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo) 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)-3- (5-Chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]) Hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide (Scheme 4)

[0413] Step 1.1 - (6-fluoro-5-methylpyridin-3-yl)ethane-1-ol: Methylmagnesium bromide (0.951 mL, 3.23 mmol) (3.4 N in 2-MeTHF) was slowly added to a solution of 6-fluoro-5-methylnicotinaldehyde (600 mg, 4.31 mmol) in 25 mL of THF, stirred at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–30% methanol / dichloromethane) to provide the title compound. MS = 156.0 (M+1).

[0414] Step 2.1 - (1-(6-fluoro-5-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester: DIAD (0.413 mL, 2.127 mmol) was slowly added to a solution of 1-(6-fluoro-5-methylpyridin-3-yl)ethane-1-ol (300 mg, 1.933 mmol), ethyl 1H-pyrazole-4-carboxylate (298 mg, 2.127 mmol), and triphenylphosphine (558 mg, 2.127 mmol) in 15 mL of THF, stirred at 0 °C. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched with NaCl (saturated aqueous solution) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (0–100% ethyl acetate / hexane), followed by purification by reversed-phase HPLC (ACN / water containing 0.05% TFA adjuster) to provide the product as a TFA salt. MS = 278.1 (M+1).

[0415] Step 3.1-(1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine- 3-yl)ethyl)-1H-pyrazole-4-carboxylic acid: Sodium hydride (24.14 mg, 1.006 mmol) was added to a solution of ethyl 1-(1-(6-fluoro-5-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate (93 mg, 0.335 mmol) and (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (90 mg, 0.671 mmol) in DMA (2 mL) under nitrogen and stirred at room temperature. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The aqueous layer was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide the product as a TFA salt. MS = 327.0 (M+1).

[0416] Step 4. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(5-methyl-6-((1R,5S)-2- Oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)- 3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo) [3.1.0] Hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide:Add 2-(cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile hydrochloride (27.7 mg, 0.114 mmol) to a solution of 1-(1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid, 2,2,2-trifluoroacetate (40 mg, 0.091 mmol), DMF (2 mL), N-ethyl-N-isopropylpropane-2-amine (0.239 mL, 1.366 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisoureon hexafluorophosphate (V) (43.3 mg, 0.114 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with NaCl (aqueous solution) and extracted with ethyl acetate (3 times). The combined organic layers were concentrated under reduced pressure and purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier). The enantiomerically pure title compound was resolved by Chiral SFC (AS-H, 55% methanol / CO2). The compound was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier). The faster elution of the enantiomer of the title compound as a TFA salt was obtained (Example 5): 1 H NMR (500MHz, methanol-d4) δ8.26 (s, 1H), 8.24 (d, J=2.1Hz, 1H), 7.97 (s, 1H), 7.69 (dd, J=5.1, 3.1Hz, 2H), 7.64 (d , J=1.9Hz, 1H), 7.44 (dd, J=8.3, 2.0Hz, 1H), 5.71 (q, J=7.0Hz, 1H), 4.62-4.48 (m, 1H), 4.28 (dd, J=10.5, 5.9 3.70 (d, J = 10.4 Hz, 1H), 3.66-3.55 (m, 1H), 2.94 (qd, J = 7.8, 2.8 Hz, 2H), 2.31-2.22 (m, 2H), 2.16-2.21 (m, 4H), 2.05 (d, J = 5.1 Hz, 1H), 1.94 (d, J = 7.1 Hz, 3H), 1.32 (td, J = 8.0, 4.6 Hz, 1H), 0.96 (q, J = 4.3 Hz, 1H). MS = 515.5 (M+1). Slower elution enantiomers of the title compound as TFA salts were obtained (Example 6): 1H NMR (500MHz, methanol-d4) δ8.26 (s, 1H), 8.25 (d, J = 2.2Hz, 1H), 7.97 (s, 1H), 7.67-7.70 (m, 2H), 7.64 (d, J = 1.9Hz, 1H), 7.44 (dd, J=8.3, 2.0Hz, 1H), 5.71 (q, J=7.1Hz, 1H), 4.56 (p, J=9.0Hz, 1H), 4.28 (dd, J=10.5, 5.9Hz, 1H), 3.70 (d, J=10.7Hz, 1H), 3.61 (ddd, J=18.0, 10.2, 7.8Hz, 1H), 2.94 (qd, J=7.7, 2.7Hz, 2H), 2.31-2.08 (m, 6H), 2.08-2.02 (m, 1H), 1.94 (d, J=7.1Hz, 3H), 1.32 (td, household 8.0, 4.6Hz, 1H), 0.95 (q, J=4.3Hz, 1H). MS=515.5 (M+1).

[0417] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Examples 5 and 6.

[0418]

[0419]

[0420] Examples 11 and 12

[0421]

[0422] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(4-methoxy-6-((1R,5S)-2- Oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)- 3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo) [3.1.0] Hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide (Scheme 5)

[0423] Step 1. (6-Chloro-4-methoxypyridin-3-yl)methanol: Lithium borohydride (7.44 mL, 14.88 mmol) (2 M in THF) was slowly added to a solution of methyl 6-chloro-4-methoxynicotinate (1000 mg, 4.96 mmol) in 20 mL THF under stirring at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 5.5 h. After the reaction was complete, the mixture was quenched with NaOH (1 M aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–20% methanol / dichloromethane) to provide the title compound. MS = 174.0 (M+1).

[0424] Step 2.6-Chloro-4-methoxynicotinaldehyde:To a solution of (6-chloro-4-methoxypyridin-3-yl)methanol (740 mg, 4.26 mmol) in DCM (25 mL) under stirring at room temperature, Dysmartin periodide (2260 mg, 5.33 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure and purified by silica gel chromatography (0–20% methanol / dichloromethane), followed by rapid silica gel chromatography (0–70% ethyl acetate / hexane) to provide the title compound. MS = 171.9 (M+1).

[0425] Step 3.1 - (6-chloro-4-methoxypyridin-3-yl)ethane-1-ol: Methylmagnesium bromide (2.057 mL, 6.99 mmol) (3.4N in 2-MeTHF) was slowly added to a solution of 6-chloro-4-methoxynicotinaldehyde (600 mg, 3.50 mmol) in THF (20 mL) under stirring at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 1 h. After the reaction was complete, the mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–30% methanol / dichloromethane) to provide the title compound. MS = 188.0 (M+1).

[0426] Step 4.1 - (1-(6-chloro-4-methoxypyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester: DIAD (0.226 mL, 1.161 mmol) was slowly added to a solution of 1-(6-chloro-4-methoxypyridin-3-yl)ethane-1-ol (200 mg, 1.055 mmol), ethyl 1H-pyrazole-4-carboxylate (163 mg, 1.161 mmol), and triphenylphosphine (304 mg, 1.161 mmol) in THF (5 mL) under stirring at room temperature. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the mixture was quenched with NaCl (saturated aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–100% ethyl acetate / hexane), followed by subsequent purification by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide the product. MS = 310.0 (M+1).

[0427] Step 5.1-(1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine Ethyl pyridine-3-yl)ethyl)-1H-pyrazole-4-carboxylate:Ethyl 1-(1-(6-chloro-4-methoxypyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate (125 mg, 0.404 mmol), cesium carbonate (394 mg, 1.211 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (81 mg, 0.605 mmol), and XantPhos Pd G3 (83 mg, 0.081 mmol) were combined and placed under a nitrogen atmosphere, followed by the addition of dioxane (2 mL), and then placed under a nitrogen atmosphere again. The reaction mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the mixture was quenched with NaCl (saturated aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0-30% methanol / dichloromethane) to provide the product. MS = 371.1(M+1).

[0428] Step 6.1-(1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine (Pyridine-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid: Lithium hydroxide (69.8 mg, 2.92 mmol) was added to a solution of ethyl 1-(1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate (108 mg, 0.292 mmol) in THF (0.5 mL), water (0.5 mL), and methanol (0.25 mL) under stirring at room temperature. The reaction mixture was stirred at room temperature for 90 min. After the reaction was complete, the mixture was concentrated under reduced pressure. The mixture was quenched with hydrogen chloride (3.50 mL, 3.50 mmol) (1 N aqueous solution), concentrated under reduced pressure, and purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide the product. MS = 343.2 (M+1).

[0429] Step 7. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(4-methoxy-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N- ((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(4-methoxy-6-((1R,5S)-2-oxo-3-nitrogen) Heterobicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide:Add 1-(1-(4-methoxy-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid, 2,2,2-trifluoroacetic acid (36.4 mg, 0.080 mmol), DMF (2 mL), and N-ethyl-N-isopropylpropane-2-amine (0.209 mL, 1...) to a mixture stirred at room temperature. 2-(cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile hydrochloride (24.29 mg, 0.100 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisoureaium hexafluorophosphate (V) (38.0 mg, 0.100 mmol) in DMF (2 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with NaCl (aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were concentrated under reduced pressure and purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers of the product as a TFA salt. The enantiomerically pure title compound was resolved by Chiral SFC (AS-H, 21 x 250 mm, 50% methanol). The compound was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier). The enantiomers of the title compound, as TFA salts, were obtained via rapid elution (Example 11): 1 H NMR (500MHz, methanol-d4) δ8.24 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.69 (d, J=8.3Hz, 1H), 7.63 (d, J=1.8Hz, 1H), 7.44 (dd, J=8.3, 1.9Hz, 1H), 7.33 (s, 1H), 5.89 (q, J=7.0Hz, 1H ), 4.56 (p, J = 8.8 Hz, 1H), 4.16–4.04 (m, 5H), 3.66–3.55 (m, 1H), 2.94 (qd, J = 7.7, 2.7 Hz, 2H), 2.32–2.19 (m, 4H), 1.90 (d, J = 7.0 Hz, 3H), 1.40 (q, J = 7.9 Hz, 1H), 0.94 (s, 1H). MS = 531.1 (M+1). Slower elution enantiomers of the title compound as a TFA salt were obtained (Example 12): 1¹H NMR (500 MHz, methanol-d⁴) δ 8.22 (s, ¹H), 8.03 (s, ¹H), 7.96 (s, ¹H), 7.69 (d, J = 8.3 Hz, ¹H), 7.63 (d, J = 1.9 Hz, ¹H), 7.50 (s, ¹H), 7.44 (dd, J = 8.3, 2.0 Hz, ¹H), 5.87 (q, J = 7.0 Hz, ¹H), 4.65–4.42 (m, 1H), 4.21-4.06 (m, 2H), 4.02 (s, 3H), 3.67-3.51 (m, 1H), 2.94 (qd, J=7.6, 2.8Hz, 2H), 2. 32-2.20 (m, 4H), 1.90 (d, J=7.1Hz, 3H), 1.37 (td, J=8.1, 4.7Hz, 1H), 0.90 (q, J=4.1Hz, 1H). MS=531.0(M+1).

[0430] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Examples 11 and 12.

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] Examples 55 and 56

[0440]

[0441] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-methyl-6-((1R,5S)-2-oxo) 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis) (Formula)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo) [3.1.0] Hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide (Scheme 6)

[0442] Step 1.1-(6-fluoro-5-methylpyridin-3-yl)ethane-1-olMethylmagnesium bromide (0.951 mL, 3.23 mmol) (3.4 N in 2-MeTHF) was slowly added to a solution of 6-fluoro-5-methylnicotinaldehyde (150 mg, 1.078 mmol) in 8 mL of THF (stirred at 0 °C). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with ethyl acetate (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0-30% methanol / dichloromethane) to provide the title compound. MS = 156.0 (M+1).

[0443] Step 2.5 - (1-azidoethyl)-2-fluoro-3-methylpyridine: To a solution of 1-(6-fluoro-5-methylpyridin-3-yl)ethane-1-ol (212 mg, 1.079 mmol) in toluene (8 mL) under stirring at 0 °C, diphenyl azidophosphate (0.278 mL, 1.295 mmol) and DBU (0.195 mL, 1.295 mmol) were slowly added. The reaction mixture was gradually warmed to room temperature and stirred overnight. After the reaction was complete, the mixture was quenched with NaCl (saturated aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–70% ethyl acetate / hexane) to provide the title compound. MS = 181.0 (M+1).

[0444] Step 3.1 - (1-(6-fluoro-5-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid ethyl ester: Ethyl propargylate (0.219 mL, 2.161 mmol) was added to a solution of 5-(1-azidoethyl)-2-fluoro-3-methylpyridine (295 mg, 1.081 mmol) in ethanol (5 mL) under stirring at room temperature, followed by a solution of sodium L-ascorbate (42.8 mg, 0.216 mmol) (in 2.5 mL water) and copper(II) sulfate pentahydrate (54.0 mg, 0.216 mmol) (in 2.5 mL water). The reaction mixture was stirred at room temperature for 1.5 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The mixture was quenched with water and extracted with dichloromethane (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–100% ethyl acetate / hexane) to provide the title compound. MS = 279.1 (M+1).

[0445] Step 4.1-(1-(5-methyl-6-((1R,5S)-2-hydro-3-azabicyclo[3.1.0]hexane-3-yl)pyridine- 3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid:Sodium hydride (20.98 mg, 0.525 mmol) was added to a solution of ethyl 1-(1-(6-fluoro-5-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (73 mg, 0.262 mmol) and (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (70.1 mg, 0.525 mmol) in DMA (1.2 mL) and stirred at room temperature under nitrogen. The reaction mixture was stirred at 100 °C for 50 min. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (once). The aqueous layer was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide the title compound as a TFA salt. MS = 328.0 (M+1).

[0446] Step 5. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-methyl-6-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide: Add 1-(1-(5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid, 2,2,2-trifluoroacetic acid (34 mg, 0.077 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.202 mL, 1.15 mmol) to a mixture stirred at room temperature. 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile hydrochloride (18.77 mg, 0.077 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea-6-hexafluorophosphate (V) (29.4 mg, 0.077 mmol) in DMF (1 mL) were added. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the mixture was quenched with NaCl (aqueous solution) and extracted with ethyl acetate (3 times). The combined organic layers were concentrated under reduced pressure and purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers as TFA salts. The enantiomerically pure title compound was resolved by Chiral SFC (AS-H, 21 x 250 mm, 45% (EtOH containing 0.2% DIPA)). The compound was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier). The enantiomers of the title compound, as TFA salts, were obtained via rapid elution (Example 55). 1H NMR (500MHz, methanol-d4) δ8.50 (s, 1H), 8.34 (d, J = 2.2Hz, 1H), 7.77 (d, J = 2.1Hz, 1H), 7.73-7.63 (m, 2H), 7.43 ( dd, J=8.3, 2.0Hz, 1H), 6.06 (q, J=7.1Hz, 1H), 4.61 (ddd, J=16.8, 9.2, 7.6Hz, 1H), 4.30 (dd, J=10.5, 5.9Hz, 1H), 3.71 (d, J = 10.5 Hz, 1H), 3.61 (ddd, J = 18.0, 10.3, 7.7 Hz, 1H), 2.93 (qd, J = 7.7, 2.8 Hz, 2H), 2.37 (qd, J = 9.3, 2.7 Hz, 2H), 2.16–2.23 (m, 4H), 2.02–2.08 (m, 4H), 1.32 (td, J = 8.0, 4.6 Hz, 1H), 0.96 (q, J = 4.4 Hz, 1H). MS = 516.4 / 518.4 (M+1). Slower elution enantiomers of the title compound as a TFA salt were obtained (Example 56): 1 H NMR (500MHz, methanol-d4) δ8.50 (s, 1H), 8.35 (d, J = 2.3Hz, 1H), 7.76 (d, J = 2.2Hz, 1H), 7.71-7.62 (m , 2H), 7.43 (dd, J=8.3, 2.0Hz, 1H), 6.06 (d, J=7.0Hz, 1H), 4.61 (t, J=7.6Hz, 1H), 4.30 (dd, J=10 .5, 5.9Hz, 1H), 3.70 (d, J=9.3Hz, 1H), 3.66-3.56 (m, 1H), 2.98-2.85 (m, 2H), 2.42-2.31 (m, 2H) , 2.00-2.08 (m, 4H), 2.04 (d, J=7.1Hz, 4H), 1.32 (td, J=8.1, 4.6Hz, 1H), 0.96 (q, J=4.4Hz, 1H). MS=516.3 / 518.4(M+1).

[0447] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Examples 55 and 56.

[0448]

[0449]

[0450]

[0451]

[0452] Examples 77 and 78

[0453]

[0454] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(2-((1R,5S)-2-oxo-3-nitrogen) Heterobicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3- (5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3- (Scheme 7) pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide

[0455] Step 1.1-(2-(methylthio)pyrimidin-5-yl)ethane-1-ol : Methylmagnesium bromide (2.480 mL, 8.43 mmol) was added to a stirred solution of 2-(methylthio)pyrimidine-5-carboxaldehyde (1000 mg, 6.49 mmol) in 20 mL of THF at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reactants were partitioned between saturated NH4Cl and EtOAc. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-50%) to yield the title compound. MS = 171.2 (M+1).

[0456] Step 2.5-(1-Azideylethyl)-2-(Methylthio)pyrimidine Diphenylphosphoazide (1.644 mL, 7.63 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.141 mL, 7.63 mmol) were added to a stirred solution of 1-(2-(methylthio)pyrimidin-5-yl)ethane-1-ol (999 mg, 5.87 mmol) in toluene (26 mL) at 0 °C, and the mixture was stirred overnight at room temperature. LCMS analysis indicated the end of the reaction. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure at room temperature. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-40%). The desired fraction was concentrated to yield the title compound. MS = 196.3 (M+1).

[0457] Step 3.1 - (1-(2-(methylthio)pyrimidin-5-yl)ethyl 1-1H-1,2,3-triazol-4-carboxylic acid ethyl ester):Ethyl propargylate (1.183 mL, 11.68 mmol) was added to a stirred solution of the starting material 5-(1-azidoethyl)-2-(methylthio)pyrimidine (1.14 g, 5.84 mmol) in EtOH (7.30 mL) at room temperature. A solution of sodium ascorbate (0.231 g, 1.168 mmol) in water (3.5 mL) was added, followed by a solution of copper(II) sulfate pentahydrate (0.292 g, 1.168 mmol) in water (3.5 mL). The reaction mixture was stirred at room temperature for 45 min. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0–80%) to yield the title compound. MS = 294.2 (M+1).

[0458] Step 4.1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid LiOH (1.012 g, 42.3 mmol) was added to a stirred solution of 1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (1.24 g, 4.23 mmol) in THF (30 mL) and water (10 mL) at room temperature, and the mixture was stirred overnight at 60 °C. LCMS analysis indicated the end of the reaction. The mixture was acidified to pH 3 with hydrochloric acid (1 M) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-100%) to yield the title compound. MS = 266.2 (M+1).

[0459] Step 5. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2-(methylthio)pyrimidin-5-yl) Ethyl)-1H-1,2,3-triazol-4-carboxamide 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (353 mg, 1.708 mmol) and Hunig's base (795 μl, 4.55 mmol) were added to a stirred solution of 1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (302 mg, 1.138 mmol) in DMF (9486 μl), followed by the addition of HATU (1082 mg, 2.85 mmol). The mixture was stirred at room temperature for 30 min. LCMS analysis indicated the end of the reaction. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-80%) to yield the title compound. MS = 454.2.0(M+1).

[0460] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2-(methylsulfonyl)pyrimidine- 5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide: MCPBA (448 mg, 2.000 mmol) was added to a stirred solution of N-(3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2-(methylthio)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide (454 mg, 1.000 mmol) in dichloromethane (6667 μl) at room temperature, and the mixture was stirred at room temperature for 6 h. LCMS analysis indicated the end of the reaction. The mixture was diluted with aqueous sodium bicarbonate solution (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-80%) to yield the title compound. MS = 486.1 (M+1).

[0461] Step 7. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(2-((1 R.5S)-2-hydrogen) 3-azabicyclo[3.1.0]hexane-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis) Formula )-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0] (hexane-3-yl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide: (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (13.99 mg, 0.144 mmol) and Cs₂CO₃ (188 mg, 0.576 mmol) were added to a stirred solution of N-(3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(2-(methanesulfonyl)pyrimidin-5-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide (70 mg, 0.144 mmol) in DMSO (1440 μl) at room temperature, and the mixture was stirred at 90 °C for 1 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO₄), and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (2 ml) and purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide a mixture of diastereomers. The enantiomerically pure title compound was resolved by chiral SFC (OD-H, 4.6 x 250 mm, 45% MeOH + 0.1% DIPA). Faster elution of the enantiomers of the title compound was obtained (Example 77). 1H NMR (500MHz, CDCl3) δ: 8.61 (s, 2H), 8.09 (s, 1H), 7.57 (d, J = 8.2Hz, 2H), 7.44 (s, 1H), 7.32 (d, J = 8.2Hz, 1H), 5.86 (q, J = 7.1Hz, 1H), 4.64 (m, 1H), 4 .16 (dd, J=11.4, 5.7Hz, 1H), 3.99 (d, J=11.5Hz, 1H), 3.59 (m, 1H), 3.05 (m , 2H), 2.22 (m, 2H), 2.05 (d, J=7.2Hz, 3H), 1.32-1.24 (m, 2H), 0.90 (m, 1H). MS=503.3(M+1). Slower elution of the enantiomer of the title compound was obtained (Example 78): 1 ¹H NMR (500 MHz, chloroform-d) δ: 8.61 (s, 1H), 8.09 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.35–7.28 (m, 3H), 5.86 (q, J = 7.1 Hz, 1H), 4.64 (h, J = 8.3 Hz, 1H), 4.17 (dd, J = 11.4, 5.7 Hz) , 1H), 4.00 (d, J=11.5Hz, 1H), 3.60 (p, J=9.6, 8.9Hz, 1H), 3.10-3.01 (m, 1H), 2.25 (dt, J=26.3, 12.4Hz, 2H), 2.05 (d, J=7.2Hz, 3H), 1.32-1.24 (m, 2H), 0.90 (d, J=3.4Hz, 1H). MS=503.3(M+1).

[0462] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Examples 77 and 78.

[0463]

[0464]

[0465] Examples 84 and 85

[0466]

[0467] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(6-methyl-5-((1R.5S)-2-hydrogen) 3-azabicyclo[3.1.0]hexane-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis) (Formula)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo) [3.1.0] Hexane-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide (Scheme 8)

[0468] Step 1.1-(5-chloro-6-methylpyrazine-2-yl)ethane-1-ol.Magnesium methyl bromide (2.71 mL, 8.14 mmol) was added to a stirred solution of 5-chloro-6-methylpyrazine-2-carboxaldehyde (980 mg, 6.26 mmol) in THF (20 mL) at -78 °C, and the mixture was stirred at 0 °C for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to yield the title compound, which was used directly in subsequent steps. MS = 173.2 (M+1).

[0469] Step 2.5 - (1-azidoethyl)-2-chloro-3-methylpyrazine: Diphenyl azidophosphate (1.669 mL, 7.74 mmol) and DBU (1.167 mL, 7.74 mmol) were added to a stirred solution of 1-(5-chloro-6-methylpyrazin-2-yl)ethane-1-ol (1.028 g, 5.96 mmol) in toluene (29.8 mL) at 0 °C, and the mixture was stirred overnight at room temperature. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-40%) to yield the title compound. MS = 198.2 (M+1).

[0470] Step 3.1-(1-(5-chloro-6-methylpyrazine-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid ethyl ester. Ethyl propargylate (0.929 mL, 9.17 mmol) was added to a stirred solution of the starting material 5-(1-azidoethyl)-2-chloro-3-methylpyrazine (906 mg, 4.58 mmol) in EtOH (5.6 mL) at room temperature. A solution of sodium ascorbate (182 mg, 0.917 mmol) in water (2.8 mL) was added, followed by a solution of copper(II) sulfate pentahydrate (229 mg, 0.917 mmol) in 2.8 mL of water. The reaction mixture was stirred at room temperature for 45 min. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-70%) to yield the title compound. MS = 296.2 (M+1).

[0471] Step 4.1-(1-(5-chloro-6-methylpyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid.Lithium hydroxide (202 mg, 8.45 mmol) was added to a stirred solution of 1-(1-(5-chloro-6-methylpyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (250 mg, 0.845 mmol) in THF (6 mL) and water (2 mL) at room temperature, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with an aqueous solution of ammonium chloride (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and lyophilized. The mixture was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 268.1 (M+1).

[0472] Step 5.1-(1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyrazine- 2-(yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid: (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (173 mg, 1.784 mmol), cesium carbonate (930 mg, 2.85 mmol), and XantPhosPdG3 (203 mg, 0.214 mmol) were added to a stirred solution of 1-(1-(5-chloro-6-methylpyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (191 mg, 0.714 mmol) in dioxane (3568 μl). The mixture was bubbled with N2 (5 min) and then stirred at 100 °C for 8 h. The mixture was diluted with water (30 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (EtOAc / hexane 0-90%) to yield the title compound. MS = 329.2 (M+1).

[0473] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(6-methyl-5-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(6-methyl-5-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide:Hunig's base (0.194 mL, 1.112 mmol) and HATU (211 mg, 0.556 mmol) were added to a stirred solution of 1-(1-(6-methyl-5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (73 mg, 0.222 mmol) in DMF (2.0 mL), followed by the addition of 4-chloro-2-((cis)-3-((2,2,2-trifluoroacetyl)-14-azaalkyl)cyclobutyl)benzyl nitrile (135 mg, 0.445 mmol), and the mixture was stirred at room temperature for 1 h. LCMS analysis indicated the end of the reaction. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The residues were purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers. The enantiomerically pure title compound was resolved by chiral SFC separation (OJ-H column) to provide a faster elution of the title compound's enantiomers (Example 84). MS = 517.3 (M+1). 1 ¹H NMR (500 MHz, chloroform-d) δ 8.37 (s, 1H), 8.23 ​​(s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 7.35–7.29 (m, 2H), 6.04 (q, J = 7.0 Hz, 1H), 4.65 (q, J = 7.8 Hz, 1H), 4.43 (dd, J = 10.5, 5.6 Hz, 1H), 3.65 (d, J = 10.9) 3.60 (t, J = 7.9 Hz, 1H), 3.08–3.02 (m, 2H), 2.44 (s, 3H), 2.25 (p, J = 10.1 Hz, 2H), 2.11 (dd, J = 13.1, 7.8 Hz, 2H), 1.98 (d, J = 7.1 Hz, 3H), 1.30 (dt, J = 13.7, 6.9 Hz, 1H), 0.94 (d, J = 3.3 Hz, 1H). Slower eluting enantiomers of the title compound (Example 85): MS = 517.3 (M+1). 1¹H NMR (500 MHz, chloroform-d) δ 8.43 (s, 1H), 8.21 (s, 1H), 7.55 (t, J = 8.1 Hz, 2H), 7.48–7.44 (m, 1H), 7.32 (dd, J = 8.2, 1.8 Hz, 1H), 6.04 (q, J = 7.1 Hz, 1H), 4.66 (h, J = 8.4 Hz, 1H), 4.37 (dd, J = 10.5, 5.2 Hz, 1H). 3.72 (d, J=10.4Hz, 1H), 3.66-3.55 (m, 1H), 3.09-3.00 (m, 2H), 2.45 (s, 3H), 2.28 (q, J=10.2Hz, 2 H), 2.19-2.11 (m, 2H), 2.02 (d, J=7.1Hz, 3H), 1.33 (td, J=8.0, 4.9Hz, 1H), 0.96 (q, J=4.2Hz, 1H).

[0474] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Examples 84 and 85.

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486] Examples 137 and 138

[0487]

[0488] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-((1R,5S)-2-oxo-3-nitrogen) Heterobicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3- (5-Chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3- (Scheme 9) pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide

[0489] Step 1.3-(1-Azideylethyl)-5-bromopyridine Diphenylphosphoazide (0.383 ml, 1.782 mmol) and DBU (0.269 ml, 1.782 mmol) were slowly added to a solution of 1-(5-bromopyridin-3-yl)ethane-1-ol (300 mg, 1.485 mmol) in toluene (12 ml) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 44 h. The mixture was quenched with NaCl (saturated aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–70% ethyl acetate / hexane) to provide the title compound. MS = 226.9 (M+1).

[0490] Step 2.1 - (1-(5-bromopyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid ethyl ester: Ethyl propargylate (0.302 mL, 2.98 mmol) was added to a solution of 3-(1-azidoethyl)-5-bromopyridine (418 mg, 1.491 mmol) in ethanol (5 mL) under stirring at room temperature, followed by a solution of sodium L-ascorbate (59.1 mg, 0.298 mmol) (in 2.5 mL water) and copper(II) sulfate pentahydrate (74.5 mg, 0.298 mmol) (in 2.5 mL water). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The mixture was quenched with water and extracted with dichloromethane (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–100% ethyl acetate / hexane) to provide the title compound MS = 324.9 (M+1).

[0491] Step 3.1-(1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl Ethyl 1H-1,2,3-triazol-4-carboxylate: Ethyl 1-(1-(5-bromopyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (195 mg, 0.600 mmol), Cs₂CO₃ (586 mg, 1.799 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (84 mg, 0.630 mmol), and XantPhos PD G3 (114 mg, 0.120 mmol) were combined and placed under a nitrogen atmosphere. Dioxane (5 mL) was added, and the reaction mixture was stirred at 100 °C for 30 hours. The mixture was quenched with NaCl (saturated aqueous solution) and extracted with ethyl acetate (x²). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0-100% ethyl acetate / hexane), followed by rapid silica gel chromatography (0-20% methanol / dichloromethane) to provide the title compound. MS = 342.0 (M+1).

[0492] Step 4.1-(1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl 1H-1,2,3-triazol-4-carboxylic acid: LiOH (71.8 mg, 3.00 mmol) was added to a solution of ethyl 1-(1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate (245 mg, 0.599 mmol) in THF (1.5 mL), water (1.5 mL), and methanol (0.8 mL) under stirring at room temperature. The reaction mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The mixture was quenched with HCl (3.60 mL, 3.60 mmol) (1 N aqueous solution), concentrated under reduced pressure, and purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide the title compound. MS = 314.0 (M+1).

[0493] Step 5. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-((1R,5S)-2-oxo) 3-Helium-hexabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis) Formula )-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-((lR,5S)-2-oxo-3-azabicyclo[3.1.0] (hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide: Add 1-(1-(5-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid, 2,2,2-trifluoroacetic acid (65 mg, 0.152 mmol), DMF (3 mL), and N-ethyl-N-isopropylpropane-2-amine (0.399 mL, 2...) to a mixture stirred at room temperature. 2-(cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile hydrochloride (37.1 mg, 0.152 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisoureaium hexafluorophosphate (V) (58.0 mg, 0.152 mmol) in DMF (2 mL) were added. The reaction mixture was stirred at room temperature for 45 min. After the reaction was complete, the mixture was quenched with NaCl (aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were concentrated under reduced pressure and purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide a mixture of diastereomers. The enantiomerically pure title compound was resolved by Chiral SFC (AD-H, 21 x 250 mm, 50% IPA with 0.2% DIPA). The compound was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier). The enantiomers of the title compound were obtained via rapid elution (Example 137): 1H NMR (500MHz, methanol-d4) δ8.87 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 8.21 (t, J=2.1Hz, 1H), 7.75-7.60 (m, 2H), 7. 43 (dd, J=8.3, 2.0Hz, 1H), 6.12 (q, J=7.1Hz, 1H), 4.67-4.53 (m, 1H), 4.12 (dd, J=10.1, 5.9Hz, 1H), 3.88 (d 3.71-3.56 (m, 1H), 2.99-2.86 (m, 2H), 2.37 (q, J = 11.5, 10.6 Hz, 2H), 2.20 (dt, J = 12.0, 6.1 Hz, 1H), 2.13 (d, J = 7.1 Hz, 1H), 2.06 (d, J = 7.1 Hz, 3H), 1.31 (td, J = 8.1, 4.7 Hz, 1H), 0.87 (q, J = 4.4 Hz, 1H). MS = 502.3 (M+1). Slower elution enantiomers of the title compound (Example 138): 1 H NMR (500MHz, methanol-d4) δ8.92 (s, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 8.27 (d, J = 2.1Hz, 1H), 7.72-7.65 (m, 2H), 7.43 ( dd, J=8.3, 2.1Hz, 1H), 6.13 (q, J=7.1Hz, 1H), 4.65-4.53 (m, 1H), 4.12 (dd, J=10.1, 5.9Hz, 1H), 3.90 (d, J=9.1 Hz, 1H), 3.62 (ddd, J=17.8, 10.3, 7.8Hz, 1H), 2.98-2.87 (m, 2H), 2.37 (q, J=11.5, 10.4Hz, 2H), 2.21 (dt, J=11 .6, 6.0Hz, 1H), 2.18-2.11 (m, 1H), 2.07 (d, J=7.1Hz, 3H), 1.32 (td, J=8.0, 4.7Hz, 1H), 0.87 (q, J=4.4Hz, 1H). MS=502.4(M+1).

[0494] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Examples 137 and 138.

[0495]

[0496] Example 141

[0497]

[0498] N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S)-1-(4,5-dimethyl-6- ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-methyl Amide (Solution 10)

[0499] Step 1. N-((cis)-3-(5-chloro-2-cyanophenyl)-3-methylcyclobutyl)-1-((S)-1-(4,5-dimethyl) 6-((1R,5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-tri Zyrazole-4-carboxamide: Add 1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (intermediate AC) (15 mg, 0.033 mmol) and N-ethyl-N-isopropylpropane-2-amine (0.023 ml, 0.132 mmol) to a mixture stirred at room temperature. 1) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea-6-fluorophosphate (V) (12.55 mg, 0.033 mmol) in DMF (1 mL) were added to 2-((cis)-3-amino-1-methylcyclobutyl)-4-chlorobenzyl nitrile hydrochloride (8.94 mg, 0.033 mmol) (intermediate R). The reaction mixture was stirred at room temperature for 20 min. The mixture was quenched with NaCl (aqueous solution) and extracted with ethyl acetate (3 times). The combined organic layers were concentrated under reduced pressure and purified by preparative reversed-phase HPLC (ACN / water with 0.05% TFA regulator) to provide the title compound. MS = 544.2 (M+1). 1 H NMR (500MHz, methanol-d4) δ8.39 (s, 1H), 8.23 ​​(s, 1H), 7.69 (d, J=8.3Hz, 1H), 7.41 (dd, J=8.3, 2.1Hz, 1H), 7.38 ( d, J=2.0Hz, 1H), 6.30-6.35 (m, 1H), 4.70-4.77 (m, 1H), 4.25 (dd, J=10.4, 5.9Hz, 1H), 3.71 (d, J=9.3Hz, 1H) , 2.77-2.90 (m, 2H), 2.55 (td, J=9.2, 2.6Hz, 2H), 2.32 (s, 3H), 2.20 (dt, J=11.8, 6.0Hz, 1H), 2.11 (s, 3H), 2.04-2.08 (m, 1H), 2.03 (d, J=7.0Hz, 3H), 1.63 (s, 3H), 1.33 (td, J=8.0, 4.7Hz, 1H), 0.99 (q, J=4.4Hz, 1H).

[0500] The following compounds were prepared using appropriate starting materials and procedures similar to those described with respect to Example 141.

[0501]

[0502]

[0503]

[0504] Example 153

[0505]

[0506] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-3-((1R,5S)-2-oxo-3-aza) Bicyclo[3.1.0]hexane-3-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)-1H-1,2,3-triazol-4-methyl Amides and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-3-((1R,5S)-2-oxo-3-azabi) Cyclo[3.1.0]hexane-3-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)-1H-1,2,3-triazol-4-carboxyl amine

[0507] Step 1.3-Chloro-6,7-dihydro-5H-cyclopentadien[c]pyridine-7-phenol Sodium borohydride (59.3 mg, 1.566 mmol) was slowly added to a solution of 3-chloro-5,6-dihydro-7H-cyclopentadieno[c]pyridin-7-one (250 mg, 1.492 mmol) in methanol (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched with NH4Cl (saturated aqueous solution), and extracted with ethyl acetate (x3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–20% dichloromethane / methanol) to provide the title compound. MS = 169.9 (M+1).

[0508] Step 2.7 - Azide-3-chloro-6,7-dihydro-5H-cyclopentadieno[c]pyridine: Diphenyl azidophosphate (0.386 mL, 1.794 mmol) and DBU (0.270 mL, 1.794 mmol) were slowly added to a solution of 3-chloro-6,7-dihydro-5H-cyclopentadieno[c]pyridine-7-phenol (338 mg, 1.495 mmol) in toluene (8 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with NaCl (saturated aqueous solution), extracted with ethyl acetate (x3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–70% ethyl acetate / hexane) to provide the title compound. MS = 195.0 (M+1).

[0509] Step 3.1-(3-chloro-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-1H-1,2,3-triazol-4-methyl Ethyl acetate:Ethyl propargylate (0.302 mL, 2.98 mmol) was added to a solution of 7-azido-3-chloro-6,7-dihydro-5H-cyclopentadieno[c]pyridine (408 mg, 1.488 mmol) in ethanol (5 mL) under stirring at room temperature, followed by a solution of sodium L-ascorbate (59.0 mg, 0.298 mmol) (42.8 mg, 0.216 mmol) (in 2.5 mL water) and copper(II) sulfate pentahydrate (74.3 mg, 0.298 mmol) (in 2.5 mL water). The reaction mixture was stirred at room temperature for 1.5 h. The mixture was concentrated under reduced pressure, quenched with water, and extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0–100% ethyl acetate / hexane) to provide the title compound. MS = 293.0 (M+1).

[0510] Step 4.1-3-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)-6,7-dihydro-5H-cyclo Ethyl pentadienyl[c]pyridin-7-yl)-1H-1,2,3-triazol-4-carboxylate: XantPhos Pd G3 (32.4 mg, 0.034 mmol) was added to a solution of ethyl 1-(3-chloro-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-1H-1,2,3-triazol-4-carboxylate (50 mg, 0.171 mmol), Cs₂CO₃ (167 mg, 0.512 mmol), and (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one hydrochloride (34.2 mg, 0.256 mmol) in dioxane (2 mL), and the solution was again placed under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 30 h, followed by stirring at room temperature for 58 h. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (x²). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by rapid silica gel chromatography (0-100% ethyl acetate / hexane) to provide the title compound. MS = 354.2 (M+1).

[0511] Step 5.1-3-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)-6,7-dihydro-5H-cyclo Pentadienyl[c]pyridin-7-yl)-1H-1,2,3-triazol-4-carboxylic acid:LiOH (36.6 mg, 1.528 mmol) was added to a solution of ethyl 1-(3-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-1H-1,2,3-triazol-4-carboxylate (54 mg, 0.153 mmol) in THF (0.5 mL), water (0.5 mL), and methanol (0.3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The mixture was quenched with HCl (2.292 mL, 2.292 mmol) (1 N aqueous solution), concentrated under reduced pressure, and purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide the title compound as a TFA salt. MS = 326.0 (M+1).

[0512] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-3-((1R.5S)-2-oxo- 3-azabicyclo[3.1.0]hexane-3-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridin-7-yl)-1H-1,2,3-tri Azoxyl-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-3-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)-6,7-dihydro-5H-cyclopentadienyl[c]pyridin-7-yl)-1H-1,2,3-triazole- 4-Formamide: 1-(3-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-6,7-dihydro-5H-cyclopentadieno[c]pyridin-7-yl)-1H-1,2,3-triazol-4-carboxylic acid, 2,2,2-trifluoroacetate (6.3 mg, 0.014 mmol), and N-ethyl-N-isopropylpropane-2-amine (27.9 mg) were stirred at room temperature. 2-(cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile hydrochloride (3.49 mg, 0.014 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisoureaium hexafluorophosphate (V) (5.46 mg, 0.014 mmol) in DMF (1 mL) were added. The reaction mixture was stirred at room temperature for 1 h and quenched with NaCl (aqueous solution) and extracted with ethyl acetate (x3). The combined organic layers were concentrated under reduced pressure and purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers as TFA salts. 1H NMR (500MHz, methanol-d4) δ8.34 (s, 1H), 8.21 (d, J=12.6Hz, 2H), 7.68 (d, J=8.3H z, 2H), 7.44 (s, 1H), 6.34 (q, 1H), 4.58-4.63 (m, 1H), 4.05-4.20 (m, 2H), 3.5 6-3.65(m, 1H), 3.10-3.17(m, 1H), 2.83-2.99(m, 4H), 2.50-2.60(m, 1H), 2 .29-2.41(m, 2H), 2.12-2.19(m, 2H), 1.30-1.34(m, 1H), 0.79-0.84(m, 1H). MS = 514.0(M+1).

[0513] Examples 154 and 155

[0514]

[0515] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-2-hydroxy-1-(6-((1R,5S)-2-oxo) 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis) (Formula)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-2-hydroxy-1-(6-((1R,5S)-2-oxo-3-azabicyclo) [3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide

[0516] Step 1. 2-Chloro-5-vinylpyridine: To a stirred solution of 5-bromo-2-chloropyridine (15 g, 78 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxabortane (15 g, 97 mmol), Na₂CO₃ (47.2 mL, 94 mmol) in ethylene glycol dimethyl ether (150 mL) and water (50 mL), tetra(triphenylphosphine)palladium(O) (4 g, 3.46 mmol) was added, and the mixture was stirred at 85 °C for 12 h under N₂. The reactants were diluted with EtOAc (40 mL), concentrated, diluted with water (30 mL), and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried, and concentrated, and the residue was purified by rapid silica gel chromatography (0–7% ethyl acetate / petroleum ether) to yield the title compound. MS = 140.0 (M+1).

[0517] Step 2.1 - (6-chloropyridin-3-yl)ethane-1,2-diol:Osmium oxide (VIII) (20.00 mL, 3.93 mmol) was added to a stirred solution of 2-chloro-5-vinylpyridine (8.7 g, 62.3 mmol), 4-methylmorpholine 4-oxide (10.95 g, 93 mmol) in water (20 mL) and MeCN (60 mL) at 25 °C; after the addition was complete, the reaction mixture was stirred at 25 °C for 12 h. Anhydrous sodium thiosulfate solid (300 mg) was added to the reaction mixture, and it was stirred for 0.5 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0–10% CH2Cl2 / MeOH) to yield the title compound. MS = 174.0 (M+1).

[0518] Step 3.2 - ((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethanol: 1H-imidazolium (3.6 g, 45.6 mmol) and tert-butyldiphenylchlorosilane (4.56 g, 16.59 mmol) were added to a solution of 1-(6-chloropyridin-3-yl)ethane-1,2-diol (3.6 g, 20.74 mmol) in DMF (20 mL) at 20 °C. The reaction mixture was stirred at 50 °C for 12 h. The mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (20 mL x 3). The organic layer was washed with saturated NaCl (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by rapid silica gel chromatography (0–16% ethyl acetate / petroleum ether) to yield the title compound. MS = 412.2 (M+1).

[0519] Step 4. 2-((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethyl methanesulfonate: MsCl (2.1 mL, 25.9 mmol) was added to a stirred mixture of Et3N (4.16 mL, 29.9 mmol) and 2-((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethanol (4.0 g, 9.95 mmol) in DCM (5 mL) at 0 °C, and the mixture was stirred at 20 °C for 2 h. An aqueous solution of ammonium chloride (10 mL saturated) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic fractions were washed with brine (20 mL saturated), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was concentrated to yield the title compound, which was used directly without further purification. MS = 490.2 (M+1).

[0520] Step 5.5-(1-Azide-2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine:18-crown-6 (27.0 mg, 0.102 mmol) and sodium azide (100 mg, 1.538 mmol) were added to a stirred mixture of 2-((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethyl methanesulfonate (500 mg, 1.020 mmol) in DMF (4 mL) and water (4 mL), and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated, and water (6 mL) was added. It was extracted with EtOAc (10 mL x 3), and the organic layer was washed with saturated NaCl (20 mL), dried over Na2SO4, and concentrated. The residue was purified by rapid silica gel chromatography (0–30% EtOAc / Pet.) to yield the title compound. MS = 436.7 (M+1).

[0521] Step 6.1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethyl)-1H-1, 2,3-Triazole-4-carboxylic acid tert-butyl ester. Sodium ascorbate (227 mg, 1.144 mmol) and Cu2SO4·5H2O (28.6 mg, 0.114 mmol) were added to a stirred solution of tert-butyl propargyl ester (94 mg, 0.744 mmol) and 5-(1-azido-2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine (250 mg, 0.572 mmol) in tert-butanol (2 mL) and water (2 mL) at 20 °C. After the addition was complete, the reaction mixture was stirred at 20 °C for 12 h. The mixture was concentrated, water (7 mL) was added, and it was extracted with EtOAc (10 mL x 3). The organic layer was washed with saturated NaCl (20 mL), dried over Na2SO4, and concentrated to produce crude tert-butyl 1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylate, which was used in the next step without further purification. MS = 563.2 (M+1).

[0522] Step 7.1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-((1R,5S)-2-oxo-3-azabi) Cyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester:Pd2(dba)3 (45.5 mg, 0.050 mmol) was added to a stirred solution of 1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-chloropyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (280 mg, 0.497 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (62.8 mg, 0.646 mmol), XANTPHOS (28.8 mg, 0.050 mmol), and cesium carbonate (324 mg, 0.994 mmol) in dioxane (4 mL). The reaction mixture was stirred at 100 °C under N2 for 12 h. The mixture was concentrated, diluted with water (10 mL), and extracted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na₂SO₄ and concentrated. The residue was purified by rapid silica gel chromatography (0–15% ethyl acetate / petroleum ether) to yield the title compound. MS = 624.3 (M+1).

[0523] Step 8.1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-((1R,5S)-2-oxo-3-azabi) Cyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid: TFA (0.4 mL, 4.17 mmol) was added to a stirred solution of 1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (260 mg, 0.417 mmol) in DCM (2 mL), and the reaction mixture was stirred at 25 °C for 6 h. The mixture was concentrated to produce a crude title compound, which was used in the next step without further purification. MS = 568.1 (M+1).

[0524] Step 9.1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-((1R,5S)-2-oxo-3-helium-bis) Cyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-1, 2,3-Triazole-4-carboxamide:To a solution of 1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (200 mg, 0.352 mmol) in ACN (2 mL), 1-methyl-1H-imidazolium (116 mg, 1.409 mmol), TCFH (119 mg, 0.423 mmol), and (cis)-2-(3-aminocyclobutyl)-4-chlorobenzyl nitrile 2,2,2-trifluoroacetate (124 mg, 0.388 mmol) were added, and the mixture was stirred at 25 °C under N2 for 2 h. The mixture was concentrated, diluted with water (10 mL), and extracted with EtOAc (15 mL x 3). The organic layer was washed with saturated NaCl (20 mL), dried over Na₂SO₄, and concentrated to produce a crude title compound, which was used in the next step without further purification. MS = 756.3 (M+1).

[0525] Step 10. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-2-hydroxy-1-(6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-2-hydroxy-1-(6-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide: TBAF (1 mL, 0.793 mmol) was added to a stirred solution of 1-(2-((tert-butyldiphenylsilyl)oxy)-1-(6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1H-1,2,3-triazol-4-carboxamide (200 mg, 0.264 mmol) in THF (1 mL). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier). The enantiomerically pure title compound was resolved by chiral SFC (DAICELCHIRALCEL OJ-H; 250 mm * 30 mm, 5 μm; 40% 0.1% NH3H2O ​​EtOH) to provide a faster elution of the isomer (Example 154). 1H NMR (400MHz, methanol-d4) δ8.53 (s, 1H), 8.38 (s, 1H), 8.22 (d, J=8.6Hz, 1H), 7.80 -7.85(m, 1H), 7.64-7.70(m, 2H), 7.39-7.44(m, 1H), 5.87(dd, J=8.0, 5.3Hz, 1H), 4.59 (s, 1H), 4.40 (dd, J=11.7, 8.2Hz, 1H), 4.15-4.20 (m, 1H), 4.04-4. 10(m, 1H), 3.55-3.65(m, 1H), 2.87-2.92(m, 1H), 2.30-2.41(m, 2H), 2.11(br d, J = 8.6 Hz, 2H), 1.63-1.70 (m, 1H), 1.40-1.46 (m, 1H), 1.23-1.28 (m, 1H), 0.77 (d, J = 3.9 Hz, 1H). 99.48% ee. MS = 518.2 (M+1). Slower eluting isomers: (Example 155). 1 H NMR (400MHz, methanol-d4) δ8.53 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=9.0Hz, 1H), 7.80-7.85 (m, 1H), 7.63-7.69 (m, 2H), 7.41 (dd, J=8.6, 2.0Hz, 1H), 5.87 (dd, J=7.6, 4.9Hz, 1H), 4.59 (t, J=7.2Hz, 1H), 4.40 (dd, J=11.7, 8.2Hz, 1H), 4.17 (dd, J=11.7, 4.7Hz, 1H), 4.04-4.09 (m, 1H), 3.59 (br t, J=7.6Hz, 1H), 2.93(br s, 1H), 2.35 (br d, J=10.2Hz, 2H), 2.11 (br d, J=7.0Hz, 2H), 1.66 (s, 1H), 1.37-1.45 (m, 1H), 1.23-1.27 (m, 1H), 0.76 (d, J=4.3Hz, 1H). 97.90%ee. MS=518.2(M+1).

[0526] Examples 156 and 157

[0527]

[0528] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((R)-1-hydroxy-1-(5-methyl-6-((1R, 5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)isoxazole-3-carboxamide and N-((cis) (Formula)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((S)-1-hydroxy-1-(5-methyl-6-((1R,5S)-2-oxo-3-nitrogen Heterobicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)isoxazole-3-carboxamide

[0529] Step 1. (R)-2-(6-chloro-5-methylpyridin-3-yl)but-3-yn-2-ol and (S)-2-(6-chloro-5-methylpyridin-3-yl)but-3-yn-2-ol (Pyridine-3-yl)but-3-yn-2-ol:Magnesium acetylenide (217 mL, 108 mmol) was added to a solution of 1-(6-chloro-5-methylpyridin-3-yl)acetone (2.3 g, 13.56 mmol) in THF (30 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under vacuum, saturated NH4Cl and water were added, and the solution was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified to the title compound by rapid silica gel chromatography (0-25% ethyl acetate / petroleum ether). MS = 196.0 (M+1).

[0530] Step 2. (R)-5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazole-3-carboxylic acid ethyl ester and (S)-5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazole-3-carboxylic acid ethyl ester: To a solution of 2-(6-chloro-5-methylpyridin-3-yl)but-3-yn-2-ol (1.3 g, 6.64 mmol) in ethyl acetate (10 mL) and water (2 mL), ethyl (Z)-2-chloro-2-(oxime)acetate (5.03 g, 33.2 mmol) and sodium bicarbonate (5.58 g, 66.4 mmol) were added. The mixture was stirred at 20 °C for 12 h. The mixture was concentrated and purified by rapid silica gel chromatography (0-25% ethyl acetate / petroleum ether) to yield the title compound. 1 H NMR (500MHz, CDCl3): δ8.34 (d, J=2.1Hz, 1H), 7.63 (dd, J=2.4, 0.6Hz, 1H), 6 .61 (s, 1H), 4.41-4.47 (m, 2H), 2.39 (s, 3H), 2.01 (s, 3H), 1.39-1.43 (m, 3H).

[0531] Step 3. (R)-5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazole-3-carboxylic acid and (S)- 5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazole-3-carboxylic acid: Lithium hydroxide hydrate (439 mg, 10.46 mmol) was added to a solution of ethyl 5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazol-3-carboxylate (650 mg, 2.092 mmol) in MeOH (10 mL) and water (2 mL). The mixture was stirred at 20 °C for 3 h. The mixture was concentrated under vacuum, 1 M HCl was added until pH 2 was reached, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield the title compound, which was used directly. MS = 283.0 (M+1).

[0532] Step 4. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((R)-1-(6-chloro-5-methylpyridine- 3-yl)-1-hydroxyethyl)isoxazole-3-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5- ((S)-1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazole-3-carboxamide:In a round-bottom flask, EDC (1017 mg, 5.31 mmol) was added to a solution of 5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazol-3-carboxylic acid (500 mg, 1.769 mmol) and 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (645 mg, 2.123 mmol) in pyridine (3 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated and purified by rapid silica gel chromatography (0-50% ethyl acetate / petroleum ether) to yield the title compound. MS = 471.0 (M+1).

[0533] Step 5. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((R)-1-hydroxy-1-(5-methyl-6-) ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)isoxazole-3-carboxamide and N- ((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-((S)-1-hydroxy-1-(5-methyl-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)isoxazole-3-carboxamide: 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (19.23 mg, 0.021 mmol) was added to a solution of N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-5-(1-(6-chloro-5-methylpyridin-3-yl)-1-hydroxyethyl)isoxazo-3-carboxamide (10 mg, 0.021 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (3.09 mg, 0.032 mmol) and Cs2CO3 (27.7 mg, 0.085 mmol) in dioxane (0.5 ml) at 20 °C. The mixture was stirred at 100 °C for 3 h. The mixture was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers. The enantiomerically pure title compound was resolved by SFC (OD (250 mm × 30 mm, 10 μm), 45% 0.1% NH3H2O ​​IPA) to give the faster-eluting isomers (Example 156). 1H NMR (400MHz, methanol-d4) δ8.39 (s, 1H), 7.81 (s, 1H), 7.57-7.70 (m, 2H), 7.39 (br d, J=8.6Hz, 1H), 6.65(s, 1H), 4.47-4.62(m, 1H), 4.24(dd, J=10.1, 6.0Hz, 1H), 3.67(br d, 10.5Hz, 1H), 3.49-3.64(m, 1H), 2.88(br d, J=10.0Hz, 2H), 2.23-2.37(m, 2H), 2.17(s, 4H), 2.01(br s, 1H), 1.93(s, 3H), 1.30(br d, J = 7.6 Hz, 1H), 0.93 (br d, J = 3.4 Hz, 1H). 100% ee. MS = 532.2 (M+1). Slower elution isomers were obtained (Example 157): 1 H NMR (400MHz, methanol-d4) δ8.32 (s, 1H), 7.72 (s, 1H), 7.52-7.61 (m, 2H), 7.31 (br d, J=8.6Hz, 1H), 6.57 (s, 1H), 4.47 (br t, J=8.3Hz, 1H), 4.16 (dd, J=10.3, 5.6Hz, 1H), 3.60 (br d, 10.5Hz, 1H), 3.40-3.53 (m, 1H), 2.80 (br d, J=10.0Hz, 2H), 2.15-2.28(m, 2H), 2.09(s, 4H), 1.94(br s, 1H), 1.85(s, 3H), 1.20(br d, J=4.6Hz, 1H), 0.85 (br d, J=3.7Hz, 1H). 99.66%ee. MS=532.2(M+1).

[0534] Example 158

[0535]

[0536] N-(cis)-3-(2-carbamoyl-5-chlorophenyl)cyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide

[0537] Step 1. N-(cis)-3-(2-carbamoyl-5-chlorophenyl)cyclobutyl)-1-((S)-1-(4,5-dimethyl-6- ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-methyl Amide:Sodium hydroxide (0.150 mL, 0.750 mmol, 5 M in water) was added to a solution of N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(4,5-dimethyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide (40 mg, 0.062 mmol) in methanol (0.25 mL) and THF (0.25 mL). The reaction mixture was stirred at 65 °C for 8 hours. The mixture was concentrated under reduced pressure. The mixture was quenched with HCl (0.809 mL, 0.809 mmol) (1 N aqueous solution), concentrated under reduced pressure, and purified by preparative reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide the title compound as a TFA salt. MS = 547.9 (M+1). 1 H NMR (500MHz, methanol-d4) δ8.39 (s, 1H), 8.23 ​​(s, 1H), 7.53 (s, 1H), 7.37 (d, J=8.1Hz, 1H), 7.29 (dd, J=8.2, 2.0Hz, 1H), 6.30-6.35 (m, 1H), 4.43-4.55 (m , 1H), 3.59-3.74(m, 2H), 2.77-2.86(m, 2H), 2.33(s, 3H), 2.17-2.31(m, 3 H), 2.11(s, 3H), 2.01-2.07(m, 5H), 1.3-1.35(m, 1H), 0.97-1.01(m, 1H).

[0538] Example 159

[0539]

[0540] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxamide

[0541] Step 1.2 - (6-chloro-4-methylpyridin-3-yl)acetonitrile:PdCl2 (dppf) (2.66 g, 3.63 mmol) was added to a mixture of 5-bromo-2-chloro-4-methylpyridine (7.5 g, 36.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)isoxazole (7.08 g, 36.3 mmol), and potassium phosphate (23.13 g, 109 mmol) in 1,4-dioxane (50 mL) and water (10 mL). The mixture was stirred at 80 °C for 36 h. The mixture was filtered and concentrated to remove the organic solvent, then diluted with water (30 mL), extracted with EtOAc (50 mL x 3), the combined organic solvent was washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by rapid silica gel chromatography (0–30% ethyl acetate / petroleum ether) to yield the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.22 (s, 1H), 3.64 (s, 2H), 2.38 (s, 3H). MS=167.1(M+1).

[0542] Step 2.1 - (6-chloro-4-methylpyridin-3-yl)cyclopropaneformonitrile: 2,3,4,6,7,8,9,10-octahydropyrimidino[1,2-a]azacycloheptatriene (411 mg, 2.70 mmol) was added to a solution of 2-(6-chloro-4-methylpyridin-3-yl)acetonitrile (450 mg, 2.70 mmol) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (979 mg, 2.70 mmol) in DMF (10 mL) at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum to produce a crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to produce the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.20 (s, 1H), 2.54 (s, 3H), 1.75 (d, J = 2.4 Hz, 2H), 1.27-1.36 (m, 2H). MS=193.1(M+1).

[0543] Step 3.1 - (6-chloro-4-methylpyridin-3-yl)cyclopropanecarboxylic acid:Potassium hydroxide (2.559 g, 45.7 mmol) was added to a solution of 1-(6-chloro-4-methylpyridin-3-yl)cyclopropanecarboxynitrile (2.2 g, 11.42 mmol) in t-BuOH (20 mL) and water (4 mL) at 20 °C. The mixture was stirred at 140 °C for 60 h. The mixture was concentrated under vacuum, saturated NaHCO3 was added to pH 8, and the mixture was extracted with EtOAc (20 mL x 5). The combined organic layers were concentrated, and the residue was purified by reversed-phase MPLC (C18 (20–35 μm), 10%–50% H2O (0.5% oTFA) / MeCN gradient) to yield 1-(6-chloro-4-methylpyridin-3-yl)cyclopropanecarboxamide. MS = 211.0 (M+1). The aqueous layer was purified by reversed-phase HPLC (ACN / water with 0.05% TFA adjuster) to yield the title compound. MS = 212.0(M+1).

[0544] Step 4.1 - (1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)hydrazine-1,2-dibutyl dicarboxylate: DBAD (653 mg, 2.83 mmol), CeCl3 (70.4 mg, 0.189 mmol), and Cs2CO3 (123 mg, 0.378 mmol) were added to a solution of 1-(6-chloro-4-methylpyridin-3-yl)cyclopropanecarboxylic acid (400 mg, 1.890 mmol) in MeCN (5 mL) at 20 °C. The reaction mixture was irradiated with Royal Blue (450 nm) LED light in an integrated photoreactor. 100% LED light power was applied. The stirring rate was 1000 rpm. The fan speed was 1500 rpm for 24 h. The mixture was filtered and the filtrate was concentrated under vacuum to produce a crude product. The crude product was purified by preparative TLC (SiO2; petroleum ether: ethyl acetate = 3:1) to produce the title compound. 1 H NMR (400MHz, CDCl3) δ8.53 (br s, 1H), 7.09 (s, 1H), 5.91-6.47 (m, 1H), 2.50 (s, 3H), 1.57 (br s, 2H), 1.31-1.54 (m, 18H), 1.24-1.28 (m, 2H). MS=398.1(M+1).

[0545] Step 5.2 - Chloro-5-(1-hydrazinocyclopropyl)-4-methylpyridine: 1-(1-(6-chloro-4-methyl) A solution of di-tert-butyl pyridin-3-yl)cyclopropyl)hydrazine-1,2-dicarboxylate (400 mg, 1.005 mmol) in 4 M HCl / dioxane (5 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum to yield the title compound. The crude product was used directly without further purification. MS = 198.2 (M+1).

[0546] Step 6.1 - (1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid ethyl ester:Ethyl 2-formyl-3-oxopropionate (277 mg, 1.922 mmol) was added to a solution of 2-chloro-5-(1-hydrazinocyclopropyl)-4-methylpyridine (190 mg, 0.961 mmol) in EtOH (10 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum to yield a crude product. The crude product was purified by preparative TLC (SiO2; petroleum ether: ethyl acetate = 3:1) to yield the title compound. MS = 306.0 (M+1).

[0547] Step 7.1 -(1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid: Lithium hydroxide hydrate (137 mg, 3.27 mmol) was added to a solution of ethyl 1-(1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxylate (200 mg, 0.654 mmol) in MeOH (5 mL) and water (1 mL). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under vacuum by adding 1 M HCl until pH 2 was reached, and the solution was extracted with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield the title compound. MS = 278.0 (M+1).

[0548] Step 8.1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine- 3-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid: Pd(dba)3 (43.7 mg, 0.054 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthone (31.3 mg, 0.054 mmol) were added to a solution of 1-(1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.540 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (62.9 mg, 0.648 mmol) and Cs2CO3 (528 mg, 1.620 mmol) in dioxane (1 mL) at 20 °C. The mixture was stirred at 100 °C for 12 h. The mixture was concentrated under vacuum and purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 339.1 (M+1).

[0549] Step 9. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2- Oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)cyclopropyl)-1H-pyrazole-4-carboxamide:Chloro-N,N,N′,N′-Tetramethylformamidinium hexafluorophosphate (41.5 mg, 0.148 mmol) and 1-methylimidazolium (36.4 mg, 0.443 mmol) were added to a solution of 1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)cyclopropyl)-1H-pyrazol-4-carboxylic acid (50 mg, 0.148 mmol) and 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (76 mg, 0.148 mmol) in MeCN (5 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under vacuum to produce a crude product. The crude product was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to produce the title compound. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.48 (s, ¹H), 8.10 (s, ¹H), 7.96 (s, ¹H), 7.83 (s, ¹H), 7.64 (d, J = 8.3 Hz, ¹H), 7.57 (s, ¹H), 7.35–7.42 (m, ¹H), 4.39–4.53 (m, ¹H), 4.10 (br) d, J=4.6Hz, 1H), 4.05 (s, 1H), 3.45-3.61 (m, 1H), 2.86 (qd, J=7.9, 2.8Hz, 2H), 2.40 (s, 3H), 2.05-2 .24 (m, 4H), 1.76-1.83 (m, 2H), 1.43 (s, 2H), 1.27 (td, J=8.0, 4.5Hz, 1H), 0.76 (brd, J=3.7Hz, 1H). MS=527.2(M+1).

[0550] Example 160

[0551]

[0552] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxamide

[0553] Step 1. (1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)tert-butyl carbamate:TEA (0.395 mL, 2.83 mmol) was added to a solution of 1-(6-chloro-4-methylpyridin-3-yl)cyclopropanecarboxylic acid (200 mg, 0.945 mmol) and DPPA (0.407 mL, 1.890 mmol) in toluene (5 mL). The reaction mixture was stirred at 60 °C for 1 h, then 2-methylpropane-2-ol (140 mg, 1.890 mmol) was added, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether: EtOAc = 3:1) to yield the title compound. MS = 283.1 (M+1).

[0554] Step 2.1 - (6-chloro-4-methylpyridin-3-yl)cyclopropane-1-amine: A solution of tert-butyl (140 mg, 0.495 mmol) in HCl / dioxane (4 N, 3 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated to the title compound and used directly without further purification. MS = 183.1 (M+1)

[0555] Step 3.5 - (1-azidocyclopropyl)-2-chloro-4-methylpyridine: DMAP (60.2 mg, 0.493 mmol) was added to a solution of 1-(6-chloro-4-methylpyridin-3-yl)cyclopropylamine (60 mg, 0.328 mmol) and 2-azido-1,3-dimethylimidazoline hexafluorophosphate (112 mg, 0.394 mmol) in ACN (0.6 mL), and the reaction mixture was stirred at 30 °C for 1.5 h. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3 mL * 2). The combined organic layers were concentrated to yield the title compound, which was used directly without further purification. MS = 209.1 (M+1).

[0556] Step 4.1 - (1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester: Cu₂SO₄·5H₂O (8.14 mg, 0.033 mmol) and tert-butyl propynate (53.4 mg, 0.424 mmol) were added to a stirred solution of 5-(1-azidocyclopropyl)-2-chloro-4-methylpyridine (68 mg, 0.326 mmol), sodium ascorbate (129 mg, 0.652 mmol), and tert-butanol (2.5 mL) and water (2.5 mL) at room temperature. The reaction mixture was stirred at 27 °C for 12 h, then concentrated and diluted with water (5 mL). The mixture was extracted with EtOAc (10 mL x 2), and the combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and concentrated. The residue was purified by preparative TLC (SiO₂, petroleum ether:EtOAc = 1:1) to yield the title compound. MS = 335.1 (M+1).

[0557] Step 5.1-(1-(4-methyl-6-((1R.5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridine- 3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester: To a solution of tert-butyl 1-(1-(6-chloro-4-methylpyridin-3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxylate (90 mg, 0.269 mmol) in toluene (3 mL), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (33.9 mg, 0.349 mmol), (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (15.55 mg, 0.027 mmol), Pd2dba3 (24.62 mg, 0.027 mmol), and cesium carbonate (175 mg, 0.538 mmol) were added. The mixture was stirred at 100 °C for 16 h. The reactants were diluted with water (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were concentrated, and the residue was purified by preparative TLC (SiO2, petroleum ether:EtOAc = 1:2) to yield the title compound. MS = 396.2 (M+1).

[0558] Step 6.1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3-yl)pyridine- 3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxylic acid: TFA (0.6 mL, 7.79 mmol) was added to a solution of 1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (47 mg, 0.119 mmol) in DCM (3 mL) at 27 °C. The mixture was stirred at 27 °C for 12 h. The mixture was concentrated to yield the title compound, which was used directly without further purification. MS = 340.1 (M+1).

[0559] Step 7. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2- Oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxamide: 1-Methyl-1H-imidazolium (29.0 mg, 0.354 mmol) was added to a mixture of 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (63.9 mg, 0.124 mmol), 1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)cyclopropyl)-1H-1,2,3-triazol-4-carboxylic acid (40 mg, 0.118 mmol), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (66.1 mg, 0.236 mmol) in MeCN (2 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. The reactants were concentrated, and the residues were purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to yield the title compound. 1H NMR (400MHz, methanol-d4) δ8.56 (s, 1H), 8.39 (s, 1H), 7.82 (br s, 1H), 7.60-7.65 (m, 2H), 7.38 (dd, J=8.2, 1.8Hz, 1H), 4.48-4.59 (m, 1H), 3.97-4.16 ( m, 2H), 3.49-3.63 (m, 1H), 2.81-2.94 (m, 2H), 2.49 (s, 3H), 2.24-2.36 (m, 2H), 2.17 (br d, J=7.8Hz, 2H), 1.91-2.00(m, 2H), 1.62(br s, 2H), 1.27-1.28 (m, 1H), 0.84ppm (br d, J=3.9Hz, 1H). MS=528.2(M+1).

[0560] Examples 161 and 162

[0561]

[0562] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(1,5-dimethyl-2-((1R,5S)- 2-O-3-azabicyclo[3.1.0]hexane-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(1,5-dimethyl-2-((1R,5S)-2-oxo) 3-azabicyclo[3.1.0]hexane-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide

[0563] Step 1.1, Ethyl 5-dimethyl-1H-imidazol-4-carboxylate: Sodium hydride (0.519 g, 12.97 mmol) was added to a stirred mixture of ethyl 5-methyl-1H-imidazolium-4-carboxylate (2 g, 12.97 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Iodomethane (0.969 mL, 15.57 mmol) was added to the mixture and the reaction mixture was stirred at 25 °C for 12 h. An aqueous solution of ammonium chloride (1 mL) was added and the mixture was dried (Na₂SO₄), filtered, and the solvent was evaporated under reduced pressure to produce a residue. The residue was purified by rapid silica gel chromatography (10% to 55% ethyl acetate / petroleum ether) to produce the title compound. 1 H NMR (400MHz, CDCl3) δ7.42 (s, 1H), 4.37 (q, J=7.3Hz, 2H), 3.59 (s, 3H), 2.54 (s, 3H), 1.41ppm (t, J=7.1Hz, 3H). MS=169.1(M+1).

[0564] Step 2.2-Bromo-1,5-dimethyl-1H-imidazol-4-carboxylic acid ethyl ester:NBS (1143 mg, 6.42 mmol) was added to a solution of ethyl 1,5-dimethyl-1H-imidazolium-4-carboxylate (900 mg, 5.35 mmol) in MeCN (15 mL) at 25 °C, and the mixture was stirred at 25 °C for 8 h. The reactants were concentrated under reduced pressure, EtOAc (20 mL) was added, and the solution was washed with water (10 mL x 3), dried over anhydrous Na₂SO₄, and concentrated to produce a residue. The residue was purified by rapid silica gel chromatography (0% to 45% ethyl acetate / petroleum ether) to produce the title compound. 1 H NMR (400MHz, CDCl3) δ4.37 (q, J=7.3Hz, 2H), 3.55 (s, 3H), 2.58 (s, 3H), 1.40ppm (t, J=7.1Hz, 3H). MS=247.0, 249.0(M+1).

[0565] Step 3. (2-Bromo-1,5-dimethyl-1H-imidazol-4-yl)methanol: DIBAL-H (29.0 mL, 29.0 mmol) was added to a stirred mixture of ethyl 2-bromo-1,5-dimethyl-1H-imidazolium-4-carboxylate (2.87 g, 11.62 mmol) in THF (30 mL) at -78 °C, and the mixture was stirred at 25 °C for 12 h. The mixture was cooled to 0 °C, diluted with THF (20 mL), and water (1.16 mL) and 1.16 mL NaOH (15%) (2.9 mL) were added sequentially with stirring. The mixture was stirred at 25 °C for 15 min, dried over MgSO4, filtered, and the filter cake was washed with EtOAc (20 mL x 3). The filtrate was evaporated under reduced pressure to produce the residue. The residue was purified by rapid silica gel chromatography (10% to 60% ethyl acetate / petroleum) to produce the title compound. 1 H NMR (400 MHz, CDCl3) δ4.52 (s, 2H), 3.50 (s, 3H), 2.24ppm (s, 3H). MS=205.1, 207.1(M+1).

[0566] Step 4.2-Bromo-1,5-dimethyl-1H-imidazol-4-formaldehyde: Manganese dioxide (3.73 g, 42.9 mmol) was added to a stirred solution of (2-bromo-1,5-dimethyl-1H-imidazol-4-yl)methanol (1.1 g, 5.36 mmol) in DCM (40 mL) at 25 °C, and the mixture was stirred at 40 °C for 12 h. The mixture was filtered, and the filter cake was washed with DCM (30 mL). The filtrate was concentrated to yield the title compound. The crude material was used directly without further purification. 1H NMR (500MHz, CDCl3) δ9.81-9.90 (m, 1H), 3.50-3.64 (m, 3H), 2.58ppm (s, 3H). MS=203.0, 205.0(M+1).

[0567] Step 5.1 - (2-bromo-1,5-dimethyl-1H-imidazol-4-yl)ethane-1-ol: Magnesium methyl bromide (3M in THF) (3.13 mL, 9.40 mmol) was added to a stirred solution of 2-bromo-1,5-dimethyl-1H-imidazol-4-carboxaldehyde (954 mg, 4.70 mmol) in THF (10 mL) at -78 °C, and the mixture was stirred at -78 °C for 2 h. An aqueous solution of ammonium chloride (saturated, 10 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic fractions were washed with brine (10 mL), dried (Na₂SO₄), filtered, and the solvent was evaporated under reduced pressure to produce the residue. The residue was purified by rapid silica gel chromatography (10% to 30% ethyl acetate / petroleum ether) to yield the title compound. 1 H NMR (500MHz, CDCl3) δ4.80 (brt, J=6.5Hz, 1H), 3.48 (s, 3H), 2.23 (s, 3H), 1.52ppm (d, J=6.4Hz, 3H). MS=219.0, 221.0(M+1).

[0568] Step 6.4 - (1-azidoethyl)-2-bromo-1,5-dimethyl-1H-imidazolium: DIAD (0.148 mL, 0.753 mmol) was added to a solution of 1-(2-bromo-1,5-dimethyl-1H-imidazol-4-yl)ethanol (110 mg, 0.502 mmol), triphenylphosphine (198 mg, 0.753 mmol), and diphenyl azidophosphate (0.541 mL, 2.51 mmol) in THF (3 mL) at 0 °C. The mixture was stirred at 45 °C for 12 h, then water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with saturated brine (10 mL), dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by rapid silica gel chromatography (100% ethyl acetate / petroleum ether) to yield the title compound. MS = 244.1, 246.1 (M+1).

[0569] Step 7.1-(1-(2-bromo-1,5-dimethyl-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester:4-(1-Azideylethyl)-2-bromo-1,5-dimethyl-1H-imidazolium (90 mg, 0.369 mmol) was added to a stirred mixture of (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-ol sodium (146 mg, 0.737 mmol), copper(II) sulfate pentahydrate (27.6 mg, 0.111 mmol), and tert-butyl propynate (60.5 mg, 0.479 mmol) in t-BuOH (4 mL) and water (4 mL) at 0 °C. The mixture was stirred at 45 °C for 1 h and then concentrated to produce a residue. Water (10 mL) was added and the mixture was extracted with EtOAc (4 x 10 mL). The combined organic fractions were washed with brine (10 mL), dried (Na₂SO₄), filtered, and the solvent was evaporated under reduced pressure to produce a residue. The residue was purified by preparative TLC on silica gel, eluted with EtOAc / petroleum ether = 1:1 to yield the title compound. MS = 370.1, 372.1 (M+1).

[0570] Step 8.1-(1-(1,5-dimethyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)- 1H-Imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester: At 25 °C, [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (19.59 mg, 0.022 mmol) was added to a stirred mixture of cesium carbonate (282 mg, 0.864 mmol), 1-(1-(2-bromo-1,5-dimethyl-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (80 mg, 0.216 mmol), and (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (31.5 mg, 0.324 mmol) in dioxane (0.5 mL). The mixture was stirred at 90 °C for 12 h, then filtered and concentrated to produce a residue. The residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to yield the title compound. MS = 387.3 (M+1).

[0571] Step 9.1-(1-(1,5-dimethyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)- 1H-Imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid:TFA (0.5 mL) was added to a stirred mixture of 1-(1-(1,5-dimethyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (5 mg, 0.013 mmol) in DCM (0.500 mL) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated to produce the title compound. The crude product was used directly without further purification. MS = 331.2 (M+1).

[0572] Step 10. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(1,5-dimethyl-2- ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazole- 4-Formamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(1,5-dimethyl-2-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-methyl Amide: 1-Methyl-1H-imidazolium (2.98 mg, 0.036 mmol) was added to a mixture of 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (3.00 mg, 0.015 mmol), 1-(1-(1,5-dimethyl-2-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)-1H-imidazol-4-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (4 mg, 0.012 mmol) and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (5.10 mg, 0.018 mmol) in MeCN (0.5 mL) at 25 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was filtered, diluted with MeCN (0.5 mL), and then purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to provide a mixture of diastereomers. The enantiomerically pure title compound was resolved by SFC (DAICELCHIRALPAK AS (250 mm * 30 mm, 10 μm), 30% 0.1% NH3H2O ​​EtOH). The faster-eluting isomer was repurified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to produce the faster-eluting isomer (Example 161). 1H NMR (400MHz, methanol-d4) δ8.34 (s, 1H), 7.62-7.71 (m, 2H), 7.41 (dd, J=8.3, 2.0Hz, 1H), 6.06 (q, J =6.8Hz, 1H), 4.50-4.65 (m, 1H), 4.09 (dd, J = 9.8, 5.9Hz, 1H), 3.73 (d, J = 9.8Hz, 1H), 3.53-3.6 5 (m, 1H), 3.41 (s, 3H), 2.84–2.96 (m, 2H), 2.31–2.40 (m, 2H), 2.28 (s, 3H), 2.16–2.27 (m, 1H), 2.02–2.11 (m, 1H), 1.94 (d, J = 7.1 Hz, 3H), 1.37 (td, J = 8.1, 5.0 Hz, 1H), 1.01–1.07 ppm (m, 1H). MS = 519.2 (M+1). The slower-eluting isomer was repurified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to produce the slower-eluting isomer (Example 162): 1 H NMR (400MHz, methanol-d4) δ8.34 (s, 1H), 7.66 (dd, J=4.8, 3.3Hz, 2H), 7.41 (dd, J=8.3, 2.0Hz, 1H), 6.08 (q, J =6.9Hz, 1H), 4.50-4.64 (m, 1H), 4.09 (dd, J = 9.8, 5.9Hz, 1H), 3.74 (d, J = 9.8Hz, 1H), 3.53-3.66 (m, 1H) , 3.42 (s, 3H), 2.84-2.97 (m, 2H), 2.32-2.41 (m, 2H), 2.30 (s, 3H), 2.24 (dt, J=11.8, 6.0Hz, 1H), 2.02- 2.13 (m, 1H), 1.96 (d, J=7.1Hz, 3H), 1.37 (td, J=8.1, 4.9Hz, 1H), 0.99-1.08ppm (m, 1H) MS=519.2 (M+1). MS=519.2(M+1).

[0573] Examples 163 and 164

[0574]

[0575] N -((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-hydroxy-4-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-hydroxy-4-methyl-6-((1R,5S)-2- oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide

[0576] Step 1. 2-Chloro-5-(1-Chloroethyl)-3-methoxy-4-methylpyridine:MsCl (0.464 mL, 5.95 mmol) was added to a stirred mixture of Et3N (1.382 mL, 9.92 mmol) and 1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethane-1-ol (400 mg, 1.984 mmol) in DCM (8 mL) at 0 °C, and the mixture was stirred at 20 °C for 12 h. The reaction mixture was added to an aqueous solution of ammonium chloride (5 mL, saturated) and water (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined organic fractions were washed with brine (1 x 20 mL, saturated), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure to yield the title compound. MS = 220.0 (M+1).

[0577] Step 2.5-(1-Azideylethyl)-2-chloro-3-methoxy-4-methylpyridine: at 0°C, to 2- Sodium azide (740 mg, 11.38 mmol) was added to a solution of chloro-5-(1-chloroethyl)-3-methoxy-4-methylpyridine (437 mg, 1.985 mmol) in N,N-dimethylformamide (8 mL), and the mixture was stirred at 50 °C for 2 h. Water (8 mL) was added, and the reaction mixture was extracted with ethyl acetate (8 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to yield the crude product. MS = 227.1 (M+1).

[0578] Step 3.1-(1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester: Sodium ascorbate (787 mg, 3.97 mmol) and Cu₂SO₄·5H₂O (49.6 mg, 0.199 mmol) were added to a solution of tert-butyl propargyl ester (326 mg, 2.58 mmol) and 5-(1-azidoethyl)-2-chloro-3-methoxy-4-methylpyridine (450 mg, 1.985 mmol) in tert-butanol (5 mL) and water (5 mL) at 20 °C. The reaction mixture was then stirred at 20 °C for 12 h. The mixture was concentrated, water (10 mL) was added, and the aqueous layer was extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, concentrated, and the residue was purified by rapid silica gel chromatography (0–30% petroleum ether / EtoAc) to yield the title compound. 1 H NMR (400MHz, CDCl3) δ 8.16 (s, 1H), 7.83 (s, 1H), 6.08 (q, J=7.1Hz, 1H), 3.85 (s, 3H), 2.24 (s, 3H), 2.02 (d, J=7.1Hz, 3H), 1.60ppm (s, 9H). MS=353.1(M+1).

[0579] Step 4.1-(1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-) 3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester: To a solution of 1-(1-(6-chloro-5-methoxy-4-methylpyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (150 mg, 0.425 mmol) in toluene (5 mL), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (53.7 mg, 0.553 mmol), XantPhos (24.60 mg, 0.043 mmol), Pd2dba3 (38.9 mg, 0.043 mmol), and cesium carbonate (277 mg, 0.850 mmol) were added, and the mixture was stirred at 120 °C for 12 h. Water (5 mL) was added, and the mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were concentrated, and the residue was purified by preparative TLC (SiO2, EtOAc) to yield the title compound. MS = 414.3(M+1).

[0580] Step 5.1-(1-(5-hydroxy-4-methyl-6-((1R,5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3- 3-(3-)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid: BBr3 (0.171 mL, 1.814 mmol) was added dropwise to a stirred solution of 1-(1-(5-methoxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid tert-butyl ester (150 mg, 0.363 mmol) in DCM (3 mL) for 10 min at 0 °C with vigorous stirring. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at 25 °C for another 12 h. The mixture was diluted with DCM (5 mL), cooled to 0 °C, and quenched by careful, continuous addition of H2O (3 mL). The mixture was concentrated, and the residue was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 344.1 (M+1).

[0581] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-hydroxy-4-methyl-6- ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-methyl Amides and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-hydroxy-4-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxamide:1-Methyl-1H-imidazolium (10.76 mg, 0.131 mmol) was added to a stirred mixture of 1-(1-(5-hydroxy-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-1,2,3-triazol-4-carboxylic acid (15 mg, 0.044 mmol), 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (10.84 mg, 0.052 mmol) and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (24.52 mg, 0.087 mmol) in MeCN (1 mL) at 25 °C, and the mixture was stirred at about 25 °C for 2 h. The reactants were concentrated, and the residues were purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers of the product. The enantiomerically pure title compound was resolved by SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm)) with 45% IPA (0.1% NH3H2O). The faster-eluting isomers were obtained (Example 163). 1 H NMR(400MHz, DMSO_d6)δ9.78(br s, 1H), 8.92 (d, J = 8.6Hz, 1H), 8.69 (s, 1H), 7.90 (s, 2H), 7.80 (d, J = 8.6Hz, 1H ), 7.51 (dd, J=8.2, 2.0Hz, 1H), 6.22 (q, J=7.0Hz, 1H), 4.48-4.61 (m, 1H), 4.2 3(dd, J=11.0, 5.1Hz, 1H), 3.87 (d, J=11.0Hz, 1H), 3.40-3.54 (m, 1H), 2.66-2 .76(m, 2H), 2.37(q, J=10.2Hz, 2H), 2.18(s, 3H), 2.11-2.17(m, 2H), 1.92(br d, J=7.0Hz, 3H), 1.21-1.25 (m, 1H), 0.87ppm (br d, J=3.5Hz, 1H). MS=532.2(M+1).

[0582] A slower-eluting isomer was obtained (Example 164): 1H NMR(400MHz, DMSO_d6)δ9.81(br s, 1H), 8.93 (d, J=8.6Hz, 1H), 8.72 (s, 1H), 7.91 (d, J=2.0Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=8.2Hz, 1H), 7.51 (dd, J=8.2 , 2.0Hz, 1H), 6.22 (d, J=7.0Hz, 1H), 4.51-4.63 (m, 1H), 4.21 (dd, J=11.3, 5.5Hz, 1H), 3.89 (d, J=11.0Hz, 1H), 3.46 (br t, J=8.2Hz, 1H), 2.70(br d, J=10.2Hz, 2H), 2.38 (br d, J=9.8Hz, 2H), 2.19 (s, 3H), 2.15 (br s, 2H), 1.92 (d, J=7.0Hz, 3H), 1.24 (br s, 1H), 0.88ppm (br d, J=3.1Hz, 1H). MS=532.2(M+1).

[0583] Examples 165 and 166

[0584]

[0585] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(4-fluoro-5-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N- ((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(4-fluoro-5-methyl-6-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide.

[0586] Step 1.2-Chloro-4-fluoro-3-methylpyridine: LDA (2M in THF and hexane) (9.12 mL, 18.25 mmol) was added dropwise to a mixture of 2-chloro-4-fluoropyridine (2 g, 15.21 mmol) in THF (10 mL) at 78 °C. The mixture was stirred at -78 °C for 0.5 h, and then iodomethane (1.046 mL, 16.73 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78 °C for 1 h, then warmed to 25 °C and stirred for another 1 h. The mixture was quenched with a saturated ammonium chloride aqueous solution (50 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to produce a crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether) to produce the title compound. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.20 (dd, J = 7.7, 6.0 Hz, 1H), 7.10–7.23 (m, 1H), 2.30 ppm (d, J = 1.7 Hz, 3H). MS = 146.1 (M+1)

[0587] Step 2. (1R,5S)-3-(4-fluoro-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one:A mixture of 2-chloro-4-fluoro-3-methylpyridine (500 mg, 3.43 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (400 mg, 4.12 mmol), Cs₂CO₃ (2238 mg, 6.87 mmol), Pd₂(dba)₃ (315 mg, 0.343 mmol), and XantPhos (199 mg, 0.343 mmol) in 1,4-dioxane (8 mL) was stirred at 100 °C for 12 h under N₂. The reaction mixture was cooled to 20 °C, filtered, and the filtrate was diluted with EtOAc (10 mL) and water (15 mL). The aqueous phase was extracted with EtOAc (20 mL x 3) and the combined organic layers were concentrated. The residue was purified by rapid silica gel chromatography (0–50% petroleum ether / EtOAc) to yield the title compound. 1 H NMR (400MHz, methanol-d4) δ8.27 (dd, J=8.1, 5.6Hz, 1H), 7.10 (dd, J=8.6, 5.6Hz, 1H), 4.29 (dd, J=10.5, 5.9Hz, 1H), 3.63-3.77(m, 1H), 2.12-2.25(m, 1H), 1.94-2.07(m, 4H), 1.20-1.38(m, 1H), 0.86-1.00ppm(m, 1H). MS=207.1(M+1)

[0588] Step 3. (1R,5S)-3-(5-bromo-4-fluoro-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2- ketone: A mixture of (1R,5S)-3-(4-fluoro-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one (420 mg, 2.037 mmol) and NBS (1450 mg, 8.15 mmol) in TFA (10 mL) was stirred at 80 °C for 14 h. A second portion of NBS (1087 mg, 6.11 mmol) was added and the mixture was stirred at 80 °C for another 4 h. The solvent was evaporated, the residue was neutralized with an aqueous solution of NaHCO3, and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0–50% petroleum ether / EtOAc) to yield the title compound. 1H NMR (400MHz, methanol-d4) δ8.42 (d, J=8.8Hz, 1H), 4.32 (dd, J=10.5, 5.9Hz, 1H), 3.70 (d, J=10.5Hz, 1H), 2.13-2 .20 (m, 1H), 2.07 (d, J=2.0Hz, 3H), 1.97-2.04 (m, 1H), 1.29 (td, J=8.0, 4.8Hz, 1H), 0.84-0.99ppm (m, 1H). MS=284.9;286.9(M+1)

[0589] Step 4.1-(1-(4-fluoro-5-methyl-6-((1R,5S)-2-hydro-3-azabicyclo[3.1.0]hexane-3-yl) tert-butyl pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate: In a glove box, (1R,5S)-3-(5-bromo-4-fluoro-3-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one (100 mg, 0.351 mmol), potassium salt of 1-(1-(trifluoro-14-boryl)ethyl)-1H-pyrazole-4-carboxylate tert-butyl ester (106 mg, 0.351 mmol), nickel(II) chloride ethylene glycol dimethyl ether, and 4,4′-di-tert-butyl-2, 2′-Dipyridine (20.54 mg, 0.042 mmol) and bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2′-bipyridyl]iridium hexafluorophosphate (9.86 mg, 8.77 μmol) were added to a solution of EtOAc (2 mL) and DMA (0.4 mL) with K2HPO4 (183 mg, 1.052 mmol). The mixture was then stirred at 25 °C for 14 h in front of a blue LED. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and the residue was purified by reversed-phase HPLC (ACN / water with 0.05% TFA modifier) ​​to yield the title compound. MS = 401.1 (M+1)

[0590] Step 5.1-(1-(4-fluoro-5-methyl-6-((1R,5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3-yl) Pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid: To a solution of 1-(1-(1-(4-fluoro-5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester (30 mg, 0.075 mmol) in DCM (1 mL), 2,2,2-trifluoroacetic acid (17.08 mg, 0.150 mmol) was added. The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated to produce a crude product, which was used directly without further purification. MS = 345.1 (M+1)

[0591] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-fluoro-5-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N- ((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-fluoro-5-methyl-6-((1R,5S)-2-oxo-3-aza) Bicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide: At 25°C, 1-methyl-1H-imidazolium (17.88 mg, 0.218 mmol), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (24.44 mg, 0.087 mmol), and 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (25.6 mg, 0.080 mmol) were added to a solution of 1-(1-(4-fluoro-5-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-carboxylic acid (25 mg, 0.073 mmol) in ACN (2 mL). The mixture was stirred at 25°C for 2 h under a N2 atmosphere, then the reaction mixture was concentrated, and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a mixture of diastereomers of the product. The enantiomerically pure title compound was resolved by SFC (DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); 35% 0.1% NH3H2O ​​EtOH). The faster eluting isomers were obtained (Example 165): 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 8.16-8.24 (m, 2H), 7.83 (s, 1H), 7.80 (d, J=8.1Hz, 1H), 7.64 (s, 1H), 7.49 (dd, J=8.3, 2.0Hz, 1H), 5.80-5.88 (m, 1H), 4.34-4.45 (m, 1H), 4.22 (dd, J=10.1, 5.7Hz, 1H), 3.57 (br d, J=10.5Hz, 1H), 3.36-3.47(m, 1H), 2.72(br d, J=8.3Hz, 2H), 2.13-2.25(m, 2H), 2.09(br 1.93-1.99 (m, 1H), 1.90 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.20-1.21 (m, 1H), 0.80 ppm (br d, J = 3.7 Hz, 1H). MS = 533.3 (M+1). A slower-eluting isomer was obtained (Example 166). 1H NMR (400MHz, DMSO_d6) δ8.30 (s, 1H), 8.18-8.26 (m, 2H), 7.82 (s, 1H), 7.80 (d, J = 8.3Hz, 1H), 7.65 (d, J = 2.0Hz, 1 H), 7.49 (dd, J=8.3, 2.0Hz, 1H), 5.83 (q, J=6.9Hz, 1H), 4.36-4.46 (m, 1H), 4.22 (dd, J=10.4, 5.7Hz, 1H), 3.58 (br d, J=10.3Hz, 1H), 3.40-3.49(m, 1H), 2.67-2.77(m, 2H), 2.14-2.25(m, 2H), 2.10(br d, J=6.6Hz, 1H), 1.94 (br d, J=7.8Hz, 1H), 1.90 (s, 3H), 1.83 (d, J=6.8Hz, 3H), 1.20-1.22 (m, 1H), 0.79-0.83ppm (m, 1H). MS=533.3(M+1)

[0592] Examples 167 and 168

[0593]

[0594] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-chloro-4-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N- ((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide

[0595] Step 1. (1R,5S)-3-(3-chloro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one: A mixture of (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (0.719 g, 7.41 mmol), 2,3-dichloro-4-methylpyridine (1 g, 6.17 mmol), Cs₂CO₃ (6.03 g, 18.52 mmol), Pd₂(dba)₃ (0.565 g, 0.617 mmol), and Xantphos (0.357 g, 0.617 mmol) in toluene (30 mL) was stirred at 90 °C for 14 h under N₂. The solvent was evaporated and 40 mL of water was added. The aqueous layer was extracted with DCM (30 mL x 3), and the combined organic layers were dried over Na₂SO₄, filtered, and evaporated to dryness. The residue was purified by rapid silica gel chromatography (0-100% EtOAc / petroleum ether) to yield the title compound. 1H NMR (400MHz, CDCl3) δ8.19 (d, J=4.9Hz, 1H), 7.07 (d, J=4.9Hz, 1H), 4.25 (td, J=2.8, 10.1Hz, 1H), 3.62 (d, J=10.3Hz, 1H), 2.38 (s, 3H), 1.99-2.09 (m, 2H), 1.14-1.25 (m, 1H), 1.00 (q, J=4.2Hz, 1H). MS=223.1(M+1).

[0596] Step 2. (1R,5S)-3-(5-bromo-3-chloro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2- ketone: A mixture of (1R,5S)-3-(3-chloro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one (750 mg, 3.37 mmol) and NBS (2398 mg, 13.47 mmol) in TFA (25 mL) was stirred at 80 °C for 14 h. Another portion of NBS (1798 mg, 10.10 mmol) was added and the mixture was stirred at 80 °C for 4 h. The solvent was evaporated and the residue was added to 20 mL of aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc (3 x 20 mL), and the combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel chromatography (0–35% EtOAc / petroleum ether) to yield the title compound. 1 H NMR (400MHz, CDCl3) δ8.40 (s, 1H), 4.25 (dd, J=4.9, 9.98Hz, 1H), 3.62 (d, J=9.8Hz, 1H) , 2.54 (s, 3H), 1.98-2.11 (m, 2H), 1.22 (dt, J=4.7, 8.02Hz, 1H), 1.01 (q, J=3.9Hz, 1H). MS=302.9(M+1).

[0597] Step 3. (1R.5S)-3-(5-acetyl-3-chloro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane Alkane-2-:A mixture of (1R,5S)-3-(5-bromo-3-chloro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one (920 mg, 3.05 mmol), tributyl(1-ethoxyvinyl)stanane (1.133 mL, 3.36 mmol), and bis(triphenylphosphine)palladium(II) dichloride (214 mg, 0.305 mmol) in toluene (15 mL) was stirred at 100 °C for 14 h under N2. The reaction mixture was cooled to room temperature, 10 mL of 6 M HCl was added, and the mixture was stirred for 1 h. 5 mL of KF aqueous solution was added, and the mixture was stirred at room temperature for 1 h. 50 mL of NaHCO3 aqueous solution was added, and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by rapid silica gel chromatography (0–60% EtOAc / petroleum ether) to yield the title compound. 1 H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 4.36 (dd, J=5.1, 10.17Hz, 1H), 3.66 (d, J=9.8Hz, 1H), 2.6 0 (s, 3H), 2.58 (s, 3H), 1.97-2.17 (m, 2H), 1.25 (dt, J=4.7, 8.0Hz, 1H), 1.05 (q, J=4.3Hz, 1H). MS=265.2(M+1).

[0598] Step 4. (1R,5S)-3-(3-chloro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo [3.1.0] Hexane-2-one: To a mixture of (1R,5S)-3-(5-acetyl-3-chloro-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one (550 mg, 2.078 mmol) in THF (10 mL), NaBH4 (157 mg, 4.16 mmol) and MeOH (1 mL) were added, and the reaction mixture was stirred at 25 °C for 1 h. 5 mL of acetone was added, and the mixture was stirred at room temperature for 1 h. The solvent was evaporated, and 20 mL of water was added. The mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by rapid silica gel chromatography (0–100% EtOAc / Pet.) to yield the title compound. MS = 267.1 (M+1).

[0599] Step 5.1-(1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl) tert-butyl pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate:A mixture of (1R,5S)-3-(3-chloro-5-(1-hydroxyethyl)-4-methylpyridin-2-yl)-3-azabicyclo[3.1.0]hexane-2-one (380 mg, 1.425 mmol), tert-butyl 1H-pyrazole-4-carboxylate (359 mg, 2.137 mmol), DBAD (656 mg, 2.85 mmol), and triphenylphosphine (747 mg, 2.85 mmol) in toluene (15 mL) was stirred at 80 °C for 5 h under N2. The solvent was evaporated and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to yield the title compound. 1 H NMR (400MHz, CDCl3) δ8.01-8.19 (m, 1H), 7.67-7.91 (m, 2H), 5.64-5.80 (m, 1H), 4.18-4.33 (m, 1H), 3.56-3.71 (m, 1H), 2.3 7 (d, J=10.56Hz, 3H), 2.02-2.11 (m, 2H), 1.84-1.96 (m, 3H), 1.54 (d, J=2.35Hz, 9H), 1.18-1.29 (m, 1H), 0.96-1.08 (m, 1H). MS=439.1(M+Na).

[0600] Step 6.1-(1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl) TFA salt of pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid: A mixture of 1-(1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester (280 mg, 0.672 mmol) in DCM (3 mL) and TFA (3 mL) was stirred at 25 °C (room temperature) for 1 h. The solvent was evaporated to produce the crude title compound, which was used directly without further purification. MS = 361.1 (M+1).

[0601] Step 7. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((R)-1-(5-chloro-4-methyl-6- ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-((S)-1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide:A mixture of 1-(1-(5-chloro-4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-carboxylic acid, TFA salt (370 mg, crude), 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile, TFA (705 mg, 0.880 mmol), N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (247 mg, 0.880 mmol) and 1-methyl-1H-imidazolium (206 mg, 2.51 mmol) in ACN (8 mL) was stirred at 25 °C for 2 h. The solvent was evaporated and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a diastereomeric mixture of the product. The enantiomerically pure title compound was resolved by SFC (column: REGIS(s,s)WHELK-O1 (250mm*30mm, 5µm) 60% 0.1% NH3H2O ​​EtOH). A faster elution isomer was obtained (Example 167). 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.17 (d, J = 12.2 Hz, 2H), 7.93 (s, 1H), 7.53–7.70 (m, 2H), 7.39 (dd, J = 1.8, 8.2 Hz, 1H), 5.93 (q, J = 6.9 Hz, 1H), 4.44–4.57 (m, 1H), 4.20 (dd, J = 5.8) , 10.2 Hz, 1H), 3.48-3.69 (m, 2H), 2.79-2.96 (m, 2H), 2.40 (s, 3H), 2.11-2.27 (m, 3H), 1.97-2.08 (m, 1H), 1.91 (d, J = 7.1 Hz, 3H), 1.23-1.30 (m, 1H), 0.94-1.02 (m, 1H). MS = 549.2 (M+1). A slower-eluting isomer was obtained (Example 168). 1 H NMR (400MHz, methanol-d4) δ8.17 (br d, J=16.9Hz, 2H), 7.94 (br s, 1H), 7.51-7.72 (m, 2H), 7.39 (br d, J=6.9Hz, 1H), 5.93 (br d, J=5.9Hz, 1H), 4.51 (br s, 1H), 4.21 (br s, 1H), 3.46-3.70 (m, 2H), 2.90 (br s, 2H), 2.41 (br s, 3H), 2.13-2.30 (m, 3H), 2.01 (br s, 1H), 1.90 (br d, J=5.9Hz, 3H), 1.27 (br s, 1H), 0.98(br s, 1H). MS = 549.2 (M+1).

[0602] Examples 169, 170, 171 and 172

[0603]

[0604] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((S)-1-hydroxyethyl)-1-((R)-1-(4- Methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4- Formamide, N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((R)-1-hydroxyethyl)-1-((R)-1-(4-methyl) 6-((1R.5S)-2-hydro-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-methyl Amide, N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((R)-1-hydroxyethyl)-1-((S)-1-(4-methyl) 6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-methyl Amides and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((S)-1-hydroxyethyl)-1-((S)-1-(4-methyl) 6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-methyl amide

[0605] Step 1. 3-Bromo-1-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester: In a round-bottom flask, at 20 °C, DBAD (2.214 g, 9.61 mmol) was added to a solution of 1-(6-chloro-4-methylpyridin-3-yl)ethanol (1.1 g, 6.41 mmol), ethyl 3-bromo-1H-pyrazole-4-carboxylate (1.404 g, 6.41 mmol), and Ph3P (2.52 g, 9.61 mmol) in THF (15 mL). The mixture was stirred at 25 °C for 4 h. The mixture was cooled to room temperature and poured into water (50 mL), then filtered, and the filtrate was extracted with EtOAc (50 mL x 3). The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to produce a crude product. The obtained crude product was purified by rapid silica gel chromatography (30% petroleum ether / EtOAc) to produce the title compound. MS = 374.1, 376.1 (M+1).

[0606] Step 2.3 Acetyl-1-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester: Tributyl(1-ethoxyvinyl)stanane (1.494 mL, 4.43 mmol) and chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (0.269 g, 0.403 mmol) were added to a solution of ethyl 3-bromo-1-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate (1.5 g, 4.03 mmol) in tert-amyl OH (15 mL) at 20 °C. The resulting mixture was stirred at 100 °C for 12 h under N2, then HCl (6 M, 10 mL) was added and stirred at 20 °C for 1 h. Water (10 mL) was added, and the aqueous layer was extracted with DCM (10 mL * 3). The organic layer was concentrated, and the residue was purified by rapid silica gel chromatography (0-35% petroleum ether / EtOAc) to yield the title compound. MS = 336.1(M+1).

[0607] Step 3.3-Acetyl-1-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid:LiOH·H₂O (94 mg, 2.234 mmol) was added to a solution of ethyl 3-acetyl-1-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylate (500 mg, 1.489 mmol) in EtOH (8 mL) and H₂O (2 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. LCMS indicated the end of the reaction. The mixture was concentrated, water (10 mL) was added, and it was extracted with DCM (5 mL x 3). HCl (1 M) was added to the aqueous layer to pH 6, and it was extracted with DCM (15 mL x 3). The combined organic layers were concentrated to yield the title compound. MS = 308.0 (M+1).

[0608] Step 4.3-Acetyl-1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane- 3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid: A mixture of (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (166 mg, 1.706 mmol), 3-acetyl-1-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1H-pyrazole-4-carboxylic acid (350 mg, 1.137 mmol), cesium carbonate (1112 mg, 3.41 mmol), Pd2(dba)3 (104 mg, 0.114 mmol), and XantPhos (65.8 mg, 0.114 mmol) in 1,4-dioxane (8 mL) was stirred at 100 °C for 5 h under N2. Water (10 mL) was added, and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce a residue. The crude product was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to yield the title compound. MS = 369.1 (M+1).

[0609] Step 5.3-Acetyl-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6- ((1R,5S)-2-oxo-3-helium bicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide:At 25 °C, 1-methyl-1H-imidazolium (178 mg, 2.172 mmol) was added to a mixture of 3-acetyl-1-(1-(4-methyl-6-((1R,5S)-2-hydro-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-4-carboxylic acid (160 mg, 0.434 mmol), 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile (269 mg, 0.521 mmol), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (244 mg, 0.869 mmol) in MeCN (2 mL). The mixture was stirred at 25 °C for 2 h. Water (10 mL) was added and the aqueous solution was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative TLC (SiO2, petroleum ether:EtOAc = 1:2) to yield the title compound. MS = 557.2 (M+1).

[0610] Step 6. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((S)-1-hydroxyethyl)-1-((R)- 1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyridine Azoxyl-4-carboxamide, N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((R)-1-hydroxyethyl)-1-((R)-1- (4-Methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole- 4-Formamide, N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((R)-1-hydroxyethyl)-1-((S)-1-(4- Methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4- Formamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-3-((S)-1-hydroxyethyl)-1-((S)-1-(4- Methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4- Formamide:Sodium tetrahydroborate (12.23 mg, 0.323 mmol) was added to a solution of 3-acetyl-N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide (150 mg, 0.269 mmol)) in THF (5 mL) and MeOH (0.8 mL), and the reaction mixture was stirred at 25 °C for 1 h. Saturated NH4Cl (5 mL) was added and the aqueous solution was extracted with EtOAc (5 mL x 3). The combined organic layers were concentrated, and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a diastereomeric mixture of the product. The enantiomerically pure title compound was resolved by SFC (column: DAICL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm) 40% EtOH (0.1% NH3H2O)) to produce three peaks. The first eluted peak provided a mixture of two diastereomers. The enantiomerically pure title compound was resolved by SFC (first eluted peak): column: DAICL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm); 40% EtOH (0.1% NH3H2O). The faster eluted isomer (from peak 1, first SFC) was obtained (Example 169). 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.17 (s, ¹H), 8.09 (s, ¹H), 8.05 (s, ¹H), 7.67 (d, J = 8.2 Hz, ¹H), 7.57 (s, ¹H), 7.39–7.44 (m, ¹H), 5.72–5.80 (m, ¹H), 4.97 (q, J = 7.2 Hz, ¹H), 4.47–4.55 (m, ¹H), 4.11–4.1 8 (m, 1H), 3.99–4.08 (m, 1H), 3.55–3.64 (m, 1H), 2.86–2.98 (m, 2H), 2.28 (s, 3H), 2.08–2.23 (m, 4H), 1.88 (d, J = 7.0 Hz, 3H), 1.50 (d, J = 6.7 Hz, 3H), 1.23–1.28 (m, 1H), 0.71–0.76 ppm (m, 1H). 99.12% ee. MS = 559.3 (M+1). Slower eluting isomers were obtained (from peak 1, first SFC) (Example 170). 1H NMR (400MHz, methanol-d4) δ8.19 (s, 1H), 8.07 (s, 1H), 8.06 (s, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.57 (d, J = 1.6Hz, 1H), 7.41 (dd, J=8.2, 2.0Hz, 1H), 5.76 (q, J=7.2Hz, 1H), 4.98 (q, J=6.4Hz, 1H), 4.45-4.55 (m, 1H), 4.09 -4.18 (m, 1H), 4.00–4.07 (m, 1H), 3.54–3.63 (m, 1H), 2.93 (dt, J = 11.2, 7.7 Hz, 2H), 2.27 (s, 3H), 2.05–2.22 (m, 4H), 1.88 (d, J = 7.0 Hz, 3H), 1.50 (d, J = 6.7 Hz, 3H), 1.23–1.28 (m, 1H), 0.74 ppm (q, J = 3.9 Hz, 1H). 99.18% ee. MS = 559.3 (M+1). The second eluted isomer (from the first SFC) was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to yield a pure compound (Example 171). 1 H NMR (400MHz, methanol-d4) δ8.14-8.21(m, 2H), 7.78(br s, 1H), 7.67 (d, J=8.2Hz, 1H), 7.57 (d, J=1.6Hz, 1H), 7.42 (dd, J=8.2, 2.0Hz, 1H), 5 .84(q, J=6.9Hz, 1H), 4.98(q, J=6.7Hz, 1H), 4.47-4.58(m, 1H), 4.09-4.15(m, 1H), 4.03-4.08 (m, 1H), 3.53-3.69 (m, 1H), 2.84-3.02 (m, 2H), 2.41 (s, 3H), 2.13-2.27 (m, 4H), 1.89 (d, J = 7.0 Hz, 3H), 1.50 (d, J = 6.7 Hz, 3H), 1.32-1.39 (m, 1H), 0.89 ppm (br s, 1H). 93.41% ee. MS = 559.3 (M+1). A third isomer was obtained (from the first SFC) (Example 172). 1H NMR (400MHz, methanol-d4) δ8.16 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.65 (d, J=8.3Hz, 1H), 7.56 (d, J =1.7Hz, 1H), 7.40 (dd, J = 8.2, 1.8Hz, 1H), 5.73-5.80 (m, 1H), 4.97 (q, J = 6.6Hz, 1H), 4.44-4.53 (m, 1H), 3.99-4.16 (m, 2H), 3.53-3.62 (m, 1H), 2.85-2.98 (m, 2H), 2.27 (s, 3H), 2.08-2.22 (m, 4 H), 1.87 (d, J=6.8Hz, 3H), 1.50 (d, J=6.6Hz, 3H), 1.21-1.27 (m, 1H), 0.75ppm (q, J=3.8Hz, 1H). 88.87%ee. MS=559.3(M+1).

[0611] Examples 173 and 174

[0612]

[0613] N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-methyl-3-((S)-1-(4-methyl-6-((1R, 5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-5-carboxamide and N- ((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-methyl-3-((R)-1-(4-methyl-6-((1R,5S)-2-oxo- 3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-5-carboxamide.

[0614] Step 1.3 - Acetyl-1H-pyrazole-5-carboxylic acid ethyl ester: Ethyl 2-diazoylacetic acid (16.22 mL, 154 mmol) was added to a solution of butyryl-3-yn-2-one (7 g, 103 mmol) in water (100 mL) at 0 °C. The mixture was stirred at 25 °C for 4 h and then filtered to produce the title compound. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.26 (br s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.36 ppm (t, J = 7.1 Hz, 3H). MS = 183.1 (M+1)

[0615] Step 2.3 - Acetyl-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester:Iodomethane (3.12 mL, 50.0 mmol) was added to a solution of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (7 g, 38.4 mmol) and cesium carbonate (18.78 g, 57.6 mmol) in DMF (100 mL) at 25 °C. EtOAc (50 mL) was added, and the organic phase was washed with water (100 mL). The aqueous fraction was extracted with EtOAc (100 mL x 3). The organic fractions were combined, dried over Na₂SO₄, filtered, concentrated under vacuum, and the residue was purified by rapid silica gel chromatography (0–30% petroleum ether / EtoAc) to yield ethyl 3-acetyl-1-methyl-1H-pyrazole-5-carboxylate and ethyl 5-acetyl-1-methyl-1H-pyrazole-3-carboxylate. MS = 197.1 (M+1)

[0616] Step 3.1-Methyl-3-(1-(2-toluenesulfonylhydrazinyl)ethyl)-1H-pyrazole-5-carboxylic acid ethyl: To a solution of ethyl 3-acetyl-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 2.55 mmol) in MeOH (8 mL), 4-methylbenzenesulfonylhydrazine (475 mg, 2.55 mmol) was added, and the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated to produce the title compound, which was used for the next step without further purification. MS = 365.1 (M+1).

[0617] Step 4.3 - (1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester: Potassium carbonate (228 mg, 1.646 mmol) was added to a stirred mixture of (6-chloro-4-methylpyridin-3-yl)boronic acid (141 mg, 0.823 mmol) and 1-methyl-3-(1-(2-toluenesulfonylamino)ethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (200 mg, 0.549 mmol) in dioxane (4 mL). The mixture was stirred at 110 °C for 2 h. The reactants were diluted with water (20 mL), extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to yield a crude product. The crude product was purified by preparative TLC (SiO₂; petroleum ether: ethyl acetate = 1:1) to yield the title compound. MS = 308.1 (M+1)

[0618] Step 5.3 -(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxylic acid:Lithium hydroxide hydrate (8.18 mg, 0.195 mmol) was added to a solution of ethyl 3-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxylate (50 mg, 0.162 mmol) in THF (0.8 mL) and water (0.2 mL). The reaction mixture was stirred at 40 °C for 12 h. The mixture was then diluted with water (5 mL), extracted with EtOAc (5 mL x 3), and the aqueous layer was adjusted to pH 3–4 with HCl. The aqueous layer was extracted with DCM (10 mL x 3), the combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to yield the title compound, which was used directly for the next step without further purification. MS = 280.1 (M+1)

[0619] Step 6. 1-Methyl-3-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3- 3-yl)pyridin-5-yl)ethyl)-1H-pyrazole-5-carboxylic acid: A mixture of 3-(1-(6-chloro-4-methylpyridin-3-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (42 mg, 0.150 mmol), (1R,5S)-3-azabicyclo[3.1.0]hexane-2-one (29.2 mg, 0.300 mmol), Cs₂CO₃ (98 mg, 0.300 mmol), Pd₂(dba)₃ (13.75 mg, 0.015 mmol), and XANTPHOS (8.69 mg, 0.015 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 12 h under N₂. The mixture was then diluted with water (5 mL), extracted with EtOAc (5 mL x 3), and the aqueous layer was adjusted to pH 3–4 with HCl. The aqueous layer was extracted with DCM (10 mL * 3), the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to yield the title compound, which was used in the next step without further purification. MS = 341.1 (M+1).

[0620] Step 7. N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-methyl-3-(1-(4-methyl-6-) ((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-5-carboxamide and N-((cis)-3-(5-chloro-2-cyanophenyl)cyclobutyl)-1-methyl-3-(1-(4-methyl-6-((1R,5S)-2-oxo-3- Azabicyclo[3.1.0]hexane-3-yl)pyridin-3-yl)ethyl)-1H-pyrazole-5-carboxamide:To a solution of 1-methyl-3-(1-(4-methyl-6-((1R,5S)-2-oxo-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)ethyl)-1H-pyrazol-5-carboxylic acid (20 mg, 0.059 mmol) in 1.5 mL of ACN, 1-methyl-1H-imidazolium (14.47 mg, 0.176 mmol), TCFH (19.78 mg, 0.071 mmol), and 2-((cis)-3-aminocyclobutyl)-4-chlorobenzyl nitrile TFA salt (20.73 mg, 0.065 mmol) were added. The mixture was stirred at 25 °C for 2 h under N2 atmosphere, concentrated, and the residue was purified by reversed-phase HPLC (ACN / water containing 0.05% TFA modifier) ​​to provide a diastereomeric mixture of the product. The enantiomerically pure title compound was resolved by SFC (column: DAICL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm); 40% 0.1% NH3H2OEtOH) to produce two isomers. The faster eluting isomer was obtained (Example 173). 1 H NMR(400MHz, DMSO_d6)δ8.48(br d, J=7.8Hz, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.79 (d, J=8.3Hz, 1H), 7.64 (d, J=1.7Hz, 1H), 7.48(dd, J=8.3, 2.0Hz, 1H), 6.52(s, 1H), 4.37-4.46(m, 1H), 4.16-4.27(m, 1H), 3.98(br s, 1H), 3.94 (s, 3H), 3.84-3.91 (m, 1H), 3.40-3.49 (m, 1H), 2.70 (br d, J = 11.5 Hz, 2H), 2.21 (s, 3H), 2.18 (br s, 1H), 2.02 (br d, J = 7.3 Hz, 2H), 1.96 (br d, J = 7.6 Hz, 1H), 1.52 (d, J = 7.1 Hz, 3H), 1.22-1.23 (m, 1H), 0.62-0.67 ppm (m, 1H). MS = 529.2 (M+1). A slower-eluting isomer was obtained (Example 174). 1H NMR (400MHz, DMSO_d6) δ8.48 (d, J=8.1Hz, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.79 (d, J=8.1Hz, 1H), 7. 65(s, 1H), 7.48(dd, J=8.3, 2.2Hz, 1H), 6.52(s, 1H), 4.35-4.48(m, 1H), 4.18-4.29(m, 1H), 3.98(br s, 1H), 3.95 (s, 3H), 3.84-3.90 (m, 1H), 3.39-3.49 (m, 1H), 2.70 (br d, J=8.1Hz, 2H), 2.22 (s, 3H), 2.00-2.04 (m, 2H), 1.93-1.99 (m, 2H), 1.51 (d, J=7.3Hz, 3H), 1.23-1.24 (m, 1H), 0.67ppm (br d, J=3.7Hz, 1H). MS=529.2(M+1)

[0621] Kallikrein assay

[0622] The effectiveness of the compounds of the present invention as kallikrein inhibitors can be determined using the relevant purified serine protease and appropriate synthetic substrates. The hydrolysis rate of the relevant serine protease on a chromogenic or fluorescent substrate is measured in the absence and presence of the compounds of the present invention. The determination is performed at room temperature or 37°C. The hydrolysis of the substrate results in the release of aminotrifluoromethylcoumarin (AFC), which is monitored by a fluorescence spectrophotometer by measuring the increase in emission at 510 nm under 405 nm excitation. A decrease in the rate of fluorescence change in the presence of the inhibitor indicates enzyme inhibition. Such methods are known to those skilled in the art. The results of this determination are expressed as the half-maximal inhibitory concentration (IC50) or inhibition constant K. i .

[0623] The kallikrein assay was performed in 50 mM HEPES buffer at pH 7.4 containing 150 mM NaCl, 5 mM CaCl2, and 0.1% PEG 8000 (polyethylene glycol; Fisher Scientific). The assay was performed using purified human plasma kallikrein (Enzyme Research Laboratories) at a final concentration of 0.5 nM and the synthetic substrate acetyl-KPR-AFC (Sigma#C6608) at a concentration of 100 mM.

[0624] Activity was determined by diluting the substrate stock solution at least tenfold to a final concentration ≤0.2 km in a solution containing the enzyme or an enzyme balanced with an inhibitor. The time required to achieve equilibrium between the enzyme and inhibitor was determined in a control experiment. The reaction was performed under linear progression conditions, and the increase in fluorescence was measured at 405 Ex / 510 Em nm. The values ​​were converted to the percentage of inhibition of the control reaction (after subtracting 100% inhibition). The IC50 was determined from the inflection point of the four-parameter logistic curve fitting. 50 Calculate Ki using the Cheng Prusoff equation: Ki = IC 50 / (1+([S] / Km)).

[0625] The activity shown in this assay indicates that the compounds of the present invention can be used therapeutically to treat or prevent various ophthalmic, 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 or embolic stroke, venous thrombosis, coronary and cerebral artery thrombosis, cerebral and pulmonary embolism, atherosclerosis, deep vein thrombosis, disseminated intravascular coagulation, re-occlusion or restenosis of reperforated vessels, hereditary angioedema, uveitis, posterior uveitis, wet age-related macular edema, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion.

[0626] The plasma kallikrein IC50 (nM) of the selected compounds are as follows:

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: Where X is CR 2 Or N; Y is or ; in Selected from or ; It is a 5-membered heteroaryl ring, optionally substituted by one or two substituents, said substituents being independently selected from the group consisting of: halogen, cyano, R. x and OR x ; G is N or CR 7 ; J is N or CR 8 ; L is N or CR 7 ; M is non-existent, N, or CR. 8 ; Each R 1 Independently selected from the following group: halogen, cyano, R x and OR x ; R 2 It is hydrogen, halogen, cyano, R x OR x CONH2 or heteroaryl, wherein the heteroaryl group is optionally substituted with a halogen; R 3 It is hydrogen, deuterium, halogen, or methyl; R 4 It is hydrogen, deuterium, halogen, hydroxyl, or methyl; or R 3 and R 4 Together with the carbon atoms between them, they form C 3-6 Cycloalkyl groups; R 5 Is it hydrogen or C? 1-3 Alkyl groups, optionally substituted with one to three substituents selected from the group consisting of halogens and hydroxyl groups; or R 5 L and the carbon atoms between them together form C 3-6 Cycloalkyl groups; R 6 Is it hydrogen, hydroxyl, or C? 1-3 alkyl; or R 5 and R 6 Together with the carbon atoms between them, they form C 3-6 Cycloalkyl groups; Each R 7 Independently selected from the following groups: hydrogen, halogen, R x and OR x ; Each R 8 Independently selected from the following groups: hydrogen, halogen, R x OR x and NH2; R 9 Is it hydrogen or C? 1-3 alkyl; R x Is it hydrogen or C? 1-6 Alkyl groups, optionally substituted with one to four substituents, said substituents being independently selected from the group consisting of halogens, hydroxyl groups, methoxy groups, and ethoxy groups; m is 1 or 2; n is an integer between 0 and 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... Selected from the group consisting of pyrrole, pyrazolyl, imidazole, triazolyl, isoxazolyl, and oxazolyl, wherein the pyrrole, pyrazolyl, imidazole, triazolyl, isoxazolyl, and oxazolyl groups are optionally substituted by one or two substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, and R. x and OR x .

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein... Selected from the group consisting of pyrazolyl, triazolyl, or isoxazolyl, wherein the pyrazolyl group is optionally R x OR x replace.

4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X is a CR 2 ;R 2 It is cyano, CONH2, fluopyrazole, R x OR x .

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 It is chlorine, fluorine, methyl, or cyano; n is 1 or 2.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Y is .

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein... yes And R 9 It is hydrogen.

8. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein J is N.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: and .

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

11. Use of the composition of claim 10 in the preparation of a medicament for treating diabetic retinopathy, diabetic macular edema, or hereditary angioedema in mammals in need of such treatment.

12. Use of the composition of claim 10 for the preparation of a medicament for the treatment of diabetic retinopathy in mammals in need of such treatment.

13. Use of the composition of claim 10 for the preparation of a medicament for the treatment of diabetic macular edema in mammals in need of such treatment.

14. Use of the compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hereditary angioedema, diabetic macular edema or diabetic retinopathy in mammals in need of such treatment.

15. The composition of claim 10, further comprising another agent selected from the group consisting of: anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

16. The use of claim 11, wherein the medicament further comprises another agent selected from the group consisting of: anti-inflammatory agents, anti-VEGF agents, immunosuppressants, anticoagulants, antiplatelet agents, and thrombolytic agents.

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